Hematology

AMSTERDAM – Patients with relapsed or refractory acute myeloid leukemia (AML) may be more likely to respond when selinexor is added to standard chemotherapy, according to investigators.

Will Pass/MDedge News

In a recent phase 2 trial, selinexor given with cytarabine and idarubicin led to a 50% overall response rate, reported lead author Walter Fiedler, MD, of University Medical Center Hamburg-Eppendorf (Germany). This response rate is at the upper end of what has been seen in published studies, Dr. Fiedler said at the annual congress of the European Hematology Association.

He also noted that giving a flat dose of selinexor improved tolerability in the trial, a significant finding in light of common adverse events and recent concerns from the Food and Drug Administration about the safety of selinexor for patients with multiple myeloma.

“The rationale to employ selinexor in this study is that there is a synergy between anthracyclines and selinexor,” Dr. Fiedler said, which may restore anthracycline sensitivity in relapsed or refractory patients. “Secondly, there is a c-myc reduction pathway that leads to a reduction of DNA damage repair genes such as Rad51 and Chk1, and this might result in inhibition of homologous recombination.”

The study involved 44 patients with relapsed or refractory AML, of whom 17 (39%) had previously received stem cell transplantation and 11 (25%) exhibited therapy-induced or secondary disease. The median patient age was 59.5 years.

Patients were given idarubicin 10 mg/m² on days 1, 3, and 5, and cytarabine 100 mg/m² on days 1-7. Initially, selinexor was given at a dose of 40 mg/m² twice per week for 4 weeks, but this led to high rates of febrile neutropenia and grade 3 or higher diarrhea, along with prolonged aplasia. In response to this issue, after the first 27 patients, the dose was reduced to a flat amount of 60 mg, given twice weekly for 3 weeks.

For patients not undergoing transplantation after the first or second induction cycle, selinexor maintenance monotherapy was offered for up to 1 year.

The primary endpoint was overall remission rate, reported as complete remission, complete remission with incomplete blood count recovery, and morphological leukemia-free status. Secondary endpoints included the rate of partial remissions, percentage of patients being transplanted after induction, early death rate, overall survival, event-free survival, and relapse-free survival.

The efficacy analysis revealed an overall response rate of 50%. A total of 9 patients had complete remission (21.4%), 11 achieved complete remission with incomplete blood count recovery (26.2%), and 1 exhibited morphological leukemia-free status (2.4%). Of note, almost half of the patients (47%) who had relapsed after previous stem cell transplantation responded, as did three-quarters who tested positive for an NPM1 mutation. After a median follow-up of 8.2 months, the median overall survival was 8.2 months, relapse-free survival was 17.7 months, and event-free survival was 4.9 months.

Adverse events occurred frequently, with a majority of patients experiencing nausea (86%), diarrhea (83%), vomiting (74%), decreased appetite (71%), febrile neutropenia (67%), fatigue (64%), leukopenia (62%), thrombocytopenia (62%), or anemia (60%).

Grade 3 or higher adverse events were almost as common, and included febrile neutropenia (67%), leukopenia (62%), thrombocytopenia (62%), anemia (57%), and diarrhea (50%). Reducing the dose did improve tolerability, with notable drops in the rate of severe diarrhea (56% vs. 40%) and febrile neutropenia (85% vs. 33%). In total, 19% of patients discontinued treatment because of adverse events.

A total of 25 patients (60%) died during the study, with about half dying from disease progression (n = 12), and fewer succumbing to infectious complications, graft-versus-host disease, multiorgan failure, multiple brain infarct, or asystole. Two deaths, one from suspected hemophagocytosis and another from systemic inflammatory response syndrome, were considered possibly related to selinexor.

“The results should be further evaluated in a phase 3 study,” Dr. Fiedler said. However, plans for this are not yet underway, he said, adding that Karyopharm Therapeutics will be focusing its efforts on selinexor for myeloma first.

The study was funded by Karyopharm. Dr. Fielder reported financial relationships with Amgen, Pfizer, Jazz Pharmaceuticals, and other companies.

SOURCE: Fiedler W et al. EHA Congress, Abstract S880.

AMSTERDAM – Patients with relapsed or refractory acute myeloid leukemia (AML) may be more likely to respond when selinexor is added to standard chemotherapy, according to investigators.

Will Pass/MDedge News

In a recent phase 2 trial, selinexor given with cytarabine and idarubicin led to a 50% overall response rate, reported lead author Walter Fiedler, MD, of University Medical Center Hamburg-Eppendorf (Germany). This response rate is at the upper end of what has been seen in published studies, Dr. Fiedler said at the annual congress of the European Hematology Association.

He also noted that giving a flat dose of selinexor improved tolerability in the trial, a significant finding in light of common adverse events and recent concerns from the Food and Drug Administration about the safety of selinexor for patients with multiple myeloma.

“The rationale to employ selinexor in this study is that there is a synergy between anthracyclines and selinexor,” Dr. Fiedler said, which may restore anthracycline sensitivity in relapsed or refractory patients. “Secondly, there is a c-myc reduction pathway that leads to a reduction of DNA damage repair genes such as Rad51 and Chk1, and this might result in inhibition of homologous recombination.”

The study involved 44 patients with relapsed or refractory AML, of whom 17 (39%) had previously received stem cell transplantation and 11 (25%) exhibited therapy-induced or secondary disease. The median patient age was 59.5 years.

Patients were given idarubicin 10 mg/m² on days 1, 3, and 5, and cytarabine 100 mg/m² on days 1-7. Initially, selinexor was given at a dose of 40 mg/m² twice per week for 4 weeks, but this led to high rates of febrile neutropenia and grade 3 or higher diarrhea, along with prolonged aplasia. In response to this issue, after the first 27 patients, the dose was reduced to a flat amount of 60 mg, given twice weekly for 3 weeks.

For patients not undergoing transplantation after the first or second induction cycle, selinexor maintenance monotherapy was offered for up to 1 year.

The primary endpoint was overall remission rate, reported as complete remission, complete remission with incomplete blood count recovery, and morphological leukemia-free status. Secondary endpoints included the rate of partial remissions, percentage of patients being transplanted after induction, early death rate, overall survival, event-free survival, and relapse-free survival.

The efficacy analysis revealed an overall response rate of 50%. A total of 9 patients had complete remission (21.4%), 11 achieved complete remission with incomplete blood count recovery (26.2%), and 1 exhibited morphological leukemia-free status (2.4%). Of note, almost half of the patients (47%) who had relapsed after previous stem cell transplantation responded, as did three-quarters who tested positive for an NPM1 mutation. After a median follow-up of 8.2 months, the median overall survival was 8.2 months, relapse-free survival was 17.7 months, and event-free survival was 4.9 months.

Adverse events occurred frequently, with a majority of patients experiencing nausea (86%), diarrhea (83%), vomiting (74%), decreased appetite (71%), febrile neutropenia (67%), fatigue (64%), leukopenia (62%), thrombocytopenia (62%), or anemia (60%).

Grade 3 or higher adverse events were almost as common, and included febrile neutropenia (67%), leukopenia (62%), thrombocytopenia (62%), anemia (57%), and diarrhea (50%). Reducing the dose did improve tolerability, with notable drops in the rate of severe diarrhea (56% vs. 40%) and febrile neutropenia (85% vs. 33%). In total, 19% of patients discontinued treatment because of adverse events.

A total of 25 patients (60%) died during the study, with about half dying from disease progression (n = 12), and fewer succumbing to infectious complications, graft-versus-host disease, multiorgan failure, multiple brain infarct, or asystole. Two deaths, one from suspected hemophagocytosis and another from systemic inflammatory response syndrome, were considered possibly related to selinexor.

“The results should be further evaluated in a phase 3 study,” Dr. Fiedler said. However, plans for this are not yet underway, he said, adding that Karyopharm Therapeutics will be focusing its efforts on selinexor for myeloma first.

The study was funded by Karyopharm. Dr. Fielder reported financial relationships with Amgen, Pfizer, Jazz Pharmaceuticals, and other companies.

SOURCE: Fiedler W et al. EHA Congress, Abstract S880.

AMSTERDAM – Patients with relapsed or refractory acute myeloid leukemia (AML) may be more likely to respond when selinexor is added to standard chemotherapy, according to investigators.

Will Pass/MDedge News

In a recent phase 2 trial, selinexor given with cytarabine and idarubicin led to a 50% overall response rate, reported lead author Walter Fiedler, MD, of University Medical Center Hamburg-Eppendorf (Germany). This response rate is at the upper end of what has been seen in published studies, Dr. Fiedler said at the annual congress of the European Hematology Association.

He also noted that giving a flat dose of selinexor improved tolerability in the trial, a significant finding in light of common adverse events and recent concerns from the Food and Drug Administration about the safety of selinexor for patients with multiple myeloma.

“The rationale to employ selinexor in this study is that there is a synergy between anthracyclines and selinexor,” Dr. Fiedler said, which may restore anthracycline sensitivity in relapsed or refractory patients. “Secondly, there is a c-myc reduction pathway that leads to a reduction of DNA damage repair genes such as Rad51 and Chk1, and this might result in inhibition of homologous recombination.”

The study involved 44 patients with relapsed or refractory AML, of whom 17 (39%) had previously received stem cell transplantation and 11 (25%) exhibited therapy-induced or secondary disease. The median patient age was 59.5 years.

Patients were given idarubicin 10 mg/m² on days 1, 3, and 5, and cytarabine 100 mg/m² on days 1-7. Initially, selinexor was given at a dose of 40 mg/m² twice per week for 4 weeks, but this led to high rates of febrile neutropenia and grade 3 or higher diarrhea, along with prolonged aplasia. In response to this issue, after the first 27 patients, the dose was reduced to a flat amount of 60 mg, given twice weekly for 3 weeks.

For patients not undergoing transplantation after the first or second induction cycle, selinexor maintenance monotherapy was offered for up to 1 year.

The primary endpoint was overall remission rate, reported as complete remission, complete remission with incomplete blood count recovery, and morphological leukemia-free status. Secondary endpoints included the rate of partial remissions, percentage of patients being transplanted after induction, early death rate, overall survival, event-free survival, and relapse-free survival.

The efficacy analysis revealed an overall response rate of 50%. A total of 9 patients had complete remission (21.4%), 11 achieved complete remission with incomplete blood count recovery (26.2%), and 1 exhibited morphological leukemia-free status (2.4%). Of note, almost half of the patients (47%) who had relapsed after previous stem cell transplantation responded, as did three-quarters who tested positive for an NPM1 mutation. After a median follow-up of 8.2 months, the median overall survival was 8.2 months, relapse-free survival was 17.7 months, and event-free survival was 4.9 months.

Adverse events occurred frequently, with a majority of patients experiencing nausea (86%), diarrhea (83%), vomiting (74%), decreased appetite (71%), febrile neutropenia (67%), fatigue (64%), leukopenia (62%), thrombocytopenia (62%), or anemia (60%).

Grade 3 or higher adverse events were almost as common, and included febrile neutropenia (67%), leukopenia (62%), thrombocytopenia (62%), anemia (57%), and diarrhea (50%). Reducing the dose did improve tolerability, with notable drops in the rate of severe diarrhea (56% vs. 40%) and febrile neutropenia (85% vs. 33%). In total, 19% of patients discontinued treatment because of adverse events.

A total of 25 patients (60%) died during the study, with about half dying from disease progression (n = 12), and fewer succumbing to infectious complications, graft-versus-host disease, multiorgan failure, multiple brain infarct, or asystole. Two deaths, one from suspected hemophagocytosis and another from systemic inflammatory response syndrome, were considered possibly related to selinexor.

“The results should be further evaluated in a phase 3 study,” Dr. Fiedler said. However, plans for this are not yet underway, he said, adding that Karyopharm Therapeutics will be focusing its efforts on selinexor for myeloma first.

The study was funded by Karyopharm. Dr. Fielder reported financial relationships with Amgen, Pfizer, Jazz Pharmaceuticals, and other companies.

SOURCE: Fiedler W et al. EHA Congress, Abstract S880.

AMSTERDAM – Rozanolixizumab, a subcutaneous antibody for the human neonatal Fc receptor, provides clinically meaningful improvements in platelet count for patients with primary immune thrombocytopenia, according to results from a recent phase 2 trial.

Rozanolixizumab was well tolerated across all dose groups, with higher doses delivering faster responses, reported lead author Tadeusz Robak, MD, PhD, of the Medical University of Lodz (Poland).

Targeting the Fc receptor interrupts recirculation of IgG, a key autoantibody in immune thrombocytopenia (ITP) pathogenesis, Dr. Robak explained during a presentation at the annual congress of the European Hematology Association. This approach represents an emerging treatment paradigm, he said, noting that rozanolixizumab is also being studied for the treatment of other IgG-driven autoimmune diseases, such as myasthenia gravis and chronic inflammatory demyelinating polyneuropathy.

The present open-label, dose-escalation study involved 54 adult patients with primary ITP of at least 3 months duration and platelet counts of less than 30 x 10⁹/L at screening and 35 x 10⁹/L at baseline. Eligibility required a previous response to ITP therapy. Enrolled patients were randomized into four dose groups: 4 mg/kg (five doses), 7 mg/kg (three doses), 10 mg/kg (two doses), or 15 mg/kg (one dose). After dosing, patients were followed for 8 weeks. Clinically relevant efficacy was defined as a platelet count of at least 50 x 10⁹/L. Decreases in IgG were also reported.

A safety analysis showed that the regimen was well tolerated across all dose groups. In total, 20.4% of patients experienced at least one treatment-related adverse event. The most common adverse events were headache (31.5%), diarrhea (11.1%), and vomiting (3.7%); all of which were mild or moderate. Headache appeared to be dose related, as 42% of patients in the 15-mg/kg group reported headache, compared with 8% in the 10-mg/kg group, 7% in the 7-mg/kg group, and none in the 4-mg/kg group. Out of four reported serious adverse events, none were considered treatment related.

Concerning efficacy, higher doses were associated with higher response rates and faster response times. In the 4-mg/kg group, 33% of patients achieved a platelet count of at least 50 x 10⁹/L, compared with 33% of the 7-mg/kg group, 50% of the 10-mg/kg group, and 67% of the 15-mg/kg group. Of the patients that achieved clinically meaningful responses, 20% of the 4-mg/kg group did so within 8 days, compared with 40% of 7-mg/kg responders, 50% of 10-mg/kg responders, and 87.5% of 15-mg/kg responders. Additional observations included dose-dependent decreases in IgG titer and longer response durations after multiple lower doses.

“Data from this study indicate that we can achieve effective increases in platelet levels, we can observe decreasing IgG levels, and the treatment was safe for the patients,” Dr. Robak said.

When asked about the intended clinical application of rozanolixizumab, Dr. Robak suggested that the agent may have a role in the postacute care setting. “We should develop a method of prolonged administration of [rozanolixizumab], as we saw that lower, multiple doses gave longer response durations.”

Still, he noted that more research is needed, since responses in diverse patient populations remain unknown. “We do not know how the drug will be active in truly refractory patients and we need this response before we establish the indication for the drug.”

The investigators reported financial relationships with Celgene, Roche, GlaxoSmithKline, Amgen, AbbVie, and other companies.

SOURCE: Robak T et al. EHA Congress, Abstract S850.

AMSTERDAM – Rozanolixizumab, a subcutaneous antibody for the human neonatal Fc receptor, provides clinically meaningful improvements in platelet count for patients with primary immune thrombocytopenia, according to results from a recent phase 2 trial.

Rozanolixizumab was well tolerated across all dose groups, with higher doses delivering faster responses, reported lead author Tadeusz Robak, MD, PhD, of the Medical University of Lodz (Poland).

Targeting the Fc receptor interrupts recirculation of IgG, a key autoantibody in immune thrombocytopenia (ITP) pathogenesis, Dr. Robak explained during a presentation at the annual congress of the European Hematology Association. This approach represents an emerging treatment paradigm, he said, noting that rozanolixizumab is also being studied for the treatment of other IgG-driven autoimmune diseases, such as myasthenia gravis and chronic inflammatory demyelinating polyneuropathy.

The present open-label, dose-escalation study involved 54 adult patients with primary ITP of at least 3 months duration and platelet counts of less than 30 x 10⁹/L at screening and 35 x 10⁹/L at baseline. Eligibility required a previous response to ITP therapy. Enrolled patients were randomized into four dose groups: 4 mg/kg (five doses), 7 mg/kg (three doses), 10 mg/kg (two doses), or 15 mg/kg (one dose). After dosing, patients were followed for 8 weeks. Clinically relevant efficacy was defined as a platelet count of at least 50 x 10⁹/L. Decreases in IgG were also reported.

A safety analysis showed that the regimen was well tolerated across all dose groups. In total, 20.4% of patients experienced at least one treatment-related adverse event. The most common adverse events were headache (31.5%), diarrhea (11.1%), and vomiting (3.7%); all of which were mild or moderate. Headache appeared to be dose related, as 42% of patients in the 15-mg/kg group reported headache, compared with 8% in the 10-mg/kg group, 7% in the 7-mg/kg group, and none in the 4-mg/kg group. Out of four reported serious adverse events, none were considered treatment related.

Concerning efficacy, higher doses were associated with higher response rates and faster response times. In the 4-mg/kg group, 33% of patients achieved a platelet count of at least 50 x 10⁹/L, compared with 33% of the 7-mg/kg group, 50% of the 10-mg/kg group, and 67% of the 15-mg/kg group. Of the patients that achieved clinically meaningful responses, 20% of the 4-mg/kg group did so within 8 days, compared with 40% of 7-mg/kg responders, 50% of 10-mg/kg responders, and 87.5% of 15-mg/kg responders. Additional observations included dose-dependent decreases in IgG titer and longer response durations after multiple lower doses.

“Data from this study indicate that we can achieve effective increases in platelet levels, we can observe decreasing IgG levels, and the treatment was safe for the patients,” Dr. Robak said.

When asked about the intended clinical application of rozanolixizumab, Dr. Robak suggested that the agent may have a role in the postacute care setting. “We should develop a method of prolonged administration of [rozanolixizumab], as we saw that lower, multiple doses gave longer response durations.”

Still, he noted that more research is needed, since responses in diverse patient populations remain unknown. “We do not know how the drug will be active in truly refractory patients and we need this response before we establish the indication for the drug.”

The investigators reported financial relationships with Celgene, Roche, GlaxoSmithKline, Amgen, AbbVie, and other companies.

SOURCE: Robak T et al. EHA Congress, Abstract S850.

AMSTERDAM – Rozanolixizumab, a subcutaneous antibody for the human neonatal Fc receptor, provides clinically meaningful improvements in platelet count for patients with primary immune thrombocytopenia, according to results from a recent phase 2 trial.

Rozanolixizumab was well tolerated across all dose groups, with higher doses delivering faster responses, reported lead author Tadeusz Robak, MD, PhD, of the Medical University of Lodz (Poland).

Targeting the Fc receptor interrupts recirculation of IgG, a key autoantibody in immune thrombocytopenia (ITP) pathogenesis, Dr. Robak explained during a presentation at the annual congress of the European Hematology Association. This approach represents an emerging treatment paradigm, he said, noting that rozanolixizumab is also being studied for the treatment of other IgG-driven autoimmune diseases, such as myasthenia gravis and chronic inflammatory demyelinating polyneuropathy.

The present open-label, dose-escalation study involved 54 adult patients with primary ITP of at least 3 months duration and platelet counts of less than 30 x 10⁹/L at screening and 35 x 10⁹/L at baseline. Eligibility required a previous response to ITP therapy. Enrolled patients were randomized into four dose groups: 4 mg/kg (five doses), 7 mg/kg (three doses), 10 mg/kg (two doses), or 15 mg/kg (one dose). After dosing, patients were followed for 8 weeks. Clinically relevant efficacy was defined as a platelet count of at least 50 x 10⁹/L. Decreases in IgG were also reported.

A safety analysis showed that the regimen was well tolerated across all dose groups. In total, 20.4% of patients experienced at least one treatment-related adverse event. The most common adverse events were headache (31.5%), diarrhea (11.1%), and vomiting (3.7%); all of which were mild or moderate. Headache appeared to be dose related, as 42% of patients in the 15-mg/kg group reported headache, compared with 8% in the 10-mg/kg group, 7% in the 7-mg/kg group, and none in the 4-mg/kg group. Out of four reported serious adverse events, none were considered treatment related.

Concerning efficacy, higher doses were associated with higher response rates and faster response times. In the 4-mg/kg group, 33% of patients achieved a platelet count of at least 50 x 10⁹/L, compared with 33% of the 7-mg/kg group, 50% of the 10-mg/kg group, and 67% of the 15-mg/kg group. Of the patients that achieved clinically meaningful responses, 20% of the 4-mg/kg group did so within 8 days, compared with 40% of 7-mg/kg responders, 50% of 10-mg/kg responders, and 87.5% of 15-mg/kg responders. Additional observations included dose-dependent decreases in IgG titer and longer response durations after multiple lower doses.

“Data from this study indicate that we can achieve effective increases in platelet levels, we can observe decreasing IgG levels, and the treatment was safe for the patients,” Dr. Robak said.

When asked about the intended clinical application of rozanolixizumab, Dr. Robak suggested that the agent may have a role in the postacute care setting. “We should develop a method of prolonged administration of [rozanolixizumab], as we saw that lower, multiple doses gave longer response durations.”

Still, he noted that more research is needed, since responses in diverse patient populations remain unknown. “We do not know how the drug will be active in truly refractory patients and we need this response before we establish the indication for the drug.”

The investigators reported financial relationships with Celgene, Roche, GlaxoSmithKline, Amgen, AbbVie, and other companies.

SOURCE: Robak T et al. EHA Congress, Abstract S850.

FORT LAUDERDALE, FLA. – When the Food and Drug Administration in 2017 approved L-glutamine (Endari) to treat the symptoms of sickle cell disease (SCD), it was the first new drug indicated for the condition in nearly two decades. But a small study of sickle cell patients in New York has found that patients are having difficulty obtaining the drug and sticking to the regimen.

bubaone/DigitalVision Vectors

“We found out that there are multiple barriers, mostly insurance related, and that after 10 months only one-fifth of the patients were still actively taking this medication,” said Ugochi Ogu, MD, assistant director of the Sickle Cell Center for Adults at Montefiore Medical Center in New York. She presented preliminary study results at the annual meeting of the Foundation for Sickle Cell Disease Research.

L-glutamine oral powder is taken twice a day to treat the symptoms of SCD. GoodRx reports that the average cash price for a 60-day supply of L-glutamine is $2,773.

The study followed 101 patients prescribed L-glutamine at the Montefiore Medical Center. When they returned to the clinic, patients were asked about barriers to obtaining the medication and adherence to the twice-a-day dosing. The center used a nearby local specialty pharmacy to fill the prescriptions.

The study also evaluated adherence by calculating the mean possession ratio (MPR) utilizing pharmacy records. The average age of the patient population was 36 years, and 56% were women.

It’s the first study of L-glutamine barriers and adherence in SCD patients in the real-world setting, Dr. Ogu said.

At the end of the 10-month study period, 21% of the patients were actively taking the medication, she said. “Forty-three percent had discontinued the medication, and 33% never filled the prescriptions; 4% had received but never started Endari,” Dr. Ogu said.

Of the patients who never filled the prescriptions, Dr. Ogu reported that 27% said their insurer denied prior authorization, 19% said their deductible was too high, and 16% cited other insurance issues.

“So we can see that insurance alone accounted for over 60% of why patients did not receive or could not start the medication,” she said.

Most patients – 94% – either had Medicare or Medicaid; the remainder had private insurance.

Among the 43% of all study patients who stopped taking the medication, reasons given include poor adherence (47%), side effects (9%), pregnancy and breast feeding (5%), and no perceived benefit (5%), Dr. Ogu said. At the outset, pharmacy records estimated adherence at 74% by using the average MPR, a rate similar to the phase 3 trial adherence rate of 77.4%.

Patient education is important to eliminate these barriers to treatment for SCD, Dr. Ogu said. “The patients need to understand why they’re taking whatever medication you prescribe. We need to educate them about the side effects, and we need to make them understand why it’s important to take certain medications or how they’re going to help them,” she said.

But even more important, she added, is a systems-based method to deal with insurance barriers. “If 62% of the patients did not get the medication due to insurance issues, I don’t think we’re doing a good job of making it accessible to them.”

Dr. Ogu reported a financial relationship with Vertex.

SOURCE: Ogu U et al. FSCDR 2019, Abstract JSCDH-D-19-00041.




 

FORT LAUDERDALE, FLA. – When the Food and Drug Administration in 2017 approved L-glutamine (Endari) to treat the symptoms of sickle cell disease (SCD), it was the first new drug indicated for the condition in nearly two decades. But a small study of sickle cell patients in New York has found that patients are having difficulty obtaining the drug and sticking to the regimen.

bubaone/DigitalVision Vectors

“We found out that there are multiple barriers, mostly insurance related, and that after 10 months only one-fifth of the patients were still actively taking this medication,” said Ugochi Ogu, MD, assistant director of the Sickle Cell Center for Adults at Montefiore Medical Center in New York. She presented preliminary study results at the annual meeting of the Foundation for Sickle Cell Disease Research.

L-glutamine oral powder is taken twice a day to treat the symptoms of SCD. GoodRx reports that the average cash price for a 60-day supply of L-glutamine is $2,773.

The study followed 101 patients prescribed L-glutamine at the Montefiore Medical Center. When they returned to the clinic, patients were asked about barriers to obtaining the medication and adherence to the twice-a-day dosing. The center used a nearby local specialty pharmacy to fill the prescriptions.

The study also evaluated adherence by calculating the mean possession ratio (MPR) utilizing pharmacy records. The average age of the patient population was 36 years, and 56% were women.

It’s the first study of L-glutamine barriers and adherence in SCD patients in the real-world setting, Dr. Ogu said.

At the end of the 10-month study period, 21% of the patients were actively taking the medication, she said. “Forty-three percent had discontinued the medication, and 33% never filled the prescriptions; 4% had received but never started Endari,” Dr. Ogu said.

Of the patients who never filled the prescriptions, Dr. Ogu reported that 27% said their insurer denied prior authorization, 19% said their deductible was too high, and 16% cited other insurance issues.

“So we can see that insurance alone accounted for over 60% of why patients did not receive or could not start the medication,” she said.

Most patients – 94% – either had Medicare or Medicaid; the remainder had private insurance.

Among the 43% of all study patients who stopped taking the medication, reasons given include poor adherence (47%), side effects (9%), pregnancy and breast feeding (5%), and no perceived benefit (5%), Dr. Ogu said. At the outset, pharmacy records estimated adherence at 74% by using the average MPR, a rate similar to the phase 3 trial adherence rate of 77.4%.

Patient education is important to eliminate these barriers to treatment for SCD, Dr. Ogu said. “The patients need to understand why they’re taking whatever medication you prescribe. We need to educate them about the side effects, and we need to make them understand why it’s important to take certain medications or how they’re going to help them,” she said.

But even more important, she added, is a systems-based method to deal with insurance barriers. “If 62% of the patients did not get the medication due to insurance issues, I don’t think we’re doing a good job of making it accessible to them.”

Dr. Ogu reported a financial relationship with Vertex.

SOURCE: Ogu U et al. FSCDR 2019, Abstract JSCDH-D-19-00041.




 

FORT LAUDERDALE, FLA. – When the Food and Drug Administration in 2017 approved L-glutamine (Endari) to treat the symptoms of sickle cell disease (SCD), it was the first new drug indicated for the condition in nearly two decades. But a small study of sickle cell patients in New York has found that patients are having difficulty obtaining the drug and sticking to the regimen.

bubaone/DigitalVision Vectors

“We found out that there are multiple barriers, mostly insurance related, and that after 10 months only one-fifth of the patients were still actively taking this medication,” said Ugochi Ogu, MD, assistant director of the Sickle Cell Center for Adults at Montefiore Medical Center in New York. She presented preliminary study results at the annual meeting of the Foundation for Sickle Cell Disease Research.

L-glutamine oral powder is taken twice a day to treat the symptoms of SCD. GoodRx reports that the average cash price for a 60-day supply of L-glutamine is $2,773.

The study followed 101 patients prescribed L-glutamine at the Montefiore Medical Center. When they returned to the clinic, patients were asked about barriers to obtaining the medication and adherence to the twice-a-day dosing. The center used a nearby local specialty pharmacy to fill the prescriptions.

The study also evaluated adherence by calculating the mean possession ratio (MPR) utilizing pharmacy records. The average age of the patient population was 36 years, and 56% were women.

It’s the first study of L-glutamine barriers and adherence in SCD patients in the real-world setting, Dr. Ogu said.

At the end of the 10-month study period, 21% of the patients were actively taking the medication, she said. “Forty-three percent had discontinued the medication, and 33% never filled the prescriptions; 4% had received but never started Endari,” Dr. Ogu said.

Of the patients who never filled the prescriptions, Dr. Ogu reported that 27% said their insurer denied prior authorization, 19% said their deductible was too high, and 16% cited other insurance issues.

“So we can see that insurance alone accounted for over 60% of why patients did not receive or could not start the medication,” she said.

Most patients – 94% – either had Medicare or Medicaid; the remainder had private insurance.

Among the 43% of all study patients who stopped taking the medication, reasons given include poor adherence (47%), side effects (9%), pregnancy and breast feeding (5%), and no perceived benefit (5%), Dr. Ogu said. At the outset, pharmacy records estimated adherence at 74% by using the average MPR, a rate similar to the phase 3 trial adherence rate of 77.4%.

Patient education is important to eliminate these barriers to treatment for SCD, Dr. Ogu said. “The patients need to understand why they’re taking whatever medication you prescribe. We need to educate them about the side effects, and we need to make them understand why it’s important to take certain medications or how they’re going to help them,” she said.

But even more important, she added, is a systems-based method to deal with insurance barriers. “If 62% of the patients did not get the medication due to insurance issues, I don’t think we’re doing a good job of making it accessible to them.”

Dr. Ogu reported a financial relationship with Vertex.

SOURCE: Ogu U et al. FSCDR 2019, Abstract JSCDH-D-19-00041.




 

AMSTERDAM – The investigational oral agent voxelotor induced rapid and sustained improvements in hemoglobin and hemolysis in both children and adults with sickle cell disease (SCD), follow-up results from the phase 3 HOPE trial show.

Neil Osterweil/MDedge News

Among 274 patients aged 12-59 years, those who were randomly assigned to receive voxelotor at a dose of 1,500 mg daily had significantly better hemoglobin responses – defined as an increase of more than 1.0 g/dL from baseline – than did patients assigned to placebo, reported Jo Howard, MD, of Guy’s and St. Thomas’ NHS Foundation Trust and King’s College in London.

“Voxelotor improves hemoglobin and reduces hemolysis in patients with sickle cell disease. This has the potential to reduce the morbidity in sickle cell disease and to improve the life of our patients,” she said at a briefing prior to her presentation of the data at the annual congress of the European Hematology Association.

There were no new safety signals and patients tolerated voxelotor well, she added.

The study was published simultaneously in the New England Journal of Medicine.

Voxelotor is a novel oral agent that increases hemoglobin’s affinity for oxygen by inhibiting hemoglobin polymerization and sickling of red blood cells, which if unchecked lead to serious consequences, such as chronic anemia and hemolysis, and subsequent organ damage, vaso-occlusion, stroke, or premature death.

In the HOPE (Hemoglobin Oxygen Affinity Modulation to Inhibit HbS Polymerization) trial, investigators enrolled 274 adolescents and adults with SCD and randomized them on a 1:1:1 basis to receive voxelotor at doses of either 1,500 mg or 900 mg daily, or placebo.

Approximately two-thirds of the patients were receiving hydroxyurea at baseline.

In a per-protocol analysis, 59.5% of patients who received the 1,500-mg dose of voxelotor had a hemoglobin response (P less than .001 compared with baseline), as did 38% of patients in the 900-mg group (P less than .001). Among patients assigned to placebo, however, just 9.2% had a hemoglobin response, a difference that was not statistically significant.

In an intention-to-treat analysis, in which patients who did not complete the study were considered to be nonresponders, the respective rates of hemoglobin response were 51.1%, 32.6%, and 6.5%.

The difference between the 1,500-mg dose and placebo was significant (P less than .001). The difference between the 900-mg group and placebo was not statistically significant.

Hemoglobin levels of 10 g/dL or higher at week 24 were seen in 41% of the participants in the 1,500-mg group, 20% in the 900-mg group, and 9% in the placebo group.

Patients on voxelotor had an improvement in hemoglobin, whether or not they were on hydroxyurea, and those with hemoglobin either below or above 7 g/dL at baseline all had an increase in hemoglobin.

The annualized adjusted incidence rate of vaso-occlusive crises was similar in the two voxelotor groups (2.77 for the 1,500-mg dose and 2.76 for the 900-mg group) – both lower than in the placebo group (3.19).

Among patients who had two or more vaso-occlusive crises within the previous year, the respective annualized incidence rates were 2.88, 3.39, and 3.50.

There was a trend toward reduced incidence of crises with voxelotor over time, Dr. Howard said.

Grade 3 or greater adverse events occurred in 26% of patients in the 1,500-mg group, 23% in the 900-mg group, and 26% in the placebo group. The most common adverse events were headache and diarrhea.

“The data presented support the achievement of the stated primary endpoint in the HOPE trial, which was to reduce anemia and hemolysis. The hemoglobin response and reduction in hemolysis observed with an orally administered, once-daily medication with side effects that minimally affect lifestyle may make voxelotor a promising advancement in the management of sickle cell disease if approved by the [Food and Drug Administration],” Alexis Thompson, MD, MPH, of Northwestern University, Chicago, noted in an editorial accompanying the study in the New England Journal of Medicine.

Global Blood Therapeutics funded the study. Dr. Howard reported consultant/advisory board activity for the company. Dr. Thompson reported grants and/or personal fees from other companies.

SOURCE: Vichinsky E et al. EHA Congress, Abstract S147. N Engl J Med. 2019 Jun 14. doi: 10.1056/NEJMoa1903212.

AMSTERDAM – The investigational oral agent voxelotor induced rapid and sustained improvements in hemoglobin and hemolysis in both children and adults with sickle cell disease (SCD), follow-up results from the phase 3 HOPE trial show.

Neil Osterweil/MDedge News

Among 274 patients aged 12-59 years, those who were randomly assigned to receive voxelotor at a dose of 1,500 mg daily had significantly better hemoglobin responses – defined as an increase of more than 1.0 g/dL from baseline – than did patients assigned to placebo, reported Jo Howard, MD, of Guy’s and St. Thomas’ NHS Foundation Trust and King’s College in London.

“Voxelotor improves hemoglobin and reduces hemolysis in patients with sickle cell disease. This has the potential to reduce the morbidity in sickle cell disease and to improve the life of our patients,” she said at a briefing prior to her presentation of the data at the annual congress of the European Hematology Association.

There were no new safety signals and patients tolerated voxelotor well, she added.

The study was published simultaneously in the New England Journal of Medicine.

Voxelotor is a novel oral agent that increases hemoglobin’s affinity for oxygen by inhibiting hemoglobin polymerization and sickling of red blood cells, which if unchecked lead to serious consequences, such as chronic anemia and hemolysis, and subsequent organ damage, vaso-occlusion, stroke, or premature death.

In the HOPE (Hemoglobin Oxygen Affinity Modulation to Inhibit HbS Polymerization) trial, investigators enrolled 274 adolescents and adults with SCD and randomized them on a 1:1:1 basis to receive voxelotor at doses of either 1,500 mg or 900 mg daily, or placebo.

Approximately two-thirds of the patients were receiving hydroxyurea at baseline.

In a per-protocol analysis, 59.5% of patients who received the 1,500-mg dose of voxelotor had a hemoglobin response (P less than .001 compared with baseline), as did 38% of patients in the 900-mg group (P less than .001). Among patients assigned to placebo, however, just 9.2% had a hemoglobin response, a difference that was not statistically significant.

In an intention-to-treat analysis, in which patients who did not complete the study were considered to be nonresponders, the respective rates of hemoglobin response were 51.1%, 32.6%, and 6.5%.

The difference between the 1,500-mg dose and placebo was significant (P less than .001). The difference between the 900-mg group and placebo was not statistically significant.

Hemoglobin levels of 10 g/dL or higher at week 24 were seen in 41% of the participants in the 1,500-mg group, 20% in the 900-mg group, and 9% in the placebo group.

Patients on voxelotor had an improvement in hemoglobin, whether or not they were on hydroxyurea, and those with hemoglobin either below or above 7 g/dL at baseline all had an increase in hemoglobin.

The annualized adjusted incidence rate of vaso-occlusive crises was similar in the two voxelotor groups (2.77 for the 1,500-mg dose and 2.76 for the 900-mg group) – both lower than in the placebo group (3.19).

Among patients who had two or more vaso-occlusive crises within the previous year, the respective annualized incidence rates were 2.88, 3.39, and 3.50.

There was a trend toward reduced incidence of crises with voxelotor over time, Dr. Howard said.

Grade 3 or greater adverse events occurred in 26% of patients in the 1,500-mg group, 23% in the 900-mg group, and 26% in the placebo group. The most common adverse events were headache and diarrhea.

“The data presented support the achievement of the stated primary endpoint in the HOPE trial, which was to reduce anemia and hemolysis. The hemoglobin response and reduction in hemolysis observed with an orally administered, once-daily medication with side effects that minimally affect lifestyle may make voxelotor a promising advancement in the management of sickle cell disease if approved by the [Food and Drug Administration],” Alexis Thompson, MD, MPH, of Northwestern University, Chicago, noted in an editorial accompanying the study in the New England Journal of Medicine.

Global Blood Therapeutics funded the study. Dr. Howard reported consultant/advisory board activity for the company. Dr. Thompson reported grants and/or personal fees from other companies.

SOURCE: Vichinsky E et al. EHA Congress, Abstract S147. N Engl J Med. 2019 Jun 14. doi: 10.1056/NEJMoa1903212.

AMSTERDAM – The investigational oral agent voxelotor induced rapid and sustained improvements in hemoglobin and hemolysis in both children and adults with sickle cell disease (SCD), follow-up results from the phase 3 HOPE trial show.

Neil Osterweil/MDedge News

Among 274 patients aged 12-59 years, those who were randomly assigned to receive voxelotor at a dose of 1,500 mg daily had significantly better hemoglobin responses – defined as an increase of more than 1.0 g/dL from baseline – than did patients assigned to placebo, reported Jo Howard, MD, of Guy’s and St. Thomas’ NHS Foundation Trust and King’s College in London.

“Voxelotor improves hemoglobin and reduces hemolysis in patients with sickle cell disease. This has the potential to reduce the morbidity in sickle cell disease and to improve the life of our patients,” she said at a briefing prior to her presentation of the data at the annual congress of the European Hematology Association.

There were no new safety signals and patients tolerated voxelotor well, she added.

The study was published simultaneously in the New England Journal of Medicine.

Voxelotor is a novel oral agent that increases hemoglobin’s affinity for oxygen by inhibiting hemoglobin polymerization and sickling of red blood cells, which if unchecked lead to serious consequences, such as chronic anemia and hemolysis, and subsequent organ damage, vaso-occlusion, stroke, or premature death.

In the HOPE (Hemoglobin Oxygen Affinity Modulation to Inhibit HbS Polymerization) trial, investigators enrolled 274 adolescents and adults with SCD and randomized them on a 1:1:1 basis to receive voxelotor at doses of either 1,500 mg or 900 mg daily, or placebo.

Approximately two-thirds of the patients were receiving hydroxyurea at baseline.

In a per-protocol analysis, 59.5% of patients who received the 1,500-mg dose of voxelotor had a hemoglobin response (P less than .001 compared with baseline), as did 38% of patients in the 900-mg group (P less than .001). Among patients assigned to placebo, however, just 9.2% had a hemoglobin response, a difference that was not statistically significant.

In an intention-to-treat analysis, in which patients who did not complete the study were considered to be nonresponders, the respective rates of hemoglobin response were 51.1%, 32.6%, and 6.5%.

The difference between the 1,500-mg dose and placebo was significant (P less than .001). The difference between the 900-mg group and placebo was not statistically significant.

Hemoglobin levels of 10 g/dL or higher at week 24 were seen in 41% of the participants in the 1,500-mg group, 20% in the 900-mg group, and 9% in the placebo group.

Patients on voxelotor had an improvement in hemoglobin, whether or not they were on hydroxyurea, and those with hemoglobin either below or above 7 g/dL at baseline all had an increase in hemoglobin.

The annualized adjusted incidence rate of vaso-occlusive crises was similar in the two voxelotor groups (2.77 for the 1,500-mg dose and 2.76 for the 900-mg group) – both lower than in the placebo group (3.19).

Among patients who had two or more vaso-occlusive crises within the previous year, the respective annualized incidence rates were 2.88, 3.39, and 3.50.

There was a trend toward reduced incidence of crises with voxelotor over time, Dr. Howard said.

Grade 3 or greater adverse events occurred in 26% of patients in the 1,500-mg group, 23% in the 900-mg group, and 26% in the placebo group. The most common adverse events were headache and diarrhea.

“The data presented support the achievement of the stated primary endpoint in the HOPE trial, which was to reduce anemia and hemolysis. The hemoglobin response and reduction in hemolysis observed with an orally administered, once-daily medication with side effects that minimally affect lifestyle may make voxelotor a promising advancement in the management of sickle cell disease if approved by the [Food and Drug Administration],” Alexis Thompson, MD, MPH, of Northwestern University, Chicago, noted in an editorial accompanying the study in the New England Journal of Medicine.

Global Blood Therapeutics funded the study. Dr. Howard reported consultant/advisory board activity for the company. Dr. Thompson reported grants and/or personal fees from other companies.

SOURCE: Vichinsky E et al. EHA Congress, Abstract S147. N Engl J Med. 2019 Jun 14. doi: 10.1056/NEJMoa1903212.

Cancer survivors have significantly higher out-of-pocket medical costs than those with no history of cancer, and a quarter of those survivors have some type of material hardship related to their diagnosis, according to the Centers for Disease Control and Prevention.

Along with those material financial hardships – the need to borrow money, go into debt, or declare bankruptcy – more than 34% of cancer survivors aged 18-64 years experienced psychological financial hardship, defined as worry about large medical bills, in 2011 and 2016, Donatus U. Ekwueme, PhD, and his associates reported in the Morbidity and Mortality Weekly Report.

Cancer survivors spend 60% more out of pocket than those with no cancer history: $1,000 a year from 2011 to 2016, compared with $622 for adults without a history of cancer. Spending was lowest among younger people (18-39 years) and increased with age, but the prevalence of both material and psychological hardships was highest in the middle age group (40-49 years) and lowest in the oldest group (50-64 years), they said.

Women had higher out-of-pocket costs than men, although the difference was smaller for those with cancer ($1,023 vs. $976) than for those without ($721 vs. $519). Material and psychological hardships were both more common among women, said Dr. Ekwueme of the CDC’s National Center for Chronic Disease Prevention and Health Promotion, Atlanta, and his associates.

Mean out-of-pocket spending was much higher for cancer survivors with private health insurance ($1,114) than for survivors with public insurance ($471), but material hardship was much more prevalent among those with public insurance (33.1% vs. 21.9%). Rates of psychological hardship, however, were much closer: 35.9% for those with public insurance and 32.5% for those with private insurance, the investigators said.

“The number of Americans with a history of cancer is projected to increase in the next decade, and the economic burden associated with living with a cancer diagnosis will likely increase as well,” they wrote, and interventions such as “systematic screening for financial hardship at cancer diagnosis and throughout the cancer care trajectory [are needed] to minimize financial hardship for cancer survivors.”

The analysis was based on data for 123,771 adults aged 18-64 years from the Medical Expenditure Panel Survey. Out-of-pocket costs were calculated using data from 2011 to 2016, with all costs adjusted to 2016 dollars, but the hardship calculations involved data from only 2011 and 2016.

[email protected]

SOURCE: Ekwueme DU et al. MMWR 2019 Jun 7;68(22):494-9.

Cancer survivors have significantly higher out-of-pocket medical costs than those with no history of cancer, and a quarter of those survivors have some type of material hardship related to their diagnosis, according to the Centers for Disease Control and Prevention.

Along with those material financial hardships – the need to borrow money, go into debt, or declare bankruptcy – more than 34% of cancer survivors aged 18-64 years experienced psychological financial hardship, defined as worry about large medical bills, in 2011 and 2016, Donatus U. Ekwueme, PhD, and his associates reported in the Morbidity and Mortality Weekly Report.

Cancer survivors spend 60% more out of pocket than those with no cancer history: $1,000 a year from 2011 to 2016, compared with $622 for adults without a history of cancer. Spending was lowest among younger people (18-39 years) and increased with age, but the prevalence of both material and psychological hardships was highest in the middle age group (40-49 years) and lowest in the oldest group (50-64 years), they said.

Women had higher out-of-pocket costs than men, although the difference was smaller for those with cancer ($1,023 vs. $976) than for those without ($721 vs. $519). Material and psychological hardships were both more common among women, said Dr. Ekwueme of the CDC’s National Center for Chronic Disease Prevention and Health Promotion, Atlanta, and his associates.

Mean out-of-pocket spending was much higher for cancer survivors with private health insurance ($1,114) than for survivors with public insurance ($471), but material hardship was much more prevalent among those with public insurance (33.1% vs. 21.9%). Rates of psychological hardship, however, were much closer: 35.9% for those with public insurance and 32.5% for those with private insurance, the investigators said.

“The number of Americans with a history of cancer is projected to increase in the next decade, and the economic burden associated with living with a cancer diagnosis will likely increase as well,” they wrote, and interventions such as “systematic screening for financial hardship at cancer diagnosis and throughout the cancer care trajectory [are needed] to minimize financial hardship for cancer survivors.”

The analysis was based on data for 123,771 adults aged 18-64 years from the Medical Expenditure Panel Survey. Out-of-pocket costs were calculated using data from 2011 to 2016, with all costs adjusted to 2016 dollars, but the hardship calculations involved data from only 2011 and 2016.

[email protected]

SOURCE: Ekwueme DU et al. MMWR 2019 Jun 7;68(22):494-9.

Cancer survivors have significantly higher out-of-pocket medical costs than those with no history of cancer, and a quarter of those survivors have some type of material hardship related to their diagnosis, according to the Centers for Disease Control and Prevention.

Along with those material financial hardships – the need to borrow money, go into debt, or declare bankruptcy – more than 34% of cancer survivors aged 18-64 years experienced psychological financial hardship, defined as worry about large medical bills, in 2011 and 2016, Donatus U. Ekwueme, PhD, and his associates reported in the Morbidity and Mortality Weekly Report.

Cancer survivors spend 60% more out of pocket than those with no cancer history: $1,000 a year from 2011 to 2016, compared with $622 for adults without a history of cancer. Spending was lowest among younger people (18-39 years) and increased with age, but the prevalence of both material and psychological hardships was highest in the middle age group (40-49 years) and lowest in the oldest group (50-64 years), they said.

Women had higher out-of-pocket costs than men, although the difference was smaller for those with cancer ($1,023 vs. $976) than for those without ($721 vs. $519). Material and psychological hardships were both more common among women, said Dr. Ekwueme of the CDC’s National Center for Chronic Disease Prevention and Health Promotion, Atlanta, and his associates.

Mean out-of-pocket spending was much higher for cancer survivors with private health insurance ($1,114) than for survivors with public insurance ($471), but material hardship was much more prevalent among those with public insurance (33.1% vs. 21.9%). Rates of psychological hardship, however, were much closer: 35.9% for those with public insurance and 32.5% for those with private insurance, the investigators said.

“The number of Americans with a history of cancer is projected to increase in the next decade, and the economic burden associated with living with a cancer diagnosis will likely increase as well,” they wrote, and interventions such as “systematic screening for financial hardship at cancer diagnosis and throughout the cancer care trajectory [are needed] to minimize financial hardship for cancer survivors.”

The analysis was based on data for 123,771 adults aged 18-64 years from the Medical Expenditure Panel Survey. Out-of-pocket costs were calculated using data from 2011 to 2016, with all costs adjusted to 2016 dollars, but the hardship calculations involved data from only 2011 and 2016.

[email protected]

SOURCE: Ekwueme DU et al. MMWR 2019 Jun 7;68(22):494-9.

CHICAGO – A fixed-duration venetoclax-obinutuzumab regimen is safe and provides a superior outcome versus standard chlorambucil-obinutuzumab in elderly patients with untreated chronic lymphocytic leukemia (CLL) and comorbidities, results of a randomized phase 3 trial showed.

At 24 months, progression-free survival was 88.2% for the venetoclax-obinutuzumab regimen, versus 64.1% for chlorambucil-obinutuzumab (hazard ratio, 0.35; 95% confidence interval, 0.23-0.53; P less than .0001) in CLL-14, an open-label, multinational trial presented at the annual meeting of the American Society of Clinical Oncology.

The regimen, given for just 12 28-day cycles, also achieved the highest rate of minimal residual disease (MRD)-negative responses ever seen in a randomized prospective CLL study, according to investigator Kirsten Fischer, MD, of the University of Cologne in Germany.

“We really think that these unprecedented MRD negativity levels will eventually translate into an improved overall survival,” Dr. Fischer said during an oral abstract presentation.

Matthew Steven Davids, MD, of Dana-Farber Cancer Institute/Harvard Medical School, Boston, said venetoclax plus obinutuzumab offers the potential for 1-year, time-limited therapy, which limits concerns over long-term adherence and has the potential for cost savings, should the therapy prove to be highly durable with further follow-up.

“A limitation of the study is that the comparator arm – chlorambucil plus obinutuzumab – is directly applicable to only a relatively small subset of our older and frailer CLL patients,” Dr. Davids said during a podium discussion of the results.

“But nonetheless, venetoclax plus obinutuzumab is a promising, time-limited regimen, and CLL14 is an immediately practice-changing study for frontline CLL treatment,” he added.

The regimen stands in contrast to ibrutinib, which offers durable responses but requires continuous dosing, and FCR (fludarabine, cyclophosphamide, and rituximab), a time-limited therapy with curative potential that is restricted to younger patients with IGHV-mutated CLL, according to Dr. Davids.

In CLL-14, 432 patients were randomized 1:1 to receive venetoclax-obinutuzumab for six cycles followed by venetoclax for six cycles, or chlorambucil-obinutuzumab for six cycles followed by chlorambucil for six cycles. The median age was 72 years in the venetoclax-obinutuzumab arm and 71 years in the chlorambucil-obinutuzumab arm.

The overall response rate was 85% for venetoclax-obinutuzumab and 71% for chlorambucil-obinutuzumab (P = .0007), Dr. Fischer reported at the meeting.

The improvement in progression-free survival seen in the overall study population was also seen in patients with TP53 deletions or mutations, and in those with unmutated IGHV, Dr. Fischer reported.

Rates of MRD negativity in peripheral blood were 76% versus 35% for the venetoclax- and chlorambucil-containing combinations, respectively (P less than .001), and similarly, MRD negativity in bone marrow was 57% versus 17% (P less than .001), she said.

There were no significant differences in the rates of grade 3 or 4 neutropenia, which occurred in 52.8% of the venetoclax–obinutuzumab treated patients and 48.1% of the chlorambucil-obinutuzumab treated patients, or in grade 3 or 4 infections, which occurred in 17.5% and 15.0%, respectively, according to a report, published simultaneously in the New England Journal of Medicine (2019;380:2225-36).

Likewise, all-cause mortality was not significantly different between the arms, at 9.3% and 7.9%, respectively.

F. Hoffmann-La Roche and AbbVie supported the study. Dr. Fischer reported travel, accommodations, or expenses from Roche in her abstract disclosure.

SOURCE: Fischer K et al. ASCO 2019, Abstract 7502.

CHICAGO – A fixed-duration venetoclax-obinutuzumab regimen is safe and provides a superior outcome versus standard chlorambucil-obinutuzumab in elderly patients with untreated chronic lymphocytic leukemia (CLL) and comorbidities, results of a randomized phase 3 trial showed.

At 24 months, progression-free survival was 88.2% for the venetoclax-obinutuzumab regimen, versus 64.1% for chlorambucil-obinutuzumab (hazard ratio, 0.35; 95% confidence interval, 0.23-0.53; P less than .0001) in CLL-14, an open-label, multinational trial presented at the annual meeting of the American Society of Clinical Oncology.

The regimen, given for just 12 28-day cycles, also achieved the highest rate of minimal residual disease (MRD)-negative responses ever seen in a randomized prospective CLL study, according to investigator Kirsten Fischer, MD, of the University of Cologne in Germany.

“We really think that these unprecedented MRD negativity levels will eventually translate into an improved overall survival,” Dr. Fischer said during an oral abstract presentation.

Matthew Steven Davids, MD, of Dana-Farber Cancer Institute/Harvard Medical School, Boston, said venetoclax plus obinutuzumab offers the potential for 1-year, time-limited therapy, which limits concerns over long-term adherence and has the potential for cost savings, should the therapy prove to be highly durable with further follow-up.

“A limitation of the study is that the comparator arm – chlorambucil plus obinutuzumab – is directly applicable to only a relatively small subset of our older and frailer CLL patients,” Dr. Davids said during a podium discussion of the results.

“But nonetheless, venetoclax plus obinutuzumab is a promising, time-limited regimen, and CLL14 is an immediately practice-changing study for frontline CLL treatment,” he added.

The regimen stands in contrast to ibrutinib, which offers durable responses but requires continuous dosing, and FCR (fludarabine, cyclophosphamide, and rituximab), a time-limited therapy with curative potential that is restricted to younger patients with IGHV-mutated CLL, according to Dr. Davids.

In CLL-14, 432 patients were randomized 1:1 to receive venetoclax-obinutuzumab for six cycles followed by venetoclax for six cycles, or chlorambucil-obinutuzumab for six cycles followed by chlorambucil for six cycles. The median age was 72 years in the venetoclax-obinutuzumab arm and 71 years in the chlorambucil-obinutuzumab arm.

The overall response rate was 85% for venetoclax-obinutuzumab and 71% for chlorambucil-obinutuzumab (P = .0007), Dr. Fischer reported at the meeting.

The improvement in progression-free survival seen in the overall study population was also seen in patients with TP53 deletions or mutations, and in those with unmutated IGHV, Dr. Fischer reported.

Rates of MRD negativity in peripheral blood were 76% versus 35% for the venetoclax- and chlorambucil-containing combinations, respectively (P less than .001), and similarly, MRD negativity in bone marrow was 57% versus 17% (P less than .001), she said.

There were no significant differences in the rates of grade 3 or 4 neutropenia, which occurred in 52.8% of the venetoclax–obinutuzumab treated patients and 48.1% of the chlorambucil-obinutuzumab treated patients, or in grade 3 or 4 infections, which occurred in 17.5% and 15.0%, respectively, according to a report, published simultaneously in the New England Journal of Medicine (2019;380:2225-36).

Likewise, all-cause mortality was not significantly different between the arms, at 9.3% and 7.9%, respectively.

F. Hoffmann-La Roche and AbbVie supported the study. Dr. Fischer reported travel, accommodations, or expenses from Roche in her abstract disclosure.

SOURCE: Fischer K et al. ASCO 2019, Abstract 7502.

CHICAGO – A fixed-duration venetoclax-obinutuzumab regimen is safe and provides a superior outcome versus standard chlorambucil-obinutuzumab in elderly patients with untreated chronic lymphocytic leukemia (CLL) and comorbidities, results of a randomized phase 3 trial showed.

At 24 months, progression-free survival was 88.2% for the venetoclax-obinutuzumab regimen, versus 64.1% for chlorambucil-obinutuzumab (hazard ratio, 0.35; 95% confidence interval, 0.23-0.53; P less than .0001) in CLL-14, an open-label, multinational trial presented at the annual meeting of the American Society of Clinical Oncology.

The regimen, given for just 12 28-day cycles, also achieved the highest rate of minimal residual disease (MRD)-negative responses ever seen in a randomized prospective CLL study, according to investigator Kirsten Fischer, MD, of the University of Cologne in Germany.

“We really think that these unprecedented MRD negativity levels will eventually translate into an improved overall survival,” Dr. Fischer said during an oral abstract presentation.

Matthew Steven Davids, MD, of Dana-Farber Cancer Institute/Harvard Medical School, Boston, said venetoclax plus obinutuzumab offers the potential for 1-year, time-limited therapy, which limits concerns over long-term adherence and has the potential for cost savings, should the therapy prove to be highly durable with further follow-up.

“A limitation of the study is that the comparator arm – chlorambucil plus obinutuzumab – is directly applicable to only a relatively small subset of our older and frailer CLL patients,” Dr. Davids said during a podium discussion of the results.

“But nonetheless, venetoclax plus obinutuzumab is a promising, time-limited regimen, and CLL14 is an immediately practice-changing study for frontline CLL treatment,” he added.

The regimen stands in contrast to ibrutinib, which offers durable responses but requires continuous dosing, and FCR (fludarabine, cyclophosphamide, and rituximab), a time-limited therapy with curative potential that is restricted to younger patients with IGHV-mutated CLL, according to Dr. Davids.

In CLL-14, 432 patients were randomized 1:1 to receive venetoclax-obinutuzumab for six cycles followed by venetoclax for six cycles, or chlorambucil-obinutuzumab for six cycles followed by chlorambucil for six cycles. The median age was 72 years in the venetoclax-obinutuzumab arm and 71 years in the chlorambucil-obinutuzumab arm.

The overall response rate was 85% for venetoclax-obinutuzumab and 71% for chlorambucil-obinutuzumab (P = .0007), Dr. Fischer reported at the meeting.

The improvement in progression-free survival seen in the overall study population was also seen in patients with TP53 deletions or mutations, and in those with unmutated IGHV, Dr. Fischer reported.

Rates of MRD negativity in peripheral blood were 76% versus 35% for the venetoclax- and chlorambucil-containing combinations, respectively (P less than .001), and similarly, MRD negativity in bone marrow was 57% versus 17% (P less than .001), she said.

There were no significant differences in the rates of grade 3 or 4 neutropenia, which occurred in 52.8% of the venetoclax–obinutuzumab treated patients and 48.1% of the chlorambucil-obinutuzumab treated patients, or in grade 3 or 4 infections, which occurred in 17.5% and 15.0%, respectively, according to a report, published simultaneously in the New England Journal of Medicine (2019;380:2225-36).

Likewise, all-cause mortality was not significantly different between the arms, at 9.3% and 7.9%, respectively.

F. Hoffmann-La Roche and AbbVie supported the study. Dr. Fischer reported travel, accommodations, or expenses from Roche in her abstract disclosure.

SOURCE: Fischer K et al. ASCO 2019, Abstract 7502.

From the Moffitt Cancer Center, Tampa, FL.

Abstract

• Objective: To outline the approach to selecting a tyrosine kinase inhibitor (TKI) for initial treatment of chronic myeloid leukemia (CML) and monitoring patients following initiation of therapy.
• Methods: Review of the literature and evidence-based guidelines.
• Results: The development and availability of TKIs has improved survival for patients diagnosed with CML. The life expectancy of patients diagnosed with chronic-phase CML (CP-CML) is similar to that of the general population, provided they receive appropriate TKI therapy and adhere to treatment. Selection of the most appropriate first-line TKI for newly diagnosed CP-CML requires incorporation of the patient’s baseline karyotype and Sokal or EURO risk score, and a clear understanding of the patient’s comorbidities. The adverse effect profile of all TKIs must be considered in conjunction with the patient’s ongoing medical issues to decrease the likelihood of worsening their current symptoms or causing a severe complication from TKI therapy. After confirming a diagnosis of CML and selecting the most appropriate TKI for first-line therapy, close monitoring and follow-up are necessary to ensure patients are meeting the desired treatment milestones. Responses in CML can be assessed based on hematologic parameters, cytogenetic results, and molecular responses.
• Conclusion: Given the successful treatments available for patients with CML, it is crucial to identify patients with this diagnosis; ensure they receive a complete, appropriate diagnostic workup including a bone marrow biopsy and aspiration with cytogenetic testing; and select the best therapy for each individual patient.

Keywords: chronic myeloid leukemia; CML; tyrosine kinase inhibitor; TKI; cancer; BCR-ABL protein.

Chronic myeloid leukemia (CML) is a rare myeloproliferative neoplasm that is characterized by the presence of the Philadelphia (Ph) chromosome and uninhibited expansion of bone marrow stem cells. The Ph chromosome arises from a reciprocal translocation between the Abelson (ABL) region on chromosome 9 and the breakpoint cluster region (BCR) of chromosome 22 (t(9;22)(q34;q11.2)), resulting in the BCR-ABL1 fusion gene and its protein product, BCR-ABL tyrosine kinase.¹ BCR-ABL has constitutive tyrosine kinase activity that promotes growth, replication, and survival of hematopoietic cells through downstream pathways, which is the driving factor in the pathogenesis of CML.¹

CML is divided into 3 phases based on the number of myeloblasts observed in the blood or bone marrow: chronic, accelerated, and blast. Most cases of CML are diagnosed in the chronic phase (CP), which is marked by proliferation of primarily the myeloid element.

Typical treatment for CML involves lifelong use of oral BCR-ABL tyrosine kinase inhibitors (TKIs). Currently, 5 TKIs have regulatory approval for treatment of this disease. The advent of TKIs, a class of small molecules targeting the tyrosine kinases, particularly the BCR-ABL tyrosine kinase, led to rapid changes in the management of CML and improved survival for patients. Patients diagnosed with chronic-phase CML (CP-CML) now have a life expectancy that is similar to that of the general population, as long as they receive appropriate TKI therapy and adhere to treatment. As such, it is crucial to identify patients with CML; ensure they receive a complete, appropriate diagnostic workup; and select the best therapy for each patient.

Epidemiology

According to SEER data estimates, 8430 new cases of CML were diagnosed in the United States in 2018. CML is a disease of older adults, with a median age of 65 years at diagnosis, and there is a slight male predominance. Between 2011 and 2015, the number of new CML cases was 1.8 per 100,000 persons. The median overall survival (OS) in patients with newly diagnosed CP-CML has not been reached.² Given the effective treatments available for managing CML, it is estimated that the prevalence of CML in the United States will plateau at 180,000 patients by 2050.³

Clinical Features

The diagnosis of CML is often suspected based on an incidental finding of leukocytosis and, in some cases, thrombocytosis. In many cases, this is an incidental finding on routine blood work, but approximately 50% of patients will present with constitutional symptoms associated with the disease. Characteristic features of the white blood cell differential include left-shifted maturation with neutrophilia and immature circulating myeloid cells. Basophilia and eosinophilia are often present as well. Splenomegaly is a common sign, present in 50% to 90% of patients at diagnosis. In those patients with symptoms related to CML at diagnosis, the most common presentation includes increasing fatigue, fevers, night sweats, early satiety, and weight loss. The diagnosis is confirmed by cytogenetic studies showing the Ph chromosome abnormality, t(9; 22)(q3.4;q1.1), and/or reverse transcriptase polymerase chain reaction (PCR) showing BCR-ABL1 transcripts.

Testing

Bone marrow biopsy. There are 3 distinct phases of CML: CP, accelerated phase (AP), and blast phase (BP). Bone marrow biopsy and aspiration at diagnosis are mandatory in order to determine the phase of the disease at diagnosis. This distinction is based on the percentage of blasts, promyelocytes, and basophils present as well as the platelet count and presence or absence of extramedullary disease.⁴ The vast majority of patients at diagnosis have CML that is in the chronic phase. The typical appearance in CP-CML is a hypercellular marrow with granulocytic and occasionally megakaryocytic hyperplasia. In many cases, basophilia and/or eosinophilia are noted as well. Dysplasia is not a typical finding in CML.⁵ Bone marrow fibrosis can be seen in up to one-third of patients at diagnosis, and may indicate a slightly worse prognosis.⁶ Although a diagnosis of CML can be made without a bone marrow biopsy, complete staging and prognostication are only possible with information gained from this test, including baseline karyotype and confirmation of CP versus a more advanced phase of CML.

Diagnostic criteria. The criteria for diagnosing AP-CML has not been agreed upon by various groups, but the modified MD Anderson Cancer Center (MDACC) criteria are used in the majority of clinical trials evaluating the efficacy of TKIs in preventing progression to advanced phases of CML. MDACC criteria define AP-CML as the presence of 1 of the following: 15% to 29% blasts in the peripheral blood or bone marrow, ≥ 30% peripheral blasts plus promyelocytes, ≥ 20% basophils in the blood or bone marrow, platelet count ≤ 100,000/μL unrelated to therapy, and clonal cytogenetic evolution in Ph-positive metaphases (Table).⁷

The defining feature of CML is the presence of the Ph chromosome abnormality. In a small subset of patients, additional chromosome abnormalities (ACA) in the Ph-positive cells may be identified at diagnosis. Some reports indicate that the presence of “major route” ACA (trisomy 8, isochromosome 17q, a second Ph chromosome, or trisomy 19) at diagnosis may negatively impact prognosis, but other reports contradict these findings.^10,11

PCR assay. The typical BCR breakpoint in CML is the major breakpoint cluster region (M-BCR), which results in a 210-kDa protein (p210). Alternate breakpoints that are less frequently identified are the minor BCR (mBCR or p190), which is more commonly found in Ph-positive acute lymphoblastic leukemia (ALL), and the micro BCR (µBCR or p230), which is much less common and is often characterized by chronic neutrophilia.¹² Identifying which BCR-ABL1 transcript is present in each patient using qualitative PCR is crucial in order to ensure proper monitoring during treatment.

The most sensitive method for detecting BCR-ABL1 mRNA transcripts is the quantitative real-time PCR (RQ-PCR) assay, which is typically done on peripheral blood. RQ-PCR is capable of detecting a single CML cell in the presence of ≥ 100,000 normal cells. This test should be done during the initial diagnostic workup in order to confirm the presence of BCR-ABL1 transcripts, and it is used as a standard method for monitoring response to TKI therapy.¹³ The International Scale (IS) is a standardized approach to reporting RQ-PCR results that was developed to allow comparison of results across various laboratories and has become the gold standard for reporting BCR-ABL1 transcript values.¹⁴

Determining Risk Scores

Calculating a patient’s Sokal score or EURO risk score at diagnosis remains an important component of the diagnostic workup in CP-CML, as this information has prognostic and therapeutic implications (an online calculator is available through European LeukemiaNet [ELN]). The risk for disease progression to the accelerated or blast phases is higher in patients with intermediate or high risk scores compared to those with a low risk score at diagnosis. The risk of progression in intermediate- or high-risk patients is lower when a second-generation TKI (dasatinib, nilotinib, or bosutinib) is used as frontline therapy compared to imatinib, and therefore, the National Comprehensive Cancer Network (NCCN) CML Panel recommends starting with a second-generation TKI in these patients.^15-19

Monitoring Response to Therapy

After confirming a diagnosis of CML and selecting the most appropriate TKI for first-line therapy, the successful management of CML patients relies on close monitoring and follow-up to ensure they are meeting the desired treatment milestones. Responses in CML can be assessed based on hematologic parameters, cytogenetic results, and molecular responses. A complete hematologic response (CHR) implies complete normalization of peripheral blood counts (with the exception of TKI-induced cytopenias) and resolution of any palpable splenomegaly. The majority of patients will achieve a CHR within 4 to 6 weeks after initiating CML-directed therapy.²⁰

Cytogenetic Response

Cytogenetic responses are defined by the decrease in the number of Ph chromosome–positive metaphases when assessed on bone marrow cytogenetics. A partial cytogenetic response (PCyR) is defined as having 1% to 35% Ph-positive metaphases, a major cytogenetic response (MCyR) as having 0% to 35% Ph-positive metaphases, and a complete cytogenetic response (CCyR) implies that no Ph-positive metaphases are identified on bone marrow cytogenetics. An ideal response is the achievement of PCyR after 3 months on a TKI and a CCyR after 12 months on a TKI.²¹

Once a patient has achieved a CCyR, monitoring their response to therapy can only be done using RQ-PCR to measure BCR-ABL1 transcripts in the peripheral blood. The NCCN and the ELN recommend monitoring RQ-PCR from the peripheral blood every 3 months in order to assess response to TKIs.^19,22 As noted, the IS has become the gold standard reporting system for all BCR-ABL1 transcript levels in the majority of laboratories worldwide.^14,23 Molecular responses are based on a log reduction in BCR-ABL1 transcripts from a standardized baseline. Many molecular responses can be correlated with cytogenetic responses such that, if reliable RQ-PCR testing is available, monitoring can be done using only peripheral blood RQ-PCR rather than repeat bone marrow biopsies. For example, an early molecular response (EMR) is defined as a RQ-PCR value of ≤ 10% IS, which is approximately equivalent to a PCyR.²⁴ A value of 1% IS is approximately equivalent to a CCyR. A major molecular response (MMR) is a ≥ 3-log reduction in BCR-ABL1 transcripts from baseline and is a value of ≤ 0.1% IS. Deeper levels of molecular response are best described by the log reduction in BCR-ABL1 transcripts, with a 4-log reduction denoted as MR4.0, a 4.5-log reduction as MR4.5, and so forth. Complete molecular response (CMR) is defined by the level of sensitivity of the RQ-PCR assay being used.¹⁴

The definition of relapsed disease in CML is dependent on the type of response the patient had previously achieved. Relapse could be the loss of a hematologic or cytogenetic response, but fluctuations in BCR-ABL1 transcripts on routine RQ-PCR do not necessarily indicate relapsed CML. A 1-log increase in the level of BCR-ABL1 transcripts with a concurrent loss of MMR should prompt a bone marrow biopsy in order to assess for the loss of CCyR, and thus a cytogenetic relapse; however, this loss of MMR does not define relapse in and of itself. In the setting of relapsed disease, testing should be done to look for possible ABL kinase domain mutations, and alternate therapy should be selected.¹⁹

Multiple reports have identified the prognostic relevance of achieving an EMR at 3 and 6 months after starting TKI therapy. Marin and colleagues reported that in 282 imatinib-treated patients, there was a significant improvement in 8-year OS, progression-free survival (PFS), and cumulative incidence of CCyR and CMR in patients who had BCR-ABL1 transcripts < 9.84% IS after 3 months on treatment.²⁴ This data highlights the importance of early molecular monitoring in order to ensure the best outcomes for patients with CP-CML.

The NCCN CML guidelines and ELN recommendations both agree that an ideal response after 3 months on a TKI is BCR-ABL1 transcripts < 10% IS, but treatment is not considered to be failing at this point if the patient marginally misses this milestone. After 6 months on treatment, an ideal response is considered BCR-ABL1 transcripts < 1%–10% IS. Ideally, patients will have BCR-ABL1 transcripts < 0.1%–1% IS by the time they complete 12 months of TKI therapy, suggesting that these patients have at least achieved a CCyR.^19,22 Even after patients achieve these early milestones, frequent monitoring by RQ-PCR is required to ensure that they are maintaining their response to treatment. This will help to ensure patient compliance with treatment and will also help to identify a select subset of patients who could potentially be considered for an attempt at TKI cessation (not discussed in detail here) after a minimum of 3 years on therapy.^19,25

Selecting First-line TKI Therapy

Selection of the most appropriate first-line TKI for newly diagnosed CP-CML patients requires incorporation of many patient-specific factors. These factors include baseline karyotype and confirmation of CP-CML through bone marrow biopsy, Sokal or EURO risk score, and a thorough patient history, including a clear understanding of the patient’s comorbidities. The adverse effect profile of all TKIs must be considered in conjunction with the patient’s ongoing medical issues in order to decrease the likelihood of worsening their current symptoms or causing a severe complication from TKI therapy.

The management of CML was revolutionized by the development and ultimate regulatory approval of imatinib mesylate in 2001. Imatinib was the first small-molecule cancer therapy developed and approved. It acts by binding to the adenosine triphosphate (ATP) binding site in the catalytic domain of BCR-ABL, thus inhibiting the oncoprotein’s tyrosine kinase activity.²⁶

The International Randomized Study of Interferon versus STI571 (IRIS) trial was a randomized phase 3 study that compared imatinib 400 mg daily to interferon alfa (IFNa) plus cytarabine. More than 1000 CP-CML patients were randomly assigned 1:1 to either imatinib or IFNa plus cytarabine and were assessed for event-free survival, hematologic and cytogenetic responses, freedom from progression to AP or BP, and toxicity. Imatinib was superior to the prior standard of care for all these outcomes.²¹ The long-term follow-up of the IRIS trial reported an 83% estimated 10-year OS and 79% estimated event-free survival for patients on the imatinib arm of this study.¹⁵ The cumulative rate of CCyR was 82.8%. Of the 204 imatinib-treated patients who could undergo a molecular response evaluation at 10 years, 93.1% had a MMR and 63.2% had a MR4.5, suggesting durable, deep molecular responses for many patients. The estimated 10-year rate of freedom from progression to AP or BP was 92.1%.

Higher doses of imatinib (600-800 mg daily) have been studied in an attempt to overcome resistance and improve cytogenetic and molecular response rates. The Tyrosine Kinase Inhibitor Optimization and Selectivity (TOPS) trial was a randomized phase 3 study that compared imatinib 800 mg daily to imatinib 400 mg daily. Although the 6-month assessments found increased rates of CCyR and a MMR in the higher-dose imatinib arm, these differences were no longer present at the 12-month assessment. Furthermore, the higher dose of imatinib led to a significantly higher incidence of grade 3/4 hematologic adverse events, and approximately 50% of patients on imatinib 800 mg daily required a dose reduction to less than 600 mg daily because of toxicity.²⁷

The Therapeutic Intensification in De Novo Leukaemia (TIDEL)-II study used plasma trough levels of imatinib on day 22 of treatment with imatinib 600 mg daily to determine if patients should escalate the imatinib dose to 800 mg daily. In patients who did not meet molecular milestones at 3, 6, or 12 months, cohort 1 was dose escalated to imatinib 800 mg daily and subsequently switched to nilotinib 400 mg twice daily for failing the same target 3 months later, and cohort 2 was switched to nilotinib. At 2 years, 73% of patients achieved MMR and 34% achieved MR4.5, suggesting that initial treatment with higher-dose imatinib, followed by a switch to nilotinib in those failing to achieve desired milestones, could be an effective strategy for managing newly diagnosed CP-CML.²⁸

Toxicity. The standard starting dose of imatinib in CP-CML patients is 400 mg. The safety profile of imatinib has been very well established. In the IRIS trial, the most common adverse events (all grades in decreasing order of frequency) were peripheral and periorbital edema (60%), nausea (50%), muscle cramps (49%), musculoskeletal pain (47%), diarrhea (45%), rash (40%), fatigue (39%), abdominal pain (37%), headache (37%), and joint pain (31%). Grade 3/4 liver enzyme elevation can occur in 5% of patients.²⁹ In the event of severe liver toxicity or fluid retention, imatinib should be held until the event resolves. At that time, imatinib can be restarted if deemed appropriate, but this is dependent on the severity of the inciting event. Fluid retention can be managed by the use of supportive care, diuretics, imatinib dose reduction, dose interruption, or imatinib discontinuation if the fluid retention is severe. Muscle cramps can be managed by the use of calcium supplements or tonic water. Management of rash can include topical or systemic steroids, or in some cases imatinib dose reduction, interruption, or discontinuation.¹⁹

Grade 3/4 imatinib-induced hematologic toxicity is not uncommon, with 17% of patients experiencing neutropenia, 9% thrombocytopenia, and 4% anemia. These adverse events occurred most commonly during the first year of therapy, and the frequency decreased over time.^15,29 Depending on the degree of cytopenias, imatinib dosing should be interrupted until recovery of the absolute neutrophil count or platelet count, and can often be resumed at 400 mg daily. However, if cytopenias recur, imatinib should be held and subsequently restarted at 300 mg daily.¹⁹

Dasatinib

Dasatinib is a second-generation TKI that has regulatory approval for treatment of adult patients with newly diagnosed CP-CML or CP-CML in patients with resistance or intolerance to prior TKIs. In addition to dasatinib’s ability to inhibit ABL kinases, it is also known to be a potent inhibitor of Src family kinases. Dasatinib has shown efficacy in patients who have developed imatinib-resistant ABL kinase domain mutations.

Dasatinib was initially approved as second-line therapy in patients with resistance or intolerance to imatinib. This indication was based on the results of the phase 3 CA180-034 trial, which ultimately identified dasatinib 100 mg daily as the optimal dose. In this trial, 74% of patients enrolled had resistance to imatinib and the remainder were intolerant. The 7-year follow-up of patients randomized to dasatinib 100 mg (n = 167) daily indicated that 46% achieved MMR while on study. Of the 124 imatinib-resistant patients on dasatinib 100 mg daily, the 7-year PFS was 39% and OS was 63%. In the 43 imatinib-intolerant patients, the 7-year PFS was 51% and OS was 70%.³⁰

Dasatinib 100 mg daily was compared to imatinib 400 mg daily in newly diagnosed CP-CML patients in the randomized phase 3 DASISION (Dasatinib versus Imatinib Study in Treatment-Naive CML Patients) trial. More patients on the dasatinib arm achieved an EMR of BCR-ABL1 transcripts ≤ 10% IS after 3 months on treatment compared to imatinib (84% versus 64%). Furthermore, the 5-year follow-up reports that the cumulative incidence of MMR and MR4.5 in dasatinib-treated patients was 76% and 42%, and was 64% and 33% with imatinib (P = 0.0022 and P = 0.0251, respectively). Fewer patients treated with dasatinib progressed to AP or BP (4.6%) compared to imatinib (7.3%), but the estimated 5-year OS was similar between the 2 arms (91% for dasatinib versus 90% for imatinib).¹⁶ Regulatory approval for dasatinib as first-line therapy in newly diagnosed CML patients was based on results of the DASISION trial.

Toxicity. Most dasatinib-related toxicities are reported as grade 1 or grade 2, but grade 3/4 hematologic adverse events are fairly common. In the DASISION trial, grade 3/4 neutropenia, anemia, and thrombocytopenia occurred in 29%, 13%, and 22% of dasatinib-treated patients, respectively. Cytopenias can generally be managed with temporary dose interruptions or dose reductions.

During the 5-year follow-up of the DASISION trial, pleural effusions were reported in 28% of patients, most of which were grade 1/2. This occurred at a rate of approximately ≤ 8% per year, suggesting a stable incidence over time, and the effusions appear to be dose-dependent.¹⁶ Depending on the severity, pleural effusion may be treated with diuretics, dose interruption, and, in some instances, steroids or a thoracentesis. Typically, dasatinib can be restarted at 1 dose level lower than the previous dose once the effusion has resolved.¹⁹ Other, less common side effects of dasatinib include pulmonary hypertension (5% of patients), as well as abdominal pain, fluid retention, headaches, fatigue, musculoskeletal pain, rash, nausea, and diarrhea. Pulmonary hypertension is typically reversible after cessation of dasatinib, and thus dasatinib should be permanently discontinued once the diagnosis is confirmed. Fluid retention is often treated with diuretics and supportive care. Nausea and diarrhea are generally manageable and occur less frequently when dasatinib is taken with food and a large glass of water. Antiemetics and antidiarrheals can be used as needed. Troublesome rash can be best managed with topical or systemic steroids as well as possible dose reduction or dose interruption.^16,19 In the DASISION trial, adverse events led to therapy discontinuation more often in the dasatinib group than in the imatinib group (16% versus 7%).¹⁶ Bleeding, particularly in the setting of thrombocytopenia, has been reported in patients being treated with dasatinib as a result of the drug-induced reversible inhibition of platelet aggregation.³¹

Nilotinib

The structure of nilotinib is similar to that of imatinib; however, it has a markedly increased affinity for the ATP‐binding site on the BCR-ABL1 protein. It was initially given regulatory approval in the setting of imatinib failure. Nilotinib was studied at a dose of 400 mg twice daily in 321 patients who were imatinib-resistant or -intolerant. It proved to be highly effective at inducing cytogenetic remissions in the second-line setting, with 59% of patients achieving a MCyR and 45% achieving a CCyR. With a median follow-up time of 4 years, the OS was 78%.³² 

Nilotinib gained regulatory approval for use as a first-line TKI after completion of the randomized phase 3 ENESTnd (Evaluating Nilotinib Efficacy and Safety in Clinical Trials-Newly Diagnosed Patients) trial. ENESTnd was a 3-arm study comparing nilotinib 300 mg twice daily versus nilotinib 400 mg twice daily versus imatinib 400 mg daily in newly diagnosed, previously untreated patients diagnosed with CP-CML. The primary endpoint of this clinical trial was rate of MMR at 12 months.³³ Nilotinib surpassed imatinib in this regard, with 44% of patients on nilotinib 300 mg twice daily achieving MMR at 12 months versus 43% of nilotinib 400 mg twice daily patients versus 22% of the imatinib-treated patients (P < 0.001 for both comparisons). Furthermore, the rate of CCyR by 12 months was significantly higher for both nilotinib arms compared with imatinib (80% for nilotinib 300 mg, 78% for nilotinib 400 mg, and 65% for imatinib) (P < 0.001).¹² Based on this data, nilotinib 300 mg twice daily was chosen as the standard dose of nilotinib in the first-line setting. After 5 years of follow-up on the ENESTnd study, there were fewer progressions to AP/BP CML in nilotinib-treated patients compared with imatinib. MMR was achieved in 77% of nilotinib 300 mg patients compared with 60.4% of patients on the imatinib arm. MR4.5 was also more common in patients treated with nilotinib 300 mg twice daily, with a rate of 53.5% at 5 years versus 31.4% in the imatinib arm.¹⁷ In spite of the deeper cytogenetic and molecular responses achieved with nilotinib, this did not translate into a significant improvement in OS. The 5-year OS rate was 93.7% in nilotinib 300 mg patients versus 91.7% in imatinib-treated patients, and this difference lacked statistical significance.¹⁷

Toxicity. Although some similarities exist between the toxicity profiles of nilotinib and imatinib, each drug has some distinct adverse events. On the ENESTnd trial, the rate of any grade 3/4 non-hematologic adverse event was fairly low; however, lower-grade toxicities were not uncommon. Patients treated with nilotinib 300 mg twice daily experienced rash (31%), headache (14%), pruritis (15%), and fatigue (11%) most commonly. The most frequently reported laboratory abnormalities included increased total bilirubin (53%), hypophosphatemia (32%), hyperglycemia (36%), elevated lipase (24%), increased alanine aminotransferase (ALT; 66%), and increased aspartate aminotransferase (AST; 40%). Any grade of neutropenia, thrombocytopenia, or anemia occurred at rates of 43%, 48%, and 38%, respectively.³³ Although nilotinib has a Black Box Warning from the US Food and Drug Administration for QT interval prolongation, no patients on the ENESTnd trial experienced a QT interval corrected for heart rate greater than 500 msec.¹²

More recent concerns have emerged regarding the potential for cardiovascular toxicity after long-term use of nilotinib. The 5-year update of ENESTnd reports cardiovascular events, including ischemic heart disease, ischemic cerebrovascular events, or peripheral arterial disease occurring in 7.5% of patients treated with nilotinib 300 mg twice daily, as compared with a rate of 2.1% in imatinib-treated patients. The frequency of these cardiovascular events increased linearly over time in both arms. Elevations in total cholesterol from baseline occurred in 27.6% of nilotinib patients compared with 3.9% of imatinib patients. Furthermore, clinically meaningful increases in low-density lipoprotein cholesterol and glycated hemoglobin occurred more frequently with nilotinib therapy.³³

Nilotinib should be taken on an empty stomach; therefore, patients should be made aware of the need to fast for 2 hours prior to each dose and 1 hour after each dose. Given the potential risk of QT interval prolongation, a baseline electrocardiogram (ECG) is recommended prior to initiating treatment to ensure the QT interval is within a normal range. A repeat ECG should be done approximately 7 days after nilotinib initiation to ensure no prolongation of the QT interval after starting. Close monitoring of potassium and magnesium levels is important to decrease the risk of cardiac arrhythmias, and concomitant use of drugs considered strong CYP3A4 inhibitors should be avoided.¹⁹

If the patient experiences any grade 3 or higher laboratory abnormalities, nilotinib should be held until resolution of the toxicity, and then restarted at a lower dose. Similarly, if patients develop significant neutropenia or thrombocytopenia, nilotinib doses should be interrupted until resolution of the cytopenias. At that point, nilotinib can be reinitiated at either the same or a lower dose. Rash can be managed by the use of topical or systemic steroids as well as potential dose reduction, interruption, or discontinuation.

Given the concerns for potential cardiovascular events with long-term use of nilotinib, caution is advised when prescribing it to any patient with a history of cardiovascular disease or peripheral arterial occlusive disease. At the first sign of new occlusive disease, nilotinib should be discontinued.¹⁹

Bosutinib

Bosutinib is a second-generation BCR-ABL TKI with activity against the Src family of kinases; it was initially approved to treat patients with CP-, AP-, or BP-CML after resistance or intolerance to imatinib. Long-term data has been reported from the phase 1/2 trial of bosutinib therapy in patients with CP-CML who developed resistance or intolerance to imatinib plus dasatinib and/or nilotinib. A total of 119 patients were included in the 4-year follow-up; 38 were resistant/intolerant to imatinib and resistant to dasatinib, 50 were resistant/intolerant to imatinib and intolerant to dasatinib, 26 were resistant/intolerant to imatinib and resistant to nilotinib, and 5 were resistant/intolerant to imatinib and intolerant to nilotinib or resistant/intolerant to dasatinib and nilotinib. Bosutinib 400 mg daily was studied in this setting. Of the 38 patients with imatinib resistance/intolerance and dasatinib resistance, 39% achieved MCyR, 22% achieved CCyR, and the OS was 67%. Of the 50 patients with imatinib resistance/intolerance and dasatinib intolerance, 42% achieved MCyR, 40% achieved CCyR, and the OS was 80%. Finally, in the 26 patients with imatinib resistance/intolerance and nilotinib resistance, 38% achieved MCyR, 31% achieved CCyR, and the OS was 87%.³⁴

Five-year follow-up from the phase 1/2 clinical trial that studied bosutinib 500 mg daily in CP-CML patients after imatinib failure reported data on 284 patients. By 5 years on study, 60% of patients had achieved MCyR and 50% achieved CCyR with a 71% and 69% probability, respectively, of maintaining these responses at 5 years. The 5-year OS was 84%.³⁵ These data led to the regulatory approval of bosutinib 500 mg daily as second-line or later therapy.

Bosutinib was initially studied in the first-line setting in the randomized phase 3 BELA (Bosutinib Efficacy and Safety in Newly Diagnosed Chronic Myeloid Leukemia) trial. This trial compared bosutinib 500 mg daily to imatinib 400 mg daily in newly diagnosed, previously untreated CP-CML patients. This trial failed to meet its primary endpoint of increased rate of CCyR at 12 months, with 70% of bosutinib patients achieving this response, compared to 68% of imatinib-treated patients (P = 0.601). In spite of this, the rate of MMR at 12 months was significantly higher in the bosutinib arm (41%) compared to the imatinib arm (27%; P = 0.001).³⁶

A second phase 3 trial (BFORE) was designed to study bosutinib 400 mg daily versus imatinib in newly diagnosed, previously untreated CP-CML patients. This study enrolled 536 patients who were randomly assigned 1:1 to bosutinib versus imatinib. The primary endpoint of this trial was rate of MMR at 12 months. A significantly higher number of bosutinib-treated patients achieved this response (47.2%) compared with imatinib-treated patients (36.9%, P = 0.02). Furthermore, by 12 months 77.2% of patients on the bosutinib arm had achieved CCyR compared with 66.4% on the imatinib arm, and this difference did meet statistical significance (P = 0.0075). A lower rate of progression to AP- or BP-CML was noted in bosutinib-treated patients as well (1.6% versus 2.5%). Based on this data, bosutinib gained regulatory approval for first-line therapy in CP-CML at a dose of 400 mg daily.¹⁸

Toxicity. On the BFORE trial, the most common treatment-emergent adverse events of any grade reported in the bosutinib-treated patients were diarrhea (70.1%), nausea (35.1%), increased ALT (30.6%), and increased AST (22.8%). Musculoskeletal pain or spasms occurred in 29.5% of patients, rash in 19.8%, fatigue in 19.4%, and headache in 18.7%. Hematologic toxicity was also reported, but most was grade 1/2. Thrombocytopenia was reported in 35.1%, anemia in 18.7%, and neutropenia in 11.2%.¹⁸

Cardiovascular events occurred in 5.2% of patients on the bosutinib arm of the BFORE trial, which was similar to the rate observed in imatinib patients. The most common cardiovascular event was QT interval prolongation, which occurred in 1.5% of patients. Pleural effusions were reported in 1.9% of patients treated with bosutinib, and none were grade 3 or higher.¹⁸

If liver enzyme elevation occurs at a value greater than 5 times the institutional upper limit of normal, bosutinib should be held until the level recovers to ≤ 2.5 times the upper limit of normal, at which point bosutinib can be restarted at a lower dose. If recovery takes longer than 4 weeks, bosutinib should be permanently discontinued. Liver enzymes elevated greater than 3 times the institutional upper limit of normal and a concurrent elevation in total bilirubin to 2 times the upper limit of normal are consistent with Hy’s law, and bosutinib should be discontinued. Although diarrhea is the most common toxicity associated with bosutinib, it is commonly low grade and transient. Diarrhea occurs most frequently in the first few days after initiating bosutinib. It can often be managed with over-the-counter antidiarrheal medications, but if the diarrhea is grade 3 or higher, bosutinib should be held until recovery to grade 1 or lower. Gastrointestinal side effects may be improved by taking bosutinib with a meal and a large glass of water. Fluid retention can be managed with diuretics and supportive care. Finally, if rash occurs, this can be addressed with topical or systemic steroids as well as bosutinib dose reduction, interruption, or discontinuation.¹⁹

Similar to other TKIs, if bosutinib-induced cytopenias occur, treatment should be held and restarted at the same or a lower dose upon blood count recovery.¹⁹

Ponatinib

The most common cause of TKI resistance in CP-CML is the development of ABL kinase domain mutations. The majority of imatinib-resistant mutations can be overcome by the use of second-generation TKIs, including dasatinib, nilotinib, or bosutinib. However, ponatinib is the only BCR-ABL TKI able to overcome a T315I mutation. The phase 2 PACE (Ponatinib Ph-positive ALL and CML Evaluation) trial enrolled patients with CP-, AP-, or BP-CML as well as patients with Ph-positive acute lymphoblastic leukemia who were resistant or intolerant to nilotinib or dasatinib, or who had evidence of a T315I mutation. The starting dose of ponatinib on this trial was 45 mg daily.³⁷ The PACE trial enrolled 267 patients with CP-CML: 203 with resistance or intolerance to nilotinib or dasatinib, and 64 with a T315I mutation. The primary endpoint in the CP cohort was rate of MCyR at any time within 12 months of starting ponatinib. The overall rate of MCyR by 12 months in the CP-CML patients was 56%. In those with a T315I mutation, 70% achieved MCyR, which compared favorably with those with resistance or intolerance to nilotinib or dasatinib, 51% of whom achieved MCyR. CCyR was achieved in 46% of CP-CML patients (40% in the resistant/intolerant cohort and 66% in the T315I cohort). In general, patients with T315I mutations received fewer prior therapies than those in the resistant/intolerant cohort, which likely contributed to the higher response rates in the T315I patients. MR4.5 was achieved in 15% of CP-CML patients by 12 months on the PACE trial.³⁷ The 5-year update to this study reported that 60%, 40%, and 24% of CP-CML patients achieved MCyR, MMR, and MR4.5, respectively. In the patients who achieved MCyR, the probability of maintaining this response for 5 years was 82% and the estimated 5-year OS was 73%.¹⁹

Toxicity. In 2013, after the regulatory approval of ponatinib, reports became available that the drug can cause an increase in arterial occlusive events, including fatal myocardial infarctions and cerebrovascular accidents. For this reason, dose reductions were implemented in patients who were deriving clinical benefit from ponatinib. In spite of these dose reductions, ≥ 90% of responders maintained their response for up to 40 months.³⁸ Although the likelihood of developing an arterial occlusive event appears higher in the first year after starting ponatinib than in later years, the cumulative incidence of events continues to increase. The 5-year follow-up to the PACE trial reports 31% of patients experiencing any grade of arterial occlusive event while on ponatinib. Aside from these events, the most common treatment-emergent adverse events in ponatinib-treated patients on the PACE trial included rash (47%), abdominal pain (46%), headache (43%), dry skin (42%), constipation (41%), and hypertension (37%). Hematologic toxicity was also common, with 46% of patients experiencing any grade of thrombocytopenia, 20% experiencing neutropenia, and 20% anemia.³⁸

Patients receiving ponatinib therapy should be monitored closely for any evidence of arterial or venous thrombosis. If an occlusive event occurs, ponatinib should be discontinued. Similarly, in the setting of any new or worsening heart failure symptoms, ponatinib should be promptly discontinued. Management of any underlying cardiovascular risk factors, including hypertension, hyperlipidemia, diabetes, or smoking history, is recommended, and these patients should be referred to a cardiologist for a full evaluation. In the absence of any contraindications to aspirin, low-dose aspirin should be considered as a means of decreasing cardiovascular risks associated with ponatinib. In patients with known risk factors, a ponatinib starting dose of 30 mg daily rather than the standard 45 mg daily may be a safer option, resulting in fewer arterial occlusive events, although the efficacy of this dose is still being studied in comparison to 45 mg daily.¹⁹

If ponatinib-induced transaminitis greater than 3 times the upper limit of normal occurs, ponatinib should be held until resolution to less than 3 times the upper limit of normal, at which point it should be resumed at a lower dose. Similarly, in the setting of elevated serum lipase or symptomatic pancreatitis, ponatinib should be held and restarted at a lower dose after resolution of symptoms.¹⁹

In the event of neutropenia or thrombocytopenia, ponatinib should be held until blood count recovery and then restarted at the same dose. If cytopenias occur for a second time, the dose of ponatinib should be lowered at the time of treatment reinitiation. If rash occurs, it can be addressed with topical or systemic steroids as well as dose reduction, interruption, or discontinuation.¹⁹

Conclusion

With the development of imatinib and the subsequent TKIs, dasatinib, nilotinib, bosutinib, and ponatinib, CP-CML has become a chronic disease with a life expectancy that is similar to that of the general population. Given the successful treatments available for these patients, it is crucial to identify patients with this diagnosis, ensure they receive a complete, appropriate diagnostic workup including a bone marrow biopsy and aspiration with cytogenetic testing, and select the best therapy for each individual patient. Once on treatment, the importance of frequent monitoring cannot be overstated. This is the only way to be certain patients are achieving the desired treatment milestones that correlate with the favorable long-term outcomes that have been observed with TKI-based treatment of CP-CML. 

Corresponding author: Kendra Sweet, MD, MS, Department of Malignant Hematology, Moffitt Cancer Center, Tampa, FL.

Financial disclosures: Dr. Sweet has served on the Advisory Board and Speakers Bureau of Novartis, Bristol-Meyers Squibb, Ariad Pharmaceuticals, and Pfizer, and has served as a consultant to Pfizer.

From the Moffitt Cancer Center, Tampa, FL.

Abstract

• Objective: To outline the approach to selecting a tyrosine kinase inhibitor (TKI) for initial treatment of chronic myeloid leukemia (CML) and monitoring patients following initiation of therapy.
• Methods: Review of the literature and evidence-based guidelines.
• Results: The development and availability of TKIs has improved survival for patients diagnosed with CML. The life expectancy of patients diagnosed with chronic-phase CML (CP-CML) is similar to that of the general population, provided they receive appropriate TKI therapy and adhere to treatment. Selection of the most appropriate first-line TKI for newly diagnosed CP-CML requires incorporation of the patient’s baseline karyotype and Sokal or EURO risk score, and a clear understanding of the patient’s comorbidities. The adverse effect profile of all TKIs must be considered in conjunction with the patient’s ongoing medical issues to decrease the likelihood of worsening their current symptoms or causing a severe complication from TKI therapy. After confirming a diagnosis of CML and selecting the most appropriate TKI for first-line therapy, close monitoring and follow-up are necessary to ensure patients are meeting the desired treatment milestones. Responses in CML can be assessed based on hematologic parameters, cytogenetic results, and molecular responses.
• Conclusion: Given the successful treatments available for patients with CML, it is crucial to identify patients with this diagnosis; ensure they receive a complete, appropriate diagnostic workup including a bone marrow biopsy and aspiration with cytogenetic testing; and select the best therapy for each individual patient.

Keywords: chronic myeloid leukemia; CML; tyrosine kinase inhibitor; TKI; cancer; BCR-ABL protein.

Chronic myeloid leukemia (CML) is a rare myeloproliferative neoplasm that is characterized by the presence of the Philadelphia (Ph) chromosome and uninhibited expansion of bone marrow stem cells. The Ph chromosome arises from a reciprocal translocation between the Abelson (ABL) region on chromosome 9 and the breakpoint cluster region (BCR) of chromosome 22 (t(9;22)(q34;q11.2)), resulting in the BCR-ABL1 fusion gene and its protein product, BCR-ABL tyrosine kinase.¹ BCR-ABL has constitutive tyrosine kinase activity that promotes growth, replication, and survival of hematopoietic cells through downstream pathways, which is the driving factor in the pathogenesis of CML.¹

CML is divided into 3 phases based on the number of myeloblasts observed in the blood or bone marrow: chronic, accelerated, and blast. Most cases of CML are diagnosed in the chronic phase (CP), which is marked by proliferation of primarily the myeloid element.

Typical treatment for CML involves lifelong use of oral BCR-ABL tyrosine kinase inhibitors (TKIs). Currently, 5 TKIs have regulatory approval for treatment of this disease. The advent of TKIs, a class of small molecules targeting the tyrosine kinases, particularly the BCR-ABL tyrosine kinase, led to rapid changes in the management of CML and improved survival for patients. Patients diagnosed with chronic-phase CML (CP-CML) now have a life expectancy that is similar to that of the general population, as long as they receive appropriate TKI therapy and adhere to treatment. As such, it is crucial to identify patients with CML; ensure they receive a complete, appropriate diagnostic workup; and select the best therapy for each patient.

Epidemiology

According to SEER data estimates, 8430 new cases of CML were diagnosed in the United States in 2018. CML is a disease of older adults, with a median age of 65 years at diagnosis, and there is a slight male predominance. Between 2011 and 2015, the number of new CML cases was 1.8 per 100,000 persons. The median overall survival (OS) in patients with newly diagnosed CP-CML has not been reached.² Given the effective treatments available for managing CML, it is estimated that the prevalence of CML in the United States will plateau at 180,000 patients by 2050.³

Clinical Features

The diagnosis of CML is often suspected based on an incidental finding of leukocytosis and, in some cases, thrombocytosis. In many cases, this is an incidental finding on routine blood work, but approximately 50% of patients will present with constitutional symptoms associated with the disease. Characteristic features of the white blood cell differential include left-shifted maturation with neutrophilia and immature circulating myeloid cells. Basophilia and eosinophilia are often present as well. Splenomegaly is a common sign, present in 50% to 90% of patients at diagnosis. In those patients with symptoms related to CML at diagnosis, the most common presentation includes increasing fatigue, fevers, night sweats, early satiety, and weight loss. The diagnosis is confirmed by cytogenetic studies showing the Ph chromosome abnormality, t(9; 22)(q3.4;q1.1), and/or reverse transcriptase polymerase chain reaction (PCR) showing BCR-ABL1 transcripts.

Testing

Bone marrow biopsy. There are 3 distinct phases of CML: CP, accelerated phase (AP), and blast phase (BP). Bone marrow biopsy and aspiration at diagnosis are mandatory in order to determine the phase of the disease at diagnosis. This distinction is based on the percentage of blasts, promyelocytes, and basophils present as well as the platelet count and presence or absence of extramedullary disease.⁴ The vast majority of patients at diagnosis have CML that is in the chronic phase. The typical appearance in CP-CML is a hypercellular marrow with granulocytic and occasionally megakaryocytic hyperplasia. In many cases, basophilia and/or eosinophilia are noted as well. Dysplasia is not a typical finding in CML.⁵ Bone marrow fibrosis can be seen in up to one-third of patients at diagnosis, and may indicate a slightly worse prognosis.⁶ Although a diagnosis of CML can be made without a bone marrow biopsy, complete staging and prognostication are only possible with information gained from this test, including baseline karyotype and confirmation of CP versus a more advanced phase of CML.

Diagnostic criteria. The criteria for diagnosing AP-CML has not been agreed upon by various groups, but the modified MD Anderson Cancer Center (MDACC) criteria are used in the majority of clinical trials evaluating the efficacy of TKIs in preventing progression to advanced phases of CML. MDACC criteria define AP-CML as the presence of 1 of the following: 15% to 29% blasts in the peripheral blood or bone marrow, ≥ 30% peripheral blasts plus promyelocytes, ≥ 20% basophils in the blood or bone marrow, platelet count ≤ 100,000/μL unrelated to therapy, and clonal cytogenetic evolution in Ph-positive metaphases (Table).⁷

The defining feature of CML is the presence of the Ph chromosome abnormality. In a small subset of patients, additional chromosome abnormalities (ACA) in the Ph-positive cells may be identified at diagnosis. Some reports indicate that the presence of “major route” ACA (trisomy 8, isochromosome 17q, a second Ph chromosome, or trisomy 19) at diagnosis may negatively impact prognosis, but other reports contradict these findings.^10,11

PCR assay. The typical BCR breakpoint in CML is the major breakpoint cluster region (M-BCR), which results in a 210-kDa protein (p210). Alternate breakpoints that are less frequently identified are the minor BCR (mBCR or p190), which is more commonly found in Ph-positive acute lymphoblastic leukemia (ALL), and the micro BCR (µBCR or p230), which is much less common and is often characterized by chronic neutrophilia.¹² Identifying which BCR-ABL1 transcript is present in each patient using qualitative PCR is crucial in order to ensure proper monitoring during treatment.

The most sensitive method for detecting BCR-ABL1 mRNA transcripts is the quantitative real-time PCR (RQ-PCR) assay, which is typically done on peripheral blood. RQ-PCR is capable of detecting a single CML cell in the presence of ≥ 100,000 normal cells. This test should be done during the initial diagnostic workup in order to confirm the presence of BCR-ABL1 transcripts, and it is used as a standard method for monitoring response to TKI therapy.¹³ The International Scale (IS) is a standardized approach to reporting RQ-PCR results that was developed to allow comparison of results across various laboratories and has become the gold standard for reporting BCR-ABL1 transcript values.¹⁴

Determining Risk Scores

Calculating a patient’s Sokal score or EURO risk score at diagnosis remains an important component of the diagnostic workup in CP-CML, as this information has prognostic and therapeutic implications (an online calculator is available through European LeukemiaNet [ELN]). The risk for disease progression to the accelerated or blast phases is higher in patients with intermediate or high risk scores compared to those with a low risk score at diagnosis. The risk of progression in intermediate- or high-risk patients is lower when a second-generation TKI (dasatinib, nilotinib, or bosutinib) is used as frontline therapy compared to imatinib, and therefore, the National Comprehensive Cancer Network (NCCN) CML Panel recommends starting with a second-generation TKI in these patients.^15-19

Monitoring Response to Therapy

After confirming a diagnosis of CML and selecting the most appropriate TKI for first-line therapy, the successful management of CML patients relies on close monitoring and follow-up to ensure they are meeting the desired treatment milestones. Responses in CML can be assessed based on hematologic parameters, cytogenetic results, and molecular responses. A complete hematologic response (CHR) implies complete normalization of peripheral blood counts (with the exception of TKI-induced cytopenias) and resolution of any palpable splenomegaly. The majority of patients will achieve a CHR within 4 to 6 weeks after initiating CML-directed therapy.²⁰

Cytogenetic Response

Cytogenetic responses are defined by the decrease in the number of Ph chromosome–positive metaphases when assessed on bone marrow cytogenetics. A partial cytogenetic response (PCyR) is defined as having 1% to 35% Ph-positive metaphases, a major cytogenetic response (MCyR) as having 0% to 35% Ph-positive metaphases, and a complete cytogenetic response (CCyR) implies that no Ph-positive metaphases are identified on bone marrow cytogenetics. An ideal response is the achievement of PCyR after 3 months on a TKI and a CCyR after 12 months on a TKI.²¹

Once a patient has achieved a CCyR, monitoring their response to therapy can only be done using RQ-PCR to measure BCR-ABL1 transcripts in the peripheral blood. The NCCN and the ELN recommend monitoring RQ-PCR from the peripheral blood every 3 months in order to assess response to TKIs.^19,22 As noted, the IS has become the gold standard reporting system for all BCR-ABL1 transcript levels in the majority of laboratories worldwide.^14,23 Molecular responses are based on a log reduction in BCR-ABL1 transcripts from a standardized baseline. Many molecular responses can be correlated with cytogenetic responses such that, if reliable RQ-PCR testing is available, monitoring can be done using only peripheral blood RQ-PCR rather than repeat bone marrow biopsies. For example, an early molecular response (EMR) is defined as a RQ-PCR value of ≤ 10% IS, which is approximately equivalent to a PCyR.²⁴ A value of 1% IS is approximately equivalent to a CCyR. A major molecular response (MMR) is a ≥ 3-log reduction in BCR-ABL1 transcripts from baseline and is a value of ≤ 0.1% IS. Deeper levels of molecular response are best described by the log reduction in BCR-ABL1 transcripts, with a 4-log reduction denoted as MR4.0, a 4.5-log reduction as MR4.5, and so forth. Complete molecular response (CMR) is defined by the level of sensitivity of the RQ-PCR assay being used.¹⁴

The definition of relapsed disease in CML is dependent on the type of response the patient had previously achieved. Relapse could be the loss of a hematologic or cytogenetic response, but fluctuations in BCR-ABL1 transcripts on routine RQ-PCR do not necessarily indicate relapsed CML. A 1-log increase in the level of BCR-ABL1 transcripts with a concurrent loss of MMR should prompt a bone marrow biopsy in order to assess for the loss of CCyR, and thus a cytogenetic relapse; however, this loss of MMR does not define relapse in and of itself. In the setting of relapsed disease, testing should be done to look for possible ABL kinase domain mutations, and alternate therapy should be selected.¹⁹

Multiple reports have identified the prognostic relevance of achieving an EMR at 3 and 6 months after starting TKI therapy. Marin and colleagues reported that in 282 imatinib-treated patients, there was a significant improvement in 8-year OS, progression-free survival (PFS), and cumulative incidence of CCyR and CMR in patients who had BCR-ABL1 transcripts < 9.84% IS after 3 months on treatment.²⁴ This data highlights the importance of early molecular monitoring in order to ensure the best outcomes for patients with CP-CML.

The NCCN CML guidelines and ELN recommendations both agree that an ideal response after 3 months on a TKI is BCR-ABL1 transcripts < 10% IS, but treatment is not considered to be failing at this point if the patient marginally misses this milestone. After 6 months on treatment, an ideal response is considered BCR-ABL1 transcripts < 1%–10% IS. Ideally, patients will have BCR-ABL1 transcripts < 0.1%–1% IS by the time they complete 12 months of TKI therapy, suggesting that these patients have at least achieved a CCyR.^19,22 Even after patients achieve these early milestones, frequent monitoring by RQ-PCR is required to ensure that they are maintaining their response to treatment. This will help to ensure patient compliance with treatment and will also help to identify a select subset of patients who could potentially be considered for an attempt at TKI cessation (not discussed in detail here) after a minimum of 3 years on therapy.^19,25

Selecting First-line TKI Therapy

Selection of the most appropriate first-line TKI for newly diagnosed CP-CML patients requires incorporation of many patient-specific factors. These factors include baseline karyotype and confirmation of CP-CML through bone marrow biopsy, Sokal or EURO risk score, and a thorough patient history, including a clear understanding of the patient’s comorbidities. The adverse effect profile of all TKIs must be considered in conjunction with the patient’s ongoing medical issues in order to decrease the likelihood of worsening their current symptoms or causing a severe complication from TKI therapy.

The management of CML was revolutionized by the development and ultimate regulatory approval of imatinib mesylate in 2001. Imatinib was the first small-molecule cancer therapy developed and approved. It acts by binding to the adenosine triphosphate (ATP) binding site in the catalytic domain of BCR-ABL, thus inhibiting the oncoprotein’s tyrosine kinase activity.²⁶

The International Randomized Study of Interferon versus STI571 (IRIS) trial was a randomized phase 3 study that compared imatinib 400 mg daily to interferon alfa (IFNa) plus cytarabine. More than 1000 CP-CML patients were randomly assigned 1:1 to either imatinib or IFNa plus cytarabine and were assessed for event-free survival, hematologic and cytogenetic responses, freedom from progression to AP or BP, and toxicity. Imatinib was superior to the prior standard of care for all these outcomes.²¹ The long-term follow-up of the IRIS trial reported an 83% estimated 10-year OS and 79% estimated event-free survival for patients on the imatinib arm of this study.¹⁵ The cumulative rate of CCyR was 82.8%. Of the 204 imatinib-treated patients who could undergo a molecular response evaluation at 10 years, 93.1% had a MMR and 63.2% had a MR4.5, suggesting durable, deep molecular responses for many patients. The estimated 10-year rate of freedom from progression to AP or BP was 92.1%.

Higher doses of imatinib (600-800 mg daily) have been studied in an attempt to overcome resistance and improve cytogenetic and molecular response rates. The Tyrosine Kinase Inhibitor Optimization and Selectivity (TOPS) trial was a randomized phase 3 study that compared imatinib 800 mg daily to imatinib 400 mg daily. Although the 6-month assessments found increased rates of CCyR and a MMR in the higher-dose imatinib arm, these differences were no longer present at the 12-month assessment. Furthermore, the higher dose of imatinib led to a significantly higher incidence of grade 3/4 hematologic adverse events, and approximately 50% of patients on imatinib 800 mg daily required a dose reduction to less than 600 mg daily because of toxicity.²⁷

The Therapeutic Intensification in De Novo Leukaemia (TIDEL)-II study used plasma trough levels of imatinib on day 22 of treatment with imatinib 600 mg daily to determine if patients should escalate the imatinib dose to 800 mg daily. In patients who did not meet molecular milestones at 3, 6, or 12 months, cohort 1 was dose escalated to imatinib 800 mg daily and subsequently switched to nilotinib 400 mg twice daily for failing the same target 3 months later, and cohort 2 was switched to nilotinib. At 2 years, 73% of patients achieved MMR and 34% achieved MR4.5, suggesting that initial treatment with higher-dose imatinib, followed by a switch to nilotinib in those failing to achieve desired milestones, could be an effective strategy for managing newly diagnosed CP-CML.²⁸

Toxicity. The standard starting dose of imatinib in CP-CML patients is 400 mg. The safety profile of imatinib has been very well established. In the IRIS trial, the most common adverse events (all grades in decreasing order of frequency) were peripheral and periorbital edema (60%), nausea (50%), muscle cramps (49%), musculoskeletal pain (47%), diarrhea (45%), rash (40%), fatigue (39%), abdominal pain (37%), headache (37%), and joint pain (31%). Grade 3/4 liver enzyme elevation can occur in 5% of patients.²⁹ In the event of severe liver toxicity or fluid retention, imatinib should be held until the event resolves. At that time, imatinib can be restarted if deemed appropriate, but this is dependent on the severity of the inciting event. Fluid retention can be managed by the use of supportive care, diuretics, imatinib dose reduction, dose interruption, or imatinib discontinuation if the fluid retention is severe. Muscle cramps can be managed by the use of calcium supplements or tonic water. Management of rash can include topical or systemic steroids, or in some cases imatinib dose reduction, interruption, or discontinuation.¹⁹

Grade 3/4 imatinib-induced hematologic toxicity is not uncommon, with 17% of patients experiencing neutropenia, 9% thrombocytopenia, and 4% anemia. These adverse events occurred most commonly during the first year of therapy, and the frequency decreased over time.^15,29 Depending on the degree of cytopenias, imatinib dosing should be interrupted until recovery of the absolute neutrophil count or platelet count, and can often be resumed at 400 mg daily. However, if cytopenias recur, imatinib should be held and subsequently restarted at 300 mg daily.¹⁹

Dasatinib

Dasatinib is a second-generation TKI that has regulatory approval for treatment of adult patients with newly diagnosed CP-CML or CP-CML in patients with resistance or intolerance to prior TKIs. In addition to dasatinib’s ability to inhibit ABL kinases, it is also known to be a potent inhibitor of Src family kinases. Dasatinib has shown efficacy in patients who have developed imatinib-resistant ABL kinase domain mutations.

Dasatinib was initially approved as second-line therapy in patients with resistance or intolerance to imatinib. This indication was based on the results of the phase 3 CA180-034 trial, which ultimately identified dasatinib 100 mg daily as the optimal dose. In this trial, 74% of patients enrolled had resistance to imatinib and the remainder were intolerant. The 7-year follow-up of patients randomized to dasatinib 100 mg (n = 167) daily indicated that 46% achieved MMR while on study. Of the 124 imatinib-resistant patients on dasatinib 100 mg daily, the 7-year PFS was 39% and OS was 63%. In the 43 imatinib-intolerant patients, the 7-year PFS was 51% and OS was 70%.³⁰

Dasatinib 100 mg daily was compared to imatinib 400 mg daily in newly diagnosed CP-CML patients in the randomized phase 3 DASISION (Dasatinib versus Imatinib Study in Treatment-Naive CML Patients) trial. More patients on the dasatinib arm achieved an EMR of BCR-ABL1 transcripts ≤ 10% IS after 3 months on treatment compared to imatinib (84% versus 64%). Furthermore, the 5-year follow-up reports that the cumulative incidence of MMR and MR4.5 in dasatinib-treated patients was 76% and 42%, and was 64% and 33% with imatinib (P = 0.0022 and P = 0.0251, respectively). Fewer patients treated with dasatinib progressed to AP or BP (4.6%) compared to imatinib (7.3%), but the estimated 5-year OS was similar between the 2 arms (91% for dasatinib versus 90% for imatinib).¹⁶ Regulatory approval for dasatinib as first-line therapy in newly diagnosed CML patients was based on results of the DASISION trial.

Toxicity. Most dasatinib-related toxicities are reported as grade 1 or grade 2, but grade 3/4 hematologic adverse events are fairly common. In the DASISION trial, grade 3/4 neutropenia, anemia, and thrombocytopenia occurred in 29%, 13%, and 22% of dasatinib-treated patients, respectively. Cytopenias can generally be managed with temporary dose interruptions or dose reductions.

During the 5-year follow-up of the DASISION trial, pleural effusions were reported in 28% of patients, most of which were grade 1/2. This occurred at a rate of approximately ≤ 8% per year, suggesting a stable incidence over time, and the effusions appear to be dose-dependent.¹⁶ Depending on the severity, pleural effusion may be treated with diuretics, dose interruption, and, in some instances, steroids or a thoracentesis. Typically, dasatinib can be restarted at 1 dose level lower than the previous dose once the effusion has resolved.¹⁹ Other, less common side effects of dasatinib include pulmonary hypertension (5% of patients), as well as abdominal pain, fluid retention, headaches, fatigue, musculoskeletal pain, rash, nausea, and diarrhea. Pulmonary hypertension is typically reversible after cessation of dasatinib, and thus dasatinib should be permanently discontinued once the diagnosis is confirmed. Fluid retention is often treated with diuretics and supportive care. Nausea and diarrhea are generally manageable and occur less frequently when dasatinib is taken with food and a large glass of water. Antiemetics and antidiarrheals can be used as needed. Troublesome rash can be best managed with topical or systemic steroids as well as possible dose reduction or dose interruption.^16,19 In the DASISION trial, adverse events led to therapy discontinuation more often in the dasatinib group than in the imatinib group (16% versus 7%).¹⁶ Bleeding, particularly in the setting of thrombocytopenia, has been reported in patients being treated with dasatinib as a result of the drug-induced reversible inhibition of platelet aggregation.³¹

Nilotinib

The structure of nilotinib is similar to that of imatinib; however, it has a markedly increased affinity for the ATP‐binding site on the BCR-ABL1 protein. It was initially given regulatory approval in the setting of imatinib failure. Nilotinib was studied at a dose of 400 mg twice daily in 321 patients who were imatinib-resistant or -intolerant. It proved to be highly effective at inducing cytogenetic remissions in the second-line setting, with 59% of patients achieving a MCyR and 45% achieving a CCyR. With a median follow-up time of 4 years, the OS was 78%.³² 

Nilotinib gained regulatory approval for use as a first-line TKI after completion of the randomized phase 3 ENESTnd (Evaluating Nilotinib Efficacy and Safety in Clinical Trials-Newly Diagnosed Patients) trial. ENESTnd was a 3-arm study comparing nilotinib 300 mg twice daily versus nilotinib 400 mg twice daily versus imatinib 400 mg daily in newly diagnosed, previously untreated patients diagnosed with CP-CML. The primary endpoint of this clinical trial was rate of MMR at 12 months.³³ Nilotinib surpassed imatinib in this regard, with 44% of patients on nilotinib 300 mg twice daily achieving MMR at 12 months versus 43% of nilotinib 400 mg twice daily patients versus 22% of the imatinib-treated patients (P < 0.001 for both comparisons). Furthermore, the rate of CCyR by 12 months was significantly higher for both nilotinib arms compared with imatinib (80% for nilotinib 300 mg, 78% for nilotinib 400 mg, and 65% for imatinib) (P < 0.001).¹² Based on this data, nilotinib 300 mg twice daily was chosen as the standard dose of nilotinib in the first-line setting. After 5 years of follow-up on the ENESTnd study, there were fewer progressions to AP/BP CML in nilotinib-treated patients compared with imatinib. MMR was achieved in 77% of nilotinib 300 mg patients compared with 60.4% of patients on the imatinib arm. MR4.5 was also more common in patients treated with nilotinib 300 mg twice daily, with a rate of 53.5% at 5 years versus 31.4% in the imatinib arm.¹⁷ In spite of the deeper cytogenetic and molecular responses achieved with nilotinib, this did not translate into a significant improvement in OS. The 5-year OS rate was 93.7% in nilotinib 300 mg patients versus 91.7% in imatinib-treated patients, and this difference lacked statistical significance.¹⁷

Toxicity. Although some similarities exist between the toxicity profiles of nilotinib and imatinib, each drug has some distinct adverse events. On the ENESTnd trial, the rate of any grade 3/4 non-hematologic adverse event was fairly low; however, lower-grade toxicities were not uncommon. Patients treated with nilotinib 300 mg twice daily experienced rash (31%), headache (14%), pruritis (15%), and fatigue (11%) most commonly. The most frequently reported laboratory abnormalities included increased total bilirubin (53%), hypophosphatemia (32%), hyperglycemia (36%), elevated lipase (24%), increased alanine aminotransferase (ALT; 66%), and increased aspartate aminotransferase (AST; 40%). Any grade of neutropenia, thrombocytopenia, or anemia occurred at rates of 43%, 48%, and 38%, respectively.³³ Although nilotinib has a Black Box Warning from the US Food and Drug Administration for QT interval prolongation, no patients on the ENESTnd trial experienced a QT interval corrected for heart rate greater than 500 msec.¹²

More recent concerns have emerged regarding the potential for cardiovascular toxicity after long-term use of nilotinib. The 5-year update of ENESTnd reports cardiovascular events, including ischemic heart disease, ischemic cerebrovascular events, or peripheral arterial disease occurring in 7.5% of patients treated with nilotinib 300 mg twice daily, as compared with a rate of 2.1% in imatinib-treated patients. The frequency of these cardiovascular events increased linearly over time in both arms. Elevations in total cholesterol from baseline occurred in 27.6% of nilotinib patients compared with 3.9% of imatinib patients. Furthermore, clinically meaningful increases in low-density lipoprotein cholesterol and glycated hemoglobin occurred more frequently with nilotinib therapy.³³

Nilotinib should be taken on an empty stomach; therefore, patients should be made aware of the need to fast for 2 hours prior to each dose and 1 hour after each dose. Given the potential risk of QT interval prolongation, a baseline electrocardiogram (ECG) is recommended prior to initiating treatment to ensure the QT interval is within a normal range. A repeat ECG should be done approximately 7 days after nilotinib initiation to ensure no prolongation of the QT interval after starting. Close monitoring of potassium and magnesium levels is important to decrease the risk of cardiac arrhythmias, and concomitant use of drugs considered strong CYP3A4 inhibitors should be avoided.¹⁹

If the patient experiences any grade 3 or higher laboratory abnormalities, nilotinib should be held until resolution of the toxicity, and then restarted at a lower dose. Similarly, if patients develop significant neutropenia or thrombocytopenia, nilotinib doses should be interrupted until resolution of the cytopenias. At that point, nilotinib can be reinitiated at either the same or a lower dose. Rash can be managed by the use of topical or systemic steroids as well as potential dose reduction, interruption, or discontinuation.

Given the concerns for potential cardiovascular events with long-term use of nilotinib, caution is advised when prescribing it to any patient with a history of cardiovascular disease or peripheral arterial occlusive disease. At the first sign of new occlusive disease, nilotinib should be discontinued.¹⁹

Bosutinib

Bosutinib is a second-generation BCR-ABL TKI with activity against the Src family of kinases; it was initially approved to treat patients with CP-, AP-, or BP-CML after resistance or intolerance to imatinib. Long-term data has been reported from the phase 1/2 trial of bosutinib therapy in patients with CP-CML who developed resistance or intolerance to imatinib plus dasatinib and/or nilotinib. A total of 119 patients were included in the 4-year follow-up; 38 were resistant/intolerant to imatinib and resistant to dasatinib, 50 were resistant/intolerant to imatinib and intolerant to dasatinib, 26 were resistant/intolerant to imatinib and resistant to nilotinib, and 5 were resistant/intolerant to imatinib and intolerant to nilotinib or resistant/intolerant to dasatinib and nilotinib. Bosutinib 400 mg daily was studied in this setting. Of the 38 patients with imatinib resistance/intolerance and dasatinib resistance, 39% achieved MCyR, 22% achieved CCyR, and the OS was 67%. Of the 50 patients with imatinib resistance/intolerance and dasatinib intolerance, 42% achieved MCyR, 40% achieved CCyR, and the OS was 80%. Finally, in the 26 patients with imatinib resistance/intolerance and nilotinib resistance, 38% achieved MCyR, 31% achieved CCyR, and the OS was 87%.³⁴

Five-year follow-up from the phase 1/2 clinical trial that studied bosutinib 500 mg daily in CP-CML patients after imatinib failure reported data on 284 patients. By 5 years on study, 60% of patients had achieved MCyR and 50% achieved CCyR with a 71% and 69% probability, respectively, of maintaining these responses at 5 years. The 5-year OS was 84%.³⁵ These data led to the regulatory approval of bosutinib 500 mg daily as second-line or later therapy.

Bosutinib was initially studied in the first-line setting in the randomized phase 3 BELA (Bosutinib Efficacy and Safety in Newly Diagnosed Chronic Myeloid Leukemia) trial. This trial compared bosutinib 500 mg daily to imatinib 400 mg daily in newly diagnosed, previously untreated CP-CML patients. This trial failed to meet its primary endpoint of increased rate of CCyR at 12 months, with 70% of bosutinib patients achieving this response, compared to 68% of imatinib-treated patients (P = 0.601). In spite of this, the rate of MMR at 12 months was significantly higher in the bosutinib arm (41%) compared to the imatinib arm (27%; P = 0.001).³⁶

A second phase 3 trial (BFORE) was designed to study bosutinib 400 mg daily versus imatinib in newly diagnosed, previously untreated CP-CML patients. This study enrolled 536 patients who were randomly assigned 1:1 to bosutinib versus imatinib. The primary endpoint of this trial was rate of MMR at 12 months. A significantly higher number of bosutinib-treated patients achieved this response (47.2%) compared with imatinib-treated patients (36.9%, P = 0.02). Furthermore, by 12 months 77.2% of patients on the bosutinib arm had achieved CCyR compared with 66.4% on the imatinib arm, and this difference did meet statistical significance (P = 0.0075). A lower rate of progression to AP- or BP-CML was noted in bosutinib-treated patients as well (1.6% versus 2.5%). Based on this data, bosutinib gained regulatory approval for first-line therapy in CP-CML at a dose of 400 mg daily.¹⁸

Toxicity. On the BFORE trial, the most common treatment-emergent adverse events of any grade reported in the bosutinib-treated patients were diarrhea (70.1%), nausea (35.1%), increased ALT (30.6%), and increased AST (22.8%). Musculoskeletal pain or spasms occurred in 29.5% of patients, rash in 19.8%, fatigue in 19.4%, and headache in 18.7%. Hematologic toxicity was also reported, but most was grade 1/2. Thrombocytopenia was reported in 35.1%, anemia in 18.7%, and neutropenia in 11.2%.¹⁸

Cardiovascular events occurred in 5.2% of patients on the bosutinib arm of the BFORE trial, which was similar to the rate observed in imatinib patients. The most common cardiovascular event was QT interval prolongation, which occurred in 1.5% of patients. Pleural effusions were reported in 1.9% of patients treated with bosutinib, and none were grade 3 or higher.¹⁸

If liver enzyme elevation occurs at a value greater than 5 times the institutional upper limit of normal, bosutinib should be held until the level recovers to ≤ 2.5 times the upper limit of normal, at which point bosutinib can be restarted at a lower dose. If recovery takes longer than 4 weeks, bosutinib should be permanently discontinued. Liver enzymes elevated greater than 3 times the institutional upper limit of normal and a concurrent elevation in total bilirubin to 2 times the upper limit of normal are consistent with Hy’s law, and bosutinib should be discontinued. Although diarrhea is the most common toxicity associated with bosutinib, it is commonly low grade and transient. Diarrhea occurs most frequently in the first few days after initiating bosutinib. It can often be managed with over-the-counter antidiarrheal medications, but if the diarrhea is grade 3 or higher, bosutinib should be held until recovery to grade 1 or lower. Gastrointestinal side effects may be improved by taking bosutinib with a meal and a large glass of water. Fluid retention can be managed with diuretics and supportive care. Finally, if rash occurs, this can be addressed with topical or systemic steroids as well as bosutinib dose reduction, interruption, or discontinuation.¹⁹

Similar to other TKIs, if bosutinib-induced cytopenias occur, treatment should be held and restarted at the same or a lower dose upon blood count recovery.¹⁹

Ponatinib

The most common cause of TKI resistance in CP-CML is the development of ABL kinase domain mutations. The majority of imatinib-resistant mutations can be overcome by the use of second-generation TKIs, including dasatinib, nilotinib, or bosutinib. However, ponatinib is the only BCR-ABL TKI able to overcome a T315I mutation. The phase 2 PACE (Ponatinib Ph-positive ALL and CML Evaluation) trial enrolled patients with CP-, AP-, or BP-CML as well as patients with Ph-positive acute lymphoblastic leukemia who were resistant or intolerant to nilotinib or dasatinib, or who had evidence of a T315I mutation. The starting dose of ponatinib on this trial was 45 mg daily.³⁷ The PACE trial enrolled 267 patients with CP-CML: 203 with resistance or intolerance to nilotinib or dasatinib, and 64 with a T315I mutation. The primary endpoint in the CP cohort was rate of MCyR at any time within 12 months of starting ponatinib. The overall rate of MCyR by 12 months in the CP-CML patients was 56%. In those with a T315I mutation, 70% achieved MCyR, which compared favorably with those with resistance or intolerance to nilotinib or dasatinib, 51% of whom achieved MCyR. CCyR was achieved in 46% of CP-CML patients (40% in the resistant/intolerant cohort and 66% in the T315I cohort). In general, patients with T315I mutations received fewer prior therapies than those in the resistant/intolerant cohort, which likely contributed to the higher response rates in the T315I patients. MR4.5 was achieved in 15% of CP-CML patients by 12 months on the PACE trial.³⁷ The 5-year update to this study reported that 60%, 40%, and 24% of CP-CML patients achieved MCyR, MMR, and MR4.5, respectively. In the patients who achieved MCyR, the probability of maintaining this response for 5 years was 82% and the estimated 5-year OS was 73%.¹⁹

Toxicity. In 2013, after the regulatory approval of ponatinib, reports became available that the drug can cause an increase in arterial occlusive events, including fatal myocardial infarctions and cerebrovascular accidents. For this reason, dose reductions were implemented in patients who were deriving clinical benefit from ponatinib. In spite of these dose reductions, ≥ 90% of responders maintained their response for up to 40 months.³⁸ Although the likelihood of developing an arterial occlusive event appears higher in the first year after starting ponatinib than in later years, the cumulative incidence of events continues to increase. The 5-year follow-up to the PACE trial reports 31% of patients experiencing any grade of arterial occlusive event while on ponatinib. Aside from these events, the most common treatment-emergent adverse events in ponatinib-treated patients on the PACE trial included rash (47%), abdominal pain (46%), headache (43%), dry skin (42%), constipation (41%), and hypertension (37%). Hematologic toxicity was also common, with 46% of patients experiencing any grade of thrombocytopenia, 20% experiencing neutropenia, and 20% anemia.³⁸

Patients receiving ponatinib therapy should be monitored closely for any evidence of arterial or venous thrombosis. If an occlusive event occurs, ponatinib should be discontinued. Similarly, in the setting of any new or worsening heart failure symptoms, ponatinib should be promptly discontinued. Management of any underlying cardiovascular risk factors, including hypertension, hyperlipidemia, diabetes, or smoking history, is recommended, and these patients should be referred to a cardiologist for a full evaluation. In the absence of any contraindications to aspirin, low-dose aspirin should be considered as a means of decreasing cardiovascular risks associated with ponatinib. In patients with known risk factors, a ponatinib starting dose of 30 mg daily rather than the standard 45 mg daily may be a safer option, resulting in fewer arterial occlusive events, although the efficacy of this dose is still being studied in comparison to 45 mg daily.¹⁹

If ponatinib-induced transaminitis greater than 3 times the upper limit of normal occurs, ponatinib should be held until resolution to less than 3 times the upper limit of normal, at which point it should be resumed at a lower dose. Similarly, in the setting of elevated serum lipase or symptomatic pancreatitis, ponatinib should be held and restarted at a lower dose after resolution of symptoms.¹⁹

In the event of neutropenia or thrombocytopenia, ponatinib should be held until blood count recovery and then restarted at the same dose. If cytopenias occur for a second time, the dose of ponatinib should be lowered at the time of treatment reinitiation. If rash occurs, it can be addressed with topical or systemic steroids as well as dose reduction, interruption, or discontinuation.¹⁹

Conclusion

With the development of imatinib and the subsequent TKIs, dasatinib, nilotinib, bosutinib, and ponatinib, CP-CML has become a chronic disease with a life expectancy that is similar to that of the general population. Given the successful treatments available for these patients, it is crucial to identify patients with this diagnosis, ensure they receive a complete, appropriate diagnostic workup including a bone marrow biopsy and aspiration with cytogenetic testing, and select the best therapy for each individual patient. Once on treatment, the importance of frequent monitoring cannot be overstated. This is the only way to be certain patients are achieving the desired treatment milestones that correlate with the favorable long-term outcomes that have been observed with TKI-based treatment of CP-CML. 

Corresponding author: Kendra Sweet, MD, MS, Department of Malignant Hematology, Moffitt Cancer Center, Tampa, FL.

Financial disclosures: Dr. Sweet has served on the Advisory Board and Speakers Bureau of Novartis, Bristol-Meyers Squibb, Ariad Pharmaceuticals, and Pfizer, and has served as a consultant to Pfizer.

From the Moffitt Cancer Center, Tampa, FL.

Abstract

• Objective: To outline the approach to selecting a tyrosine kinase inhibitor (TKI) for initial treatment of chronic myeloid leukemia (CML) and monitoring patients following initiation of therapy.
• Methods: Review of the literature and evidence-based guidelines.
• Results: The development and availability of TKIs has improved survival for patients diagnosed with CML. The life expectancy of patients diagnosed with chronic-phase CML (CP-CML) is similar to that of the general population, provided they receive appropriate TKI therapy and adhere to treatment. Selection of the most appropriate first-line TKI for newly diagnosed CP-CML requires incorporation of the patient’s baseline karyotype and Sokal or EURO risk score, and a clear understanding of the patient’s comorbidities. The adverse effect profile of all TKIs must be considered in conjunction with the patient’s ongoing medical issues to decrease the likelihood of worsening their current symptoms or causing a severe complication from TKI therapy. After confirming a diagnosis of CML and selecting the most appropriate TKI for first-line therapy, close monitoring and follow-up are necessary to ensure patients are meeting the desired treatment milestones. Responses in CML can be assessed based on hematologic parameters, cytogenetic results, and molecular responses.
• Conclusion: Given the successful treatments available for patients with CML, it is crucial to identify patients with this diagnosis; ensure they receive a complete, appropriate diagnostic workup including a bone marrow biopsy and aspiration with cytogenetic testing; and select the best therapy for each individual patient.

Keywords: chronic myeloid leukemia; CML; tyrosine kinase inhibitor; TKI; cancer; BCR-ABL protein.

Chronic myeloid leukemia (CML) is a rare myeloproliferative neoplasm that is characterized by the presence of the Philadelphia (Ph) chromosome and uninhibited expansion of bone marrow stem cells. The Ph chromosome arises from a reciprocal translocation between the Abelson (ABL) region on chromosome 9 and the breakpoint cluster region (BCR) of chromosome 22 (t(9;22)(q34;q11.2)), resulting in the BCR-ABL1 fusion gene and its protein product, BCR-ABL tyrosine kinase.¹ BCR-ABL has constitutive tyrosine kinase activity that promotes growth, replication, and survival of hematopoietic cells through downstream pathways, which is the driving factor in the pathogenesis of CML.¹

CML is divided into 3 phases based on the number of myeloblasts observed in the blood or bone marrow: chronic, accelerated, and blast. Most cases of CML are diagnosed in the chronic phase (CP), which is marked by proliferation of primarily the myeloid element.

Typical treatment for CML involves lifelong use of oral BCR-ABL tyrosine kinase inhibitors (TKIs). Currently, 5 TKIs have regulatory approval for treatment of this disease. The advent of TKIs, a class of small molecules targeting the tyrosine kinases, particularly the BCR-ABL tyrosine kinase, led to rapid changes in the management of CML and improved survival for patients. Patients diagnosed with chronic-phase CML (CP-CML) now have a life expectancy that is similar to that of the general population, as long as they receive appropriate TKI therapy and adhere to treatment. As such, it is crucial to identify patients with CML; ensure they receive a complete, appropriate diagnostic workup; and select the best therapy for each patient.

Epidemiology

According to SEER data estimates, 8430 new cases of CML were diagnosed in the United States in 2018. CML is a disease of older adults, with a median age of 65 years at diagnosis, and there is a slight male predominance. Between 2011 and 2015, the number of new CML cases was 1.8 per 100,000 persons. The median overall survival (OS) in patients with newly diagnosed CP-CML has not been reached.² Given the effective treatments available for managing CML, it is estimated that the prevalence of CML in the United States will plateau at 180,000 patients by 2050.³

Clinical Features

The diagnosis of CML is often suspected based on an incidental finding of leukocytosis and, in some cases, thrombocytosis. In many cases, this is an incidental finding on routine blood work, but approximately 50% of patients will present with constitutional symptoms associated with the disease. Characteristic features of the white blood cell differential include left-shifted maturation with neutrophilia and immature circulating myeloid cells. Basophilia and eosinophilia are often present as well. Splenomegaly is a common sign, present in 50% to 90% of patients at diagnosis. In those patients with symptoms related to CML at diagnosis, the most common presentation includes increasing fatigue, fevers, night sweats, early satiety, and weight loss. The diagnosis is confirmed by cytogenetic studies showing the Ph chromosome abnormality, t(9; 22)(q3.4;q1.1), and/or reverse transcriptase polymerase chain reaction (PCR) showing BCR-ABL1 transcripts.

Testing

Bone marrow biopsy. There are 3 distinct phases of CML: CP, accelerated phase (AP), and blast phase (BP). Bone marrow biopsy and aspiration at diagnosis are mandatory in order to determine the phase of the disease at diagnosis. This distinction is based on the percentage of blasts, promyelocytes, and basophils present as well as the platelet count and presence or absence of extramedullary disease.⁴ The vast majority of patients at diagnosis have CML that is in the chronic phase. The typical appearance in CP-CML is a hypercellular marrow with granulocytic and occasionally megakaryocytic hyperplasia. In many cases, basophilia and/or eosinophilia are noted as well. Dysplasia is not a typical finding in CML.⁵ Bone marrow fibrosis can be seen in up to one-third of patients at diagnosis, and may indicate a slightly worse prognosis.⁶ Although a diagnosis of CML can be made without a bone marrow biopsy, complete staging and prognostication are only possible with information gained from this test, including baseline karyotype and confirmation of CP versus a more advanced phase of CML.

Diagnostic criteria. The criteria for diagnosing AP-CML has not been agreed upon by various groups, but the modified MD Anderson Cancer Center (MDACC) criteria are used in the majority of clinical trials evaluating the efficacy of TKIs in preventing progression to advanced phases of CML. MDACC criteria define AP-CML as the presence of 1 of the following: 15% to 29% blasts in the peripheral blood or bone marrow, ≥ 30% peripheral blasts plus promyelocytes, ≥ 20% basophils in the blood or bone marrow, platelet count ≤ 100,000/μL unrelated to therapy, and clonal cytogenetic evolution in Ph-positive metaphases (Table).⁷

The defining feature of CML is the presence of the Ph chromosome abnormality. In a small subset of patients, additional chromosome abnormalities (ACA) in the Ph-positive cells may be identified at diagnosis. Some reports indicate that the presence of “major route” ACA (trisomy 8, isochromosome 17q, a second Ph chromosome, or trisomy 19) at diagnosis may negatively impact prognosis, but other reports contradict these findings.^10,11

PCR assay. The typical BCR breakpoint in CML is the major breakpoint cluster region (M-BCR), which results in a 210-kDa protein (p210). Alternate breakpoints that are less frequently identified are the minor BCR (mBCR or p190), which is more commonly found in Ph-positive acute lymphoblastic leukemia (ALL), and the micro BCR (µBCR or p230), which is much less common and is often characterized by chronic neutrophilia.¹² Identifying which BCR-ABL1 transcript is present in each patient using qualitative PCR is crucial in order to ensure proper monitoring during treatment.

The most sensitive method for detecting BCR-ABL1 mRNA transcripts is the quantitative real-time PCR (RQ-PCR) assay, which is typically done on peripheral blood. RQ-PCR is capable of detecting a single CML cell in the presence of ≥ 100,000 normal cells. This test should be done during the initial diagnostic workup in order to confirm the presence of BCR-ABL1 transcripts, and it is used as a standard method for monitoring response to TKI therapy.¹³ The International Scale (IS) is a standardized approach to reporting RQ-PCR results that was developed to allow comparison of results across various laboratories and has become the gold standard for reporting BCR-ABL1 transcript values.¹⁴

Determining Risk Scores

Calculating a patient’s Sokal score or EURO risk score at diagnosis remains an important component of the diagnostic workup in CP-CML, as this information has prognostic and therapeutic implications (an online calculator is available through European LeukemiaNet [ELN]). The risk for disease progression to the accelerated or blast phases is higher in patients with intermediate or high risk scores compared to those with a low risk score at diagnosis. The risk of progression in intermediate- or high-risk patients is lower when a second-generation TKI (dasatinib, nilotinib, or bosutinib) is used as frontline therapy compared to imatinib, and therefore, the National Comprehensive Cancer Network (NCCN) CML Panel recommends starting with a second-generation TKI in these patients.^15-19

Monitoring Response to Therapy

After confirming a diagnosis of CML and selecting the most appropriate TKI for first-line therapy, the successful management of CML patients relies on close monitoring and follow-up to ensure they are meeting the desired treatment milestones. Responses in CML can be assessed based on hematologic parameters, cytogenetic results, and molecular responses. A complete hematologic response (CHR) implies complete normalization of peripheral blood counts (with the exception of TKI-induced cytopenias) and resolution of any palpable splenomegaly. The majority of patients will achieve a CHR within 4 to 6 weeks after initiating CML-directed therapy.²⁰

Cytogenetic Response

Cytogenetic responses are defined by the decrease in the number of Ph chromosome–positive metaphases when assessed on bone marrow cytogenetics. A partial cytogenetic response (PCyR) is defined as having 1% to 35% Ph-positive metaphases, a major cytogenetic response (MCyR) as having 0% to 35% Ph-positive metaphases, and a complete cytogenetic response (CCyR) implies that no Ph-positive metaphases are identified on bone marrow cytogenetics. An ideal response is the achievement of PCyR after 3 months on a TKI and a CCyR after 12 months on a TKI.²¹

Once a patient has achieved a CCyR, monitoring their response to therapy can only be done using RQ-PCR to measure BCR-ABL1 transcripts in the peripheral blood. The NCCN and the ELN recommend monitoring RQ-PCR from the peripheral blood every 3 months in order to assess response to TKIs.^19,22 As noted, the IS has become the gold standard reporting system for all BCR-ABL1 transcript levels in the majority of laboratories worldwide.^14,23 Molecular responses are based on a log reduction in BCR-ABL1 transcripts from a standardized baseline. Many molecular responses can be correlated with cytogenetic responses such that, if reliable RQ-PCR testing is available, monitoring can be done using only peripheral blood RQ-PCR rather than repeat bone marrow biopsies. For example, an early molecular response (EMR) is defined as a RQ-PCR value of ≤ 10% IS, which is approximately equivalent to a PCyR.²⁴ A value of 1% IS is approximately equivalent to a CCyR. A major molecular response (MMR) is a ≥ 3-log reduction in BCR-ABL1 transcripts from baseline and is a value of ≤ 0.1% IS. Deeper levels of molecular response are best described by the log reduction in BCR-ABL1 transcripts, with a 4-log reduction denoted as MR4.0, a 4.5-log reduction as MR4.5, and so forth. Complete molecular response (CMR) is defined by the level of sensitivity of the RQ-PCR assay being used.¹⁴

The definition of relapsed disease in CML is dependent on the type of response the patient had previously achieved. Relapse could be the loss of a hematologic or cytogenetic response, but fluctuations in BCR-ABL1 transcripts on routine RQ-PCR do not necessarily indicate relapsed CML. A 1-log increase in the level of BCR-ABL1 transcripts with a concurrent loss of MMR should prompt a bone marrow biopsy in order to assess for the loss of CCyR, and thus a cytogenetic relapse; however, this loss of MMR does not define relapse in and of itself. In the setting of relapsed disease, testing should be done to look for possible ABL kinase domain mutations, and alternate therapy should be selected.¹⁹

Multiple reports have identified the prognostic relevance of achieving an EMR at 3 and 6 months after starting TKI therapy. Marin and colleagues reported that in 282 imatinib-treated patients, there was a significant improvement in 8-year OS, progression-free survival (PFS), and cumulative incidence of CCyR and CMR in patients who had BCR-ABL1 transcripts < 9.84% IS after 3 months on treatment.²⁴ This data highlights the importance of early molecular monitoring in order to ensure the best outcomes for patients with CP-CML.

The NCCN CML guidelines and ELN recommendations both agree that an ideal response after 3 months on a TKI is BCR-ABL1 transcripts < 10% IS, but treatment is not considered to be failing at this point if the patient marginally misses this milestone. After 6 months on treatment, an ideal response is considered BCR-ABL1 transcripts < 1%–10% IS. Ideally, patients will have BCR-ABL1 transcripts < 0.1%–1% IS by the time they complete 12 months of TKI therapy, suggesting that these patients have at least achieved a CCyR.^19,22 Even after patients achieve these early milestones, frequent monitoring by RQ-PCR is required to ensure that they are maintaining their response to treatment. This will help to ensure patient compliance with treatment and will also help to identify a select subset of patients who could potentially be considered for an attempt at TKI cessation (not discussed in detail here) after a minimum of 3 years on therapy.^19,25

Selecting First-line TKI Therapy

Selection of the most appropriate first-line TKI for newly diagnosed CP-CML patients requires incorporation of many patient-specific factors. These factors include baseline karyotype and confirmation of CP-CML through bone marrow biopsy, Sokal or EURO risk score, and a thorough patient history, including a clear understanding of the patient’s comorbidities. The adverse effect profile of all TKIs must be considered in conjunction with the patient’s ongoing medical issues in order to decrease the likelihood of worsening their current symptoms or causing a severe complication from TKI therapy.

The management of CML was revolutionized by the development and ultimate regulatory approval of imatinib mesylate in 2001. Imatinib was the first small-molecule cancer therapy developed and approved. It acts by binding to the adenosine triphosphate (ATP) binding site in the catalytic domain of BCR-ABL, thus inhibiting the oncoprotein’s tyrosine kinase activity.²⁶

The International Randomized Study of Interferon versus STI571 (IRIS) trial was a randomized phase 3 study that compared imatinib 400 mg daily to interferon alfa (IFNa) plus cytarabine. More than 1000 CP-CML patients were randomly assigned 1:1 to either imatinib or IFNa plus cytarabine and were assessed for event-free survival, hematologic and cytogenetic responses, freedom from progression to AP or BP, and toxicity. Imatinib was superior to the prior standard of care for all these outcomes.²¹ The long-term follow-up of the IRIS trial reported an 83% estimated 10-year OS and 79% estimated event-free survival for patients on the imatinib arm of this study.¹⁵ The cumulative rate of CCyR was 82.8%. Of the 204 imatinib-treated patients who could undergo a molecular response evaluation at 10 years, 93.1% had a MMR and 63.2% had a MR4.5, suggesting durable, deep molecular responses for many patients. The estimated 10-year rate of freedom from progression to AP or BP was 92.1%.

Higher doses of imatinib (600-800 mg daily) have been studied in an attempt to overcome resistance and improve cytogenetic and molecular response rates. The Tyrosine Kinase Inhibitor Optimization and Selectivity (TOPS) trial was a randomized phase 3 study that compared imatinib 800 mg daily to imatinib 400 mg daily. Although the 6-month assessments found increased rates of CCyR and a MMR in the higher-dose imatinib arm, these differences were no longer present at the 12-month assessment. Furthermore, the higher dose of imatinib led to a significantly higher incidence of grade 3/4 hematologic adverse events, and approximately 50% of patients on imatinib 800 mg daily required a dose reduction to less than 600 mg daily because of toxicity.²⁷

The Therapeutic Intensification in De Novo Leukaemia (TIDEL)-II study used plasma trough levels of imatinib on day 22 of treatment with imatinib 600 mg daily to determine if patients should escalate the imatinib dose to 800 mg daily. In patients who did not meet molecular milestones at 3, 6, or 12 months, cohort 1 was dose escalated to imatinib 800 mg daily and subsequently switched to nilotinib 400 mg twice daily for failing the same target 3 months later, and cohort 2 was switched to nilotinib. At 2 years, 73% of patients achieved MMR and 34% achieved MR4.5, suggesting that initial treatment with higher-dose imatinib, followed by a switch to nilotinib in those failing to achieve desired milestones, could be an effective strategy for managing newly diagnosed CP-CML.²⁸

Toxicity. The standard starting dose of imatinib in CP-CML patients is 400 mg. The safety profile of imatinib has been very well established. In the IRIS trial, the most common adverse events (all grades in decreasing order of frequency) were peripheral and periorbital edema (60%), nausea (50%), muscle cramps (49%), musculoskeletal pain (47%), diarrhea (45%), rash (40%), fatigue (39%), abdominal pain (37%), headache (37%), and joint pain (31%). Grade 3/4 liver enzyme elevation can occur in 5% of patients.²⁹ In the event of severe liver toxicity or fluid retention, imatinib should be held until the event resolves. At that time, imatinib can be restarted if deemed appropriate, but this is dependent on the severity of the inciting event. Fluid retention can be managed by the use of supportive care, diuretics, imatinib dose reduction, dose interruption, or imatinib discontinuation if the fluid retention is severe. Muscle cramps can be managed by the use of calcium supplements or tonic water. Management of rash can include topical or systemic steroids, or in some cases imatinib dose reduction, interruption, or discontinuation.¹⁹

Grade 3/4 imatinib-induced hematologic toxicity is not uncommon, with 17% of patients experiencing neutropenia, 9% thrombocytopenia, and 4% anemia. These adverse events occurred most commonly during the first year of therapy, and the frequency decreased over time.^15,29 Depending on the degree of cytopenias, imatinib dosing should be interrupted until recovery of the absolute neutrophil count or platelet count, and can often be resumed at 400 mg daily. However, if cytopenias recur, imatinib should be held and subsequently restarted at 300 mg daily.¹⁹

Dasatinib

Dasatinib is a second-generation TKI that has regulatory approval for treatment of adult patients with newly diagnosed CP-CML or CP-CML in patients with resistance or intolerance to prior TKIs. In addition to dasatinib’s ability to inhibit ABL kinases, it is also known to be a potent inhibitor of Src family kinases. Dasatinib has shown efficacy in patients who have developed imatinib-resistant ABL kinase domain mutations.

Dasatinib was initially approved as second-line therapy in patients with resistance or intolerance to imatinib. This indication was based on the results of the phase 3 CA180-034 trial, which ultimately identified dasatinib 100 mg daily as the optimal dose. In this trial, 74% of patients enrolled had resistance to imatinib and the remainder were intolerant. The 7-year follow-up of patients randomized to dasatinib 100 mg (n = 167) daily indicated that 46% achieved MMR while on study. Of the 124 imatinib-resistant patients on dasatinib 100 mg daily, the 7-year PFS was 39% and OS was 63%. In the 43 imatinib-intolerant patients, the 7-year PFS was 51% and OS was 70%.³⁰

Dasatinib 100 mg daily was compared to imatinib 400 mg daily in newly diagnosed CP-CML patients in the randomized phase 3 DASISION (Dasatinib versus Imatinib Study in Treatment-Naive CML Patients) trial. More patients on the dasatinib arm achieved an EMR of BCR-ABL1 transcripts ≤ 10% IS after 3 months on treatment compared to imatinib (84% versus 64%). Furthermore, the 5-year follow-up reports that the cumulative incidence of MMR and MR4.5 in dasatinib-treated patients was 76% and 42%, and was 64% and 33% with imatinib (P = 0.0022 and P = 0.0251, respectively). Fewer patients treated with dasatinib progressed to AP or BP (4.6%) compared to imatinib (7.3%), but the estimated 5-year OS was similar between the 2 arms (91% for dasatinib versus 90% for imatinib).¹⁶ Regulatory approval for dasatinib as first-line therapy in newly diagnosed CML patients was based on results of the DASISION trial.

Toxicity. Most dasatinib-related toxicities are reported as grade 1 or grade 2, but grade 3/4 hematologic adverse events are fairly common. In the DASISION trial, grade 3/4 neutropenia, anemia, and thrombocytopenia occurred in 29%, 13%, and 22% of dasatinib-treated patients, respectively. Cytopenias can generally be managed with temporary dose interruptions or dose reductions.

During the 5-year follow-up of the DASISION trial, pleural effusions were reported in 28% of patients, most of which were grade 1/2. This occurred at a rate of approximately ≤ 8% per year, suggesting a stable incidence over time, and the effusions appear to be dose-dependent.¹⁶ Depending on the severity, pleural effusion may be treated with diuretics, dose interruption, and, in some instances, steroids or a thoracentesis. Typically, dasatinib can be restarted at 1 dose level lower than the previous dose once the effusion has resolved.¹⁹ Other, less common side effects of dasatinib include pulmonary hypertension (5% of patients), as well as abdominal pain, fluid retention, headaches, fatigue, musculoskeletal pain, rash, nausea, and diarrhea. Pulmonary hypertension is typically reversible after cessation of dasatinib, and thus dasatinib should be permanently discontinued once the diagnosis is confirmed. Fluid retention is often treated with diuretics and supportive care. Nausea and diarrhea are generally manageable and occur less frequently when dasatinib is taken with food and a large glass of water. Antiemetics and antidiarrheals can be used as needed. Troublesome rash can be best managed with topical or systemic steroids as well as possible dose reduction or dose interruption.^16,19 In the DASISION trial, adverse events led to therapy discontinuation more often in the dasatinib group than in the imatinib group (16% versus 7%).¹⁶ Bleeding, particularly in the setting of thrombocytopenia, has been reported in patients being treated with dasatinib as a result of the drug-induced reversible inhibition of platelet aggregation.³¹

Nilotinib

The structure of nilotinib is similar to that of imatinib; however, it has a markedly increased affinity for the ATP‐binding site on the BCR-ABL1 protein. It was initially given regulatory approval in the setting of imatinib failure. Nilotinib was studied at a dose of 400 mg twice daily in 321 patients who were imatinib-resistant or -intolerant. It proved to be highly effective at inducing cytogenetic remissions in the second-line setting, with 59% of patients achieving a MCyR and 45% achieving a CCyR. With a median follow-up time of 4 years, the OS was 78%.³² 

Nilotinib gained regulatory approval for use as a first-line TKI after completion of the randomized phase 3 ENESTnd (Evaluating Nilotinib Efficacy and Safety in Clinical Trials-Newly Diagnosed Patients) trial. ENESTnd was a 3-arm study comparing nilotinib 300 mg twice daily versus nilotinib 400 mg twice daily versus imatinib 400 mg daily in newly diagnosed, previously untreated patients diagnosed with CP-CML. The primary endpoint of this clinical trial was rate of MMR at 12 months.³³ Nilotinib surpassed imatinib in this regard, with 44% of patients on nilotinib 300 mg twice daily achieving MMR at 12 months versus 43% of nilotinib 400 mg twice daily patients versus 22% of the imatinib-treated patients (P < 0.001 for both comparisons). Furthermore, the rate of CCyR by 12 months was significantly higher for both nilotinib arms compared with imatinib (80% for nilotinib 300 mg, 78% for nilotinib 400 mg, and 65% for imatinib) (P < 0.001).¹² Based on this data, nilotinib 300 mg twice daily was chosen as the standard dose of nilotinib in the first-line setting. After 5 years of follow-up on the ENESTnd study, there were fewer progressions to AP/BP CML in nilotinib-treated patients compared with imatinib. MMR was achieved in 77% of nilotinib 300 mg patients compared with 60.4% of patients on the imatinib arm. MR4.5 was also more common in patients treated with nilotinib 300 mg twice daily, with a rate of 53.5% at 5 years versus 31.4% in the imatinib arm.¹⁷ In spite of the deeper cytogenetic and molecular responses achieved with nilotinib, this did not translate into a significant improvement in OS. The 5-year OS rate was 93.7% in nilotinib 300 mg patients versus 91.7% in imatinib-treated patients, and this difference lacked statistical significance.¹⁷

Toxicity. Although some similarities exist between the toxicity profiles of nilotinib and imatinib, each drug has some distinct adverse events. On the ENESTnd trial, the rate of any grade 3/4 non-hematologic adverse event was fairly low; however, lower-grade toxicities were not uncommon. Patients treated with nilotinib 300 mg twice daily experienced rash (31%), headache (14%), pruritis (15%), and fatigue (11%) most commonly. The most frequently reported laboratory abnormalities included increased total bilirubin (53%), hypophosphatemia (32%), hyperglycemia (36%), elevated lipase (24%), increased alanine aminotransferase (ALT; 66%), and increased aspartate aminotransferase (AST; 40%). Any grade of neutropenia, thrombocytopenia, or anemia occurred at rates of 43%, 48%, and 38%, respectively.³³ Although nilotinib has a Black Box Warning from the US Food and Drug Administration for QT interval prolongation, no patients on the ENESTnd trial experienced a QT interval corrected for heart rate greater than 500 msec.¹²

More recent concerns have emerged regarding the potential for cardiovascular toxicity after long-term use of nilotinib. The 5-year update of ENESTnd reports cardiovascular events, including ischemic heart disease, ischemic cerebrovascular events, or peripheral arterial disease occurring in 7.5% of patients treated with nilotinib 300 mg twice daily, as compared with a rate of 2.1% in imatinib-treated patients. The frequency of these cardiovascular events increased linearly over time in both arms. Elevations in total cholesterol from baseline occurred in 27.6% of nilotinib patients compared with 3.9% of imatinib patients. Furthermore, clinically meaningful increases in low-density lipoprotein cholesterol and glycated hemoglobin occurred more frequently with nilotinib therapy.³³

Nilotinib should be taken on an empty stomach; therefore, patients should be made aware of the need to fast for 2 hours prior to each dose and 1 hour after each dose. Given the potential risk of QT interval prolongation, a baseline electrocardiogram (ECG) is recommended prior to initiating treatment to ensure the QT interval is within a normal range. A repeat ECG should be done approximately 7 days after nilotinib initiation to ensure no prolongation of the QT interval after starting. Close monitoring of potassium and magnesium levels is important to decrease the risk of cardiac arrhythmias, and concomitant use of drugs considered strong CYP3A4 inhibitors should be avoided.¹⁹

If the patient experiences any grade 3 or higher laboratory abnormalities, nilotinib should be held until resolution of the toxicity, and then restarted at a lower dose. Similarly, if patients develop significant neutropenia or thrombocytopenia, nilotinib doses should be interrupted until resolution of the cytopenias. At that point, nilotinib can be reinitiated at either the same or a lower dose. Rash can be managed by the use of topical or systemic steroids as well as potential dose reduction, interruption, or discontinuation.

Given the concerns for potential cardiovascular events with long-term use of nilotinib, caution is advised when prescribing it to any patient with a history of cardiovascular disease or peripheral arterial occlusive disease. At the first sign of new occlusive disease, nilotinib should be discontinued.¹⁹

Bosutinib

Bosutinib is a second-generation BCR-ABL TKI with activity against the Src family of kinases; it was initially approved to treat patients with CP-, AP-, or BP-CML after resistance or intolerance to imatinib. Long-term data has been reported from the phase 1/2 trial of bosutinib therapy in patients with CP-CML who developed resistance or intolerance to imatinib plus dasatinib and/or nilotinib. A total of 119 patients were included in the 4-year follow-up; 38 were resistant/intolerant to imatinib and resistant to dasatinib, 50 were resistant/intolerant to imatinib and intolerant to dasatinib, 26 were resistant/intolerant to imatinib and resistant to nilotinib, and 5 were resistant/intolerant to imatinib and intolerant to nilotinib or resistant/intolerant to dasatinib and nilotinib. Bosutinib 400 mg daily was studied in this setting. Of the 38 patients with imatinib resistance/intolerance and dasatinib resistance, 39% achieved MCyR, 22% achieved CCyR, and the OS was 67%. Of the 50 patients with imatinib resistance/intolerance and dasatinib intolerance, 42% achieved MCyR, 40% achieved CCyR, and the OS was 80%. Finally, in the 26 patients with imatinib resistance/intolerance and nilotinib resistance, 38% achieved MCyR, 31% achieved CCyR, and the OS was 87%.³⁴

Five-year follow-up from the phase 1/2 clinical trial that studied bosutinib 500 mg daily in CP-CML patients after imatinib failure reported data on 284 patients. By 5 years on study, 60% of patients had achieved MCyR and 50% achieved CCyR with a 71% and 69% probability, respectively, of maintaining these responses at 5 years. The 5-year OS was 84%.³⁵ These data led to the regulatory approval of bosutinib 500 mg daily as second-line or later therapy.

Bosutinib was initially studied in the first-line setting in the randomized phase 3 BELA (Bosutinib Efficacy and Safety in Newly Diagnosed Chronic Myeloid Leukemia) trial. This trial compared bosutinib 500 mg daily to imatinib 400 mg daily in newly diagnosed, previously untreated CP-CML patients. This trial failed to meet its primary endpoint of increased rate of CCyR at 12 months, with 70% of bosutinib patients achieving this response, compared to 68% of imatinib-treated patients (P = 0.601). In spite of this, the rate of MMR at 12 months was significantly higher in the bosutinib arm (41%) compared to the imatinib arm (27%; P = 0.001).³⁶

A second phase 3 trial (BFORE) was designed to study bosutinib 400 mg daily versus imatinib in newly diagnosed, previously untreated CP-CML patients. This study enrolled 536 patients who were randomly assigned 1:1 to bosutinib versus imatinib. The primary endpoint of this trial was rate of MMR at 12 months. A significantly higher number of bosutinib-treated patients achieved this response (47.2%) compared with imatinib-treated patients (36.9%, P = 0.02). Furthermore, by 12 months 77.2% of patients on the bosutinib arm had achieved CCyR compared with 66.4% on the imatinib arm, and this difference did meet statistical significance (P = 0.0075). A lower rate of progression to AP- or BP-CML was noted in bosutinib-treated patients as well (1.6% versus 2.5%). Based on this data, bosutinib gained regulatory approval for first-line therapy in CP-CML at a dose of 400 mg daily.¹⁸

Toxicity. On the BFORE trial, the most common treatment-emergent adverse events of any grade reported in the bosutinib-treated patients were diarrhea (70.1%), nausea (35.1%), increased ALT (30.6%), and increased AST (22.8%). Musculoskeletal pain or spasms occurred in 29.5% of patients, rash in 19.8%, fatigue in 19.4%, and headache in 18.7%. Hematologic toxicity was also reported, but most was grade 1/2. Thrombocytopenia was reported in 35.1%, anemia in 18.7%, and neutropenia in 11.2%.¹⁸

Cardiovascular events occurred in 5.2% of patients on the bosutinib arm of the BFORE trial, which was similar to the rate observed in imatinib patients. The most common cardiovascular event was QT interval prolongation, which occurred in 1.5% of patients. Pleural effusions were reported in 1.9% of patients treated with bosutinib, and none were grade 3 or higher.¹⁸

If liver enzyme elevation occurs at a value greater than 5 times the institutional upper limit of normal, bosutinib should be held until the level recovers to ≤ 2.5 times the upper limit of normal, at which point bosutinib can be restarted at a lower dose. If recovery takes longer than 4 weeks, bosutinib should be permanently discontinued. Liver enzymes elevated greater than 3 times the institutional upper limit of normal and a concurrent elevation in total bilirubin to 2 times the upper limit of normal are consistent with Hy’s law, and bosutinib should be discontinued. Although diarrhea is the most common toxicity associated with bosutinib, it is commonly low grade and transient. Diarrhea occurs most frequently in the first few days after initiating bosutinib. It can often be managed with over-the-counter antidiarrheal medications, but if the diarrhea is grade 3 or higher, bosutinib should be held until recovery to grade 1 or lower. Gastrointestinal side effects may be improved by taking bosutinib with a meal and a large glass of water. Fluid retention can be managed with diuretics and supportive care. Finally, if rash occurs, this can be addressed with topical or systemic steroids as well as bosutinib dose reduction, interruption, or discontinuation.¹⁹

Similar to other TKIs, if bosutinib-induced cytopenias occur, treatment should be held and restarted at the same or a lower dose upon blood count recovery.¹⁹

Ponatinib

The most common cause of TKI resistance in CP-CML is the development of ABL kinase domain mutations. The majority of imatinib-resistant mutations can be overcome by the use of second-generation TKIs, including dasatinib, nilotinib, or bosutinib. However, ponatinib is the only BCR-ABL TKI able to overcome a T315I mutation. The phase 2 PACE (Ponatinib Ph-positive ALL and CML Evaluation) trial enrolled patients with CP-, AP-, or BP-CML as well as patients with Ph-positive acute lymphoblastic leukemia who were resistant or intolerant to nilotinib or dasatinib, or who had evidence of a T315I mutation. The starting dose of ponatinib on this trial was 45 mg daily.³⁷ The PACE trial enrolled 267 patients with CP-CML: 203 with resistance or intolerance to nilotinib or dasatinib, and 64 with a T315I mutation. The primary endpoint in the CP cohort was rate of MCyR at any time within 12 months of starting ponatinib. The overall rate of MCyR by 12 months in the CP-CML patients was 56%. In those with a T315I mutation, 70% achieved MCyR, which compared favorably with those with resistance or intolerance to nilotinib or dasatinib, 51% of whom achieved MCyR. CCyR was achieved in 46% of CP-CML patients (40% in the resistant/intolerant cohort and 66% in the T315I cohort). In general, patients with T315I mutations received fewer prior therapies than those in the resistant/intolerant cohort, which likely contributed to the higher response rates in the T315I patients. MR4.5 was achieved in 15% of CP-CML patients by 12 months on the PACE trial.³⁷ The 5-year update to this study reported that 60%, 40%, and 24% of CP-CML patients achieved MCyR, MMR, and MR4.5, respectively. In the patients who achieved MCyR, the probability of maintaining this response for 5 years was 82% and the estimated 5-year OS was 73%.¹⁹

Toxicity. In 2013, after the regulatory approval of ponatinib, reports became available that the drug can cause an increase in arterial occlusive events, including fatal myocardial infarctions and cerebrovascular accidents. For this reason, dose reductions were implemented in patients who were deriving clinical benefit from ponatinib. In spite of these dose reductions, ≥ 90% of responders maintained their response for up to 40 months.³⁸ Although the likelihood of developing an arterial occlusive event appears higher in the first year after starting ponatinib than in later years, the cumulative incidence of events continues to increase. The 5-year follow-up to the PACE trial reports 31% of patients experiencing any grade of arterial occlusive event while on ponatinib. Aside from these events, the most common treatment-emergent adverse events in ponatinib-treated patients on the PACE trial included rash (47%), abdominal pain (46%), headache (43%), dry skin (42%), constipation (41%), and hypertension (37%). Hematologic toxicity was also common, with 46% of patients experiencing any grade of thrombocytopenia, 20% experiencing neutropenia, and 20% anemia.³⁸

Patients receiving ponatinib therapy should be monitored closely for any evidence of arterial or venous thrombosis. If an occlusive event occurs, ponatinib should be discontinued. Similarly, in the setting of any new or worsening heart failure symptoms, ponatinib should be promptly discontinued. Management of any underlying cardiovascular risk factors, including hypertension, hyperlipidemia, diabetes, or smoking history, is recommended, and these patients should be referred to a cardiologist for a full evaluation. In the absence of any contraindications to aspirin, low-dose aspirin should be considered as a means of decreasing cardiovascular risks associated with ponatinib. In patients with known risk factors, a ponatinib starting dose of 30 mg daily rather than the standard 45 mg daily may be a safer option, resulting in fewer arterial occlusive events, although the efficacy of this dose is still being studied in comparison to 45 mg daily.¹⁹

If ponatinib-induced transaminitis greater than 3 times the upper limit of normal occurs, ponatinib should be held until resolution to less than 3 times the upper limit of normal, at which point it should be resumed at a lower dose. Similarly, in the setting of elevated serum lipase or symptomatic pancreatitis, ponatinib should be held and restarted at a lower dose after resolution of symptoms.¹⁹

In the event of neutropenia or thrombocytopenia, ponatinib should be held until blood count recovery and then restarted at the same dose. If cytopenias occur for a second time, the dose of ponatinib should be lowered at the time of treatment reinitiation. If rash occurs, it can be addressed with topical or systemic steroids as well as dose reduction, interruption, or discontinuation.¹⁹

Conclusion

With the development of imatinib and the subsequent TKIs, dasatinib, nilotinib, bosutinib, and ponatinib, CP-CML has become a chronic disease with a life expectancy that is similar to that of the general population. Given the successful treatments available for these patients, it is crucial to identify patients with this diagnosis, ensure they receive a complete, appropriate diagnostic workup including a bone marrow biopsy and aspiration with cytogenetic testing, and select the best therapy for each individual patient. Once on treatment, the importance of frequent monitoring cannot be overstated. This is the only way to be certain patients are achieving the desired treatment milestones that correlate with the favorable long-term outcomes that have been observed with TKI-based treatment of CP-CML. 

Corresponding author: Kendra Sweet, MD, MS, Department of Malignant Hematology, Moffitt Cancer Center, Tampa, FL.

Financial disclosures: Dr. Sweet has served on the Advisory Board and Speakers Bureau of Novartis, Bristol-Meyers Squibb, Ariad Pharmaceuticals, and Pfizer, and has served as a consultant to Pfizer.

From Tufts Medical Center, Boston, MA.

Abstract

• Objective: Audits at our academic medical center revealed near 100% compliance with protocols for perioperative venous thromboembolism (VTE) prophylaxis, but recent National Surgical Quality Improvement Program data demonstrated a higher than expected incidence of VTE (observed/expected = 1.32). The objective of this study was to identify potential causes of this discrepancy.
• Design: Retrospective case-control study.
• Setting: Urban academic medical center with high case-mix indices (Medicare approximately 2.4, non-Medicare approximately 2.0).
• Participants: 102 surgical inpatients with VTE (September 2012 to October 2015) matched with controls for age, gender, and type of procedure.
• Measurements: Prevalence of common VTE risk factors, length of stay, number of procedures, index operation times, and postoperative bed rest > 12 hours were assessed. Utilization of and compliance with our VTE risk assessment tool was also investigated.
• Results: Cases underwent more procedures and had longer lengths of stay and index procedures than controls. In addition, cases were more likely to have had > 12 hours of postoperative bed rest and central venous access than controls. Cases had more infections and were more likely to have severe lung disease, thrombophilia, and a history of prior VTE than controls. No differences in body mass index, tobacco use, current or previous malignancy, or VTE risk assessment form use were observed. Overall, care complexity and risk factors were equally important in determining VTE incidence. Our analyses also revealed lack of strict adherence to our VTE risk stratification protocol and frequent use of suboptimal prophylactic regimens.
• Conclusion: Well-accepted risk factors and overall care complexity determine VTE risk. Preventing VTE in high-risk patients requires assiduous attention to detail in VTE risk assessment and in delivery of optimal prophylaxis. Patients at especially high risk may require customized prophylactic regimens.

Keywords: hospital-acquired venous thromboembolic disease; VTE prophylaxis, surgical patients.

Deep vein thrombosis (DVT) and pulmonary embolism (PE) are well-recognized causes of morbidity and mortality in surgical patients. Between 350,000 and 600,000 cases of venous thromboembolism (VTE) occur each year in the United States, and it is responsible for approximately 10% of preventable in-hospital fatalities.^1-3 Given VTE’s impact on patients and the healthcare system and the fact that it is preventable, intense effort has been focused on developing more effective prophylactic measures to decrease its incidence.^2-4 In 2008, the surgeon general issued a “call to action” for increased efforts to prevent VTE.⁵

The American College of Chest Physicians (ACCP) guidelines subcategorize patients based on type of surgery. In addition, the ACCP guidelines support the use of a Caprini-based scoring system to aid in risk stratification and improve clinical decision-making (Table 1).^4,6-9 In general, scores ≥ 5 qualify individuals as high risk. Based on their risk category, patients receive mechanical prophylaxis, chemical prophylaxis, or a combination of the 2. Lower-risk patients who are ambulatory typically receive only mechanical prophylaxis while in bed, whereas higher-risk patients receive a combination of mechanical prophylaxis and chemoprophylaxis measures.⁷ In general, low-molecular-weight heparin (40 mg daily) and low-dose unfractionated heparin (5000 units 3 times daily) have been the standard evidence-based options for chemoprophylaxis in surgical patients. Absolute contraindications for prophylaxis include active bleeding and known increased risk of bleeding based on patient- or procedure-specific factors.

Our hospital, a 350-bed academic medical center in downtown Boston, MA, serving a diverse population with a very high case-mix index (2.4 Medicare and 2.0 non-Medicare), has strict protocols for VTE prophylaxis consistent with the ACCP guidelines and based on the Surgical Care Improvement Project (SCIP) measures published in 2006.¹⁰ The SCIP mandates allow for considerable surgeon discretion in the use of chemoprophylaxis for neurosurgical cases and general and orthopedic surgery cases deemed to be at high risk for bleeding. In addition, SCIP requires only that prophylaxis be initiated within 24 hours of surgical end time. Although recent audits revealed nearly 100% compliance with SCIP-mandated protocols, National Surgical Quality Improvement Program (NSQIP) data showed that the incidence of VTE events at our institution was higher than expected (observed/expected [O/E] = 1.32).

In order to determine the reasons for this mismatch between process and outcome performance, we investigated whether there were characteristics of our patient population that contributed to the higher than expected rates of VTE, and we scrutinized our VTE prophylaxis protocol to determine if there were aspects of our process that were also contributory.

Methods

Study Sample

This is a retrospective case-control study of surgical inpatients at our hospital during the period September 2012 to October 2015. Cases were identified as patients diagnosed with a VTE (DVT or PE). Controls were identified from a pool of surgical patients whose courses were not complicated by VTE during the same time frame as the cases and who were matched as closely as possible by procedure code, age, and gender.

Patient and hospital course variables that were analyzed included demographics, comorbidities, length of stay, number of procedures, index operation times, duration of postoperative bed rest, use of mechanical prophylaxis, and type of chemoprophylaxis and time frame within which it was initiated. Data were collected via chart review using International Classification of Diseases-9 and -10 codes to identify surgical cases within the allotted time period who were diagnosed with VTE. Demographic variables included age, sex, and ethnicity. Comorbidities included hypertension, diabetes, coronary artery disease, serious lung disease, previous or current malignancy, documented hypercoagulable state, and previous history of VTE. Body mass index (BMI) was also recorded. The aforementioned disease-specific variables were not matched between the case and control groups, as this data was obtained retrospectively during data collection.

Analysis

Associations between case and matched control were analyzed using the paired t-test for continuous variables and McNemar’s test for categorical variables. P values < 0.05 were considered statistically significant. SAS Enterprise Guide 7.15 (Cary, NC) was used for all statistical analyses.

The requirement for informed consent was waived by our Institutional Review Board, as the study was initially deemed to be a quality improvement project, and all data used for this report were de-identified.

Results

Our retrospective case-control analysis included a sample of 102 surgical patients whose courses were complicated by VTE between September 2012 and October 2015. The cases were distributed among 6 different surgical categories (Figure 1): trauma (20%), cancer (10%), cardiovascular (21%), noncancer neurosurgery (28%), elective orthopedics (11%), and miscellaneous general surgery (10%).

Comparisons between cases and controls in terms of patient demographics and risk factors are shown in Table 2. No statistically significant difference was observed in ethnicity or race between the 2 groups. Overall, cases had more hip/pelvis/leg fractures at presentation (P = 0.0008). The case group also had higher proportions of patients with postoperative bed rest greater than 12 hours (P = 0.009), central venous access (P < 0.0001), infection (P < 0.0001), and lower extremity edema documented during the hospitalization prior to development of DVT (P < 0.0001). Additionally, cases had significantly greater rates of previous VTE (P = 0.0004), inherited or acquired thrombophilia (P = 0.03), history of stroke (P = 0.0003), and severe lung disease, including pneumonia (P = 0.0008). No significant differences were noted between cases and matched controls in BMI (P = 0.43), current tobacco use (P = 0.71), current malignancy (P = 0.80), previous malignancy (P = 0.83), head trauma (P = 0.17), or acute cardiac disease (myocardial infarction or congestive heart failure; P = 0.12).

Variables felt to indicate overall complexity of hospital course for cases as compared to controls are outlined in Table 3. Cases were found to have significantly longer lengths of stay (median, 15.5 days versus 3 days, P < 0.0001). To account for the possibility that the development of VTE contributed to the increased length of stay in the cases, we also looked at the duration between admission date and the date of VTE diagnosis and determined that cases still had a longer length of stay when this was accounted for (median, 7 days versus 3 days, P < 0.0001). A much higher proportion of cases underwent more than 1 procedure compared to controls (P < 0.0001), and cases had significantly longer index operations as compared to controls (P = 0.002).

Seventeen cases received heparin on induction during their index procedure, compared to 23 controls (P = 0.24). Additionally, 63 cases began a prophylaxis regimen within 24 hours of surgery end time, compared to 68 controls (P = 0.24). The chemoprophylactic regimens utilized in cases and in controls are summarized in Figure 2. Of note, only 26 cases and 32 controls received standard prophylactic regimens with no missed doses (heparin 5000 units 3 times daily or enoxaparin 40 mg daily). Additionally, in over half of cases and a third of controls, nonstandard regimens were ordered. Examples of nonstandard regimens included nonstandard heparin or enoxaparin doses, low-dose warfarin, or aspirin alone. In most cases, nonstandard regimens were justified on the basis of high risk for bleeding.

Mechanical prophylaxis with pneumatic sequential compression devices (SCDs) was ordered in 93 (91%) cases and 87 (85%) controls; however, we were unable to accurately document uniform compliance in the use of these devices.

With regard to evaluation of our process measures, we found only 17% of cases and controls combined actually had a VTE risk assessment in their chart, and when it was present, it was often incomplete or was completed inaccurately.

Discussion

The goal of this study was to identify factors (patient characteristics and/or processes of care) that may be contributing to the higher than expected incidence of VTE events at our medical center, despite internal audits suggesting near perfect compliance with SCIP-mandated protocols. We found that in addition to usual risk factors for VTE, an overarching theme of our case cohort was their high complexity of illness. At baseline, these patients had significantly greater rates of stroke, thrombophilia, severe lung disease, infection, and history of VTE than controls. Moreover, the hospital courses of cases were significantly more complex than those of controls, as these patients had more procedures, longer lengths of stay and longer index operations, higher rates of postoperative bed rest exceeding 12 hours, and more prevalent central venous access than controls (Table 2). Several of these risk factors have been found to contribute to VTE development despite compliance with prophylaxis protocols.

Cassidy et al reviewed a cohort of nontrauma general surgery patients who developed VTE despite receiving appropriate prophylaxis and found that both multiple operations and emergency procedures contributed to the failure of VTE prophylaxis.¹¹ Similarly, Wang et al identified several independent risk factors for VTE despite thromboprophylaxis, including central venous access and infection, as well as intensive care unit admission, hospitalization for cranial surgery, and admission from a long-term care facility.¹² While our study did not capture some of these additional factors considered by Wang et al, the presence of risk factors not captured in traditional assessment tools suggests that additional consideration for complex patients is warranted.

In addition to these nonmodifiable patient characteristics, aspects of our VTE prophylaxis processes likely contributed to the higher than expected rate of VTE. While the electronic medical record at our institution does contain a VTE risk assessment tool based on the Caprini score, we found it often is not used at all or is used incorrectly/incompletely, which likely reflects the fact that physicians are neither prompted nor required to complete the assessment prior to prescribing VTE prophylaxis.

There is a significant body of evidence demonstrating that mandatory computerized VTE risk assessments can effectively reduce VTE rates and that improved outcomes occur shortly after implementation. Cassidy et al demonstrated the benefits of instituting a hospital-wide, mandatory, Caprini-based computerized VTE risk assessment that provides prophylaxis/early ambulation recommendations. Two years after implementing this system, they observed an 84% reduction in DVTs (P < 0.001) and a 55% reduction in PEs (P < 0.001).¹³ Nimeri et al had similarly impressive success, achieving a reduction in their NSQIP O/E for PE/DVT in general surgery from 6.00 in 2010 to 0.82 (for DVTs) and 0.78 (for PEs) 5 years after implementation of mandatory VTE risk assessment (though they noted that the most dramatic reduction occurred 1 year after implementation).¹⁴ Additionally, a recent systematic review and meta-analysis by Borab et al found computerized VTE risk assessments to be associated with a significant decrease in VTE events.¹⁵

The risk assessment tool used at our institution is qualitative in nature, and current literature suggests that employing a more quantitative tool may yield improved outcomes. Numerous studies have highlighted the importance of identifying patients at very high risk for VTE, as higher risk may necessitate more careful consideration of their prophylactic regimens. Obi et al found patients with Caprini scores higher than 8 to be at significantly greater risk of developing VTE compared to patients with scores of 7 or 8. Also, patients with scores of 7 or 8 were significantly more likely to have a VTE compared to those with scores of 5 or 6.¹⁶ In another study, Lobastov et al identified Caprini scores of 11 or higher as representing an extremely high-risk category for which standard prophylaxis regimens may not be effective.¹⁷ Thus, while having mandatory risk assessment has been shown to dramatically decrease VTE incidence, it is important to consider the magnitude of the numerical risk score. This is of particular importance at medical centers with high case-mix indices where patients at the highest risk might need to be managed with different prophylactic guidelines.

Another notable aspect of the process at our hospital was the great variation in the types of prophylactic regimens ordered, and the adherence to what was ordered. Only 25.5% of patients were maintained on a standard prophylactic regimen with no missed doses (heparin 5000 every 8 hours or enoxaparin 40 mg daily). Thus, the vast majority of the patients who went on to develop VTE either were prescribed a nontraditional prophylaxis regimen or missed doses of standard agents. The need for secondary surgical procedures or other invasive interventions may explain many, but not all, of the missed doses.

The timing of prophylaxis initiation for our patients was also found to deviate from accepted standards. Only 16.8% of cases received prophylaxis upon induction of anesthesia, and furthermore, 38% of cases did not receive any anticoagulation within 24 hours of their index operation. While this variability in prophylaxis implementation was acceptable within the SCIP guidelines based on “high risk for bleeding” or other considerations, it likely contributed to our suboptimal outcomes. The variations and interruptions in prophylactic regimens speak to barriers that have previously been reported as contributing factors to noncompliance with VTE prophylaxis.¹⁸

Given these known barriers and the observed underutilization and improper use of our risk assessment tool, we have recently changed our surgical admission order sets such that a mandatory quantitative risk assessment must be done for every surgical patient at the time of admission/operation before other orders can be completed. Following completion of the assessment, the physician will be presented with an appropriate standard regimen based on the individual patient’s risk assessment. Early results of our VTE quality improvement project have been satisfying: in the most recent NSQIP semi-annual report, our O/E for VTE was 0.74, placing us in the first decile. Some of these early reports may simply be the product of the Hawthorne effect; however, we are encouraged by the early improvements seen in other research. While we are hopeful that these changes will result in sustainable improvements in outcomes, patients at extremely high risk may require novel weight-based or otherwise customized aggressive prophylactic regimens. Such regimens have already been proposed for arthroplasty and other high-risk patients.

Future research may identify other risk factors not captured by traditional risk assessments. In addition, research should continue to explore the use and efficacy of standard prophylactic regimens in these populations to help determine if they are sufficient. Currently, weight-based low-molecular-weight heparin dosing and alternative regimens employing fondaparinux are under investigation for very-high-risk patients.¹⁹

There were several limitations to the present study. First, due to the retrospective design of our study, we could collect only data that had been uniformly recorded in the charts throughout the study period. Second, we were unable to accurately assess compliance with mechanical prophylaxis. While our chart review showed that the vast majority of cases and controls were ordered to have mechanical prophylaxis, it is impossible to document how often these devices were used appropriately in a retrospective analysis. Anecdotal observation suggests that once patients are out of post-anesthesia or critical care units, SCD use is not standardized. The inability to measure compliance precisely may be leading to an overestimation of our compliance with prophylaxis. Finally, because our study included only patients who underwent surgery at our hospital, our observations may not be generalizable outside our institution.

Conclusion

Our study findings reinforce the importance of attention to detail in VTE risk assessment and in ordering and administering VTE prophylactic regimens, especially in high-risk surgical patients. While we adhered to the SCIP-mandated prophylaxis requirements, the complexity of our patients and our lack of a truly standardized approach to risk assessment and prophylactic regimens resulted in suboptimal outcomes. Stricter and more quantitative mandatory VTE risk assessment, along with highly standardized VTE prophylaxis regimens, are required to achieve optimal outcomes.

Corresponding author: Jason C. DeGiovanni, MS, BA, [email protected].

Financial disclosures: None.

From Tufts Medical Center, Boston, MA.

Abstract

• Objective: Audits at our academic medical center revealed near 100% compliance with protocols for perioperative venous thromboembolism (VTE) prophylaxis, but recent National Surgical Quality Improvement Program data demonstrated a higher than expected incidence of VTE (observed/expected = 1.32). The objective of this study was to identify potential causes of this discrepancy.
• Design: Retrospective case-control study.
• Setting: Urban academic medical center with high case-mix indices (Medicare approximately 2.4, non-Medicare approximately 2.0).
• Participants: 102 surgical inpatients with VTE (September 2012 to October 2015) matched with controls for age, gender, and type of procedure.
• Measurements: Prevalence of common VTE risk factors, length of stay, number of procedures, index operation times, and postoperative bed rest > 12 hours were assessed. Utilization of and compliance with our VTE risk assessment tool was also investigated.
• Results: Cases underwent more procedures and had longer lengths of stay and index procedures than controls. In addition, cases were more likely to have had > 12 hours of postoperative bed rest and central venous access than controls. Cases had more infections and were more likely to have severe lung disease, thrombophilia, and a history of prior VTE than controls. No differences in body mass index, tobacco use, current or previous malignancy, or VTE risk assessment form use were observed. Overall, care complexity and risk factors were equally important in determining VTE incidence. Our analyses also revealed lack of strict adherence to our VTE risk stratification protocol and frequent use of suboptimal prophylactic regimens.
• Conclusion: Well-accepted risk factors and overall care complexity determine VTE risk. Preventing VTE in high-risk patients requires assiduous attention to detail in VTE risk assessment and in delivery of optimal prophylaxis. Patients at especially high risk may require customized prophylactic regimens.

Keywords: hospital-acquired venous thromboembolic disease; VTE prophylaxis, surgical patients.

Deep vein thrombosis (DVT) and pulmonary embolism (PE) are well-recognized causes of morbidity and mortality in surgical patients. Between 350,000 and 600,000 cases of venous thromboembolism (VTE) occur each year in the United States, and it is responsible for approximately 10% of preventable in-hospital fatalities.^1-3 Given VTE’s impact on patients and the healthcare system and the fact that it is preventable, intense effort has been focused on developing more effective prophylactic measures to decrease its incidence.^2-4 In 2008, the surgeon general issued a “call to action” for increased efforts to prevent VTE.⁵

The American College of Chest Physicians (ACCP) guidelines subcategorize patients based on type of surgery. In addition, the ACCP guidelines support the use of a Caprini-based scoring system to aid in risk stratification and improve clinical decision-making (Table 1).^4,6-9 In general, scores ≥ 5 qualify individuals as high risk. Based on their risk category, patients receive mechanical prophylaxis, chemical prophylaxis, or a combination of the 2. Lower-risk patients who are ambulatory typically receive only mechanical prophylaxis while in bed, whereas higher-risk patients receive a combination of mechanical prophylaxis and chemoprophylaxis measures.⁷ In general, low-molecular-weight heparin (40 mg daily) and low-dose unfractionated heparin (5000 units 3 times daily) have been the standard evidence-based options for chemoprophylaxis in surgical patients. Absolute contraindications for prophylaxis include active bleeding and known increased risk of bleeding based on patient- or procedure-specific factors.

Our hospital, a 350-bed academic medical center in downtown Boston, MA, serving a diverse population with a very high case-mix index (2.4 Medicare and 2.0 non-Medicare), has strict protocols for VTE prophylaxis consistent with the ACCP guidelines and based on the Surgical Care Improvement Project (SCIP) measures published in 2006.¹⁰ The SCIP mandates allow for considerable surgeon discretion in the use of chemoprophylaxis for neurosurgical cases and general and orthopedic surgery cases deemed to be at high risk for bleeding. In addition, SCIP requires only that prophylaxis be initiated within 24 hours of surgical end time. Although recent audits revealed nearly 100% compliance with SCIP-mandated protocols, National Surgical Quality Improvement Program (NSQIP) data showed that the incidence of VTE events at our institution was higher than expected (observed/expected [O/E] = 1.32).

In order to determine the reasons for this mismatch between process and outcome performance, we investigated whether there were characteristics of our patient population that contributed to the higher than expected rates of VTE, and we scrutinized our VTE prophylaxis protocol to determine if there were aspects of our process that were also contributory.

Methods

Study Sample

This is a retrospective case-control study of surgical inpatients at our hospital during the period September 2012 to October 2015. Cases were identified as patients diagnosed with a VTE (DVT or PE). Controls were identified from a pool of surgical patients whose courses were not complicated by VTE during the same time frame as the cases and who were matched as closely as possible by procedure code, age, and gender.

Patient and hospital course variables that were analyzed included demographics, comorbidities, length of stay, number of procedures, index operation times, duration of postoperative bed rest, use of mechanical prophylaxis, and type of chemoprophylaxis and time frame within which it was initiated. Data were collected via chart review using International Classification of Diseases-9 and -10 codes to identify surgical cases within the allotted time period who were diagnosed with VTE. Demographic variables included age, sex, and ethnicity. Comorbidities included hypertension, diabetes, coronary artery disease, serious lung disease, previous or current malignancy, documented hypercoagulable state, and previous history of VTE. Body mass index (BMI) was also recorded. The aforementioned disease-specific variables were not matched between the case and control groups, as this data was obtained retrospectively during data collection.

Analysis

Associations between case and matched control were analyzed using the paired t-test for continuous variables and McNemar’s test for categorical variables. P values < 0.05 were considered statistically significant. SAS Enterprise Guide 7.15 (Cary, NC) was used for all statistical analyses.

The requirement for informed consent was waived by our Institutional Review Board, as the study was initially deemed to be a quality improvement project, and all data used for this report were de-identified.

Results

Our retrospective case-control analysis included a sample of 102 surgical patients whose courses were complicated by VTE between September 2012 and October 2015. The cases were distributed among 6 different surgical categories (Figure 1): trauma (20%), cancer (10%), cardiovascular (21%), noncancer neurosurgery (28%), elective orthopedics (11%), and miscellaneous general surgery (10%).

Comparisons between cases and controls in terms of patient demographics and risk factors are shown in Table 2. No statistically significant difference was observed in ethnicity or race between the 2 groups. Overall, cases had more hip/pelvis/leg fractures at presentation (P = 0.0008). The case group also had higher proportions of patients with postoperative bed rest greater than 12 hours (P = 0.009), central venous access (P < 0.0001), infection (P < 0.0001), and lower extremity edema documented during the hospitalization prior to development of DVT (P < 0.0001). Additionally, cases had significantly greater rates of previous VTE (P = 0.0004), inherited or acquired thrombophilia (P = 0.03), history of stroke (P = 0.0003), and severe lung disease, including pneumonia (P = 0.0008). No significant differences were noted between cases and matched controls in BMI (P = 0.43), current tobacco use (P = 0.71), current malignancy (P = 0.80), previous malignancy (P = 0.83), head trauma (P = 0.17), or acute cardiac disease (myocardial infarction or congestive heart failure; P = 0.12).

Variables felt to indicate overall complexity of hospital course for cases as compared to controls are outlined in Table 3. Cases were found to have significantly longer lengths of stay (median, 15.5 days versus 3 days, P < 0.0001). To account for the possibility that the development of VTE contributed to the increased length of stay in the cases, we also looked at the duration between admission date and the date of VTE diagnosis and determined that cases still had a longer length of stay when this was accounted for (median, 7 days versus 3 days, P < 0.0001). A much higher proportion of cases underwent more than 1 procedure compared to controls (P < 0.0001), and cases had significantly longer index operations as compared to controls (P = 0.002).

Seventeen cases received heparin on induction during their index procedure, compared to 23 controls (P = 0.24). Additionally, 63 cases began a prophylaxis regimen within 24 hours of surgery end time, compared to 68 controls (P = 0.24). The chemoprophylactic regimens utilized in cases and in controls are summarized in Figure 2. Of note, only 26 cases and 32 controls received standard prophylactic regimens with no missed doses (heparin 5000 units 3 times daily or enoxaparin 40 mg daily). Additionally, in over half of cases and a third of controls, nonstandard regimens were ordered. Examples of nonstandard regimens included nonstandard heparin or enoxaparin doses, low-dose warfarin, or aspirin alone. In most cases, nonstandard regimens were justified on the basis of high risk for bleeding.

Mechanical prophylaxis with pneumatic sequential compression devices (SCDs) was ordered in 93 (91%) cases and 87 (85%) controls; however, we were unable to accurately document uniform compliance in the use of these devices.

With regard to evaluation of our process measures, we found only 17% of cases and controls combined actually had a VTE risk assessment in their chart, and when it was present, it was often incomplete or was completed inaccurately.

Discussion

The goal of this study was to identify factors (patient characteristics and/or processes of care) that may be contributing to the higher than expected incidence of VTE events at our medical center, despite internal audits suggesting near perfect compliance with SCIP-mandated protocols. We found that in addition to usual risk factors for VTE, an overarching theme of our case cohort was their high complexity of illness. At baseline, these patients had significantly greater rates of stroke, thrombophilia, severe lung disease, infection, and history of VTE than controls. Moreover, the hospital courses of cases were significantly more complex than those of controls, as these patients had more procedures, longer lengths of stay and longer index operations, higher rates of postoperative bed rest exceeding 12 hours, and more prevalent central venous access than controls (Table 2). Several of these risk factors have been found to contribute to VTE development despite compliance with prophylaxis protocols.

Cassidy et al reviewed a cohort of nontrauma general surgery patients who developed VTE despite receiving appropriate prophylaxis and found that both multiple operations and emergency procedures contributed to the failure of VTE prophylaxis.¹¹ Similarly, Wang et al identified several independent risk factors for VTE despite thromboprophylaxis, including central venous access and infection, as well as intensive care unit admission, hospitalization for cranial surgery, and admission from a long-term care facility.¹² While our study did not capture some of these additional factors considered by Wang et al, the presence of risk factors not captured in traditional assessment tools suggests that additional consideration for complex patients is warranted.

In addition to these nonmodifiable patient characteristics, aspects of our VTE prophylaxis processes likely contributed to the higher than expected rate of VTE. While the electronic medical record at our institution does contain a VTE risk assessment tool based on the Caprini score, we found it often is not used at all or is used incorrectly/incompletely, which likely reflects the fact that physicians are neither prompted nor required to complete the assessment prior to prescribing VTE prophylaxis.

There is a significant body of evidence demonstrating that mandatory computerized VTE risk assessments can effectively reduce VTE rates and that improved outcomes occur shortly after implementation. Cassidy et al demonstrated the benefits of instituting a hospital-wide, mandatory, Caprini-based computerized VTE risk assessment that provides prophylaxis/early ambulation recommendations. Two years after implementing this system, they observed an 84% reduction in DVTs (P < 0.001) and a 55% reduction in PEs (P < 0.001).¹³ Nimeri et al had similarly impressive success, achieving a reduction in their NSQIP O/E for PE/DVT in general surgery from 6.00 in 2010 to 0.82 (for DVTs) and 0.78 (for PEs) 5 years after implementation of mandatory VTE risk assessment (though they noted that the most dramatic reduction occurred 1 year after implementation).¹⁴ Additionally, a recent systematic review and meta-analysis by Borab et al found computerized VTE risk assessments to be associated with a significant decrease in VTE events.¹⁵

The risk assessment tool used at our institution is qualitative in nature, and current literature suggests that employing a more quantitative tool may yield improved outcomes. Numerous studies have highlighted the importance of identifying patients at very high risk for VTE, as higher risk may necessitate more careful consideration of their prophylactic regimens. Obi et al found patients with Caprini scores higher than 8 to be at significantly greater risk of developing VTE compared to patients with scores of 7 or 8. Also, patients with scores of 7 or 8 were significantly more likely to have a VTE compared to those with scores of 5 or 6.¹⁶ In another study, Lobastov et al identified Caprini scores of 11 or higher as representing an extremely high-risk category for which standard prophylaxis regimens may not be effective.¹⁷ Thus, while having mandatory risk assessment has been shown to dramatically decrease VTE incidence, it is important to consider the magnitude of the numerical risk score. This is of particular importance at medical centers with high case-mix indices where patients at the highest risk might need to be managed with different prophylactic guidelines.

Another notable aspect of the process at our hospital was the great variation in the types of prophylactic regimens ordered, and the adherence to what was ordered. Only 25.5% of patients were maintained on a standard prophylactic regimen with no missed doses (heparin 5000 every 8 hours or enoxaparin 40 mg daily). Thus, the vast majority of the patients who went on to develop VTE either were prescribed a nontraditional prophylaxis regimen or missed doses of standard agents. The need for secondary surgical procedures or other invasive interventions may explain many, but not all, of the missed doses.

The timing of prophylaxis initiation for our patients was also found to deviate from accepted standards. Only 16.8% of cases received prophylaxis upon induction of anesthesia, and furthermore, 38% of cases did not receive any anticoagulation within 24 hours of their index operation. While this variability in prophylaxis implementation was acceptable within the SCIP guidelines based on “high risk for bleeding” or other considerations, it likely contributed to our suboptimal outcomes. The variations and interruptions in prophylactic regimens speak to barriers that have previously been reported as contributing factors to noncompliance with VTE prophylaxis.¹⁸

Given these known barriers and the observed underutilization and improper use of our risk assessment tool, we have recently changed our surgical admission order sets such that a mandatory quantitative risk assessment must be done for every surgical patient at the time of admission/operation before other orders can be completed. Following completion of the assessment, the physician will be presented with an appropriate standard regimen based on the individual patient’s risk assessment. Early results of our VTE quality improvement project have been satisfying: in the most recent NSQIP semi-annual report, our O/E for VTE was 0.74, placing us in the first decile. Some of these early reports may simply be the product of the Hawthorne effect; however, we are encouraged by the early improvements seen in other research. While we are hopeful that these changes will result in sustainable improvements in outcomes, patients at extremely high risk may require novel weight-based or otherwise customized aggressive prophylactic regimens. Such regimens have already been proposed for arthroplasty and other high-risk patients.

Future research may identify other risk factors not captured by traditional risk assessments. In addition, research should continue to explore the use and efficacy of standard prophylactic regimens in these populations to help determine if they are sufficient. Currently, weight-based low-molecular-weight heparin dosing and alternative regimens employing fondaparinux are under investigation for very-high-risk patients.¹⁹

There were several limitations to the present study. First, due to the retrospective design of our study, we could collect only data that had been uniformly recorded in the charts throughout the study period. Second, we were unable to accurately assess compliance with mechanical prophylaxis. While our chart review showed that the vast majority of cases and controls were ordered to have mechanical prophylaxis, it is impossible to document how often these devices were used appropriately in a retrospective analysis. Anecdotal observation suggests that once patients are out of post-anesthesia or critical care units, SCD use is not standardized. The inability to measure compliance precisely may be leading to an overestimation of our compliance with prophylaxis. Finally, because our study included only patients who underwent surgery at our hospital, our observations may not be generalizable outside our institution.

Conclusion

Our study findings reinforce the importance of attention to detail in VTE risk assessment and in ordering and administering VTE prophylactic regimens, especially in high-risk surgical patients. While we adhered to the SCIP-mandated prophylaxis requirements, the complexity of our patients and our lack of a truly standardized approach to risk assessment and prophylactic regimens resulted in suboptimal outcomes. Stricter and more quantitative mandatory VTE risk assessment, along with highly standardized VTE prophylaxis regimens, are required to achieve optimal outcomes.

Corresponding author: Jason C. DeGiovanni, MS, BA, [email protected].

Financial disclosures: None.

From Tufts Medical Center, Boston, MA.

Abstract

• Objective: Audits at our academic medical center revealed near 100% compliance with protocols for perioperative venous thromboembolism (VTE) prophylaxis, but recent National Surgical Quality Improvement Program data demonstrated a higher than expected incidence of VTE (observed/expected = 1.32). The objective of this study was to identify potential causes of this discrepancy.
• Design: Retrospective case-control study.
• Setting: Urban academic medical center with high case-mix indices (Medicare approximately 2.4, non-Medicare approximately 2.0).
• Participants: 102 surgical inpatients with VTE (September 2012 to October 2015) matched with controls for age, gender, and type of procedure.
• Measurements: Prevalence of common VTE risk factors, length of stay, number of procedures, index operation times, and postoperative bed rest > 12 hours were assessed. Utilization of and compliance with our VTE risk assessment tool was also investigated.
• Results: Cases underwent more procedures and had longer lengths of stay and index procedures than controls. In addition, cases were more likely to have had > 12 hours of postoperative bed rest and central venous access than controls. Cases had more infections and were more likely to have severe lung disease, thrombophilia, and a history of prior VTE than controls. No differences in body mass index, tobacco use, current or previous malignancy, or VTE risk assessment form use were observed. Overall, care complexity and risk factors were equally important in determining VTE incidence. Our analyses also revealed lack of strict adherence to our VTE risk stratification protocol and frequent use of suboptimal prophylactic regimens.
• Conclusion: Well-accepted risk factors and overall care complexity determine VTE risk. Preventing VTE in high-risk patients requires assiduous attention to detail in VTE risk assessment and in delivery of optimal prophylaxis. Patients at especially high risk may require customized prophylactic regimens.

Keywords: hospital-acquired venous thromboembolic disease; VTE prophylaxis, surgical patients.

Deep vein thrombosis (DVT) and pulmonary embolism (PE) are well-recognized causes of morbidity and mortality in surgical patients. Between 350,000 and 600,000 cases of venous thromboembolism (VTE) occur each year in the United States, and it is responsible for approximately 10% of preventable in-hospital fatalities.^1-3 Given VTE’s impact on patients and the healthcare system and the fact that it is preventable, intense effort has been focused on developing more effective prophylactic measures to decrease its incidence.^2-4 In 2008, the surgeon general issued a “call to action” for increased efforts to prevent VTE.⁵

The American College of Chest Physicians (ACCP) guidelines subcategorize patients based on type of surgery. In addition, the ACCP guidelines support the use of a Caprini-based scoring system to aid in risk stratification and improve clinical decision-making (Table 1).^4,6-9 In general, scores ≥ 5 qualify individuals as high risk. Based on their risk category, patients receive mechanical prophylaxis, chemical prophylaxis, or a combination of the 2. Lower-risk patients who are ambulatory typically receive only mechanical prophylaxis while in bed, whereas higher-risk patients receive a combination of mechanical prophylaxis and chemoprophylaxis measures.⁷ In general, low-molecular-weight heparin (40 mg daily) and low-dose unfractionated heparin (5000 units 3 times daily) have been the standard evidence-based options for chemoprophylaxis in surgical patients. Absolute contraindications for prophylaxis include active bleeding and known increased risk of bleeding based on patient- or procedure-specific factors.

Our hospital, a 350-bed academic medical center in downtown Boston, MA, serving a diverse population with a very high case-mix index (2.4 Medicare and 2.0 non-Medicare), has strict protocols for VTE prophylaxis consistent with the ACCP guidelines and based on the Surgical Care Improvement Project (SCIP) measures published in 2006.¹⁰ The SCIP mandates allow for considerable surgeon discretion in the use of chemoprophylaxis for neurosurgical cases and general and orthopedic surgery cases deemed to be at high risk for bleeding. In addition, SCIP requires only that prophylaxis be initiated within 24 hours of surgical end time. Although recent audits revealed nearly 100% compliance with SCIP-mandated protocols, National Surgical Quality Improvement Program (NSQIP) data showed that the incidence of VTE events at our institution was higher than expected (observed/expected [O/E] = 1.32).

In order to determine the reasons for this mismatch between process and outcome performance, we investigated whether there were characteristics of our patient population that contributed to the higher than expected rates of VTE, and we scrutinized our VTE prophylaxis protocol to determine if there were aspects of our process that were also contributory.

Methods

Study Sample

This is a retrospective case-control study of surgical inpatients at our hospital during the period September 2012 to October 2015. Cases were identified as patients diagnosed with a VTE (DVT or PE). Controls were identified from a pool of surgical patients whose courses were not complicated by VTE during the same time frame as the cases and who were matched as closely as possible by procedure code, age, and gender.

Patient and hospital course variables that were analyzed included demographics, comorbidities, length of stay, number of procedures, index operation times, duration of postoperative bed rest, use of mechanical prophylaxis, and type of chemoprophylaxis and time frame within which it was initiated. Data were collected via chart review using International Classification of Diseases-9 and -10 codes to identify surgical cases within the allotted time period who were diagnosed with VTE. Demographic variables included age, sex, and ethnicity. Comorbidities included hypertension, diabetes, coronary artery disease, serious lung disease, previous or current malignancy, documented hypercoagulable state, and previous history of VTE. Body mass index (BMI) was also recorded. The aforementioned disease-specific variables were not matched between the case and control groups, as this data was obtained retrospectively during data collection.

Analysis

Associations between case and matched control were analyzed using the paired t-test for continuous variables and McNemar’s test for categorical variables. P values < 0.05 were considered statistically significant. SAS Enterprise Guide 7.15 (Cary, NC) was used for all statistical analyses.

The requirement for informed consent was waived by our Institutional Review Board, as the study was initially deemed to be a quality improvement project, and all data used for this report were de-identified.

Results

Our retrospective case-control analysis included a sample of 102 surgical patients whose courses were complicated by VTE between September 2012 and October 2015. The cases were distributed among 6 different surgical categories (Figure 1): trauma (20%), cancer (10%), cardiovascular (21%), noncancer neurosurgery (28%), elective orthopedics (11%), and miscellaneous general surgery (10%).

Comparisons between cases and controls in terms of patient demographics and risk factors are shown in Table 2. No statistically significant difference was observed in ethnicity or race between the 2 groups. Overall, cases had more hip/pelvis/leg fractures at presentation (P = 0.0008). The case group also had higher proportions of patients with postoperative bed rest greater than 12 hours (P = 0.009), central venous access (P < 0.0001), infection (P < 0.0001), and lower extremity edema documented during the hospitalization prior to development of DVT (P < 0.0001). Additionally, cases had significantly greater rates of previous VTE (P = 0.0004), inherited or acquired thrombophilia (P = 0.03), history of stroke (P = 0.0003), and severe lung disease, including pneumonia (P = 0.0008). No significant differences were noted between cases and matched controls in BMI (P = 0.43), current tobacco use (P = 0.71), current malignancy (P = 0.80), previous malignancy (P = 0.83), head trauma (P = 0.17), or acute cardiac disease (myocardial infarction or congestive heart failure; P = 0.12).

Variables felt to indicate overall complexity of hospital course for cases as compared to controls are outlined in Table 3. Cases were found to have significantly longer lengths of stay (median, 15.5 days versus 3 days, P < 0.0001). To account for the possibility that the development of VTE contributed to the increased length of stay in the cases, we also looked at the duration between admission date and the date of VTE diagnosis and determined that cases still had a longer length of stay when this was accounted for (median, 7 days versus 3 days, P < 0.0001). A much higher proportion of cases underwent more than 1 procedure compared to controls (P < 0.0001), and cases had significantly longer index operations as compared to controls (P = 0.002).

Seventeen cases received heparin on induction during their index procedure, compared to 23 controls (P = 0.24). Additionally, 63 cases began a prophylaxis regimen within 24 hours of surgery end time, compared to 68 controls (P = 0.24). The chemoprophylactic regimens utilized in cases and in controls are summarized in Figure 2. Of note, only 26 cases and 32 controls received standard prophylactic regimens with no missed doses (heparin 5000 units 3 times daily or enoxaparin 40 mg daily). Additionally, in over half of cases and a third of controls, nonstandard regimens were ordered. Examples of nonstandard regimens included nonstandard heparin or enoxaparin doses, low-dose warfarin, or aspirin alone. In most cases, nonstandard regimens were justified on the basis of high risk for bleeding.

Mechanical prophylaxis with pneumatic sequential compression devices (SCDs) was ordered in 93 (91%) cases and 87 (85%) controls; however, we were unable to accurately document uniform compliance in the use of these devices.

With regard to evaluation of our process measures, we found only 17% of cases and controls combined actually had a VTE risk assessment in their chart, and when it was present, it was often incomplete or was completed inaccurately.

Discussion

The goal of this study was to identify factors (patient characteristics and/or processes of care) that may be contributing to the higher than expected incidence of VTE events at our medical center, despite internal audits suggesting near perfect compliance with SCIP-mandated protocols. We found that in addition to usual risk factors for VTE, an overarching theme of our case cohort was their high complexity of illness. At baseline, these patients had significantly greater rates of stroke, thrombophilia, severe lung disease, infection, and history of VTE than controls. Moreover, the hospital courses of cases were significantly more complex than those of controls, as these patients had more procedures, longer lengths of stay and longer index operations, higher rates of postoperative bed rest exceeding 12 hours, and more prevalent central venous access than controls (Table 2). Several of these risk factors have been found to contribute to VTE development despite compliance with prophylaxis protocols.

Cassidy et al reviewed a cohort of nontrauma general surgery patients who developed VTE despite receiving appropriate prophylaxis and found that both multiple operations and emergency procedures contributed to the failure of VTE prophylaxis.¹¹ Similarly, Wang et al identified several independent risk factors for VTE despite thromboprophylaxis, including central venous access and infection, as well as intensive care unit admission, hospitalization for cranial surgery, and admission from a long-term care facility.¹² While our study did not capture some of these additional factors considered by Wang et al, the presence of risk factors not captured in traditional assessment tools suggests that additional consideration for complex patients is warranted.

In addition to these nonmodifiable patient characteristics, aspects of our VTE prophylaxis processes likely contributed to the higher than expected rate of VTE. While the electronic medical record at our institution does contain a VTE risk assessment tool based on the Caprini score, we found it often is not used at all or is used incorrectly/incompletely, which likely reflects the fact that physicians are neither prompted nor required to complete the assessment prior to prescribing VTE prophylaxis.

There is a significant body of evidence demonstrating that mandatory computerized VTE risk assessments can effectively reduce VTE rates and that improved outcomes occur shortly after implementation. Cassidy et al demonstrated the benefits of instituting a hospital-wide, mandatory, Caprini-based computerized VTE risk assessment that provides prophylaxis/early ambulation recommendations. Two years after implementing this system, they observed an 84% reduction in DVTs (P < 0.001) and a 55% reduction in PEs (P < 0.001).¹³ Nimeri et al had similarly impressive success, achieving a reduction in their NSQIP O/E for PE/DVT in general surgery from 6.00 in 2010 to 0.82 (for DVTs) and 0.78 (for PEs) 5 years after implementation of mandatory VTE risk assessment (though they noted that the most dramatic reduction occurred 1 year after implementation).¹⁴ Additionally, a recent systematic review and meta-analysis by Borab et al found computerized VTE risk assessments to be associated with a significant decrease in VTE events.¹⁵

The risk assessment tool used at our institution is qualitative in nature, and current literature suggests that employing a more quantitative tool may yield improved outcomes. Numerous studies have highlighted the importance of identifying patients at very high risk for VTE, as higher risk may necessitate more careful consideration of their prophylactic regimens. Obi et al found patients with Caprini scores higher than 8 to be at significantly greater risk of developing VTE compared to patients with scores of 7 or 8. Also, patients with scores of 7 or 8 were significantly more likely to have a VTE compared to those with scores of 5 or 6.¹⁶ In another study, Lobastov et al identified Caprini scores of 11 or higher as representing an extremely high-risk category for which standard prophylaxis regimens may not be effective.¹⁷ Thus, while having mandatory risk assessment has been shown to dramatically decrease VTE incidence, it is important to consider the magnitude of the numerical risk score. This is of particular importance at medical centers with high case-mix indices where patients at the highest risk might need to be managed with different prophylactic guidelines.

Another notable aspect of the process at our hospital was the great variation in the types of prophylactic regimens ordered, and the adherence to what was ordered. Only 25.5% of patients were maintained on a standard prophylactic regimen with no missed doses (heparin 5000 every 8 hours or enoxaparin 40 mg daily). Thus, the vast majority of the patients who went on to develop VTE either were prescribed a nontraditional prophylaxis regimen or missed doses of standard agents. The need for secondary surgical procedures or other invasive interventions may explain many, but not all, of the missed doses.

The timing of prophylaxis initiation for our patients was also found to deviate from accepted standards. Only 16.8% of cases received prophylaxis upon induction of anesthesia, and furthermore, 38% of cases did not receive any anticoagulation within 24 hours of their index operation. While this variability in prophylaxis implementation was acceptable within the SCIP guidelines based on “high risk for bleeding” or other considerations, it likely contributed to our suboptimal outcomes. The variations and interruptions in prophylactic regimens speak to barriers that have previously been reported as contributing factors to noncompliance with VTE prophylaxis.¹⁸

Given these known barriers and the observed underutilization and improper use of our risk assessment tool, we have recently changed our surgical admission order sets such that a mandatory quantitative risk assessment must be done for every surgical patient at the time of admission/operation before other orders can be completed. Following completion of the assessment, the physician will be presented with an appropriate standard regimen based on the individual patient’s risk assessment. Early results of our VTE quality improvement project have been satisfying: in the most recent NSQIP semi-annual report, our O/E for VTE was 0.74, placing us in the first decile. Some of these early reports may simply be the product of the Hawthorne effect; however, we are encouraged by the early improvements seen in other research. While we are hopeful that these changes will result in sustainable improvements in outcomes, patients at extremely high risk may require novel weight-based or otherwise customized aggressive prophylactic regimens. Such regimens have already been proposed for arthroplasty and other high-risk patients.

Future research may identify other risk factors not captured by traditional risk assessments. In addition, research should continue to explore the use and efficacy of standard prophylactic regimens in these populations to help determine if they are sufficient. Currently, weight-based low-molecular-weight heparin dosing and alternative regimens employing fondaparinux are under investigation for very-high-risk patients.¹⁹

There were several limitations to the present study. First, due to the retrospective design of our study, we could collect only data that had been uniformly recorded in the charts throughout the study period. Second, we were unable to accurately assess compliance with mechanical prophylaxis. While our chart review showed that the vast majority of cases and controls were ordered to have mechanical prophylaxis, it is impossible to document how often these devices were used appropriately in a retrospective analysis. Anecdotal observation suggests that once patients are out of post-anesthesia or critical care units, SCD use is not standardized. The inability to measure compliance precisely may be leading to an overestimation of our compliance with prophylaxis. Finally, because our study included only patients who underwent surgery at our hospital, our observations may not be generalizable outside our institution.

Conclusion

Our study findings reinforce the importance of attention to detail in VTE risk assessment and in ordering and administering VTE prophylactic regimens, especially in high-risk surgical patients. While we adhered to the SCIP-mandated prophylaxis requirements, the complexity of our patients and our lack of a truly standardized approach to risk assessment and prophylactic regimens resulted in suboptimal outcomes. Stricter and more quantitative mandatory VTE risk assessment, along with highly standardized VTE prophylaxis regimens, are required to achieve optimal outcomes.

Corresponding author: Jason C. DeGiovanni, MS, BA, [email protected].

Financial disclosures: None.

CHICAGO – In 2014, the average time from diagnosis to treatment initiation for new cancer patients at the Cleveland Clinic was 29-41 days, depending on whether the patient was diagnosed internally or externally. That figure was not acceptable, said Brian J. Bolwell, MD, chairman of the Cleveland Clinic’s Taussig Cancer Institute.

Since then, the time-to-treat metric has improved dramatically, dropping 33%. Today, time to treat for new cancer patients is 25-31 days, depending on the site of diagnosis.

To get there, leaders at the cancer center examined the causes of delay within each of their disease programs. The analysis revealed that less than 20% of the time it was patient preferences that slowed down the initiation of treatment, but that more than 80% of the time the delay was on the part of their institution.

Dr. Bolwell said this led them to start tracking every newly diagnosed patient who came through the cancer center to ensure they didn’t fall through the cracks, and that they were treated as rapidly as possible.

But figuring out how to get patients to treatment quicker depended on the type of cancer they had, since each type of cancer had different challenges and different points of entry to the health care system.

“So for breast cancer, it turns out a lot of the challenges might be coordination of surgery because sometimes a general surgeon has to work with a reconstructive-plastic surgeon and coordinating the surgical schedules might drastically lengthen time to treat,” he said during an interview at the annual meeting of the American Society of Clinical Oncology.

They helped address that problem by scheduling breast cancer patients for surgery by the next available operating room slot, rather than doing the scheduling by surgeon.

There are additional barriers to achieving a rapid time to treat standard, including prior authorization, Dr. Bolwell said. But they are continuing to chip away at the metric, working within each cancer type to lower the obstacles to treatment. “I don’t think we’ll ever be satisfied with where we are,” Dr. Bolwell said.

Dr. Bolwell reported having no relevant financial disclosures.

[email protected]

CHICAGO – In 2014, the average time from diagnosis to treatment initiation for new cancer patients at the Cleveland Clinic was 29-41 days, depending on whether the patient was diagnosed internally or externally. That figure was not acceptable, said Brian J. Bolwell, MD, chairman of the Cleveland Clinic’s Taussig Cancer Institute.

Since then, the time-to-treat metric has improved dramatically, dropping 33%. Today, time to treat for new cancer patients is 25-31 days, depending on the site of diagnosis.

To get there, leaders at the cancer center examined the causes of delay within each of their disease programs. The analysis revealed that less than 20% of the time it was patient preferences that slowed down the initiation of treatment, but that more than 80% of the time the delay was on the part of their institution.

Dr. Bolwell said this led them to start tracking every newly diagnosed patient who came through the cancer center to ensure they didn’t fall through the cracks, and that they were treated as rapidly as possible.

But figuring out how to get patients to treatment quicker depended on the type of cancer they had, since each type of cancer had different challenges and different points of entry to the health care system.

“So for breast cancer, it turns out a lot of the challenges might be coordination of surgery because sometimes a general surgeon has to work with a reconstructive-plastic surgeon and coordinating the surgical schedules might drastically lengthen time to treat,” he said during an interview at the annual meeting of the American Society of Clinical Oncology.

They helped address that problem by scheduling breast cancer patients for surgery by the next available operating room slot, rather than doing the scheduling by surgeon.

There are additional barriers to achieving a rapid time to treat standard, including prior authorization, Dr. Bolwell said. But they are continuing to chip away at the metric, working within each cancer type to lower the obstacles to treatment. “I don’t think we’ll ever be satisfied with where we are,” Dr. Bolwell said.

Dr. Bolwell reported having no relevant financial disclosures.

[email protected]

CHICAGO – In 2014, the average time from diagnosis to treatment initiation for new cancer patients at the Cleveland Clinic was 29-41 days, depending on whether the patient was diagnosed internally or externally. That figure was not acceptable, said Brian J. Bolwell, MD, chairman of the Cleveland Clinic’s Taussig Cancer Institute.

Since then, the time-to-treat metric has improved dramatically, dropping 33%. Today, time to treat for new cancer patients is 25-31 days, depending on the site of diagnosis.

To get there, leaders at the cancer center examined the causes of delay within each of their disease programs. The analysis revealed that less than 20% of the time it was patient preferences that slowed down the initiation of treatment, but that more than 80% of the time the delay was on the part of their institution.

Dr. Bolwell said this led them to start tracking every newly diagnosed patient who came through the cancer center to ensure they didn’t fall through the cracks, and that they were treated as rapidly as possible.

But figuring out how to get patients to treatment quicker depended on the type of cancer they had, since each type of cancer had different challenges and different points of entry to the health care system.

“So for breast cancer, it turns out a lot of the challenges might be coordination of surgery because sometimes a general surgeon has to work with a reconstructive-plastic surgeon and coordinating the surgical schedules might drastically lengthen time to treat,” he said during an interview at the annual meeting of the American Society of Clinical Oncology.

They helped address that problem by scheduling breast cancer patients for surgery by the next available operating room slot, rather than doing the scheduling by surgeon.

There are additional barriers to achieving a rapid time to treat standard, including prior authorization, Dr. Bolwell said. But they are continuing to chip away at the metric, working within each cancer type to lower the obstacles to treatment. “I don’t think we’ll ever be satisfied with where we are,” Dr. Bolwell said.

Dr. Bolwell reported having no relevant financial disclosures.

[email protected]

Should clinicians abandon the activated partial thromboplastin time (aPTT) for monitoring heparin therapy in favor of tests that measure the activity of the patient’s plasma against activated factor X (anti-Xa assays)?

Although other anticoagulants are now available for preventing and treating arterial and venous thromboembolism, unfractionated heparin—which requires laboratory monitoring of therapy—is still widely used. And this monitoring can be challenging. Despite its wide use, the aPTT lacks standardization, and the role of alternative monitoring assays such as the anti-Xa assay is not well defined.

This article reviews the advantages, limitations, and clinical applicability of anti-Xa assays for monitoring therapy with unfractionated heparin and other anticoagulants.

UNFRACTIONATED HEPARIN AND WARFARIN ARE STILL WIDELY USED

Until the mid-1990s, unfractionated heparin and oral vitamin K antagonists (eg, warfarin) were the only anticoagulants widely available for clinical use. These agents have complex pharmacokinetic and pharmacodynamic properties, resulting in highly variable dosing requirements (both between patients and in individual patients) and narrow therapeutic windows, making frequent laboratory monitoring and dose adjustments mandatory.

Over the past 3 decades, other anticoagulants have been approved, including low-molecular-weight heparins, fondaparinux, parenteral direct thrombin inhibitors, and direct oral anticoagulants. While these agents have expanded the options for preventing and treating thromboembolism, unfractionated heparin and warfarin are still the most appropriate choices for many patients, eg, those with stage 4 chronic kidney disease and end-stage renal disease on dialysis, and those with mechanical heart valves.

In addition, unfractionated heparin remains the anticoagulant of choice during procedures such as hemodialysis, percutaneous transluminal angioplasty, and cardiopulmonary bypass, as well as in hospitalized and critically ill patients, who often have acute kidney injury or require frequent interruptions of therapy for invasive procedures. In these scenarios, unfractionated heparin is typically preferred because of its short plasma half-life, complete reversibility by protamine, safety regardless of renal function, and low cost compared with parenteral direct thrombin inhibitors.

As long as unfractionated heparin and warfarin remain important therapies, the need for their laboratory monitoring continues. For warfarin monitoring, the prothrombin time and international normalized ratio are validated and widely reproducible methods. But monitoring unfractionated heparin therapy remains a challenge.

UNFRACTIONATED HEPARIN’S EFFECT IS UNPREDICTABLE

Unfractionated heparin, a negatively charged mucopolysaccharide, inhibits coagulation by binding to antithrombin through the high-affinity pentasaccharide sequence.^1–6 Such binding induces a conformational change in the antithrombin molecule, converting it to a rapid inhibitor of several coagulation proteins, especially factors IIa and Xa.^2–4

Unfractionated heparin inhibits factors IIa and Xa in a 1:1 ratio, but low-molecular-weight heparins inhibit factor Xa more than factor IIa, with IIa-Xa inhibition ratios ranging from 1:2 to 1:4, owing to their smaller molecular size.⁷

One of the most important reasons for the unpredictable and highly variable individual responses to unfractionated heparin is that, infused into the blood, the large and negatively charged unfractionated heparin molecules bind nonspecifically to positively charged plasma proteins.⁷ In patients who are critically ill, have acute infections or inflammatory states, or have undergone major surgery, unfractionated heparin binds to acute-phase proteins that are elevated, particularly factor VIII. This results in fewer free heparin molecules and a variable anticoagulant effect.⁸

In contrast, low-molecular-weight heparins have longer half-lives and bind less to plasma proteins, resulting in more predictable plasma levels following subcutaneous injection.⁹

In 1960, Barritt and Jordan¹⁰ conducted a small but landmark trial that established the clinical importance of unfractionated heparin for treating venous thromboembolism. None of the patients who received unfractionated heparin for acute pulmonary embolism developed a recurrence during the subsequent 2 weeks, while 50% of those who did not receive it had recurrent pulmonary embolism, fatal in half of the cases.

The importance of achieving a specific aPTT therapeutic target was not demonstrated until a 1972 study by Basu et al,¹¹ in which 162 patients with venous thromboembolism were treated with heparin with a target aPTT of 1.5 to 2.5 times the control value. Patients who suffered recurrent events had subtherapeutic aPTT values on 71% of treatment days, while the rest of the patients, with no recurrences, had subtherapeutic aPTT values only 28% of treatment days. The different outcomes could not be explained by the average daily dose of unfractionated heparin, which was similar in the patients regardless of recurrence.

Subsequent studies showed that the best outcomes occur when unfractionated heparin is given in doses high enough to rapidly achieve a therapeutic prolongation of the aPTT,^12–14 and that the total daily dose is also important in preventing recurrences.^15,16 Failure to achieve a target aPTT within 24 hours of starting unfractionated heparin is associated with increased risk of recurrent venous thromboembolism.^13,17

Raschke et al¹⁷ found that patients prospectively randomized to weight-based doses of intravenous unfractionated heparin (bolus plus infusion) achieved significantly higher rates of therapeutic aPTT within 6 hours and 24 hours after starting the infusion, and had significantly lower rates of recurrent venous thromboembolism than those randomized to a fixed unfractionated heparin protocol, without an increase in major bleeding.

Smith et al,¹⁸ in a study of 400 consecutive patients with acute pulmonary embolism treated with unfractionated heparin, found that patients who achieved a therapeutic aPTT within 24 hours had lower in-hospital and 30-day mortality rates than those who did not achieve the first therapeutic aPTT until more than 24 hours after starting unfractionated heparin infusion.

Such data lend support to the widely accepted practice and current guideline recommendation⁸ of using laboratory assays to adjust the dose of unfractionated heparin to achieve and maintain a therapeutic target. The use of dosing nomograms significantly reduces the time to achieve a therapeutic aPTT while minimizing subtherapeutic and supratherapeutic unfractionated heparin levels.^19,20

THE aPTT REFLECTS THROMBIN INHIBITION

The aPTT has a log-linear relationship with plasma concentrations of unfractionated heparin,²¹ but it was not developed specifically for monitoring unfractionated heparin therapy. Originally described in 1953 as a screening tool for hemophilia,^22–24 the aPTT is prolonged in the setting of factor deficiencies (typically with levels < 45%, except for factors VII and XIII), as well as lupus anticoagulants and therapy with parenteral direct thrombin inhibitors.^8,25,26

Because thrombin (factor IIa) is 10 times more sensitive than factor Xa to inhibition by the heparin-antithrombin complex,^4,7 thrombin inhibition appears to be the most likely mechanism by which unfractionated heparin prolongs the aPTT. In contrast, aPTT is minimally or not at all prolonged by low-molecular-weight heparins, which are predominantly factor Xa inhibitors.⁷

HEPARIN ASSAYS MEASURE UNFRACTIONATED HEPARIN ACTIVITY

While the aPTT is a surrogate marker of unfractionated heparin activity in plasma, unfractionated heparin activity can be measured more precisely by so-called heparin assays, which are typically not direct measures of the plasma concentration of heparins, but rather functional assays that provide indirect estimates. They include protamine sulfate titration assays and anti-Xa assays.

Protamine sulfate titration assays measure the amount of protamine sulfate required to neutralize heparin: the more protamine required, the greater the estimated concentration of unfractionated heparin in plasma.^8,27–29 Protamine titration assays are technically demanding, so they are rarely used clinically.

Anti-Xa assays provide a measure of the functional level of heparins in plasma.^29–33 Chromogenic anti-Xa assays are available on automated analyzers with standardized kits^29,33,34 and may be faster to perform than the aPTT.³⁵

Experiments in rabbits show that unfractionated heparin inhibits thrombus formation and extension at concentrations of 0.2 to 0.4 U/mL as measured by the protamine titration assay,²⁷ which correlated with an anti-Xa activity of 0.35 to 0.67 U/mL in a randomized controlled trial.³²

Assays that directly measure the plasma concentration of heparin exist but are not clinically relevant because they also measure heparin molecules lacking the pentasaccharide sequence, which have no anticoagulant activity.³⁶

Anti-Xa assays are more expensive than the aPTT and are not available in all hospitals. For these reasons, the aPTT remains the most commonly used laboratory assay for monitoring unfractionated heparin therapy.

However, the aPTT correlates poorly with the activity level of unfractionated heparin in plasma. In one study, an anti-Xa level of 0.3 U/mL corresponded to aPTT results ranging from 47 to 108 seconds.³¹ Furthermore, in studies that used a heparin therapeutic target based on an aPTT ratio 1.5 to 2.5 times the control aPTT value, the lower end of that target range was often associated with subtherapeutic plasma unfractionated heparin activity measured by anti-Xa and protamine titration assays.^28,31

Because of these limitations, individual laboratories should determine their own aPTT therapeutic target ranges for unfractionated heparin based on the response curves obtained with the reagent and coagulometer used. The optimal therapeutic aPTT range for treating acute venous thromboembolism should be defined as the aPTT range (in seconds) that correlates with a plasma activity level of unfractionated heparin of 0.3 to 0.7 U/mL based on a chromogenic anti-Xa assay, or 0.2 to 0.4 U/mL based on a protamine titration assay.^32,34–36

Nevertheless, the anticoagulant effect of unfractionated heparin as measured by the aPTT can be unpredictable and can vary widely among individuals and in the same patient.⁷ This wide variability can be explained by a number of technical and biologic variables. Different commercial aPTT reagents, different lots of the same reagent, and different reagent and instrument combinations have different sensitivities to unfractionated heparin, which can lead to variable aPTT results.³⁷ Moreover, high plasma levels of acute-phase proteins, low plasma antithrombin levels, consumptive coagulopathies, liver failure, and lupus anticoagulants may also affect the aPTT.^{7,25,32,36–41} These variables account for the poor correlation—ranging from 25% to 66%—reported between aPTT and anti-Xa assays.^32,42–48

Such discrepancies may have serious clinical implications: if a patient’s aPTT is low (subtherapeutic) or high (supratherapeutic) but the anti-Xa assay result is within the therapeutic range (0.3–0.7 units/mL), changing the dose of unfractionated heparin (guided by an aPTT nomogram) may increase the risk of bleeding or of recurrent thromboembolism.

CLINICAL APPLICABILITY OF THE ANTI-Xa ASSAY

Neither anti-Xa nor protamine titration assays are standardized across reference laboratories, but chromogenic anti-Xa assays have better interlaboratory correlation than the aPTT^49,50 and can be calibrated specifically for unfractionated or low-molecular-weight heparins.^29,33

Although reagent costs are higher for chromogenic anti-Xa assays than for the aPTT, some technical variables (described below) may partially offset the cost difference.^29,33,41 In addition, unlike the aPTT, anti-Xa assays do not need local calibration; the therapeutic range for unfractionated heparin is the same (0.3–0.7 U/mL) regardless of instrument or reagent.^33,41

Most important, studies have found that patients monitored by anti-Xa assay achieve significantly higher rates of therapeutic anticoagulation within 24 and 48 hours after starting unfractionated heparin infusion than those monitored by the aPTT. Fewer dose adjustments and repeat tests are required, which may also result in lower cost.^32,51–55

While these studies found chromogenic anti-Xa assays better for achieving laboratory end points, data regarding relevant clinical outcomes are more limited. In a retrospective, observational cohort study,⁵¹ the rate of venous thromboembolism or bleeding-related death was 2% in patients receiving unfractionated heparin therapy monitored by anti-Xa assay and 6% in patients monitored by aPTT (P = .62). Rates of major hemorrhage were also not significantly different.

In a randomized controlled trial³² in 131 patients with acute venous thromboembolism and heparin resistance, rates of recurrent venous thromboembolism were 4.6% and 6.1% in the groups randomized to anti-Xa and aPTT monitoring, respectively, whereas overall bleeding rates were 1.5% and 6.1%, respectively. Again, the differences were not statistically significant.

Heparin resistance. Some patients require unusually high doses of unfractionated heparin to achieve a therapeutic aPTT: typically, more than 35,000 U over 24 hours,^7,8,32 or total daily doses that exceed their estimated weight-based requirements. Heparin resistance has been observed in various clinical settings.^{7,8,32,37–40,59–61} Patients with heparin resistance monitored by anti-Xa had similar rates of recurrent venous thromboembolism while receiving significantly lower doses of unfractionated heparin than those monitored by the aPTT.³²

Lupus anticoagulant. Patients with the specific antiphospholipid antibody known as lupus anticoagulant frequently have a prolonged baseline aPTT,²⁵ making it an unreliable marker of anticoagulant effect for intravenous unfractionated heparin therapy.

Critically ill infants and children. Arachchillage et al³⁵ found that infants (< 1 year old) treated with intravenous unfractionated heparin in an intensive care department had only a 32.4% correlation between aPTT and anti-Xa levels, which was lower than that found in children ages 1 to 15 (66%) and adults (52%). In two-thirds of cases of discordant aPTT and anti-Xa levels, the aPTT was elevated (supratherapeutic) while the anti-Xa assay was within the therapeutic range (0.3–0.7 U/mL). Despite the lack of data on clinical outcomes (eg, rates of thrombosis and bleeding) with the use of an anti-Xa assay, it has been considered the method of choice for unfractionated heparin monitoring in critically ill children, and especially in those under age 1.^{41,44,62–64}

While anti-Xa assays may also be better for unfractionated heparin monitoring in critically ill adults, the lack of clinical outcome data from large-scale randomized trials has precluded evidence-based recommendations favoring them over the aPTT.^8,34

Anti-Xa assays are hampered by some technical limitations:

Samples must be processed within 1 hour to avoid heparin neutralization.³⁴

Samples must be clear. Hemolyzed or opaque samples (eg, due to bilirubin levels > 6.6 mg/dL or triglyceride levels > 360 mg/dL) cannot be processed, as they can cause falsely low levels.

Exposure to other anticoagulants can interfere with the results. The anti-Xa assay may be unreliable for unfractionated heparin monitoring in patients who are transitioned from low-molecular-weight heparins, fondaparinux, or an oral factor Xa inhibitor (apixaban, betrixaban, edoxaban, rivaroxaban) to intravenous unfractionated heparin, eg, due to hospitalization or acute kidney injury.^65,66 Different reports have found that anti-Xa assays may be elevated for as long as 63 to 96 hours after the last dose of oral Xa inhibitors,^67–69 potentially resulting in underdosing of unfractionated heparin. In such settings, unfractionated heparin therapy should be monitored by the aPTT.

ANTI-Xa ASSAYS AND LOW-MOLECULAR-WEIGHT HEPARINS

Most patients receiving low-molecular-weight heparins do not need laboratory monitoring.⁸ Alhenc-Gelas et al⁷⁰ randomized patients to receive dalteparin in doses either based on weight or guided by anti-Xa assay results, and found that dose adjustments were rare and lacked clinical benefit.

The suggested therapeutic anti-Xa levels for low-molecular-weight heparins are:

• 0.5–1.2 U/mL for twice-daily enoxaparin
• 1.0–2.0 U/mL for once-daily enoxaparin or dalteparin.

Levels should be measured at peak plasma level (ie, 3–4 hours after subcutaneous injection, except during pregnancy, when it is 4–6 hours), and only after at least 3 doses of low-molecular-weight heparin.^8,71 Unlike the anti-Xa therapeutic range recommended for unfractionated heparin therapy, these ranges are not based on prospective data, and if the assay result is outside the suggested therapeutic target range, current guidelines offer no advice on safely adjusting the dose.^8,71

Measuring anti-Xa activity is particularly important for pregnant women with a mechanical prosthetic heart valve who are treated with low-molecular-weight heparins. In this setting, valve thrombosis and cardioembolic events have been reported in patients with peak low-molecular-weight heparin anti-Xa assay levels below or even at the lower end of the therapeutic range, and increased bleeding risk has been reported with elevated anti-Xa levels.^71–74 Measuring trough low-molecular-weight heparin anti-Xa levels has been suggested to guide dose adjustments during pregnancy.⁷⁵

Clearance of low-molecular-weight heparins as measured by the anti-Xa assay is highly correlated with creatinine clearance.^76,77 A strong linear correlation has been demonstrated between creatine clearance and anti-Xa levels of enoxaparin after multiple therapeutic doses, and low-molecular-weight heparins accumulate in the plasma, especially in patients with creatine clearance less than 30 mL/min.⁷⁸ The risk of major bleeding is significantly increased in patients with severe renal insufficiency (creatinine clearance < 30 mL/min) not on dialysis who are treated with either prophylactic or therapeutic doses of low-molecular-weight heparin.^79–81 In a meta-analysis, the risk of bleeding with therapeutic-intensity doses of enoxaparin was 4 times higher than with prophylactic-intensity doses.⁷⁹ Although bleeding risk appears to be reduced when the enoxaparin dose is reduced by 50%,⁸ the efficacy and safety of this strategy has not been determined by prospective trials.

ANTI-Xa ASSAYS IN PATIENTS RECEIVING DIRECT ORAL ANTICOAGULANTS

Direct oral factor Xa inhibitors cannot be measured accurately by heparin anti-Xa assays. Nevertheless, such assays may be useful to assess whether clinically relevant plasma levels are present in cases of major bleeding, suspected anticoagulant failure, or patient noncompliance.⁸²

Intense research has focused on developing drug-specific chromogenic anti-Xa assays using calibrators and standards for apixaban, edoxaban, and rivaroxaban,^82,83 and good linear correlation has been shown with some assays.^82,84 In patients treated with oral factor Xa inhibitors who need to undergo an urgent invasive procedure associated with high bleeding risk, use of a specific reversal agent may be considered with drug concentrations more than 30 ng/mL measured by a drug-specific anti-Xa assay. A similar suggestion has been made for drug concentrations more than 50 ng/mL in the setting of major bleeding.⁸⁵ Unfortunately, such assays are not widely available at this time.^82,86

While drug-specific anti-Xa assays could become clinically important to guide reversal strategies, their relevance for drug monitoring remains uncertain. This is because no therapeutic target ranges have been established for any of the direct oral anticoagulants, which were approved on the basis of favorable clinical trial outcomes that neither measured nor were correlated with specific drug levels in plasma. Therefore, a specific anti-Xa level cannot yet be used as a marker of clinical efficacy for any specific oral direct Xa inhibitor.

Should clinicians abandon the activated partial thromboplastin time (aPTT) for monitoring heparin therapy in favor of tests that measure the activity of the patient’s plasma against activated factor X (anti-Xa assays)?

Although other anticoagulants are now available for preventing and treating arterial and venous thromboembolism, unfractionated heparin—which requires laboratory monitoring of therapy—is still widely used. And this monitoring can be challenging. Despite its wide use, the aPTT lacks standardization, and the role of alternative monitoring assays such as the anti-Xa assay is not well defined.

This article reviews the advantages, limitations, and clinical applicability of anti-Xa assays for monitoring therapy with unfractionated heparin and other anticoagulants.

UNFRACTIONATED HEPARIN AND WARFARIN ARE STILL WIDELY USED

Until the mid-1990s, unfractionated heparin and oral vitamin K antagonists (eg, warfarin) were the only anticoagulants widely available for clinical use. These agents have complex pharmacokinetic and pharmacodynamic properties, resulting in highly variable dosing requirements (both between patients and in individual patients) and narrow therapeutic windows, making frequent laboratory monitoring and dose adjustments mandatory.

Over the past 3 decades, other anticoagulants have been approved, including low-molecular-weight heparins, fondaparinux, parenteral direct thrombin inhibitors, and direct oral anticoagulants. While these agents have expanded the options for preventing and treating thromboembolism, unfractionated heparin and warfarin are still the most appropriate choices for many patients, eg, those with stage 4 chronic kidney disease and end-stage renal disease on dialysis, and those with mechanical heart valves.

In addition, unfractionated heparin remains the anticoagulant of choice during procedures such as hemodialysis, percutaneous transluminal angioplasty, and cardiopulmonary bypass, as well as in hospitalized and critically ill patients, who often have acute kidney injury or require frequent interruptions of therapy for invasive procedures. In these scenarios, unfractionated heparin is typically preferred because of its short plasma half-life, complete reversibility by protamine, safety regardless of renal function, and low cost compared with parenteral direct thrombin inhibitors.

As long as unfractionated heparin and warfarin remain important therapies, the need for their laboratory monitoring continues. For warfarin monitoring, the prothrombin time and international normalized ratio are validated and widely reproducible methods. But monitoring unfractionated heparin therapy remains a challenge.

UNFRACTIONATED HEPARIN’S EFFECT IS UNPREDICTABLE

Unfractionated heparin, a negatively charged mucopolysaccharide, inhibits coagulation by binding to antithrombin through the high-affinity pentasaccharide sequence.^1–6 Such binding induces a conformational change in the antithrombin molecule, converting it to a rapid inhibitor of several coagulation proteins, especially factors IIa and Xa.^2–4

Unfractionated heparin inhibits factors IIa and Xa in a 1:1 ratio, but low-molecular-weight heparins inhibit factor Xa more than factor IIa, with IIa-Xa inhibition ratios ranging from 1:2 to 1:4, owing to their smaller molecular size.⁷

One of the most important reasons for the unpredictable and highly variable individual responses to unfractionated heparin is that, infused into the blood, the large and negatively charged unfractionated heparin molecules bind nonspecifically to positively charged plasma proteins.⁷ In patients who are critically ill, have acute infections or inflammatory states, or have undergone major surgery, unfractionated heparin binds to acute-phase proteins that are elevated, particularly factor VIII. This results in fewer free heparin molecules and a variable anticoagulant effect.⁸

In contrast, low-molecular-weight heparins have longer half-lives and bind less to plasma proteins, resulting in more predictable plasma levels following subcutaneous injection.⁹

In 1960, Barritt and Jordan¹⁰ conducted a small but landmark trial that established the clinical importance of unfractionated heparin for treating venous thromboembolism. None of the patients who received unfractionated heparin for acute pulmonary embolism developed a recurrence during the subsequent 2 weeks, while 50% of those who did not receive it had recurrent pulmonary embolism, fatal in half of the cases.

The importance of achieving a specific aPTT therapeutic target was not demonstrated until a 1972 study by Basu et al,¹¹ in which 162 patients with venous thromboembolism were treated with heparin with a target aPTT of 1.5 to 2.5 times the control value. Patients who suffered recurrent events had subtherapeutic aPTT values on 71% of treatment days, while the rest of the patients, with no recurrences, had subtherapeutic aPTT values only 28% of treatment days. The different outcomes could not be explained by the average daily dose of unfractionated heparin, which was similar in the patients regardless of recurrence.

Subsequent studies showed that the best outcomes occur when unfractionated heparin is given in doses high enough to rapidly achieve a therapeutic prolongation of the aPTT,^12–14 and that the total daily dose is also important in preventing recurrences.^15,16 Failure to achieve a target aPTT within 24 hours of starting unfractionated heparin is associated with increased risk of recurrent venous thromboembolism.^13,17

Raschke et al¹⁷ found that patients prospectively randomized to weight-based doses of intravenous unfractionated heparin (bolus plus infusion) achieved significantly higher rates of therapeutic aPTT within 6 hours and 24 hours after starting the infusion, and had significantly lower rates of recurrent venous thromboembolism than those randomized to a fixed unfractionated heparin protocol, without an increase in major bleeding.

Smith et al,¹⁸ in a study of 400 consecutive patients with acute pulmonary embolism treated with unfractionated heparin, found that patients who achieved a therapeutic aPTT within 24 hours had lower in-hospital and 30-day mortality rates than those who did not achieve the first therapeutic aPTT until more than 24 hours after starting unfractionated heparin infusion.

Such data lend support to the widely accepted practice and current guideline recommendation⁸ of using laboratory assays to adjust the dose of unfractionated heparin to achieve and maintain a therapeutic target. The use of dosing nomograms significantly reduces the time to achieve a therapeutic aPTT while minimizing subtherapeutic and supratherapeutic unfractionated heparin levels.^19,20

THE aPTT REFLECTS THROMBIN INHIBITION

The aPTT has a log-linear relationship with plasma concentrations of unfractionated heparin,²¹ but it was not developed specifically for monitoring unfractionated heparin therapy. Originally described in 1953 as a screening tool for hemophilia,^22–24 the aPTT is prolonged in the setting of factor deficiencies (typically with levels < 45%, except for factors VII and XIII), as well as lupus anticoagulants and therapy with parenteral direct thrombin inhibitors.^8,25,26

Because thrombin (factor IIa) is 10 times more sensitive than factor Xa to inhibition by the heparin-antithrombin complex,^4,7 thrombin inhibition appears to be the most likely mechanism by which unfractionated heparin prolongs the aPTT. In contrast, aPTT is minimally or not at all prolonged by low-molecular-weight heparins, which are predominantly factor Xa inhibitors.⁷

HEPARIN ASSAYS MEASURE UNFRACTIONATED HEPARIN ACTIVITY

While the aPTT is a surrogate marker of unfractionated heparin activity in plasma, unfractionated heparin activity can be measured more precisely by so-called heparin assays, which are typically not direct measures of the plasma concentration of heparins, but rather functional assays that provide indirect estimates. They include protamine sulfate titration assays and anti-Xa assays.

Protamine sulfate titration assays measure the amount of protamine sulfate required to neutralize heparin: the more protamine required, the greater the estimated concentration of unfractionated heparin in plasma.^8,27–29 Protamine titration assays are technically demanding, so they are rarely used clinically.

Anti-Xa assays provide a measure of the functional level of heparins in plasma.^29–33 Chromogenic anti-Xa assays are available on automated analyzers with standardized kits^29,33,34 and may be faster to perform than the aPTT.³⁵

Experiments in rabbits show that unfractionated heparin inhibits thrombus formation and extension at concentrations of 0.2 to 0.4 U/mL as measured by the protamine titration assay,²⁷ which correlated with an anti-Xa activity of 0.35 to 0.67 U/mL in a randomized controlled trial.³²

Assays that directly measure the plasma concentration of heparin exist but are not clinically relevant because they also measure heparin molecules lacking the pentasaccharide sequence, which have no anticoagulant activity.³⁶

Anti-Xa assays are more expensive than the aPTT and are not available in all hospitals. For these reasons, the aPTT remains the most commonly used laboratory assay for monitoring unfractionated heparin therapy.

However, the aPTT correlates poorly with the activity level of unfractionated heparin in plasma. In one study, an anti-Xa level of 0.3 U/mL corresponded to aPTT results ranging from 47 to 108 seconds.³¹ Furthermore, in studies that used a heparin therapeutic target based on an aPTT ratio 1.5 to 2.5 times the control aPTT value, the lower end of that target range was often associated with subtherapeutic plasma unfractionated heparin activity measured by anti-Xa and protamine titration assays.^28,31

Because of these limitations, individual laboratories should determine their own aPTT therapeutic target ranges for unfractionated heparin based on the response curves obtained with the reagent and coagulometer used. The optimal therapeutic aPTT range for treating acute venous thromboembolism should be defined as the aPTT range (in seconds) that correlates with a plasma activity level of unfractionated heparin of 0.3 to 0.7 U/mL based on a chromogenic anti-Xa assay, or 0.2 to 0.4 U/mL based on a protamine titration assay.^32,34–36

Nevertheless, the anticoagulant effect of unfractionated heparin as measured by the aPTT can be unpredictable and can vary widely among individuals and in the same patient.⁷ This wide variability can be explained by a number of technical and biologic variables. Different commercial aPTT reagents, different lots of the same reagent, and different reagent and instrument combinations have different sensitivities to unfractionated heparin, which can lead to variable aPTT results.³⁷ Moreover, high plasma levels of acute-phase proteins, low plasma antithrombin levels, consumptive coagulopathies, liver failure, and lupus anticoagulants may also affect the aPTT.^{7,25,32,36–41} These variables account for the poor correlation—ranging from 25% to 66%—reported between aPTT and anti-Xa assays.^32,42–48

Such discrepancies may have serious clinical implications: if a patient’s aPTT is low (subtherapeutic) or high (supratherapeutic) but the anti-Xa assay result is within the therapeutic range (0.3–0.7 units/mL), changing the dose of unfractionated heparin (guided by an aPTT nomogram) may increase the risk of bleeding or of recurrent thromboembolism.

CLINICAL APPLICABILITY OF THE ANTI-Xa ASSAY

Neither anti-Xa nor protamine titration assays are standardized across reference laboratories, but chromogenic anti-Xa assays have better interlaboratory correlation than the aPTT^49,50 and can be calibrated specifically for unfractionated or low-molecular-weight heparins.^29,33

Although reagent costs are higher for chromogenic anti-Xa assays than for the aPTT, some technical variables (described below) may partially offset the cost difference.^29,33,41 In addition, unlike the aPTT, anti-Xa assays do not need local calibration; the therapeutic range for unfractionated heparin is the same (0.3–0.7 U/mL) regardless of instrument or reagent.^33,41

Most important, studies have found that patients monitored by anti-Xa assay achieve significantly higher rates of therapeutic anticoagulation within 24 and 48 hours after starting unfractionated heparin infusion than those monitored by the aPTT. Fewer dose adjustments and repeat tests are required, which may also result in lower cost.^32,51–55

While these studies found chromogenic anti-Xa assays better for achieving laboratory end points, data regarding relevant clinical outcomes are more limited. In a retrospective, observational cohort study,⁵¹ the rate of venous thromboembolism or bleeding-related death was 2% in patients receiving unfractionated heparin therapy monitored by anti-Xa assay and 6% in patients monitored by aPTT (P = .62). Rates of major hemorrhage were also not significantly different.

In a randomized controlled trial³² in 131 patients with acute venous thromboembolism and heparin resistance, rates of recurrent venous thromboembolism were 4.6% and 6.1% in the groups randomized to anti-Xa and aPTT monitoring, respectively, whereas overall bleeding rates were 1.5% and 6.1%, respectively. Again, the differences were not statistically significant.

Heparin resistance. Some patients require unusually high doses of unfractionated heparin to achieve a therapeutic aPTT: typically, more than 35,000 U over 24 hours,^7,8,32 or total daily doses that exceed their estimated weight-based requirements. Heparin resistance has been observed in various clinical settings.^{7,8,32,37–40,59–61} Patients with heparin resistance monitored by anti-Xa had similar rates of recurrent venous thromboembolism while receiving significantly lower doses of unfractionated heparin than those monitored by the aPTT.³²

Lupus anticoagulant. Patients with the specific antiphospholipid antibody known as lupus anticoagulant frequently have a prolonged baseline aPTT,²⁵ making it an unreliable marker of anticoagulant effect for intravenous unfractionated heparin therapy.

Critically ill infants and children. Arachchillage et al³⁵ found that infants (< 1 year old) treated with intravenous unfractionated heparin in an intensive care department had only a 32.4% correlation between aPTT and anti-Xa levels, which was lower than that found in children ages 1 to 15 (66%) and adults (52%). In two-thirds of cases of discordant aPTT and anti-Xa levels, the aPTT was elevated (supratherapeutic) while the anti-Xa assay was within the therapeutic range (0.3–0.7 U/mL). Despite the lack of data on clinical outcomes (eg, rates of thrombosis and bleeding) with the use of an anti-Xa assay, it has been considered the method of choice for unfractionated heparin monitoring in critically ill children, and especially in those under age 1.^{41,44,62–64}

While anti-Xa assays may also be better for unfractionated heparin monitoring in critically ill adults, the lack of clinical outcome data from large-scale randomized trials has precluded evidence-based recommendations favoring them over the aPTT.^8,34

Anti-Xa assays are hampered by some technical limitations:

Samples must be processed within 1 hour to avoid heparin neutralization.³⁴

Samples must be clear. Hemolyzed or opaque samples (eg, due to bilirubin levels > 6.6 mg/dL or triglyceride levels > 360 mg/dL) cannot be processed, as they can cause falsely low levels.

Exposure to other anticoagulants can interfere with the results. The anti-Xa assay may be unreliable for unfractionated heparin monitoring in patients who are transitioned from low-molecular-weight heparins, fondaparinux, or an oral factor Xa inhibitor (apixaban, betrixaban, edoxaban, rivaroxaban) to intravenous unfractionated heparin, eg, due to hospitalization or acute kidney injury.^65,66 Different reports have found that anti-Xa assays may be elevated for as long as 63 to 96 hours after the last dose of oral Xa inhibitors,^67–69 potentially resulting in underdosing of unfractionated heparin. In such settings, unfractionated heparin therapy should be monitored by the aPTT.

ANTI-Xa ASSAYS AND LOW-MOLECULAR-WEIGHT HEPARINS

Most patients receiving low-molecular-weight heparins do not need laboratory monitoring.⁸ Alhenc-Gelas et al⁷⁰ randomized patients to receive dalteparin in doses either based on weight or guided by anti-Xa assay results, and found that dose adjustments were rare and lacked clinical benefit.

The suggested therapeutic anti-Xa levels for low-molecular-weight heparins are:

• 0.5–1.2 U/mL for twice-daily enoxaparin
• 1.0–2.0 U/mL for once-daily enoxaparin or dalteparin.

Levels should be measured at peak plasma level (ie, 3–4 hours after subcutaneous injection, except during pregnancy, when it is 4–6 hours), and only after at least 3 doses of low-molecular-weight heparin.^8,71 Unlike the anti-Xa therapeutic range recommended for unfractionated heparin therapy, these ranges are not based on prospective data, and if the assay result is outside the suggested therapeutic target range, current guidelines offer no advice on safely adjusting the dose.^8,71

Measuring anti-Xa activity is particularly important for pregnant women with a mechanical prosthetic heart valve who are treated with low-molecular-weight heparins. In this setting, valve thrombosis and cardioembolic events have been reported in patients with peak low-molecular-weight heparin anti-Xa assay levels below or even at the lower end of the therapeutic range, and increased bleeding risk has been reported with elevated anti-Xa levels.^71–74 Measuring trough low-molecular-weight heparin anti-Xa levels has been suggested to guide dose adjustments during pregnancy.⁷⁵

Clearance of low-molecular-weight heparins as measured by the anti-Xa assay is highly correlated with creatinine clearance.^76,77 A strong linear correlation has been demonstrated between creatine clearance and anti-Xa levels of enoxaparin after multiple therapeutic doses, and low-molecular-weight heparins accumulate in the plasma, especially in patients with creatine clearance less than 30 mL/min.⁷⁸ The risk of major bleeding is significantly increased in patients with severe renal insufficiency (creatinine clearance < 30 mL/min) not on dialysis who are treated with either prophylactic or therapeutic doses of low-molecular-weight heparin.^79–81 In a meta-analysis, the risk of bleeding with therapeutic-intensity doses of enoxaparin was 4 times higher than with prophylactic-intensity doses.⁷⁹ Although bleeding risk appears to be reduced when the enoxaparin dose is reduced by 50%,⁸ the efficacy and safety of this strategy has not been determined by prospective trials.

ANTI-Xa ASSAYS IN PATIENTS RECEIVING DIRECT ORAL ANTICOAGULANTS

Direct oral factor Xa inhibitors cannot be measured accurately by heparin anti-Xa assays. Nevertheless, such assays may be useful to assess whether clinically relevant plasma levels are present in cases of major bleeding, suspected anticoagulant failure, or patient noncompliance.⁸²

Intense research has focused on developing drug-specific chromogenic anti-Xa assays using calibrators and standards for apixaban, edoxaban, and rivaroxaban,^82,83 and good linear correlation has been shown with some assays.^82,84 In patients treated with oral factor Xa inhibitors who need to undergo an urgent invasive procedure associated with high bleeding risk, use of a specific reversal agent may be considered with drug concentrations more than 30 ng/mL measured by a drug-specific anti-Xa assay. A similar suggestion has been made for drug concentrations more than 50 ng/mL in the setting of major bleeding.⁸⁵ Unfortunately, such assays are not widely available at this time.^82,86

While drug-specific anti-Xa assays could become clinically important to guide reversal strategies, their relevance for drug monitoring remains uncertain. This is because no therapeutic target ranges have been established for any of the direct oral anticoagulants, which were approved on the basis of favorable clinical trial outcomes that neither measured nor were correlated with specific drug levels in plasma. Therefore, a specific anti-Xa level cannot yet be used as a marker of clinical efficacy for any specific oral direct Xa inhibitor.

Should clinicians abandon the activated partial thromboplastin time (aPTT) for monitoring heparin therapy in favor of tests that measure the activity of the patient’s plasma against activated factor X (anti-Xa assays)?

Although other anticoagulants are now available for preventing and treating arterial and venous thromboembolism, unfractionated heparin—which requires laboratory monitoring of therapy—is still widely used. And this monitoring can be challenging. Despite its wide use, the aPTT lacks standardization, and the role of alternative monitoring assays such as the anti-Xa assay is not well defined.

This article reviews the advantages, limitations, and clinical applicability of anti-Xa assays for monitoring therapy with unfractionated heparin and other anticoagulants.

UNFRACTIONATED HEPARIN AND WARFARIN ARE STILL WIDELY USED

Until the mid-1990s, unfractionated heparin and oral vitamin K antagonists (eg, warfarin) were the only anticoagulants widely available for clinical use. These agents have complex pharmacokinetic and pharmacodynamic properties, resulting in highly variable dosing requirements (both between patients and in individual patients) and narrow therapeutic windows, making frequent laboratory monitoring and dose adjustments mandatory.

Over the past 3 decades, other anticoagulants have been approved, including low-molecular-weight heparins, fondaparinux, parenteral direct thrombin inhibitors, and direct oral anticoagulants. While these agents have expanded the options for preventing and treating thromboembolism, unfractionated heparin and warfarin are still the most appropriate choices for many patients, eg, those with stage 4 chronic kidney disease and end-stage renal disease on dialysis, and those with mechanical heart valves.

In addition, unfractionated heparin remains the anticoagulant of choice during procedures such as hemodialysis, percutaneous transluminal angioplasty, and cardiopulmonary bypass, as well as in hospitalized and critically ill patients, who often have acute kidney injury or require frequent interruptions of therapy for invasive procedures. In these scenarios, unfractionated heparin is typically preferred because of its short plasma half-life, complete reversibility by protamine, safety regardless of renal function, and low cost compared with parenteral direct thrombin inhibitors.

As long as unfractionated heparin and warfarin remain important therapies, the need for their laboratory monitoring continues. For warfarin monitoring, the prothrombin time and international normalized ratio are validated and widely reproducible methods. But monitoring unfractionated heparin therapy remains a challenge.

UNFRACTIONATED HEPARIN’S EFFECT IS UNPREDICTABLE

Unfractionated heparin, a negatively charged mucopolysaccharide, inhibits coagulation by binding to antithrombin through the high-affinity pentasaccharide sequence.^1–6 Such binding induces a conformational change in the antithrombin molecule, converting it to a rapid inhibitor of several coagulation proteins, especially factors IIa and Xa.^2–4

Unfractionated heparin inhibits factors IIa and Xa in a 1:1 ratio, but low-molecular-weight heparins inhibit factor Xa more than factor IIa, with IIa-Xa inhibition ratios ranging from 1:2 to 1:4, owing to their smaller molecular size.⁷

One of the most important reasons for the unpredictable and highly variable individual responses to unfractionated heparin is that, infused into the blood, the large and negatively charged unfractionated heparin molecules bind nonspecifically to positively charged plasma proteins.⁷ In patients who are critically ill, have acute infections or inflammatory states, or have undergone major surgery, unfractionated heparin binds to acute-phase proteins that are elevated, particularly factor VIII. This results in fewer free heparin molecules and a variable anticoagulant effect.⁸

In contrast, low-molecular-weight heparins have longer half-lives and bind less to plasma proteins, resulting in more predictable plasma levels following subcutaneous injection.⁹

In 1960, Barritt and Jordan¹⁰ conducted a small but landmark trial that established the clinical importance of unfractionated heparin for treating venous thromboembolism. None of the patients who received unfractionated heparin for acute pulmonary embolism developed a recurrence during the subsequent 2 weeks, while 50% of those who did not receive it had recurrent pulmonary embolism, fatal in half of the cases.

The importance of achieving a specific aPTT therapeutic target was not demonstrated until a 1972 study by Basu et al,¹¹ in which 162 patients with venous thromboembolism were treated with heparin with a target aPTT of 1.5 to 2.5 times the control value. Patients who suffered recurrent events had subtherapeutic aPTT values on 71% of treatment days, while the rest of the patients, with no recurrences, had subtherapeutic aPTT values only 28% of treatment days. The different outcomes could not be explained by the average daily dose of unfractionated heparin, which was similar in the patients regardless of recurrence.

Subsequent studies showed that the best outcomes occur when unfractionated heparin is given in doses high enough to rapidly achieve a therapeutic prolongation of the aPTT,^12–14 and that the total daily dose is also important in preventing recurrences.^15,16 Failure to achieve a target aPTT within 24 hours of starting unfractionated heparin is associated with increased risk of recurrent venous thromboembolism.^13,17

Raschke et al¹⁷ found that patients prospectively randomized to weight-based doses of intravenous unfractionated heparin (bolus plus infusion) achieved significantly higher rates of therapeutic aPTT within 6 hours and 24 hours after starting the infusion, and had significantly lower rates of recurrent venous thromboembolism than those randomized to a fixed unfractionated heparin protocol, without an increase in major bleeding.

Smith et al,¹⁸ in a study of 400 consecutive patients with acute pulmonary embolism treated with unfractionated heparin, found that patients who achieved a therapeutic aPTT within 24 hours had lower in-hospital and 30-day mortality rates than those who did not achieve the first therapeutic aPTT until more than 24 hours after starting unfractionated heparin infusion.

Such data lend support to the widely accepted practice and current guideline recommendation⁸ of using laboratory assays to adjust the dose of unfractionated heparin to achieve and maintain a therapeutic target. The use of dosing nomograms significantly reduces the time to achieve a therapeutic aPTT while minimizing subtherapeutic and supratherapeutic unfractionated heparin levels.^19,20

THE aPTT REFLECTS THROMBIN INHIBITION

The aPTT has a log-linear relationship with plasma concentrations of unfractionated heparin,²¹ but it was not developed specifically for monitoring unfractionated heparin therapy. Originally described in 1953 as a screening tool for hemophilia,^22–24 the aPTT is prolonged in the setting of factor deficiencies (typically with levels < 45%, except for factors VII and XIII), as well as lupus anticoagulants and therapy with parenteral direct thrombin inhibitors.^8,25,26

Because thrombin (factor IIa) is 10 times more sensitive than factor Xa to inhibition by the heparin-antithrombin complex,^4,7 thrombin inhibition appears to be the most likely mechanism by which unfractionated heparin prolongs the aPTT. In contrast, aPTT is minimally or not at all prolonged by low-molecular-weight heparins, which are predominantly factor Xa inhibitors.⁷

HEPARIN ASSAYS MEASURE UNFRACTIONATED HEPARIN ACTIVITY

While the aPTT is a surrogate marker of unfractionated heparin activity in plasma, unfractionated heparin activity can be measured more precisely by so-called heparin assays, which are typically not direct measures of the plasma concentration of heparins, but rather functional assays that provide indirect estimates. They include protamine sulfate titration assays and anti-Xa assays.

Protamine sulfate titration assays measure the amount of protamine sulfate required to neutralize heparin: the more protamine required, the greater the estimated concentration of unfractionated heparin in plasma.^8,27–29 Protamine titration assays are technically demanding, so they are rarely used clinically.

Anti-Xa assays provide a measure of the functional level of heparins in plasma.^29–33 Chromogenic anti-Xa assays are available on automated analyzers with standardized kits^29,33,34 and may be faster to perform than the aPTT.³⁵

Experiments in rabbits show that unfractionated heparin inhibits thrombus formation and extension at concentrations of 0.2 to 0.4 U/mL as measured by the protamine titration assay,²⁷ which correlated with an anti-Xa activity of 0.35 to 0.67 U/mL in a randomized controlled trial.³²

Assays that directly measure the plasma concentration of heparin exist but are not clinically relevant because they also measure heparin molecules lacking the pentasaccharide sequence, which have no anticoagulant activity.³⁶

Anti-Xa assays are more expensive than the aPTT and are not available in all hospitals. For these reasons, the aPTT remains the most commonly used laboratory assay for monitoring unfractionated heparin therapy.

However, the aPTT correlates poorly with the activity level of unfractionated heparin in plasma. In one study, an anti-Xa level of 0.3 U/mL corresponded to aPTT results ranging from 47 to 108 seconds.³¹ Furthermore, in studies that used a heparin therapeutic target based on an aPTT ratio 1.5 to 2.5 times the control aPTT value, the lower end of that target range was often associated with subtherapeutic plasma unfractionated heparin activity measured by anti-Xa and protamine titration assays.^28,31

Because of these limitations, individual laboratories should determine their own aPTT therapeutic target ranges for unfractionated heparin based on the response curves obtained with the reagent and coagulometer used. The optimal therapeutic aPTT range for treating acute venous thromboembolism should be defined as the aPTT range (in seconds) that correlates with a plasma activity level of unfractionated heparin of 0.3 to 0.7 U/mL based on a chromogenic anti-Xa assay, or 0.2 to 0.4 U/mL based on a protamine titration assay.^32,34–36

Nevertheless, the anticoagulant effect of unfractionated heparin as measured by the aPTT can be unpredictable and can vary widely among individuals and in the same patient.⁷ This wide variability can be explained by a number of technical and biologic variables. Different commercial aPTT reagents, different lots of the same reagent, and different reagent and instrument combinations have different sensitivities to unfractionated heparin, which can lead to variable aPTT results.³⁷ Moreover, high plasma levels of acute-phase proteins, low plasma antithrombin levels, consumptive coagulopathies, liver failure, and lupus anticoagulants may also affect the aPTT.^{7,25,32,36–41} These variables account for the poor correlation—ranging from 25% to 66%—reported between aPTT and anti-Xa assays.^32,42–48

Such discrepancies may have serious clinical implications: if a patient’s aPTT is low (subtherapeutic) or high (supratherapeutic) but the anti-Xa assay result is within the therapeutic range (0.3–0.7 units/mL), changing the dose of unfractionated heparin (guided by an aPTT nomogram) may increase the risk of bleeding or of recurrent thromboembolism.

CLINICAL APPLICABILITY OF THE ANTI-Xa ASSAY

Neither anti-Xa nor protamine titration assays are standardized across reference laboratories, but chromogenic anti-Xa assays have better interlaboratory correlation than the aPTT^49,50 and can be calibrated specifically for unfractionated or low-molecular-weight heparins.^29,33

Although reagent costs are higher for chromogenic anti-Xa assays than for the aPTT, some technical variables (described below) may partially offset the cost difference.^29,33,41 In addition, unlike the aPTT, anti-Xa assays do not need local calibration; the therapeutic range for unfractionated heparin is the same (0.3–0.7 U/mL) regardless of instrument or reagent.^33,41

Most important, studies have found that patients monitored by anti-Xa assay achieve significantly higher rates of therapeutic anticoagulation within 24 and 48 hours after starting unfractionated heparin infusion than those monitored by the aPTT. Fewer dose adjustments and repeat tests are required, which may also result in lower cost.^32,51–55

While these studies found chromogenic anti-Xa assays better for achieving laboratory end points, data regarding relevant clinical outcomes are more limited. In a retrospective, observational cohort study,⁵¹ the rate of venous thromboembolism or bleeding-related death was 2% in patients receiving unfractionated heparin therapy monitored by anti-Xa assay and 6% in patients monitored by aPTT (P = .62). Rates of major hemorrhage were also not significantly different.

In a randomized controlled trial³² in 131 patients with acute venous thromboembolism and heparin resistance, rates of recurrent venous thromboembolism were 4.6% and 6.1% in the groups randomized to anti-Xa and aPTT monitoring, respectively, whereas overall bleeding rates were 1.5% and 6.1%, respectively. Again, the differences were not statistically significant.

Heparin resistance. Some patients require unusually high doses of unfractionated heparin to achieve a therapeutic aPTT: typically, more than 35,000 U over 24 hours,^7,8,32 or total daily doses that exceed their estimated weight-based requirements. Heparin resistance has been observed in various clinical settings.^{7,8,32,37–40,59–61} Patients with heparin resistance monitored by anti-Xa had similar rates of recurrent venous thromboembolism while receiving significantly lower doses of unfractionated heparin than those monitored by the aPTT.³²

Lupus anticoagulant. Patients with the specific antiphospholipid antibody known as lupus anticoagulant frequently have a prolonged baseline aPTT,²⁵ making it an unreliable marker of anticoagulant effect for intravenous unfractionated heparin therapy.

Critically ill infants and children. Arachchillage et al³⁵ found that infants (< 1 year old) treated with intravenous unfractionated heparin in an intensive care department had only a 32.4% correlation between aPTT and anti-Xa levels, which was lower than that found in children ages 1 to 15 (66%) and adults (52%). In two-thirds of cases of discordant aPTT and anti-Xa levels, the aPTT was elevated (supratherapeutic) while the anti-Xa assay was within the therapeutic range (0.3–0.7 U/mL). Despite the lack of data on clinical outcomes (eg, rates of thrombosis and bleeding) with the use of an anti-Xa assay, it has been considered the method of choice for unfractionated heparin monitoring in critically ill children, and especially in those under age 1.^{41,44,62–64}

While anti-Xa assays may also be better for unfractionated heparin monitoring in critically ill adults, the lack of clinical outcome data from large-scale randomized trials has precluded evidence-based recommendations favoring them over the aPTT.^8,34

Anti-Xa assays are hampered by some technical limitations:

Samples must be processed within 1 hour to avoid heparin neutralization.³⁴

Samples must be clear. Hemolyzed or opaque samples (eg, due to bilirubin levels > 6.6 mg/dL or triglyceride levels > 360 mg/dL) cannot be processed, as they can cause falsely low levels.

Exposure to other anticoagulants can interfere with the results. The anti-Xa assay may be unreliable for unfractionated heparin monitoring in patients who are transitioned from low-molecular-weight heparins, fondaparinux, or an oral factor Xa inhibitor (apixaban, betrixaban, edoxaban, rivaroxaban) to intravenous unfractionated heparin, eg, due to hospitalization or acute kidney injury.^65,66 Different reports have found that anti-Xa assays may be elevated for as long as 63 to 96 hours after the last dose of oral Xa inhibitors,^67–69 potentially resulting in underdosing of unfractionated heparin. In such settings, unfractionated heparin therapy should be monitored by the aPTT.

ANTI-Xa ASSAYS AND LOW-MOLECULAR-WEIGHT HEPARINS

Most patients receiving low-molecular-weight heparins do not need laboratory monitoring.⁸ Alhenc-Gelas et al⁷⁰ randomized patients to receive dalteparin in doses either based on weight or guided by anti-Xa assay results, and found that dose adjustments were rare and lacked clinical benefit.

The suggested therapeutic anti-Xa levels for low-molecular-weight heparins are:

• 0.5–1.2 U/mL for twice-daily enoxaparin
• 1.0–2.0 U/mL for once-daily enoxaparin or dalteparin.

Levels should be measured at peak plasma level (ie, 3–4 hours after subcutaneous injection, except during pregnancy, when it is 4–6 hours), and only after at least 3 doses of low-molecular-weight heparin.^8,71 Unlike the anti-Xa therapeutic range recommended for unfractionated heparin therapy, these ranges are not based on prospective data, and if the assay result is outside the suggested therapeutic target range, current guidelines offer no advice on safely adjusting the dose.^8,71

Measuring anti-Xa activity is particularly important for pregnant women with a mechanical prosthetic heart valve who are treated with low-molecular-weight heparins. In this setting, valve thrombosis and cardioembolic events have been reported in patients with peak low-molecular-weight heparin anti-Xa assay levels below or even at the lower end of the therapeutic range, and increased bleeding risk has been reported with elevated anti-Xa levels.^71–74 Measuring trough low-molecular-weight heparin anti-Xa levels has been suggested to guide dose adjustments during pregnancy.⁷⁵

Clearance of low-molecular-weight heparins as measured by the anti-Xa assay is highly correlated with creatinine clearance.^76,77 A strong linear correlation has been demonstrated between creatine clearance and anti-Xa levels of enoxaparin after multiple therapeutic doses, and low-molecular-weight heparins accumulate in the plasma, especially in patients with creatine clearance less than 30 mL/min.⁷⁸ The risk of major bleeding is significantly increased in patients with severe renal insufficiency (creatinine clearance < 30 mL/min) not on dialysis who are treated with either prophylactic or therapeutic doses of low-molecular-weight heparin.^79–81 In a meta-analysis, the risk of bleeding with therapeutic-intensity doses of enoxaparin was 4 times higher than with prophylactic-intensity doses.⁷⁹ Although bleeding risk appears to be reduced when the enoxaparin dose is reduced by 50%,⁸ the efficacy and safety of this strategy has not been determined by prospective trials.

ANTI-Xa ASSAYS IN PATIENTS RECEIVING DIRECT ORAL ANTICOAGULANTS

Direct oral factor Xa inhibitors cannot be measured accurately by heparin anti-Xa assays. Nevertheless, such assays may be useful to assess whether clinically relevant plasma levels are present in cases of major bleeding, suspected anticoagulant failure, or patient noncompliance.⁸²

Intense research has focused on developing drug-specific chromogenic anti-Xa assays using calibrators and standards for apixaban, edoxaban, and rivaroxaban,^82,83 and good linear correlation has been shown with some assays.^82,84 In patients treated with oral factor Xa inhibitors who need to undergo an urgent invasive procedure associated with high bleeding risk, use of a specific reversal agent may be considered with drug concentrations more than 30 ng/mL measured by a drug-specific anti-Xa assay. A similar suggestion has been made for drug concentrations more than 50 ng/mL in the setting of major bleeding.⁸⁵ Unfortunately, such assays are not widely available at this time.^82,86

While drug-specific anti-Xa assays could become clinically important to guide reversal strategies, their relevance for drug monitoring remains uncertain. This is because no therapeutic target ranges have been established for any of the direct oral anticoagulants, which were approved on the basis of favorable clinical trial outcomes that neither measured nor were correlated with specific drug levels in plasma. Therefore, a specific anti-Xa level cannot yet be used as a marker of clinical efficacy for any specific oral direct Xa inhibitor.