User login
Studies of donor CAR T cells placed on hold
The US Food and Drug Administration (FDA) has placed a clinical hold on both phase 1 studies of UCART123, a universal (allogeneic) chimeric antigen receptor (CAR) T-cell therapy targeting CD123.
One study was designed for patients with acute myeloid leukemia (AML), and the other was designed for patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN).
The clinical hold is due to the death of the first patient treated in the BPDCN trial.
The hold means no new subjects can be enrolled in either trial, and there can be no further dosing of subjects who are already enrolled.
BPDCN patient
The first patient treated in the BPDCN trial was a 78-year-old male who had received 1 prior therapy. He presented with relapsed/refractory BPDCN with 30% blasts in his bone marrow and cutaneous lesions (biopsy-proven BPDCN) at baseline.
The patient first received pre-conditioning with fludarabine (30 mg/m²/day for 4 days) and cyclophosphamide (1 g/m²/day for 3 days).
On August 16, 2017 (Day 0), the patient received UCART123 at 6.25 x 105 cells/kg, the first dose level explored in the protocol, without complication.
By Day 5, the patient had developed grade 2 cytokine release syndrome (CRS) and a grade 3 lung infection, which improved after a first dose of tocilizumab and the administration of broad-spectrum, intravenous antibiotics.
On Day 8, the patient was found to have more severe CRS (ultimately grade 5) and grade 4 capillary leak syndrome. Despite receiving treatment in keeping with CRS management, including the administration of corticosteroids and tociluzumab as well as intensive care unit support, the patient died on Day 9.
AML patient
The first patient treated in the AML study experienced similar adverse effects as the BPDCN patient but is still alive.
The AML patient was a 58-year-old woman with 84% blasts in her bone marrow at baseline.
On June 27, 2017 (Day 0), the patient received the same pre-conditioning regimen and the same dose of UCART123 as the BPDCN patient, without complication.
By Day 8, the AML patient had developed grade 2 CRS. This worsened to grade 3 on Day 9 and resolved on Day 11 with treatment in the intensive care unit.
The patient also experienced grade 4 capillary leak syndrome on Day 9 that resolved on Day 12.
Next steps
The data safety monitoring board for these trials met on August 28 and recommended lowering the dose of UCART123 to 6.25 x 104 cells/kg in both studies and capping cyclophosphamide to a total dose of 4 g over 3 days.
Cellectis, the company developing UCART123, said it is working with study investigators and the FDA to resume both trials with an amended protocol that includes these dose adjustments. 
The US Food and Drug Administration (FDA) has placed a clinical hold on both phase 1 studies of UCART123, a universal (allogeneic) chimeric antigen receptor (CAR) T-cell therapy targeting CD123.
One study was designed for patients with acute myeloid leukemia (AML), and the other was designed for patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN).
The clinical hold is due to the death of the first patient treated in the BPDCN trial.
The hold means no new subjects can be enrolled in either trial, and there can be no further dosing of subjects who are already enrolled.
BPDCN patient
The first patient treated in the BPDCN trial was a 78-year-old male who had received 1 prior therapy. He presented with relapsed/refractory BPDCN with 30% blasts in his bone marrow and cutaneous lesions (biopsy-proven BPDCN) at baseline.
The patient first received pre-conditioning with fludarabine (30 mg/m²/day for 4 days) and cyclophosphamide (1 g/m²/day for 3 days).
On August 16, 2017 (Day 0), the patient received UCART123 at 6.25 x 105 cells/kg, the first dose level explored in the protocol, without complication.
By Day 5, the patient had developed grade 2 cytokine release syndrome (CRS) and a grade 3 lung infection, which improved after a first dose of tocilizumab and the administration of broad-spectrum, intravenous antibiotics.
On Day 8, the patient was found to have more severe CRS (ultimately grade 5) and grade 4 capillary leak syndrome. Despite receiving treatment in keeping with CRS management, including the administration of corticosteroids and tociluzumab as well as intensive care unit support, the patient died on Day 9.
AML patient
The first patient treated in the AML study experienced similar adverse effects as the BPDCN patient but is still alive.
The AML patient was a 58-year-old woman with 84% blasts in her bone marrow at baseline.
On June 27, 2017 (Day 0), the patient received the same pre-conditioning regimen and the same dose of UCART123 as the BPDCN patient, without complication.
By Day 8, the AML patient had developed grade 2 CRS. This worsened to grade 3 on Day 9 and resolved on Day 11 with treatment in the intensive care unit.
The patient also experienced grade 4 capillary leak syndrome on Day 9 that resolved on Day 12.
Next steps
The data safety monitoring board for these trials met on August 28 and recommended lowering the dose of UCART123 to 6.25 x 104 cells/kg in both studies and capping cyclophosphamide to a total dose of 4 g over 3 days.
Cellectis, the company developing UCART123, said it is working with study investigators and the FDA to resume both trials with an amended protocol that includes these dose adjustments.
The US Food and Drug Administration (FDA) has placed a clinical hold on both phase 1 studies of UCART123, a universal (allogeneic) chimeric antigen receptor (CAR) T-cell therapy targeting CD123.
One study was designed for patients with acute myeloid leukemia (AML), and the other was designed for patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN).
The clinical hold is due to the death of the first patient treated in the BPDCN trial.
The hold means no new subjects can be enrolled in either trial, and there can be no further dosing of subjects who are already enrolled.
BPDCN patient
The first patient treated in the BPDCN trial was a 78-year-old male who had received 1 prior therapy. He presented with relapsed/refractory BPDCN with 30% blasts in his bone marrow and cutaneous lesions (biopsy-proven BPDCN) at baseline.
The patient first received pre-conditioning with fludarabine (30 mg/m²/day for 4 days) and cyclophosphamide (1 g/m²/day for 3 days).
On August 16, 2017 (Day 0), the patient received UCART123 at 6.25 x 105 cells/kg, the first dose level explored in the protocol, without complication.
By Day 5, the patient had developed grade 2 cytokine release syndrome (CRS) and a grade 3 lung infection, which improved after a first dose of tocilizumab and the administration of broad-spectrum, intravenous antibiotics.
On Day 8, the patient was found to have more severe CRS (ultimately grade 5) and grade 4 capillary leak syndrome. Despite receiving treatment in keeping with CRS management, including the administration of corticosteroids and tociluzumab as well as intensive care unit support, the patient died on Day 9.
AML patient
The first patient treated in the AML study experienced similar adverse effects as the BPDCN patient but is still alive.
The AML patient was a 58-year-old woman with 84% blasts in her bone marrow at baseline.
On June 27, 2017 (Day 0), the patient received the same pre-conditioning regimen and the same dose of UCART123 as the BPDCN patient, without complication.
By Day 8, the AML patient had developed grade 2 CRS. This worsened to grade 3 on Day 9 and resolved on Day 11 with treatment in the intensive care unit.
The patient also experienced grade 4 capillary leak syndrome on Day 9 that resolved on Day 12.
Next steps
The data safety monitoring board for these trials met on August 28 and recommended lowering the dose of UCART123 to 6.25 x 104 cells/kg in both studies and capping cyclophosphamide to a total dose of 4 g over 3 days.
Cellectis, the company developing UCART123, said it is working with study investigators and the FDA to resume both trials with an amended protocol that includes these dose adjustments.
Withdrawn AML drug back on market in US
The US Food and Drug Administration (FDA) has approved use of gemtuzumab ozogamicin (GO, Mylotarg), a treatment that was initially approved by the agency in 2000 but later pulled from the US market.
GO is an antibody-drug conjugate that consists of the cytotoxic agent calicheamicin attached to a monoclonal antibody targeting CD33.
GO is now approved to treat adults with newly diagnosed, CD33-positive acute myeloid leukemia (AML) and patients age 2 and older with CD33-positive, relapsed or refractory AML.
GO can be given alone or in combination with daunorubicin and cytarabine.
The prescribing information for GO includes a boxed warning detailing the risk of hepatotoxicity, including veno-occlusive disease or sinusoidal obstruction syndrome, associated with GO.
GO originates from a collaboration between Pfizer and Celltech, now UCB. Pfizer has sole responsibility for all manufacturing, clinical development, and commercialization activities for this molecule.
Market withdrawal and subsequent trials
GO was originally approved under the FDA’s accelerated approval program in 2000 for use as a single agent in patients with CD33-positive AML who had experienced their first relapse and were 60 years of age or older.
In 2010, Pfizer voluntarily withdrew GO from the US market due to the results of a confirmatory phase 3 trial, SWOG S0106.
This trial showed there was no clinical benefit for patients who received GO plus daunorubicin and cytarabine over patients who received only daunorubicin and cytarabine.
In addition, the rate of fatal, treatment-related toxicity was significantly higher in the GO arm of the study.
Because of the unmet need for effective treatments in AML, investigators expressed an interest in evaluating different doses and schedules of GO.
These independent investigators, with Pfizer’s support, conducted clinical trials that yielded more information on the efficacy and safety of GO.
The trials—ALFA-0701, AML-19, and MyloFrance-1—supported the new approval of GO. Updated data from these trials are included in the prescribing information, which is available for download at www.mylotarg.com.
The US Food and Drug Administration (FDA) has approved use of gemtuzumab ozogamicin (GO, Mylotarg), a treatment that was initially approved by the agency in 2000 but later pulled from the US market.
GO is an antibody-drug conjugate that consists of the cytotoxic agent calicheamicin attached to a monoclonal antibody targeting CD33.
GO is now approved to treat adults with newly diagnosed, CD33-positive acute myeloid leukemia (AML) and patients age 2 and older with CD33-positive, relapsed or refractory AML.
GO can be given alone or in combination with daunorubicin and cytarabine.
The prescribing information for GO includes a boxed warning detailing the risk of hepatotoxicity, including veno-occlusive disease or sinusoidal obstruction syndrome, associated with GO.
GO originates from a collaboration between Pfizer and Celltech, now UCB. Pfizer has sole responsibility for all manufacturing, clinical development, and commercialization activities for this molecule.
Market withdrawal and subsequent trials
GO was originally approved under the FDA’s accelerated approval program in 2000 for use as a single agent in patients with CD33-positive AML who had experienced their first relapse and were 60 years of age or older.
In 2010, Pfizer voluntarily withdrew GO from the US market due to the results of a confirmatory phase 3 trial, SWOG S0106.
This trial showed there was no clinical benefit for patients who received GO plus daunorubicin and cytarabine over patients who received only daunorubicin and cytarabine.
In addition, the rate of fatal, treatment-related toxicity was significantly higher in the GO arm of the study.
Because of the unmet need for effective treatments in AML, investigators expressed an interest in evaluating different doses and schedules of GO.
These independent investigators, with Pfizer’s support, conducted clinical trials that yielded more information on the efficacy and safety of GO.
The trials—ALFA-0701, AML-19, and MyloFrance-1—supported the new approval of GO. Updated data from these trials are included in the prescribing information, which is available for download at www.mylotarg.com.
The US Food and Drug Administration (FDA) has approved use of gemtuzumab ozogamicin (GO, Mylotarg), a treatment that was initially approved by the agency in 2000 but later pulled from the US market.
GO is an antibody-drug conjugate that consists of the cytotoxic agent calicheamicin attached to a monoclonal antibody targeting CD33.
GO is now approved to treat adults with newly diagnosed, CD33-positive acute myeloid leukemia (AML) and patients age 2 and older with CD33-positive, relapsed or refractory AML.
GO can be given alone or in combination with daunorubicin and cytarabine.
The prescribing information for GO includes a boxed warning detailing the risk of hepatotoxicity, including veno-occlusive disease or sinusoidal obstruction syndrome, associated with GO.
GO originates from a collaboration between Pfizer and Celltech, now UCB. Pfizer has sole responsibility for all manufacturing, clinical development, and commercialization activities for this molecule.
Market withdrawal and subsequent trials
GO was originally approved under the FDA’s accelerated approval program in 2000 for use as a single agent in patients with CD33-positive AML who had experienced their first relapse and were 60 years of age or older.
In 2010, Pfizer voluntarily withdrew GO from the US market due to the results of a confirmatory phase 3 trial, SWOG S0106.
This trial showed there was no clinical benefit for patients who received GO plus daunorubicin and cytarabine over patients who received only daunorubicin and cytarabine.
In addition, the rate of fatal, treatment-related toxicity was significantly higher in the GO arm of the study.
Because of the unmet need for effective treatments in AML, investigators expressed an interest in evaluating different doses and schedules of GO.
These independent investigators, with Pfizer’s support, conducted clinical trials that yielded more information on the efficacy and safety of GO.
The trials—ALFA-0701, AML-19, and MyloFrance-1—supported the new approval of GO. Updated data from these trials are included in the prescribing information, which is available for download at www.mylotarg.com.
FDA reapproves gemtuzumab ozogamicin for CD33-positive AML treatment
The Food and Drug Administration has approved gemtuzumab ozogamicin (Mylotarg) for the treatment of newly diagnosed CD33-positive acute myeloid leukemia in adults, according to a press release.
Approval was based on results from three clinical trials. In the first, newly diagnosed AML patients who received gemtuzumab ozogamicin plus chemotherapy had significantly longer event-free survival than did patients who received chemotherapy alone. In a second trial, patients who received gemtuzumab ozogamicin alone had better overall survival compared to those who received only best supportive care. In the third clinical trial, 26% of patients who had experienced a relapse and received gemtuzumab ozogamicin experienced a remission.
Common side effects of gemtuzumab ozogamicin include fever, nausea, infection, vomiting, bleeding, thrombocytopenia, stomatitis, constipation, rash, headache, elevated liver function tests, and neutropenia; it is not recommended for women who are pregnant or breastfeeding.
Gemtuzumab ozogamicin was also approved to treat patients older than 2 years old who have experienced a relapse or have not responded to initial treatment.
“Mylotarg’s history underscores the importance of examining alternative dosing, scheduling, and administration of therapies for patients with cancer, especially in those who may be most vulnerable to the side effects of treatment,” Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence, said in the press release.
The Food and Drug Administration has approved gemtuzumab ozogamicin (Mylotarg) for the treatment of newly diagnosed CD33-positive acute myeloid leukemia in adults, according to a press release.
Approval was based on results from three clinical trials. In the first, newly diagnosed AML patients who received gemtuzumab ozogamicin plus chemotherapy had significantly longer event-free survival than did patients who received chemotherapy alone. In a second trial, patients who received gemtuzumab ozogamicin alone had better overall survival compared to those who received only best supportive care. In the third clinical trial, 26% of patients who had experienced a relapse and received gemtuzumab ozogamicin experienced a remission.
Common side effects of gemtuzumab ozogamicin include fever, nausea, infection, vomiting, bleeding, thrombocytopenia, stomatitis, constipation, rash, headache, elevated liver function tests, and neutropenia; it is not recommended for women who are pregnant or breastfeeding.
Gemtuzumab ozogamicin was also approved to treat patients older than 2 years old who have experienced a relapse or have not responded to initial treatment.
“Mylotarg’s history underscores the importance of examining alternative dosing, scheduling, and administration of therapies for patients with cancer, especially in those who may be most vulnerable to the side effects of treatment,” Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence, said in the press release.
The Food and Drug Administration has approved gemtuzumab ozogamicin (Mylotarg) for the treatment of newly diagnosed CD33-positive acute myeloid leukemia in adults, according to a press release.
Approval was based on results from three clinical trials. In the first, newly diagnosed AML patients who received gemtuzumab ozogamicin plus chemotherapy had significantly longer event-free survival than did patients who received chemotherapy alone. In a second trial, patients who received gemtuzumab ozogamicin alone had better overall survival compared to those who received only best supportive care. In the third clinical trial, 26% of patients who had experienced a relapse and received gemtuzumab ozogamicin experienced a remission.
Common side effects of gemtuzumab ozogamicin include fever, nausea, infection, vomiting, bleeding, thrombocytopenia, stomatitis, constipation, rash, headache, elevated liver function tests, and neutropenia; it is not recommended for women who are pregnant or breastfeeding.
Gemtuzumab ozogamicin was also approved to treat patients older than 2 years old who have experienced a relapse or have not responded to initial treatment.
“Mylotarg’s history underscores the importance of examining alternative dosing, scheduling, and administration of therapies for patients with cancer, especially in those who may be most vulnerable to the side effects of treatment,” Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence, said in the press release.
Enasidenib data in IDH2-mutated AML are basis for combination therapy trials
Enasidenib was a well-tolerated, efficacious alternative to cytotoxic chemotherapy for patients with IDH2-mutated relapsed or refractory acute myeloid leukemia (AML), the results of a phase 1/2 study showed.
The Food and Drug Administration recently approved enasidenib (Idhifa, formerly AG-221; Celgene) for the treatment of adult patients with relapsed or refractory AML having an IDH2 mutation as detected by a companion diagnostic test (RealTime IDH2 Assay; Abbott Molecular Inc.). The drug was generally safe and well tolerated, according to reported trial results (Blood. 2017 Aug. 10;130[6]:722-31). The main grade 3-4 enasidenib-related adverse events were hyperbilirubinemia (12%) and IDH inhibitor–associated differentiation syndrome (6%).
The drug is an oral selective inhibitor of mutant isocitrate dehydrogenase 2 (IDH2) enzymes that is not myeloablative. Although enasidenib appears to work by inducing myeloblast differentiation, predictors of response to the drug generally remain elusive, according to Eytan M. Stein, MD, a hematologic oncologist at Memorial Sloan Kettering Cancer Center, New York, and his coauthors.
About 12% of patients with AML have an IDH2 mutation. This genetic defect leads to accumulation of the metabolite 2-hydroxyglutarate (2-HG), causing DNA and histone hypermethylation. Hypermethylation, in turn, blocks hematopoietic cellular differentiation.
In a phase 1/2 trial sponsored by Celgene and Agios Pharmaceuticals, the investigators tested daily enasidenib monotherapy among 239 patients with IDH2-mutated advanced myeloid malignancies.
Among the 176 patients with relapsed or refractory AML (more than half of whom had already received at least two regimens directed against the disease), the overall response rate was 40.3%, and the complete response/remission rate was 19.3%. The median duration of response was 5.8 months.
Evaluation of serial bone marrow aspirates showed that responses were associated with myeloid cellular differentiation and maturation, generally without evidence of aplasia or hypoplasia.
With a median follow-up of 7.7 months, median overall survival was 9.3 months in the entire AML cohort and 19.7 months in the subset achieving complete response/remission. Ten percent of patients went on to allogeneic stem cell transplantation.
Although nearly all patients had a marked reduction in plasma levels of 2-HG, the extent of reduction did not predict response, suggesting that this metabolite is not a biomarker for benefit, and additional mechanisms are at play.
“Continuous daily enasidenib treatment was generally well tolerated and induced hematologic responses in patients for whom prior AML therapy had failed,” Dr. Stein and his coinvestigators wrote. “Inducing differentiation of myeloblasts, not cytotoxicity, seems to drive the clinical efficacy of enasidenib.”
They noted that an ongoing multicenter, randomized phase 3 trial, called IDHENTIFY (NCT02577406), is testing enasidenib against conventional regimens in older adults with late-stage AML harboring an IDH2 mutation.
In a companion translational study, investigators led by Michael D. Amatangelo, PhD, a scientist with Celgene in Summit, N.J., further explored mechanisms of enasidenib response and sought to identify alternative biomarkers for benefit in the AML cohort. They measured 2-HG levels, mutant IDH2 allele burden, and co-occurring somatic mutations in samples serially collected during the trial, and used flow cytometry to assess inhibition of mutant IDH2 on hematopoietic differentiation.
Enasidenib therapy induced 2-HG suppression regardless of whether patients’ IDH2 mutation affected the R140 or the R172 residue, according to reported results (Blood. 2017 Aug. 10;130[6]:732-41). However, analyses confirmed that 2-HG suppression alone did not predict response, as most nonresponders also had suppression.
In some patients with complete remission, mutant IDH2 persisted, but there was normalization of hematopoietic stem and progenitor compartments, and emergence of functional neutrophils having the IDH2 mutation. And some patients saw a reduction in mutant IDH2 allele burden, with levels remaining undetectable during response.
Analyses failed to identify any single mutation predictive of response to enasidenib. However, patients who did not achieve a response more commonly had mutations in NRAS and other MAPK pathway effectors, suggesting that RAS signaling plays a role in primary resistance to the drug.
“Although this is only a subgroup analysis of a large single-arm experience, taken together, the clinical response and translational data demonstrate that single-agent [mutant IDH2] inhibition by enasidenib in [relapsed or refractory AML] represents a critical and novel differentiation therapy,” Dr. Amatangelo and his coinvestigators wrote.
“Although enasidenib responses are clinically durable, the genetic heterogeneity observed in our patients suggests that combination with other therapies may be required to achieve long-term disease remission in more patients,” they added. “Current clinical studies combining enasidenib with combination chemotherapy or azacitidine (NCT02677922 and NCT02632708) and future orthogonal targeted therapies will address this question.”
Dr. Stein disclosed that he received grants and personal fees from Celgene and Agios Pharmaceuticals. Dr. Amatangelo disclosed that he is employed by and owns equity in Celgene.
Stein et al. provide for the first time answers to the questions of whether IDH inhibitors are tolerated in patients and whether these compounds induce clinical responses and, excitingly, both answers are positive.
Data from the phase 1/2 trial are encouraging, given that the population studied has a notoriously dismal prognosis when treated with conventional modalities.
Findings from the companion translational study suggest heterogeneity in the dynamics of response to enasidenib, with some responding patients retaining mutant alleles in mature cells, and a smaller group of responding patients clearing the mutation.
These findings raise the important question of whether enasidenib can target leukemic stem cells, the holy grail of AML therapy. Additional questions arising from the research pertain to the long-term effects of the drug, whether it will induce clonal selection, and how it affects leukemic cells that lack an IDH2 mutation.
Together, the results of these studies argue for the further clinical exploration of IDH inhibitors. It is expected that for more powerful responses, differentiation-based IDH2 inhibition will need to be combined with orthogonal treatment modalities, such as standard chemotherapy or other types of mechanism-based targeted therapy. Obviously, in the next phase, enasidenib-based regimens should be compared head to head to standard regimens in a randomized controlled fashion. Such studies, and studies with other IDH2 and IDH1 inhibitors, will address the full role of IDH inhibition in AML treatment.
Bas J. Wouters, MD, PhD, a hematologist at Erasmus University Medical Center, Rotterdam, the Netherlands, made his remarks in a related commentary ( Blood. 2017;130:693-4 ). Dr. Wouters reported no competing financial interests.
Stein et al. provide for the first time answers to the questions of whether IDH inhibitors are tolerated in patients and whether these compounds induce clinical responses and, excitingly, both answers are positive.
Data from the phase 1/2 trial are encouraging, given that the population studied has a notoriously dismal prognosis when treated with conventional modalities.
Findings from the companion translational study suggest heterogeneity in the dynamics of response to enasidenib, with some responding patients retaining mutant alleles in mature cells, and a smaller group of responding patients clearing the mutation.
These findings raise the important question of whether enasidenib can target leukemic stem cells, the holy grail of AML therapy. Additional questions arising from the research pertain to the long-term effects of the drug, whether it will induce clonal selection, and how it affects leukemic cells that lack an IDH2 mutation.
Together, the results of these studies argue for the further clinical exploration of IDH inhibitors. It is expected that for more powerful responses, differentiation-based IDH2 inhibition will need to be combined with orthogonal treatment modalities, such as standard chemotherapy or other types of mechanism-based targeted therapy. Obviously, in the next phase, enasidenib-based regimens should be compared head to head to standard regimens in a randomized controlled fashion. Such studies, and studies with other IDH2 and IDH1 inhibitors, will address the full role of IDH inhibition in AML treatment.
Bas J. Wouters, MD, PhD, a hematologist at Erasmus University Medical Center, Rotterdam, the Netherlands, made his remarks in a related commentary ( Blood. 2017;130:693-4 ). Dr. Wouters reported no competing financial interests.
Stein et al. provide for the first time answers to the questions of whether IDH inhibitors are tolerated in patients and whether these compounds induce clinical responses and, excitingly, both answers are positive.
Data from the phase 1/2 trial are encouraging, given that the population studied has a notoriously dismal prognosis when treated with conventional modalities.
Findings from the companion translational study suggest heterogeneity in the dynamics of response to enasidenib, with some responding patients retaining mutant alleles in mature cells, and a smaller group of responding patients clearing the mutation.
These findings raise the important question of whether enasidenib can target leukemic stem cells, the holy grail of AML therapy. Additional questions arising from the research pertain to the long-term effects of the drug, whether it will induce clonal selection, and how it affects leukemic cells that lack an IDH2 mutation.
Together, the results of these studies argue for the further clinical exploration of IDH inhibitors. It is expected that for more powerful responses, differentiation-based IDH2 inhibition will need to be combined with orthogonal treatment modalities, such as standard chemotherapy or other types of mechanism-based targeted therapy. Obviously, in the next phase, enasidenib-based regimens should be compared head to head to standard regimens in a randomized controlled fashion. Such studies, and studies with other IDH2 and IDH1 inhibitors, will address the full role of IDH inhibition in AML treatment.
Bas J. Wouters, MD, PhD, a hematologist at Erasmus University Medical Center, Rotterdam, the Netherlands, made his remarks in a related commentary ( Blood. 2017;130:693-4 ). Dr. Wouters reported no competing financial interests.
Enasidenib was a well-tolerated, efficacious alternative to cytotoxic chemotherapy for patients with IDH2-mutated relapsed or refractory acute myeloid leukemia (AML), the results of a phase 1/2 study showed.
The Food and Drug Administration recently approved enasidenib (Idhifa, formerly AG-221; Celgene) for the treatment of adult patients with relapsed or refractory AML having an IDH2 mutation as detected by a companion diagnostic test (RealTime IDH2 Assay; Abbott Molecular Inc.). The drug was generally safe and well tolerated, according to reported trial results (Blood. 2017 Aug. 10;130[6]:722-31). The main grade 3-4 enasidenib-related adverse events were hyperbilirubinemia (12%) and IDH inhibitor–associated differentiation syndrome (6%).
The drug is an oral selective inhibitor of mutant isocitrate dehydrogenase 2 (IDH2) enzymes that is not myeloablative. Although enasidenib appears to work by inducing myeloblast differentiation, predictors of response to the drug generally remain elusive, according to Eytan M. Stein, MD, a hematologic oncologist at Memorial Sloan Kettering Cancer Center, New York, and his coauthors.
About 12% of patients with AML have an IDH2 mutation. This genetic defect leads to accumulation of the metabolite 2-hydroxyglutarate (2-HG), causing DNA and histone hypermethylation. Hypermethylation, in turn, blocks hematopoietic cellular differentiation.
In a phase 1/2 trial sponsored by Celgene and Agios Pharmaceuticals, the investigators tested daily enasidenib monotherapy among 239 patients with IDH2-mutated advanced myeloid malignancies.
Among the 176 patients with relapsed or refractory AML (more than half of whom had already received at least two regimens directed against the disease), the overall response rate was 40.3%, and the complete response/remission rate was 19.3%. The median duration of response was 5.8 months.
Evaluation of serial bone marrow aspirates showed that responses were associated with myeloid cellular differentiation and maturation, generally without evidence of aplasia or hypoplasia.
With a median follow-up of 7.7 months, median overall survival was 9.3 months in the entire AML cohort and 19.7 months in the subset achieving complete response/remission. Ten percent of patients went on to allogeneic stem cell transplantation.
Although nearly all patients had a marked reduction in plasma levels of 2-HG, the extent of reduction did not predict response, suggesting that this metabolite is not a biomarker for benefit, and additional mechanisms are at play.
“Continuous daily enasidenib treatment was generally well tolerated and induced hematologic responses in patients for whom prior AML therapy had failed,” Dr. Stein and his coinvestigators wrote. “Inducing differentiation of myeloblasts, not cytotoxicity, seems to drive the clinical efficacy of enasidenib.”
They noted that an ongoing multicenter, randomized phase 3 trial, called IDHENTIFY (NCT02577406), is testing enasidenib against conventional regimens in older adults with late-stage AML harboring an IDH2 mutation.
In a companion translational study, investigators led by Michael D. Amatangelo, PhD, a scientist with Celgene in Summit, N.J., further explored mechanisms of enasidenib response and sought to identify alternative biomarkers for benefit in the AML cohort. They measured 2-HG levels, mutant IDH2 allele burden, and co-occurring somatic mutations in samples serially collected during the trial, and used flow cytometry to assess inhibition of mutant IDH2 on hematopoietic differentiation.
Enasidenib therapy induced 2-HG suppression regardless of whether patients’ IDH2 mutation affected the R140 or the R172 residue, according to reported results (Blood. 2017 Aug. 10;130[6]:732-41). However, analyses confirmed that 2-HG suppression alone did not predict response, as most nonresponders also had suppression.
In some patients with complete remission, mutant IDH2 persisted, but there was normalization of hematopoietic stem and progenitor compartments, and emergence of functional neutrophils having the IDH2 mutation. And some patients saw a reduction in mutant IDH2 allele burden, with levels remaining undetectable during response.
Analyses failed to identify any single mutation predictive of response to enasidenib. However, patients who did not achieve a response more commonly had mutations in NRAS and other MAPK pathway effectors, suggesting that RAS signaling plays a role in primary resistance to the drug.
“Although this is only a subgroup analysis of a large single-arm experience, taken together, the clinical response and translational data demonstrate that single-agent [mutant IDH2] inhibition by enasidenib in [relapsed or refractory AML] represents a critical and novel differentiation therapy,” Dr. Amatangelo and his coinvestigators wrote.
“Although enasidenib responses are clinically durable, the genetic heterogeneity observed in our patients suggests that combination with other therapies may be required to achieve long-term disease remission in more patients,” they added. “Current clinical studies combining enasidenib with combination chemotherapy or azacitidine (NCT02677922 and NCT02632708) and future orthogonal targeted therapies will address this question.”
Dr. Stein disclosed that he received grants and personal fees from Celgene and Agios Pharmaceuticals. Dr. Amatangelo disclosed that he is employed by and owns equity in Celgene.
Enasidenib was a well-tolerated, efficacious alternative to cytotoxic chemotherapy for patients with IDH2-mutated relapsed or refractory acute myeloid leukemia (AML), the results of a phase 1/2 study showed.
The Food and Drug Administration recently approved enasidenib (Idhifa, formerly AG-221; Celgene) for the treatment of adult patients with relapsed or refractory AML having an IDH2 mutation as detected by a companion diagnostic test (RealTime IDH2 Assay; Abbott Molecular Inc.). The drug was generally safe and well tolerated, according to reported trial results (Blood. 2017 Aug. 10;130[6]:722-31). The main grade 3-4 enasidenib-related adverse events were hyperbilirubinemia (12%) and IDH inhibitor–associated differentiation syndrome (6%).
The drug is an oral selective inhibitor of mutant isocitrate dehydrogenase 2 (IDH2) enzymes that is not myeloablative. Although enasidenib appears to work by inducing myeloblast differentiation, predictors of response to the drug generally remain elusive, according to Eytan M. Stein, MD, a hematologic oncologist at Memorial Sloan Kettering Cancer Center, New York, and his coauthors.
About 12% of patients with AML have an IDH2 mutation. This genetic defect leads to accumulation of the metabolite 2-hydroxyglutarate (2-HG), causing DNA and histone hypermethylation. Hypermethylation, in turn, blocks hematopoietic cellular differentiation.
In a phase 1/2 trial sponsored by Celgene and Agios Pharmaceuticals, the investigators tested daily enasidenib monotherapy among 239 patients with IDH2-mutated advanced myeloid malignancies.
Among the 176 patients with relapsed or refractory AML (more than half of whom had already received at least two regimens directed against the disease), the overall response rate was 40.3%, and the complete response/remission rate was 19.3%. The median duration of response was 5.8 months.
Evaluation of serial bone marrow aspirates showed that responses were associated with myeloid cellular differentiation and maturation, generally without evidence of aplasia or hypoplasia.
With a median follow-up of 7.7 months, median overall survival was 9.3 months in the entire AML cohort and 19.7 months in the subset achieving complete response/remission. Ten percent of patients went on to allogeneic stem cell transplantation.
Although nearly all patients had a marked reduction in plasma levels of 2-HG, the extent of reduction did not predict response, suggesting that this metabolite is not a biomarker for benefit, and additional mechanisms are at play.
“Continuous daily enasidenib treatment was generally well tolerated and induced hematologic responses in patients for whom prior AML therapy had failed,” Dr. Stein and his coinvestigators wrote. “Inducing differentiation of myeloblasts, not cytotoxicity, seems to drive the clinical efficacy of enasidenib.”
They noted that an ongoing multicenter, randomized phase 3 trial, called IDHENTIFY (NCT02577406), is testing enasidenib against conventional regimens in older adults with late-stage AML harboring an IDH2 mutation.
In a companion translational study, investigators led by Michael D. Amatangelo, PhD, a scientist with Celgene in Summit, N.J., further explored mechanisms of enasidenib response and sought to identify alternative biomarkers for benefit in the AML cohort. They measured 2-HG levels, mutant IDH2 allele burden, and co-occurring somatic mutations in samples serially collected during the trial, and used flow cytometry to assess inhibition of mutant IDH2 on hematopoietic differentiation.
Enasidenib therapy induced 2-HG suppression regardless of whether patients’ IDH2 mutation affected the R140 or the R172 residue, according to reported results (Blood. 2017 Aug. 10;130[6]:732-41). However, analyses confirmed that 2-HG suppression alone did not predict response, as most nonresponders also had suppression.
In some patients with complete remission, mutant IDH2 persisted, but there was normalization of hematopoietic stem and progenitor compartments, and emergence of functional neutrophils having the IDH2 mutation. And some patients saw a reduction in mutant IDH2 allele burden, with levels remaining undetectable during response.
Analyses failed to identify any single mutation predictive of response to enasidenib. However, patients who did not achieve a response more commonly had mutations in NRAS and other MAPK pathway effectors, suggesting that RAS signaling plays a role in primary resistance to the drug.
“Although this is only a subgroup analysis of a large single-arm experience, taken together, the clinical response and translational data demonstrate that single-agent [mutant IDH2] inhibition by enasidenib in [relapsed or refractory AML] represents a critical and novel differentiation therapy,” Dr. Amatangelo and his coinvestigators wrote.
“Although enasidenib responses are clinically durable, the genetic heterogeneity observed in our patients suggests that combination with other therapies may be required to achieve long-term disease remission in more patients,” they added. “Current clinical studies combining enasidenib with combination chemotherapy or azacitidine (NCT02677922 and NCT02632708) and future orthogonal targeted therapies will address this question.”
Dr. Stein disclosed that he received grants and personal fees from Celgene and Agios Pharmaceuticals. Dr. Amatangelo disclosed that he is employed by and owns equity in Celgene.
FROM BLOOD
Key clinical point:
Major finding: The overall response rate was 40.3%; 2-HG levels and co-occurring mutations were not reliable predictors of response.
Data source: A phase 1/2 trial of enasidenib monotherapy including 176 patients with relapsed or refractory IDH2-mutated AML, and a companion translational study of mechanisms and biomarkers of response in the same patients.
Disclosures: Dr. Stein disclosed that he received grants and personal fees from Celgene and Agios Pharmaceuticals, the trial sponsors. Dr. Amatangelo disclosed that he is employed by and owns equity in Celgene. The study was supported by the National Institutes of Health, National Cancer Institute.
Vitamin C regulates HSCs, curbs AML development
Researchers have described a molecular mechanism that could help explain the link between low vitamin C (ascorbate) levels and acute myeloid leukemia (AML).
The team found that mice with low levels of ascorbate in their blood experience a notable increase in hematopoietic stem cell (HSC) frequency and function.
This, in turn, accelerates AML development, partly by inhibiting the tumor suppressor Tet2.
Sean Morrison, PhD, of the University of Texas Southwestern Medical Center in Dallas, and his colleagues reported these findings in Nature.
“We have known for a while that people with lower levels of ascorbate (vitamin C) are at increased cancer risk, but we haven’t fully understood why,” Dr Morrison said. “Our research provides part of the explanation, at least for the blood-forming system.”
Dr Morrison and his colleagues developed a technique for analyzing the metabolic profiles of rare cell populations and used it to compare HSCs to restricted hematopoietic progenitors.
The researchers found that each hematopoietic cell type had a “distinct metabolic signature,” and both human and mouse HSCs had “unusually high” levels of ascorbate, which decreased as the cells differentiated.
To determine if ascorbate is important for HSC function, the team studied mice that lacked gulonolactone oxidase (Gulo), an enzyme mice use to synthesize their own ascorbate. Loss of the enzyme requires Gulo-deficient mice to obtain ascorbate exclusively through their diet like humans do.
So when the researchers fed the mice a standard diet, which contains little ascorbate, the animals’ ascorbate levels were depleted.
The team expected ascorbate depletion might lead to loss of HSC function, but they found the opposite was true. HSCs actually gained function, and this increased the incidence of AML in the mice.
This increase is partly tied to how ascorbate affects Tet2. The researchers found that ascorbate depletion can limit Tet2 function in tissues in a way that increases the risk of AML.
In addition, ascorbate depletion cooperated with Flt3 internal tandem duplication mutations to accelerate leukemogenesis. But the researchers were able to suppress leukemogenesis by feeding animals higher levels of ascorbate.
“Stem cells use ascorbate to regulate the abundance of certain chemical modifications on DNA, which are part of the epigenome,” said study author Michalis Agathocleous, PhD, of the University of Texas Southwestern Medical Center.
“So when stem cells don’t receive enough vitamin C, the epigenome can become damaged in a way that increases stem cell function but also increases the risk of leukemia.”
The researchers said further studies are needed to better understand the potential clinical implications of these findings.
However, the findings may have implications for older patients with clonal hematopoiesis. This condition increases a person’s risk of developing leukemia, but it is not well understood why certain patients develop leukemia and others do not. The results of this study might offer an explanation.
“One of the most common mutations in patients with clonal hematopoiesis is a loss of one copy of TET2,” Dr Morrison said. “Our results suggest patients with clonal hematopoiesis and a TET2 mutation should be particularly careful to get 100% of their daily vitamin C requirement. Because these patients only have one good copy of TET2 left, they need to maximize the residual TET2 tumor-suppressor activity to protect themselves from cancer.”
Researchers have described a molecular mechanism that could help explain the link between low vitamin C (ascorbate) levels and acute myeloid leukemia (AML).
The team found that mice with low levels of ascorbate in their blood experience a notable increase in hematopoietic stem cell (HSC) frequency and function.
This, in turn, accelerates AML development, partly by inhibiting the tumor suppressor Tet2.
Sean Morrison, PhD, of the University of Texas Southwestern Medical Center in Dallas, and his colleagues reported these findings in Nature.
“We have known for a while that people with lower levels of ascorbate (vitamin C) are at increased cancer risk, but we haven’t fully understood why,” Dr Morrison said. “Our research provides part of the explanation, at least for the blood-forming system.”
Dr Morrison and his colleagues developed a technique for analyzing the metabolic profiles of rare cell populations and used it to compare HSCs to restricted hematopoietic progenitors.
The researchers found that each hematopoietic cell type had a “distinct metabolic signature,” and both human and mouse HSCs had “unusually high” levels of ascorbate, which decreased as the cells differentiated.
To determine if ascorbate is important for HSC function, the team studied mice that lacked gulonolactone oxidase (Gulo), an enzyme mice use to synthesize their own ascorbate. Loss of the enzyme requires Gulo-deficient mice to obtain ascorbate exclusively through their diet like humans do.
So when the researchers fed the mice a standard diet, which contains little ascorbate, the animals’ ascorbate levels were depleted.
The team expected ascorbate depletion might lead to loss of HSC function, but they found the opposite was true. HSCs actually gained function, and this increased the incidence of AML in the mice.
This increase is partly tied to how ascorbate affects Tet2. The researchers found that ascorbate depletion can limit Tet2 function in tissues in a way that increases the risk of AML.
In addition, ascorbate depletion cooperated with Flt3 internal tandem duplication mutations to accelerate leukemogenesis. But the researchers were able to suppress leukemogenesis by feeding animals higher levels of ascorbate.
“Stem cells use ascorbate to regulate the abundance of certain chemical modifications on DNA, which are part of the epigenome,” said study author Michalis Agathocleous, PhD, of the University of Texas Southwestern Medical Center.
“So when stem cells don’t receive enough vitamin C, the epigenome can become damaged in a way that increases stem cell function but also increases the risk of leukemia.”
The researchers said further studies are needed to better understand the potential clinical implications of these findings.
However, the findings may have implications for older patients with clonal hematopoiesis. This condition increases a person’s risk of developing leukemia, but it is not well understood why certain patients develop leukemia and others do not. The results of this study might offer an explanation.
“One of the most common mutations in patients with clonal hematopoiesis is a loss of one copy of TET2,” Dr Morrison said. “Our results suggest patients with clonal hematopoiesis and a TET2 mutation should be particularly careful to get 100% of their daily vitamin C requirement. Because these patients only have one good copy of TET2 left, they need to maximize the residual TET2 tumor-suppressor activity to protect themselves from cancer.”
Researchers have described a molecular mechanism that could help explain the link between low vitamin C (ascorbate) levels and acute myeloid leukemia (AML).
The team found that mice with low levels of ascorbate in their blood experience a notable increase in hematopoietic stem cell (HSC) frequency and function.
This, in turn, accelerates AML development, partly by inhibiting the tumor suppressor Tet2.
Sean Morrison, PhD, of the University of Texas Southwestern Medical Center in Dallas, and his colleagues reported these findings in Nature.
“We have known for a while that people with lower levels of ascorbate (vitamin C) are at increased cancer risk, but we haven’t fully understood why,” Dr Morrison said. “Our research provides part of the explanation, at least for the blood-forming system.”
Dr Morrison and his colleagues developed a technique for analyzing the metabolic profiles of rare cell populations and used it to compare HSCs to restricted hematopoietic progenitors.
The researchers found that each hematopoietic cell type had a “distinct metabolic signature,” and both human and mouse HSCs had “unusually high” levels of ascorbate, which decreased as the cells differentiated.
To determine if ascorbate is important for HSC function, the team studied mice that lacked gulonolactone oxidase (Gulo), an enzyme mice use to synthesize their own ascorbate. Loss of the enzyme requires Gulo-deficient mice to obtain ascorbate exclusively through their diet like humans do.
So when the researchers fed the mice a standard diet, which contains little ascorbate, the animals’ ascorbate levels were depleted.
The team expected ascorbate depletion might lead to loss of HSC function, but they found the opposite was true. HSCs actually gained function, and this increased the incidence of AML in the mice.
This increase is partly tied to how ascorbate affects Tet2. The researchers found that ascorbate depletion can limit Tet2 function in tissues in a way that increases the risk of AML.
In addition, ascorbate depletion cooperated with Flt3 internal tandem duplication mutations to accelerate leukemogenesis. But the researchers were able to suppress leukemogenesis by feeding animals higher levels of ascorbate.
“Stem cells use ascorbate to regulate the abundance of certain chemical modifications on DNA, which are part of the epigenome,” said study author Michalis Agathocleous, PhD, of the University of Texas Southwestern Medical Center.
“So when stem cells don’t receive enough vitamin C, the epigenome can become damaged in a way that increases stem cell function but also increases the risk of leukemia.”
The researchers said further studies are needed to better understand the potential clinical implications of these findings.
However, the findings may have implications for older patients with clonal hematopoiesis. This condition increases a person’s risk of developing leukemia, but it is not well understood why certain patients develop leukemia and others do not. The results of this study might offer an explanation.
“One of the most common mutations in patients with clonal hematopoiesis is a loss of one copy of TET2,” Dr Morrison said. “Our results suggest patients with clonal hematopoiesis and a TET2 mutation should be particularly careful to get 100% of their daily vitamin C requirement. Because these patients only have one good copy of TET2 left, they need to maximize the residual TET2 tumor-suppressor activity to protect themselves from cancer.”
Antibody could treat AML, MM, and NHL
An investigational antibody has demonstrated activity against acute myeloid leukemia (AML), multiple myeloma (MM), and non-Hodgkin lymphoma (NHL), according to researchers.
PF-06747143 is a humanized CXCR4 immunoglobulin G1 (IgG1) antibody that binds to CXCR4 and inhibits both CXCL12-mediated signaling pathways and cell migration.
Whether given alone or in combination with chemotherapy, PF-06747143 demonstrated efficacy in mouse models of NHL, MM, and AML.
Treatment involving PF-06747143—alone or in combination—eradicated more cancer cells than did standard treatment options.
These results were published in Blood Advances. The research was sponsored by Pfizer, Inc., the company developing PF-06747143.
“One of the major limitations we see in treating blood cancers is the failure to clear cancer cells from the bone marrow,” said study author Flavia Pernasetti, PhD, of Pfizer Oncology Research and Development.
“Because the bone marrow allows the cancer cells to flourish, removing these cells is an essential step in treating these malignancies effectively.”
With this goal in mind, Dr Pernasetti and her colleagues looked to the mechanisms that control the movement of cells into the bone marrow (BM) in the first place—the chemokine receptor CXCR4 and its ligand CXCL12.
The researchers created PF-06747143, which attacks and kills cancer cells directly but also removes cancer cells from the BM so they can be killed by other treatments.
Results in NHL
The researchers first tested PF-06747143 in an NHL Ramos xenograft model. Mice received PF-06747143 or a control IgG1 antibody at 10 mg/kg on days 1 and 8.
PF-06747143 significantly inhibited tumor growth compared to the control antibody (P<0.0001). Seventy percent of PF-06747143-treated mice had tumor volumes below their initial size at the end of the study.
PF-06747143 produced a dose-dependent response that was sustained until the end of the study, even after treatment was stopped.
Results in MM
The researchers tested PF-06747143 in a disseminated MM model, in which the OPM2-Luc tumor cells were implanted intravenously and migrated spontaneously to the BM.
Mice received PF-06747143 or IgG1 control at 10 mg/kg weekly for 5 doses. Other mice received melphalan at 1 mg/kg twice a week for a total of 4 cycles.
On day 30, PF-06747143 had significantly inhibited BM tumor growth compared to the control antibody or melphalan (P<0.0001).
PF-06747143-treated mice also had a significant survival benefit. The median survival was 33.5 days for mice that received the control antibody and 36 days for mice treated with melphalan. However, there were no deaths in the PF-06747143-treated mice by day 50, which marked the end of the study (P<0.0001).
The researchers also tested PF-06747143 at a lower dose (1 mg/kg weekly for a total of 7 doses), both alone and in combination with bortezomib (0.5 mg/kg twice a week for a total of 4 cycles).
The median survival was 34 days in the control mice, 44 days in mice that received bortezomib alone, and 47 days in mice that received PF-06747143 alone. However, there were no deaths in the combination arm at day 51, which was the end of the study (P<0.0003).
Results in AML
The researchers tested PF-06747143 in an AML disseminated tumor model using MV4-11 cells.
They compared PF-06747143 (given at 0.1, 1, or 10 mg/kg weekly for 4 doses) to the chemotherapeutic agent daunorubicin (2 mg/kg on days 1, 3, and 5), the FLT3 inhibitor crenolanib (7.5 mg/kg twice a day, on days 11-15 and 25-29), and a control IgG1 antibody (10 mg/kg weekly for 4 doses).
PF-06747143 (at 10 mg/kg), daunorubicin, and crenolanib all significantly reduced the number of tumor cells in the peripheral blood and BM when compared with the control antibody (P<0.05).
PF-06746143 treatment (at 10 mg/kg) reduced the number of AML cells in the BM by 95.9%, while daunorubicin reduced them by 84.5% and crenolanib by 80.5%.
The median survival was 36 days for mice that received PF-06747143 at 0.1 mg/kg, 41 days for mice that received the control antibody, 47 days for mice that received PF-06747143 at 1 mg/kg, and 63 days for mice that received PF-06747143 at 10 mg/kg.
The researchers also found that PF-06747143 had a “strong combinatorial effect” with daunorubicin and cytarabine in a chemotherapy-resistant model of AML. The team noted that only 36% of BM cells are positive for CXCR4 in this model.
Treatment with PF-06747143 alone reduced the percentage of AML cells in the BM to 80%, combination daunorubicin and cytarabine reduced it to 27%, and combination PF-06747143, daunorubicin, and cytarabine reduced the percentage of AML cells in the BM to 0.3%.
“Our preliminary preclinical results are encouraging,” Dr Pernasetti said, “and we are very excited to see how our antibody fares in clinical testing.”
PF-06747143 is currently being evaluated in a phase 1 trial of AML patients.
An investigational antibody has demonstrated activity against acute myeloid leukemia (AML), multiple myeloma (MM), and non-Hodgkin lymphoma (NHL), according to researchers.
PF-06747143 is a humanized CXCR4 immunoglobulin G1 (IgG1) antibody that binds to CXCR4 and inhibits both CXCL12-mediated signaling pathways and cell migration.
Whether given alone or in combination with chemotherapy, PF-06747143 demonstrated efficacy in mouse models of NHL, MM, and AML.
Treatment involving PF-06747143—alone or in combination—eradicated more cancer cells than did standard treatment options.
These results were published in Blood Advances. The research was sponsored by Pfizer, Inc., the company developing PF-06747143.
“One of the major limitations we see in treating blood cancers is the failure to clear cancer cells from the bone marrow,” said study author Flavia Pernasetti, PhD, of Pfizer Oncology Research and Development.
“Because the bone marrow allows the cancer cells to flourish, removing these cells is an essential step in treating these malignancies effectively.”
With this goal in mind, Dr Pernasetti and her colleagues looked to the mechanisms that control the movement of cells into the bone marrow (BM) in the first place—the chemokine receptor CXCR4 and its ligand CXCL12.
The researchers created PF-06747143, which attacks and kills cancer cells directly but also removes cancer cells from the BM so they can be killed by other treatments.
Results in NHL
The researchers first tested PF-06747143 in an NHL Ramos xenograft model. Mice received PF-06747143 or a control IgG1 antibody at 10 mg/kg on days 1 and 8.
PF-06747143 significantly inhibited tumor growth compared to the control antibody (P<0.0001). Seventy percent of PF-06747143-treated mice had tumor volumes below their initial size at the end of the study.
PF-06747143 produced a dose-dependent response that was sustained until the end of the study, even after treatment was stopped.
Results in MM
The researchers tested PF-06747143 in a disseminated MM model, in which the OPM2-Luc tumor cells were implanted intravenously and migrated spontaneously to the BM.
Mice received PF-06747143 or IgG1 control at 10 mg/kg weekly for 5 doses. Other mice received melphalan at 1 mg/kg twice a week for a total of 4 cycles.
On day 30, PF-06747143 had significantly inhibited BM tumor growth compared to the control antibody or melphalan (P<0.0001).
PF-06747143-treated mice also had a significant survival benefit. The median survival was 33.5 days for mice that received the control antibody and 36 days for mice treated with melphalan. However, there were no deaths in the PF-06747143-treated mice by day 50, which marked the end of the study (P<0.0001).
The researchers also tested PF-06747143 at a lower dose (1 mg/kg weekly for a total of 7 doses), both alone and in combination with bortezomib (0.5 mg/kg twice a week for a total of 4 cycles).
The median survival was 34 days in the control mice, 44 days in mice that received bortezomib alone, and 47 days in mice that received PF-06747143 alone. However, there were no deaths in the combination arm at day 51, which was the end of the study (P<0.0003).
Results in AML
The researchers tested PF-06747143 in an AML disseminated tumor model using MV4-11 cells.
They compared PF-06747143 (given at 0.1, 1, or 10 mg/kg weekly for 4 doses) to the chemotherapeutic agent daunorubicin (2 mg/kg on days 1, 3, and 5), the FLT3 inhibitor crenolanib (7.5 mg/kg twice a day, on days 11-15 and 25-29), and a control IgG1 antibody (10 mg/kg weekly for 4 doses).
PF-06747143 (at 10 mg/kg), daunorubicin, and crenolanib all significantly reduced the number of tumor cells in the peripheral blood and BM when compared with the control antibody (P<0.05).
PF-06746143 treatment (at 10 mg/kg) reduced the number of AML cells in the BM by 95.9%, while daunorubicin reduced them by 84.5% and crenolanib by 80.5%.
The median survival was 36 days for mice that received PF-06747143 at 0.1 mg/kg, 41 days for mice that received the control antibody, 47 days for mice that received PF-06747143 at 1 mg/kg, and 63 days for mice that received PF-06747143 at 10 mg/kg.
The researchers also found that PF-06747143 had a “strong combinatorial effect” with daunorubicin and cytarabine in a chemotherapy-resistant model of AML. The team noted that only 36% of BM cells are positive for CXCR4 in this model.
Treatment with PF-06747143 alone reduced the percentage of AML cells in the BM to 80%, combination daunorubicin and cytarabine reduced it to 27%, and combination PF-06747143, daunorubicin, and cytarabine reduced the percentage of AML cells in the BM to 0.3%.
“Our preliminary preclinical results are encouraging,” Dr Pernasetti said, “and we are very excited to see how our antibody fares in clinical testing.”
PF-06747143 is currently being evaluated in a phase 1 trial of AML patients.
An investigational antibody has demonstrated activity against acute myeloid leukemia (AML), multiple myeloma (MM), and non-Hodgkin lymphoma (NHL), according to researchers.
PF-06747143 is a humanized CXCR4 immunoglobulin G1 (IgG1) antibody that binds to CXCR4 and inhibits both CXCL12-mediated signaling pathways and cell migration.
Whether given alone or in combination with chemotherapy, PF-06747143 demonstrated efficacy in mouse models of NHL, MM, and AML.
Treatment involving PF-06747143—alone or in combination—eradicated more cancer cells than did standard treatment options.
These results were published in Blood Advances. The research was sponsored by Pfizer, Inc., the company developing PF-06747143.
“One of the major limitations we see in treating blood cancers is the failure to clear cancer cells from the bone marrow,” said study author Flavia Pernasetti, PhD, of Pfizer Oncology Research and Development.
“Because the bone marrow allows the cancer cells to flourish, removing these cells is an essential step in treating these malignancies effectively.”
With this goal in mind, Dr Pernasetti and her colleagues looked to the mechanisms that control the movement of cells into the bone marrow (BM) in the first place—the chemokine receptor CXCR4 and its ligand CXCL12.
The researchers created PF-06747143, which attacks and kills cancer cells directly but also removes cancer cells from the BM so they can be killed by other treatments.
Results in NHL
The researchers first tested PF-06747143 in an NHL Ramos xenograft model. Mice received PF-06747143 or a control IgG1 antibody at 10 mg/kg on days 1 and 8.
PF-06747143 significantly inhibited tumor growth compared to the control antibody (P<0.0001). Seventy percent of PF-06747143-treated mice had tumor volumes below their initial size at the end of the study.
PF-06747143 produced a dose-dependent response that was sustained until the end of the study, even after treatment was stopped.
Results in MM
The researchers tested PF-06747143 in a disseminated MM model, in which the OPM2-Luc tumor cells were implanted intravenously and migrated spontaneously to the BM.
Mice received PF-06747143 or IgG1 control at 10 mg/kg weekly for 5 doses. Other mice received melphalan at 1 mg/kg twice a week for a total of 4 cycles.
On day 30, PF-06747143 had significantly inhibited BM tumor growth compared to the control antibody or melphalan (P<0.0001).
PF-06747143-treated mice also had a significant survival benefit. The median survival was 33.5 days for mice that received the control antibody and 36 days for mice treated with melphalan. However, there were no deaths in the PF-06747143-treated mice by day 50, which marked the end of the study (P<0.0001).
The researchers also tested PF-06747143 at a lower dose (1 mg/kg weekly for a total of 7 doses), both alone and in combination with bortezomib (0.5 mg/kg twice a week for a total of 4 cycles).
The median survival was 34 days in the control mice, 44 days in mice that received bortezomib alone, and 47 days in mice that received PF-06747143 alone. However, there were no deaths in the combination arm at day 51, which was the end of the study (P<0.0003).
Results in AML
The researchers tested PF-06747143 in an AML disseminated tumor model using MV4-11 cells.
They compared PF-06747143 (given at 0.1, 1, or 10 mg/kg weekly for 4 doses) to the chemotherapeutic agent daunorubicin (2 mg/kg on days 1, 3, and 5), the FLT3 inhibitor crenolanib (7.5 mg/kg twice a day, on days 11-15 and 25-29), and a control IgG1 antibody (10 mg/kg weekly for 4 doses).
PF-06747143 (at 10 mg/kg), daunorubicin, and crenolanib all significantly reduced the number of tumor cells in the peripheral blood and BM when compared with the control antibody (P<0.05).
PF-06746143 treatment (at 10 mg/kg) reduced the number of AML cells in the BM by 95.9%, while daunorubicin reduced them by 84.5% and crenolanib by 80.5%.
The median survival was 36 days for mice that received PF-06747143 at 0.1 mg/kg, 41 days for mice that received the control antibody, 47 days for mice that received PF-06747143 at 1 mg/kg, and 63 days for mice that received PF-06747143 at 10 mg/kg.
The researchers also found that PF-06747143 had a “strong combinatorial effect” with daunorubicin and cytarabine in a chemotherapy-resistant model of AML. The team noted that only 36% of BM cells are positive for CXCR4 in this model.
Treatment with PF-06747143 alone reduced the percentage of AML cells in the BM to 80%, combination daunorubicin and cytarabine reduced it to 27%, and combination PF-06747143, daunorubicin, and cytarabine reduced the percentage of AML cells in the BM to 0.3%.
“Our preliminary preclinical results are encouraging,” Dr Pernasetti said, “and we are very excited to see how our antibody fares in clinical testing.”
PF-06747143 is currently being evaluated in a phase 1 trial of AML patients.
FDA grants drug orphan designation for AML
The US Food and Drug Administration (FDA) has granted orphan drug designation to SY-1425 for the treatment of acute myeloid leukemia (AML).
SY-1425 is an oral, first-in-class, selective retinoic acid receptor alpha (RARα) agonist. It is currently under investigation in a phase 2 trial of patients with AML and myelodysplastic syndromes (MDS).
“We believe that SY-1425 may provide a meaningful benefit for subsets of AML patients whose disease is driven by abnormally high expression of the RARA or IRF8 genes,” said David A. Roth, MD, chief medical officer at Syros Pharmaceuticals, the company developing SY-1425.
“Receiving orphan drug designation is an important regulatory milestone in the development of SY-1425. We’re pleased with the continued progress of the ongoing phase 2 clinical trial, and we look forward to presenting initial clinical data in the fourth quarter of this year.”
Using its gene control platform, Syros discovered subsets of AML and MDS patients with super-enhancers associated with RARA or IRF8. These super-enhancers are believed to drive overexpression of the RARA or IRF8 genes, locking cells in an immature, undifferentiated, and proliferative state and leading to disease.
In preclinical studies, SY-1425 promoted differentiation of AML cells with high RARA or IRF8 expression and inhibited tumor growth and prolonged survival in patient-derived xenograft models of AML with high RARA expression.
In the ongoing phase 2 trial, researchers are assessing the safety and efficacy of SY-1425 as a single agent in 4 AML and MDS patient populations, as well as SY-1425 in combination with azacitidine in newly diagnosed AML patients who are not suitable candidates for standard chemotherapy.
All patients are prospectively selected using biomarkers for high expression of RARA or IRF8. Additional details about the trial can be found at https://clinicaltrials.gov/ct2/show/NCT02807558.
About orphan designation
The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.
The US Food and Drug Administration (FDA) has granted orphan drug designation to SY-1425 for the treatment of acute myeloid leukemia (AML).
SY-1425 is an oral, first-in-class, selective retinoic acid receptor alpha (RARα) agonist. It is currently under investigation in a phase 2 trial of patients with AML and myelodysplastic syndromes (MDS).
“We believe that SY-1425 may provide a meaningful benefit for subsets of AML patients whose disease is driven by abnormally high expression of the RARA or IRF8 genes,” said David A. Roth, MD, chief medical officer at Syros Pharmaceuticals, the company developing SY-1425.
“Receiving orphan drug designation is an important regulatory milestone in the development of SY-1425. We’re pleased with the continued progress of the ongoing phase 2 clinical trial, and we look forward to presenting initial clinical data in the fourth quarter of this year.”
Using its gene control platform, Syros discovered subsets of AML and MDS patients with super-enhancers associated with RARA or IRF8. These super-enhancers are believed to drive overexpression of the RARA or IRF8 genes, locking cells in an immature, undifferentiated, and proliferative state and leading to disease.
In preclinical studies, SY-1425 promoted differentiation of AML cells with high RARA or IRF8 expression and inhibited tumor growth and prolonged survival in patient-derived xenograft models of AML with high RARA expression.
In the ongoing phase 2 trial, researchers are assessing the safety and efficacy of SY-1425 as a single agent in 4 AML and MDS patient populations, as well as SY-1425 in combination with azacitidine in newly diagnosed AML patients who are not suitable candidates for standard chemotherapy.
All patients are prospectively selected using biomarkers for high expression of RARA or IRF8. Additional details about the trial can be found at https://clinicaltrials.gov/ct2/show/NCT02807558.
About orphan designation
The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.
The US Food and Drug Administration (FDA) has granted orphan drug designation to SY-1425 for the treatment of acute myeloid leukemia (AML).
SY-1425 is an oral, first-in-class, selective retinoic acid receptor alpha (RARα) agonist. It is currently under investigation in a phase 2 trial of patients with AML and myelodysplastic syndromes (MDS).
“We believe that SY-1425 may provide a meaningful benefit for subsets of AML patients whose disease is driven by abnormally high expression of the RARA or IRF8 genes,” said David A. Roth, MD, chief medical officer at Syros Pharmaceuticals, the company developing SY-1425.
“Receiving orphan drug designation is an important regulatory milestone in the development of SY-1425. We’re pleased with the continued progress of the ongoing phase 2 clinical trial, and we look forward to presenting initial clinical data in the fourth quarter of this year.”
Using its gene control platform, Syros discovered subsets of AML and MDS patients with super-enhancers associated with RARA or IRF8. These super-enhancers are believed to drive overexpression of the RARA or IRF8 genes, locking cells in an immature, undifferentiated, and proliferative state and leading to disease.
In preclinical studies, SY-1425 promoted differentiation of AML cells with high RARA or IRF8 expression and inhibited tumor growth and prolonged survival in patient-derived xenograft models of AML with high RARA expression.
In the ongoing phase 2 trial, researchers are assessing the safety and efficacy of SY-1425 as a single agent in 4 AML and MDS patient populations, as well as SY-1425 in combination with azacitidine in newly diagnosed AML patients who are not suitable candidates for standard chemotherapy.
All patients are prospectively selected using biomarkers for high expression of RARA or IRF8. Additional details about the trial can be found at https://clinicaltrials.gov/ct2/show/NCT02807558.
About orphan designation
The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.
FDA grants drug orphan designation for AML, CMML
The US Food and Drug Administration (FDA) has granted orphan drug designation to H3B-8800 as a treatment for patients with acute myelogenous leukemia (AML) or chronic myelomonocytic leukemia (CMML).
The FDA grants orphan designation to drugs and biologics intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.
About H3B-8800
H3B-8800 is an orally bioavailable small-molecule modulator of wild-type and mutant SF3b complexes. The SF3b complex is a key component of the spliceosome that is found in the cell nucleus and is responsible for the removal of noncoding introns from a transcribed pre-messenger RNA.
Recurrent heterozygous mutations in several core members of the spliceosome (SF3B1, U2AF1, SRSF2, and ZRSR2) have been identified in solid tumor and hematologic malignancies. Mutations in the core spliceosome components lead to aberrant mRNA splicing that may contribute to disease pathogenesis.
Preclinical data have suggested that H3B-8800 modulates RNA splicing and shows preferential antitumor activity in spliceosome-mutant cancer models, including models of AML and CMML. H3B-8800 showed dose-dependent modulation of canonical and aberrant splicing when administered at tolerated doses.
Results from this research were presented at the 2017 AACR Annual Meeting (abstract 1185).
H3B-8800 is currently under investigation in a phase 1 trial of patients with AML, CMML, and myelodysplastic syndromes that may carry mutations in the core spliceosome genes.
H3B-8800 is being developed by H3 Biomedicine Inc.
The US Food and Drug Administration (FDA) has granted orphan drug designation to H3B-8800 as a treatment for patients with acute myelogenous leukemia (AML) or chronic myelomonocytic leukemia (CMML).
The FDA grants orphan designation to drugs and biologics intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.
About H3B-8800
H3B-8800 is an orally bioavailable small-molecule modulator of wild-type and mutant SF3b complexes. The SF3b complex is a key component of the spliceosome that is found in the cell nucleus and is responsible for the removal of noncoding introns from a transcribed pre-messenger RNA.
Recurrent heterozygous mutations in several core members of the spliceosome (SF3B1, U2AF1, SRSF2, and ZRSR2) have been identified in solid tumor and hematologic malignancies. Mutations in the core spliceosome components lead to aberrant mRNA splicing that may contribute to disease pathogenesis.
Preclinical data have suggested that H3B-8800 modulates RNA splicing and shows preferential antitumor activity in spliceosome-mutant cancer models, including models of AML and CMML. H3B-8800 showed dose-dependent modulation of canonical and aberrant splicing when administered at tolerated doses.
Results from this research were presented at the 2017 AACR Annual Meeting (abstract 1185).
H3B-8800 is currently under investigation in a phase 1 trial of patients with AML, CMML, and myelodysplastic syndromes that may carry mutations in the core spliceosome genes.
H3B-8800 is being developed by H3 Biomedicine Inc.
The US Food and Drug Administration (FDA) has granted orphan drug designation to H3B-8800 as a treatment for patients with acute myelogenous leukemia (AML) or chronic myelomonocytic leukemia (CMML).
The FDA grants orphan designation to drugs and biologics intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.
About H3B-8800
H3B-8800 is an orally bioavailable small-molecule modulator of wild-type and mutant SF3b complexes. The SF3b complex is a key component of the spliceosome that is found in the cell nucleus and is responsible for the removal of noncoding introns from a transcribed pre-messenger RNA.
Recurrent heterozygous mutations in several core members of the spliceosome (SF3B1, U2AF1, SRSF2, and ZRSR2) have been identified in solid tumor and hematologic malignancies. Mutations in the core spliceosome components lead to aberrant mRNA splicing that may contribute to disease pathogenesis.
Preclinical data have suggested that H3B-8800 modulates RNA splicing and shows preferential antitumor activity in spliceosome-mutant cancer models, including models of AML and CMML. H3B-8800 showed dose-dependent modulation of canonical and aberrant splicing when administered at tolerated doses.
Results from this research were presented at the 2017 AACR Annual Meeting (abstract 1185).
H3B-8800 is currently under investigation in a phase 1 trial of patients with AML, CMML, and myelodysplastic syndromes that may carry mutations in the core spliceosome genes.
H3B-8800 is being developed by H3 Biomedicine Inc.
Hospice care underused in older patients with de novo AML
Although adults older than 65 newly diagnosed with acute myeloid leukemia (AML) have a generally poor prognosis and short life expectancy, fewer than half were enrolled in hospice, and of those patients who were enrolled, two-thirds entered hospice within the last week of life, results of a retrospective cohort study show.
The findings suggest that there is substantial room for improvement in the care of older patients with AML in their last days of life, said investigators led by Rong Wang, PhD, and colleagues from Yale University in New Haven, Connecticut.
“[We] found that the current end-of-life care for older patients with AML is suboptimal, as reflected by low hospice enrollment and high use of potentially aggressive treatment. Transfer in and out of hospice was associated with the receipt of transfusions. Changes to current hospice services, such as enabling the provision of transfusion support, and improvements in physician-patient communications, may help facilitate better end-of-life care in this patient population,” they wrote (J Clin Oncol. 2017 Aug 7. doi: 10.1200/JCO.2017.72.7149)
Patients aged 65 and over with AML have a median overall survival (OS) of only about 2 months, and the older the patient, the worse the survival, with patients 85 and older having a median OS of just 1 month, the investigators noted.
“Hence, end-of-life care is particularly relevant for this patient population,” they wrote.
To get a better idea of how clinicians prescribe hospice and palliative care for older patients with AML, Dr. Wang and colleagues conducted a population-based, retrospective cohort study of patients with AML who were 66 or older at diagnosis, received a diagnosis from 1999 through 2011, and died before the end of 2012.
They reviewed Medicare claims data on 13,156 patients to see whether patients were receiving aggressive care such as chemotherapy and whether and when they were enrolled in hospice.
The investigators found that the proportion of patients who were enrolled in hospice after an AML diagnosis increased from 31.3% in 1999 to 56.4% in 2012 (P for trend less than .01).
They also discovered, however, that most of the increase was attributable to patients who were enrolled within the last week of life.
When they compared patients who died within 30 days of diagnosis to those who lived longer than 30 days after diagnosis, they found that the longer-lived patients were significantly more likely to have been enrolled in hospice (48.1% vs. 30.7%, P less than .01). Additionally, of those patients who were enrolled in hospice, 51.2% of those who died within 30 days of entering hospice had been enrolled in the last 3 days of life, compared with 24.9% of those who survived for more than a month after entering hospice (P value not shown).
Over the course of the study 1,528 patients (11.6%) had chemotherapy within their last two weeks of life. The proportion of patients undergoing chemotherapy within their last 14 days increased from 7.7% in 1999 to 18.8% in 2012 (P for trend less than .01).
Patients who had end-of-life chemotherapy were significantly more likely to have had an ICU stay in the last month of life (43.0% vs. 28.4%; P less than .01) and were significantly more likely to be enrolled in hospice (22.1% vs. 47.4%, P less than .01) than patients who did not get chemotherapy with the last 14 days of life.
Predictors for end-of-life chemotherapy were male sex, being married, and dying in more recent years. Patients who were older, had state Medicaid buy-in (an optional program for workers with disabilities), or who lived outside the Northeast or major metropolitan areas were less likely to be subjected to chemotherapy in their final days.
Overall, 3,956 patients (30.1%) were admitted to the ICU within 30 days of their deaths. The percentage of ICU admissions just before death increased from 25.2% in 1999 to 31.3% in 2012 (P for trend .01).
Predictors for late-life ICU admission were similar to those for chemotherapy, except that patients with state Medicaid buy-in had 19% greater odds of being admitted to an ICU within 30 days of death (P less than .01).
The study was funded by the National Cancer Institute. Dr. Wang reported no relevant conflicts of interests. Multiple coauthors reported financial relationships with various companies.
Although adults older than 65 newly diagnosed with acute myeloid leukemia (AML) have a generally poor prognosis and short life expectancy, fewer than half were enrolled in hospice, and of those patients who were enrolled, two-thirds entered hospice within the last week of life, results of a retrospective cohort study show.
The findings suggest that there is substantial room for improvement in the care of older patients with AML in their last days of life, said investigators led by Rong Wang, PhD, and colleagues from Yale University in New Haven, Connecticut.
“[We] found that the current end-of-life care for older patients with AML is suboptimal, as reflected by low hospice enrollment and high use of potentially aggressive treatment. Transfer in and out of hospice was associated with the receipt of transfusions. Changes to current hospice services, such as enabling the provision of transfusion support, and improvements in physician-patient communications, may help facilitate better end-of-life care in this patient population,” they wrote (J Clin Oncol. 2017 Aug 7. doi: 10.1200/JCO.2017.72.7149)
Patients aged 65 and over with AML have a median overall survival (OS) of only about 2 months, and the older the patient, the worse the survival, with patients 85 and older having a median OS of just 1 month, the investigators noted.
“Hence, end-of-life care is particularly relevant for this patient population,” they wrote.
To get a better idea of how clinicians prescribe hospice and palliative care for older patients with AML, Dr. Wang and colleagues conducted a population-based, retrospective cohort study of patients with AML who were 66 or older at diagnosis, received a diagnosis from 1999 through 2011, and died before the end of 2012.
They reviewed Medicare claims data on 13,156 patients to see whether patients were receiving aggressive care such as chemotherapy and whether and when they were enrolled in hospice.
The investigators found that the proportion of patients who were enrolled in hospice after an AML diagnosis increased from 31.3% in 1999 to 56.4% in 2012 (P for trend less than .01).
They also discovered, however, that most of the increase was attributable to patients who were enrolled within the last week of life.
When they compared patients who died within 30 days of diagnosis to those who lived longer than 30 days after diagnosis, they found that the longer-lived patients were significantly more likely to have been enrolled in hospice (48.1% vs. 30.7%, P less than .01). Additionally, of those patients who were enrolled in hospice, 51.2% of those who died within 30 days of entering hospice had been enrolled in the last 3 days of life, compared with 24.9% of those who survived for more than a month after entering hospice (P value not shown).
Over the course of the study 1,528 patients (11.6%) had chemotherapy within their last two weeks of life. The proportion of patients undergoing chemotherapy within their last 14 days increased from 7.7% in 1999 to 18.8% in 2012 (P for trend less than .01).
Patients who had end-of-life chemotherapy were significantly more likely to have had an ICU stay in the last month of life (43.0% vs. 28.4%; P less than .01) and were significantly more likely to be enrolled in hospice (22.1% vs. 47.4%, P less than .01) than patients who did not get chemotherapy with the last 14 days of life.
Predictors for end-of-life chemotherapy were male sex, being married, and dying in more recent years. Patients who were older, had state Medicaid buy-in (an optional program for workers with disabilities), or who lived outside the Northeast or major metropolitan areas were less likely to be subjected to chemotherapy in their final days.
Overall, 3,956 patients (30.1%) were admitted to the ICU within 30 days of their deaths. The percentage of ICU admissions just before death increased from 25.2% in 1999 to 31.3% in 2012 (P for trend .01).
Predictors for late-life ICU admission were similar to those for chemotherapy, except that patients with state Medicaid buy-in had 19% greater odds of being admitted to an ICU within 30 days of death (P less than .01).
The study was funded by the National Cancer Institute. Dr. Wang reported no relevant conflicts of interests. Multiple coauthors reported financial relationships with various companies.
Although adults older than 65 newly diagnosed with acute myeloid leukemia (AML) have a generally poor prognosis and short life expectancy, fewer than half were enrolled in hospice, and of those patients who were enrolled, two-thirds entered hospice within the last week of life, results of a retrospective cohort study show.
The findings suggest that there is substantial room for improvement in the care of older patients with AML in their last days of life, said investigators led by Rong Wang, PhD, and colleagues from Yale University in New Haven, Connecticut.
“[We] found that the current end-of-life care for older patients with AML is suboptimal, as reflected by low hospice enrollment and high use of potentially aggressive treatment. Transfer in and out of hospice was associated with the receipt of transfusions. Changes to current hospice services, such as enabling the provision of transfusion support, and improvements in physician-patient communications, may help facilitate better end-of-life care in this patient population,” they wrote (J Clin Oncol. 2017 Aug 7. doi: 10.1200/JCO.2017.72.7149)
Patients aged 65 and over with AML have a median overall survival (OS) of only about 2 months, and the older the patient, the worse the survival, with patients 85 and older having a median OS of just 1 month, the investigators noted.
“Hence, end-of-life care is particularly relevant for this patient population,” they wrote.
To get a better idea of how clinicians prescribe hospice and palliative care for older patients with AML, Dr. Wang and colleagues conducted a population-based, retrospective cohort study of patients with AML who were 66 or older at diagnosis, received a diagnosis from 1999 through 2011, and died before the end of 2012.
They reviewed Medicare claims data on 13,156 patients to see whether patients were receiving aggressive care such as chemotherapy and whether and when they were enrolled in hospice.
The investigators found that the proportion of patients who were enrolled in hospice after an AML diagnosis increased from 31.3% in 1999 to 56.4% in 2012 (P for trend less than .01).
They also discovered, however, that most of the increase was attributable to patients who were enrolled within the last week of life.
When they compared patients who died within 30 days of diagnosis to those who lived longer than 30 days after diagnosis, they found that the longer-lived patients were significantly more likely to have been enrolled in hospice (48.1% vs. 30.7%, P less than .01). Additionally, of those patients who were enrolled in hospice, 51.2% of those who died within 30 days of entering hospice had been enrolled in the last 3 days of life, compared with 24.9% of those who survived for more than a month after entering hospice (P value not shown).
Over the course of the study 1,528 patients (11.6%) had chemotherapy within their last two weeks of life. The proportion of patients undergoing chemotherapy within their last 14 days increased from 7.7% in 1999 to 18.8% in 2012 (P for trend less than .01).
Patients who had end-of-life chemotherapy were significantly more likely to have had an ICU stay in the last month of life (43.0% vs. 28.4%; P less than .01) and were significantly more likely to be enrolled in hospice (22.1% vs. 47.4%, P less than .01) than patients who did not get chemotherapy with the last 14 days of life.
Predictors for end-of-life chemotherapy were male sex, being married, and dying in more recent years. Patients who were older, had state Medicaid buy-in (an optional program for workers with disabilities), or who lived outside the Northeast or major metropolitan areas were less likely to be subjected to chemotherapy in their final days.
Overall, 3,956 patients (30.1%) were admitted to the ICU within 30 days of their deaths. The percentage of ICU admissions just before death increased from 25.2% in 1999 to 31.3% in 2012 (P for trend .01).
Predictors for late-life ICU admission were similar to those for chemotherapy, except that patients with state Medicaid buy-in had 19% greater odds of being admitted to an ICU within 30 days of death (P less than .01).
The study was funded by the National Cancer Institute. Dr. Wang reported no relevant conflicts of interests. Multiple coauthors reported financial relationships with various companies.
FROM JOURNAL OF CLINICAL ONCOLOGY
Key clinical point: End-of-life care for patients 65 and older with acute myeloid leukemia is suboptimal.
Major finding: Patients who lived more than 30 days after an AML diagnosis were significantly more likely to have been enrolled in hospice than those who died within 30 days of diagnosis.
Data source: Retrospective cohort study of 13,156 patients diagnosed with AML at age 66 or older from 1999 through 2012.
Disclosures: The study was funded by the National Cancer Institute. Dr. Wang reported no relevant conflicts of interests. Multiple coauthors reported financial relationships with various companies.
VSTs can treat 5 different viral infections after HSCT
New research suggests virus-specific T cells (VSTs) can protect patients from severe viral infections that sometimes occur after hematopoietic stem cell transplant (HSCT).
The VSTs proved effective against 5 different viruses—Epstein-Barr virus (EBV), adenovirus (AdV), cytomegalovirus (CMV), BK virus (BKV), and human herpesvirus 6 (HHV-6).
Ifigeneia Tzannou, MD, of Baylor College of Medicine in Houston, Texas, and her colleagues reported these findings in the Journal of Clinical Oncology.
“In this study, we continued our previous work . . . in which we showed that patients who had developed an Epstein-Barr virus infection after a transplant . . . could be helped by receiving immune cells specialized in eliminating that particular virus,” Dr Tzannou said. “Then, we and others successfully targeted other viruses—namely, adenoviruses and cytomegalovirus.”
“The novel contribution of this study is that we have targeted additional viruses, the BK virus and the HHV-6 virus, which had not been targeted this way before,” added study author Bilal Omer, MD, of Baylor College of Medicine.
“This is important because the BK virus does not have an effective treatment, and the complications are significant, including severe pain and bleeding. These patients are in the hospital for weeks, months sometimes, and, now, we have a treatment option.”
The researchers tested their VSTs in a phase 2 trial of 38 HSCT recipients with at least 1 of the aforementioned viruses.
“[To prepare the VSTs,] we take blood from healthy donors who have already been exposed to these viruses and who we have confirmed have immune cells that can fight the infections,” Dr Tzannou said.
“We isolate the cells and let them multiply in culture. The final product is a mixture of cells that, together, can target all 5 viruses. We prepared 59 sets of virus-specific cells from different donors following this procedure.”
“Our strategy is to prepare a number of sets of virus-specific cells ahead of time and store them in a freezer, ready to use when a patient needs them,” Dr Omer noted. “To match patient and donor, we use elaborate matching algorithms.”
Patients
The trial included 38 patients who had undergone HSCT to treat acute myeloid leukemia/myelodysplastic syndromes (n=20), acute lymphoblastic leukemia (n=9), lymphoma/myeloma (n=3), or nonmalignant disorders (n=6).
These 38 patients had a total of 45 infections—CMV (n=17), EBV (n=2), AdV (n=7), BKV (n=16), and HHV-6 (n=3).
Response
The researchers monitored virus levels and other clinical responses in the 37 evaluable patients.
Six weeks after the first VST infusion, the overall response rate was 91.9%.
Seventeen patients received VSTs for persistent CMV. Sixteen of these patients (94.1%) responded, 6 with complete responses (CRs) and 10 with partial responses (PRs).
Two patients received VSTs for EBV, and both achieved a virologic CR.
Seven patients received VSTs for persistent AdV. The response rate was 71.4%. Four patients achieved a CR, 1 had a PR, and 2 patients did not respond.
Three patients received VSTs to treat HHV-6 reactivations. The response rate was 67%. Two patients had a PR, and 1 was not evaluable.
Sixteen patients received VSTs for BKV-associated hemorrhagic cystitis (n= 14) or BKV-associated nephritis (n=2).
All 16 patients responded. One had a clinical and virologic CR. Six had a clinical CR but a virologic PR. Seven had a virologic and clinical PR. And 2 patients had only a virologic PR.
A total of 15 patients received a second VST infusion—1 due to lack of response, 7 who had a PR, and 7 due to recurrence. Ten of these patients responded to the second infusion—1 with a CR and 9 with a PR.
Four patients received a third infusion of VSTs. Two achieved a CR, 1 had a PR, and 1 did not respond.
Toxicity
One patient developed an isolated fever within 24 hours of VST infusion, but the researchers did not observe any other immediate toxicities.
One of the patients with BKV-associated hemorrhagic cystitis experienced transient hydronephrosis and a decrease in renal function associated with a concomitant bacterial urinary tract infection.
Nineteen patients had prior grade 2 to 4 graft-versus-host disease (GVHD)—15 with grade 2 and 4 with grade 3. All GVHD was quiescent at the time of VST infusion.
One patient developed recurrent grade 3 gastrointestinal GVHD after VST infusion and rapid corticosteroid taper. Five patients developed recurrent (n=3) or de novo (n=2) grade 1 to 2 skin GVHD, which resolved with topical treatment (n=4) and reinitiation of corticosteroid treatment (n=1).
Two patients had a flare of upper-gastrointestinal GVHD, which resolved after a brief corticosteroid course.
“We didn’t have any significant toxicities,” Dr Tzannou said. “Taken together, the results of this trial suggest that it is reasonable to consider this treatment as an early option for these patients. We hope that the results of a future multicenter, phase 3 clinical trial will help raise awareness in both physicians and patients that this treatment, which is safe and effective, is available.”
New research suggests virus-specific T cells (VSTs) can protect patients from severe viral infections that sometimes occur after hematopoietic stem cell transplant (HSCT).
The VSTs proved effective against 5 different viruses—Epstein-Barr virus (EBV), adenovirus (AdV), cytomegalovirus (CMV), BK virus (BKV), and human herpesvirus 6 (HHV-6).
Ifigeneia Tzannou, MD, of Baylor College of Medicine in Houston, Texas, and her colleagues reported these findings in the Journal of Clinical Oncology.
“In this study, we continued our previous work . . . in which we showed that patients who had developed an Epstein-Barr virus infection after a transplant . . . could be helped by receiving immune cells specialized in eliminating that particular virus,” Dr Tzannou said. “Then, we and others successfully targeted other viruses—namely, adenoviruses and cytomegalovirus.”
“The novel contribution of this study is that we have targeted additional viruses, the BK virus and the HHV-6 virus, which had not been targeted this way before,” added study author Bilal Omer, MD, of Baylor College of Medicine.
“This is important because the BK virus does not have an effective treatment, and the complications are significant, including severe pain and bleeding. These patients are in the hospital for weeks, months sometimes, and, now, we have a treatment option.”
The researchers tested their VSTs in a phase 2 trial of 38 HSCT recipients with at least 1 of the aforementioned viruses.
“[To prepare the VSTs,] we take blood from healthy donors who have already been exposed to these viruses and who we have confirmed have immune cells that can fight the infections,” Dr Tzannou said.
“We isolate the cells and let them multiply in culture. The final product is a mixture of cells that, together, can target all 5 viruses. We prepared 59 sets of virus-specific cells from different donors following this procedure.”
“Our strategy is to prepare a number of sets of virus-specific cells ahead of time and store them in a freezer, ready to use when a patient needs them,” Dr Omer noted. “To match patient and donor, we use elaborate matching algorithms.”
Patients
The trial included 38 patients who had undergone HSCT to treat acute myeloid leukemia/myelodysplastic syndromes (n=20), acute lymphoblastic leukemia (n=9), lymphoma/myeloma (n=3), or nonmalignant disorders (n=6).
These 38 patients had a total of 45 infections—CMV (n=17), EBV (n=2), AdV (n=7), BKV (n=16), and HHV-6 (n=3).
Response
The researchers monitored virus levels and other clinical responses in the 37 evaluable patients.
Six weeks after the first VST infusion, the overall response rate was 91.9%.
Seventeen patients received VSTs for persistent CMV. Sixteen of these patients (94.1%) responded, 6 with complete responses (CRs) and 10 with partial responses (PRs).
Two patients received VSTs for EBV, and both achieved a virologic CR.
Seven patients received VSTs for persistent AdV. The response rate was 71.4%. Four patients achieved a CR, 1 had a PR, and 2 patients did not respond.
Three patients received VSTs to treat HHV-6 reactivations. The response rate was 67%. Two patients had a PR, and 1 was not evaluable.
Sixteen patients received VSTs for BKV-associated hemorrhagic cystitis (n= 14) or BKV-associated nephritis (n=2).
All 16 patients responded. One had a clinical and virologic CR. Six had a clinical CR but a virologic PR. Seven had a virologic and clinical PR. And 2 patients had only a virologic PR.
A total of 15 patients received a second VST infusion—1 due to lack of response, 7 who had a PR, and 7 due to recurrence. Ten of these patients responded to the second infusion—1 with a CR and 9 with a PR.
Four patients received a third infusion of VSTs. Two achieved a CR, 1 had a PR, and 1 did not respond.
Toxicity
One patient developed an isolated fever within 24 hours of VST infusion, but the researchers did not observe any other immediate toxicities.
One of the patients with BKV-associated hemorrhagic cystitis experienced transient hydronephrosis and a decrease in renal function associated with a concomitant bacterial urinary tract infection.
Nineteen patients had prior grade 2 to 4 graft-versus-host disease (GVHD)—15 with grade 2 and 4 with grade 3. All GVHD was quiescent at the time of VST infusion.
One patient developed recurrent grade 3 gastrointestinal GVHD after VST infusion and rapid corticosteroid taper. Five patients developed recurrent (n=3) or de novo (n=2) grade 1 to 2 skin GVHD, which resolved with topical treatment (n=4) and reinitiation of corticosteroid treatment (n=1).
Two patients had a flare of upper-gastrointestinal GVHD, which resolved after a brief corticosteroid course.
“We didn’t have any significant toxicities,” Dr Tzannou said. “Taken together, the results of this trial suggest that it is reasonable to consider this treatment as an early option for these patients. We hope that the results of a future multicenter, phase 3 clinical trial will help raise awareness in both physicians and patients that this treatment, which is safe and effective, is available.”
New research suggests virus-specific T cells (VSTs) can protect patients from severe viral infections that sometimes occur after hematopoietic stem cell transplant (HSCT).
The VSTs proved effective against 5 different viruses—Epstein-Barr virus (EBV), adenovirus (AdV), cytomegalovirus (CMV), BK virus (BKV), and human herpesvirus 6 (HHV-6).
Ifigeneia Tzannou, MD, of Baylor College of Medicine in Houston, Texas, and her colleagues reported these findings in the Journal of Clinical Oncology.
“In this study, we continued our previous work . . . in which we showed that patients who had developed an Epstein-Barr virus infection after a transplant . . . could be helped by receiving immune cells specialized in eliminating that particular virus,” Dr Tzannou said. “Then, we and others successfully targeted other viruses—namely, adenoviruses and cytomegalovirus.”
“The novel contribution of this study is that we have targeted additional viruses, the BK virus and the HHV-6 virus, which had not been targeted this way before,” added study author Bilal Omer, MD, of Baylor College of Medicine.
“This is important because the BK virus does not have an effective treatment, and the complications are significant, including severe pain and bleeding. These patients are in the hospital for weeks, months sometimes, and, now, we have a treatment option.”
The researchers tested their VSTs in a phase 2 trial of 38 HSCT recipients with at least 1 of the aforementioned viruses.
“[To prepare the VSTs,] we take blood from healthy donors who have already been exposed to these viruses and who we have confirmed have immune cells that can fight the infections,” Dr Tzannou said.
“We isolate the cells and let them multiply in culture. The final product is a mixture of cells that, together, can target all 5 viruses. We prepared 59 sets of virus-specific cells from different donors following this procedure.”
“Our strategy is to prepare a number of sets of virus-specific cells ahead of time and store them in a freezer, ready to use when a patient needs them,” Dr Omer noted. “To match patient and donor, we use elaborate matching algorithms.”
Patients
The trial included 38 patients who had undergone HSCT to treat acute myeloid leukemia/myelodysplastic syndromes (n=20), acute lymphoblastic leukemia (n=9), lymphoma/myeloma (n=3), or nonmalignant disorders (n=6).
These 38 patients had a total of 45 infections—CMV (n=17), EBV (n=2), AdV (n=7), BKV (n=16), and HHV-6 (n=3).
Response
The researchers monitored virus levels and other clinical responses in the 37 evaluable patients.
Six weeks after the first VST infusion, the overall response rate was 91.9%.
Seventeen patients received VSTs for persistent CMV. Sixteen of these patients (94.1%) responded, 6 with complete responses (CRs) and 10 with partial responses (PRs).
Two patients received VSTs for EBV, and both achieved a virologic CR.
Seven patients received VSTs for persistent AdV. The response rate was 71.4%. Four patients achieved a CR, 1 had a PR, and 2 patients did not respond.
Three patients received VSTs to treat HHV-6 reactivations. The response rate was 67%. Two patients had a PR, and 1 was not evaluable.
Sixteen patients received VSTs for BKV-associated hemorrhagic cystitis (n= 14) or BKV-associated nephritis (n=2).
All 16 patients responded. One had a clinical and virologic CR. Six had a clinical CR but a virologic PR. Seven had a virologic and clinical PR. And 2 patients had only a virologic PR.
A total of 15 patients received a second VST infusion—1 due to lack of response, 7 who had a PR, and 7 due to recurrence. Ten of these patients responded to the second infusion—1 with a CR and 9 with a PR.
Four patients received a third infusion of VSTs. Two achieved a CR, 1 had a PR, and 1 did not respond.
Toxicity
One patient developed an isolated fever within 24 hours of VST infusion, but the researchers did not observe any other immediate toxicities.
One of the patients with BKV-associated hemorrhagic cystitis experienced transient hydronephrosis and a decrease in renal function associated with a concomitant bacterial urinary tract infection.
Nineteen patients had prior grade 2 to 4 graft-versus-host disease (GVHD)—15 with grade 2 and 4 with grade 3. All GVHD was quiescent at the time of VST infusion.
One patient developed recurrent grade 3 gastrointestinal GVHD after VST infusion and rapid corticosteroid taper. Five patients developed recurrent (n=3) or de novo (n=2) grade 1 to 2 skin GVHD, which resolved with topical treatment (n=4) and reinitiation of corticosteroid treatment (n=1).
Two patients had a flare of upper-gastrointestinal GVHD, which resolved after a brief corticosteroid course.
“We didn’t have any significant toxicities,” Dr Tzannou said. “Taken together, the results of this trial suggest that it is reasonable to consider this treatment as an early option for these patients. We hope that the results of a future multicenter, phase 3 clinical trial will help raise awareness in both physicians and patients that this treatment, which is safe and effective, is available.”