AML

AMSTERDAM – Patients with acute myeloid leukemia who were in morphological complete remission prior to allogeneic hematopoietic cell transplant but had genomic evidence of a lingering AML variant had worse posttransplant outcomes when they underwent reduced-intensity conditioning, rather than myeloablative conditioning, investigators reported.

Among adults with AML in remission after induction therapy who were randomized in a clinical trial to either reduced-intensity conditioning (RIC) or myeloablative conditioning prior to transplant, those with known AML variants detected with ultra-deep genomic sequencing who underwent RIC had significantly greater risk for relapse, decreased disease-free survival (DFS), and worse overall survival (OS), compared with similar patients who underwent myeloablative conditioning (MAC), reported Christopher S. Hourigan, DM, DPhil, of the Laboratory of Myeloid Malignancies at the National Heart, Lung, and Blood Institute in Bethesda, Md.

The findings suggest that those patients with pretransplant AML variants who can tolerate MAC should get it, and that investigators need to find new options for patients who can’t, he said in an interview at the annual congress of the European Hematology Association.

“If I wasn’t a lab investigator and was a clinical trialist, I would be very excited about doing some randomized trials now to try see about novel targeted agents. For example, we have FLT3 inhibitors, we have IDH1 and IDH2 inhibitors, and I would be looking to try to combine reduced-intensity conditioning with additional therapy to try to lower the relapse rate for that group at the highest risk,” he said.

Previous studies have shown that, regardless of the method used – flow cytometry, quantitative polymerase chain reaction, or next-generation sequencing – minimal residual disease (MRD) detected in patients with AML in complete remission prior to transplant is associated with both cumulative incidence of relapse and worse overall survival.
 

Measurable, not minimal

Dr. Hourigan contends that the word “minimal” – the “M” in “MRD” – is a misnomer and should be replaced by the word “measurable,” because MRD really reflects the limitations of disease-detection technology.

“If you tell patients ‘you have minimal residual disease, and you have a huge chance of dying over the next few years,’ there’s nothing minimal about that,” he said.

The fundamental question that Dr. Hourigan and colleagues asked is, “is MRD just useful for predicting prognosis? Is this fate, or can we as doctors do something about it?”

To get answers, they examined whole-blood samples from patients enrolled in the BMT CTN 0901 trial, which compared survival and other outcomes following allogeneic hematopoietic stem cell transplants (allo-HSCT) with either RIC or MAC for pretransplant conditioning in patients with AML or the myelodysplastic syndrome.

The trial was halted early after just 272 of a planned 356 patients were enrolled, following evidence of a significantly higher relapse rate among patients who had undergone RIC.

“Strikingly, over half the AML patients receiving RIC relapsed within 18 months after getting transplants,” Dr. Hourigan said.
 

Relapse, survival differences

For this substudy, the National Institutes of Health investigators developed a custom 13-gene panel that would detect at least one AML variant in approximately 80% of patients who were included in a previous study of genomic classification and prognosis in AML.

They used ultra-deep genomic sequencing to look for variants in blood samples from 188 patients in BMT CTN 0901. There were no variants detected in the blood of 31% of patients who had undergone MAC or in 33% of those who had undergone RIC.

Among patients who did have detectable variants, the average number of variants per patient was 2.5.

In this cohort, transplant-related mortality (TRM) was higher with MAC at 27% vs. 20% with RIC at 3 years, but there were no differences in TRM within conditioning arms for patients, with or without AML variants.

Relapse rates in the cohort studied by Dr. Hourigan and his colleagues were virtually identical to those seen in the full study set, with an 18-month relapse rate of 16% for patients treated with MAC vs. 51% for those treated with RIC.

Among patients randomized to RIC, 3-year relapse rates were 57% for patients with detectable pretransplant AML variants, compared with 32% for those without variants (P less than .001).

Although there were no significant differences in 3-year OS by variant status among patients assigned to MAC, variant-positive patients assigned to RIC had significantly worse 3-year OS than those without variants (P = .04).

Among patients with no detectable variants, there were no significant differences in OS between the MAC or RIC arms. However, among patients with variants, survival was significantly worse with RIC (P = .02).

In multivariate analysis controlling for disease risk and donor group among patients who tested positive for an AML variant pretransplant, RIC was significantly associated with an increased risk for relapse (hazard ratio, 5.98; P less than .001); decreased DFS (HR, 2.80; P less than .001), and worse OS (HR, 2.16; P = .003).

“This study provides evidence that intervention for AML patients with evidence of MRD can result in improved survival,” Dr. Hourigan said.

Questions that still need to be addressed include whether variants in different genes confer different degrees of relapse risk, whether next-generation sequencing positivity is equivalent to MRD positivity, and whether the 13-gene panel could be improved upon to lower the chance for false negatives, he said.

The study was supported by the NIH. Dr. Hourigan reported research funding from Merck and Sellas Life Sciences AG, research collaboration with Qiagen and Archer, advisory board participation as an NIH official duty for Janssen and Novartis, and part-time employment with the Johns Hopkins School of Medicine.

SOURCE: Hourigan CS et al. EHA Congress, Abstract LB2600.

AMSTERDAM – Patients with acute myeloid leukemia who were in morphological complete remission prior to allogeneic hematopoietic cell transplant but had genomic evidence of a lingering AML variant had worse posttransplant outcomes when they underwent reduced-intensity conditioning, rather than myeloablative conditioning, investigators reported.

Among adults with AML in remission after induction therapy who were randomized in a clinical trial to either reduced-intensity conditioning (RIC) or myeloablative conditioning prior to transplant, those with known AML variants detected with ultra-deep genomic sequencing who underwent RIC had significantly greater risk for relapse, decreased disease-free survival (DFS), and worse overall survival (OS), compared with similar patients who underwent myeloablative conditioning (MAC), reported Christopher S. Hourigan, DM, DPhil, of the Laboratory of Myeloid Malignancies at the National Heart, Lung, and Blood Institute in Bethesda, Md.

The findings suggest that those patients with pretransplant AML variants who can tolerate MAC should get it, and that investigators need to find new options for patients who can’t, he said in an interview at the annual congress of the European Hematology Association.

“If I wasn’t a lab investigator and was a clinical trialist, I would be very excited about doing some randomized trials now to try see about novel targeted agents. For example, we have FLT3 inhibitors, we have IDH1 and IDH2 inhibitors, and I would be looking to try to combine reduced-intensity conditioning with additional therapy to try to lower the relapse rate for that group at the highest risk,” he said.

Previous studies have shown that, regardless of the method used – flow cytometry, quantitative polymerase chain reaction, or next-generation sequencing – minimal residual disease (MRD) detected in patients with AML in complete remission prior to transplant is associated with both cumulative incidence of relapse and worse overall survival.
 

Measurable, not minimal

Dr. Hourigan contends that the word “minimal” – the “M” in “MRD” – is a misnomer and should be replaced by the word “measurable,” because MRD really reflects the limitations of disease-detection technology.

“If you tell patients ‘you have minimal residual disease, and you have a huge chance of dying over the next few years,’ there’s nothing minimal about that,” he said.

The fundamental question that Dr. Hourigan and colleagues asked is, “is MRD just useful for predicting prognosis? Is this fate, or can we as doctors do something about it?”

To get answers, they examined whole-blood samples from patients enrolled in the BMT CTN 0901 trial, which compared survival and other outcomes following allogeneic hematopoietic stem cell transplants (allo-HSCT) with either RIC or MAC for pretransplant conditioning in patients with AML or the myelodysplastic syndrome.

The trial was halted early after just 272 of a planned 356 patients were enrolled, following evidence of a significantly higher relapse rate among patients who had undergone RIC.

“Strikingly, over half the AML patients receiving RIC relapsed within 18 months after getting transplants,” Dr. Hourigan said.
 

Relapse, survival differences

For this substudy, the National Institutes of Health investigators developed a custom 13-gene panel that would detect at least one AML variant in approximately 80% of patients who were included in a previous study of genomic classification and prognosis in AML.

They used ultra-deep genomic sequencing to look for variants in blood samples from 188 patients in BMT CTN 0901. There were no variants detected in the blood of 31% of patients who had undergone MAC or in 33% of those who had undergone RIC.

Among patients who did have detectable variants, the average number of variants per patient was 2.5.

In this cohort, transplant-related mortality (TRM) was higher with MAC at 27% vs. 20% with RIC at 3 years, but there were no differences in TRM within conditioning arms for patients, with or without AML variants.

Relapse rates in the cohort studied by Dr. Hourigan and his colleagues were virtually identical to those seen in the full study set, with an 18-month relapse rate of 16% for patients treated with MAC vs. 51% for those treated with RIC.

Among patients randomized to RIC, 3-year relapse rates were 57% for patients with detectable pretransplant AML variants, compared with 32% for those without variants (P less than .001).

Although there were no significant differences in 3-year OS by variant status among patients assigned to MAC, variant-positive patients assigned to RIC had significantly worse 3-year OS than those without variants (P = .04).

Among patients with no detectable variants, there were no significant differences in OS between the MAC or RIC arms. However, among patients with variants, survival was significantly worse with RIC (P = .02).

In multivariate analysis controlling for disease risk and donor group among patients who tested positive for an AML variant pretransplant, RIC was significantly associated with an increased risk for relapse (hazard ratio, 5.98; P less than .001); decreased DFS (HR, 2.80; P less than .001), and worse OS (HR, 2.16; P = .003).

“This study provides evidence that intervention for AML patients with evidence of MRD can result in improved survival,” Dr. Hourigan said.

Questions that still need to be addressed include whether variants in different genes confer different degrees of relapse risk, whether next-generation sequencing positivity is equivalent to MRD positivity, and whether the 13-gene panel could be improved upon to lower the chance for false negatives, he said.

The study was supported by the NIH. Dr. Hourigan reported research funding from Merck and Sellas Life Sciences AG, research collaboration with Qiagen and Archer, advisory board participation as an NIH official duty for Janssen and Novartis, and part-time employment with the Johns Hopkins School of Medicine.

SOURCE: Hourigan CS et al. EHA Congress, Abstract LB2600.

AMSTERDAM – Patients with acute myeloid leukemia who were in morphological complete remission prior to allogeneic hematopoietic cell transplant but had genomic evidence of a lingering AML variant had worse posttransplant outcomes when they underwent reduced-intensity conditioning, rather than myeloablative conditioning, investigators reported.

Among adults with AML in remission after induction therapy who were randomized in a clinical trial to either reduced-intensity conditioning (RIC) or myeloablative conditioning prior to transplant, those with known AML variants detected with ultra-deep genomic sequencing who underwent RIC had significantly greater risk for relapse, decreased disease-free survival (DFS), and worse overall survival (OS), compared with similar patients who underwent myeloablative conditioning (MAC), reported Christopher S. Hourigan, DM, DPhil, of the Laboratory of Myeloid Malignancies at the National Heart, Lung, and Blood Institute in Bethesda, Md.

The findings suggest that those patients with pretransplant AML variants who can tolerate MAC should get it, and that investigators need to find new options for patients who can’t, he said in an interview at the annual congress of the European Hematology Association.

“If I wasn’t a lab investigator and was a clinical trialist, I would be very excited about doing some randomized trials now to try see about novel targeted agents. For example, we have FLT3 inhibitors, we have IDH1 and IDH2 inhibitors, and I would be looking to try to combine reduced-intensity conditioning with additional therapy to try to lower the relapse rate for that group at the highest risk,” he said.

Previous studies have shown that, regardless of the method used – flow cytometry, quantitative polymerase chain reaction, or next-generation sequencing – minimal residual disease (MRD) detected in patients with AML in complete remission prior to transplant is associated with both cumulative incidence of relapse and worse overall survival.
 

Measurable, not minimal

Dr. Hourigan contends that the word “minimal” – the “M” in “MRD” – is a misnomer and should be replaced by the word “measurable,” because MRD really reflects the limitations of disease-detection technology.

“If you tell patients ‘you have minimal residual disease, and you have a huge chance of dying over the next few years,’ there’s nothing minimal about that,” he said.

The fundamental question that Dr. Hourigan and colleagues asked is, “is MRD just useful for predicting prognosis? Is this fate, or can we as doctors do something about it?”

To get answers, they examined whole-blood samples from patients enrolled in the BMT CTN 0901 trial, which compared survival and other outcomes following allogeneic hematopoietic stem cell transplants (allo-HSCT) with either RIC or MAC for pretransplant conditioning in patients with AML or the myelodysplastic syndrome.

The trial was halted early after just 272 of a planned 356 patients were enrolled, following evidence of a significantly higher relapse rate among patients who had undergone RIC.

“Strikingly, over half the AML patients receiving RIC relapsed within 18 months after getting transplants,” Dr. Hourigan said.
 

Relapse, survival differences

For this substudy, the National Institutes of Health investigators developed a custom 13-gene panel that would detect at least one AML variant in approximately 80% of patients who were included in a previous study of genomic classification and prognosis in AML.

They used ultra-deep genomic sequencing to look for variants in blood samples from 188 patients in BMT CTN 0901. There were no variants detected in the blood of 31% of patients who had undergone MAC or in 33% of those who had undergone RIC.

Among patients who did have detectable variants, the average number of variants per patient was 2.5.

In this cohort, transplant-related mortality (TRM) was higher with MAC at 27% vs. 20% with RIC at 3 years, but there were no differences in TRM within conditioning arms for patients, with or without AML variants.

Relapse rates in the cohort studied by Dr. Hourigan and his colleagues were virtually identical to those seen in the full study set, with an 18-month relapse rate of 16% for patients treated with MAC vs. 51% for those treated with RIC.

Among patients randomized to RIC, 3-year relapse rates were 57% for patients with detectable pretransplant AML variants, compared with 32% for those without variants (P less than .001).

Although there were no significant differences in 3-year OS by variant status among patients assigned to MAC, variant-positive patients assigned to RIC had significantly worse 3-year OS than those without variants (P = .04).

Among patients with no detectable variants, there were no significant differences in OS between the MAC or RIC arms. However, among patients with variants, survival was significantly worse with RIC (P = .02).

In multivariate analysis controlling for disease risk and donor group among patients who tested positive for an AML variant pretransplant, RIC was significantly associated with an increased risk for relapse (hazard ratio, 5.98; P less than .001); decreased DFS (HR, 2.80; P less than .001), and worse OS (HR, 2.16; P = .003).

“This study provides evidence that intervention for AML patients with evidence of MRD can result in improved survival,” Dr. Hourigan said.

Questions that still need to be addressed include whether variants in different genes confer different degrees of relapse risk, whether next-generation sequencing positivity is equivalent to MRD positivity, and whether the 13-gene panel could be improved upon to lower the chance for false negatives, he said.

The study was supported by the NIH. Dr. Hourigan reported research funding from Merck and Sellas Life Sciences AG, research collaboration with Qiagen and Archer, advisory board participation as an NIH official duty for Janssen and Novartis, and part-time employment with the Johns Hopkins School of Medicine.

SOURCE: Hourigan CS et al. EHA Congress, Abstract LB2600.

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

Will Pass/MDedge News

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Will Pass/MDedge News

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Will Pass/MDedge News

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

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

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

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

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

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

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

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

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

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

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

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

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

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

CHICAGO – A novel antibody against CD47 – the “do not eat me” protein – is well tolerated and active in patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS), according to initial results of a phase 1b study.

Combined with azacitidine, the antibody Hu5F9-G4 (5F9) produced an overall response rate of 64% in untreated AML (9 of 14 patients) and 91% in untreated MDS (10 of 11 patients), according to investigator David A. Sallman, MD, of Moffitt Cancer Center, Tampa, Fla.

With a median follow-up of 3.8 months, none of those patients had yet progressed on the 5F9/azacitidine combination, Dr. Sallman reported during a poster presentation at the annual meeting of the American Society of Clinical Oncology.

A maximum tolerated dose of 5F9 plus the hypomethylating agent was not reached in the study, according to the investigators.

“This was a well-tolerated and safe combination, with encouraging efficacy data in this small cohort that hasn’t been followed for too, too long,” Tara L. Lin, MD, of the University of Kansas Cancer Center, Kansas City, said during a poster discussion session.

“Most interesting is the fact that the combination seems to eliminate the leukemia stem cell population in those patients who respond,” she added.

The fact that 5F9 plus azacitidine eradicated leukemia stem cells in responding patients provides a mechanism for potential long-term durability of response, according to Dr. Sallman and his colleagues.

This first-in-class antibody targets CD47, a “do not eat me” macrophage checkpoint that is overexpressed on tumors, enabling immune invasion, they reported.

However, since CD47 is also expressed on older red blood cells, 5F9 is associated with transient anemia in the first cycle of treatment, Dr. Sallman told attendees at the poster discussion session.

“We do mitigate that with a priming dose of 5F9 that saturates these old red blood cells,” he said. “Over time, going along with the response, the patients have marked hemoglobin improvement, and we do not see worsening of other infection-related complications or cytopenias outside of anemia.”

Based on these results, expansion cohorts have been initiated in both AML and MDS, according to the investigators’ report.

When asked if 5F9 could be tolerable as part of more intensive regimens for fit patients, Dr. Sallman said there are a “whole host of combinations” that may possibly make sense.

“How chemotherapies and other novel agents impact these ‘eat me’ signals – I think some of that needs to be further investigated to come up with the most rational combination,” he said during a question and answer session.

Research funding for the study came from Forty Seven and the California Institute for Regenerative Medicine. Dr. Salman reported having no relationships to disclose. Study coauthors reported relationships with Abbvie, Agios, Celgene, Incyte, and Novartis, among other companies.

SOURCE: Sallman DA et al. ASCO 2019, Abstract 7009.

CHICAGO – A novel antibody against CD47 – the “do not eat me” protein – is well tolerated and active in patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS), according to initial results of a phase 1b study.

Combined with azacitidine, the antibody Hu5F9-G4 (5F9) produced an overall response rate of 64% in untreated AML (9 of 14 patients) and 91% in untreated MDS (10 of 11 patients), according to investigator David A. Sallman, MD, of Moffitt Cancer Center, Tampa, Fla.

With a median follow-up of 3.8 months, none of those patients had yet progressed on the 5F9/azacitidine combination, Dr. Sallman reported during a poster presentation at the annual meeting of the American Society of Clinical Oncology.

A maximum tolerated dose of 5F9 plus the hypomethylating agent was not reached in the study, according to the investigators.

“This was a well-tolerated and safe combination, with encouraging efficacy data in this small cohort that hasn’t been followed for too, too long,” Tara L. Lin, MD, of the University of Kansas Cancer Center, Kansas City, said during a poster discussion session.

“Most interesting is the fact that the combination seems to eliminate the leukemia stem cell population in those patients who respond,” she added.

The fact that 5F9 plus azacitidine eradicated leukemia stem cells in responding patients provides a mechanism for potential long-term durability of response, according to Dr. Sallman and his colleagues.

This first-in-class antibody targets CD47, a “do not eat me” macrophage checkpoint that is overexpressed on tumors, enabling immune invasion, they reported.

However, since CD47 is also expressed on older red blood cells, 5F9 is associated with transient anemia in the first cycle of treatment, Dr. Sallman told attendees at the poster discussion session.

“We do mitigate that with a priming dose of 5F9 that saturates these old red blood cells,” he said. “Over time, going along with the response, the patients have marked hemoglobin improvement, and we do not see worsening of other infection-related complications or cytopenias outside of anemia.”

Based on these results, expansion cohorts have been initiated in both AML and MDS, according to the investigators’ report.

When asked if 5F9 could be tolerable as part of more intensive regimens for fit patients, Dr. Sallman said there are a “whole host of combinations” that may possibly make sense.

“How chemotherapies and other novel agents impact these ‘eat me’ signals – I think some of that needs to be further investigated to come up with the most rational combination,” he said during a question and answer session.

Research funding for the study came from Forty Seven and the California Institute for Regenerative Medicine. Dr. Salman reported having no relationships to disclose. Study coauthors reported relationships with Abbvie, Agios, Celgene, Incyte, and Novartis, among other companies.

SOURCE: Sallman DA et al. ASCO 2019, Abstract 7009.

CHICAGO – A novel antibody against CD47 – the “do not eat me” protein – is well tolerated and active in patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS), according to initial results of a phase 1b study.

Combined with azacitidine, the antibody Hu5F9-G4 (5F9) produced an overall response rate of 64% in untreated AML (9 of 14 patients) and 91% in untreated MDS (10 of 11 patients), according to investigator David A. Sallman, MD, of Moffitt Cancer Center, Tampa, Fla.

With a median follow-up of 3.8 months, none of those patients had yet progressed on the 5F9/azacitidine combination, Dr. Sallman reported during a poster presentation at the annual meeting of the American Society of Clinical Oncology.

A maximum tolerated dose of 5F9 plus the hypomethylating agent was not reached in the study, according to the investigators.

“This was a well-tolerated and safe combination, with encouraging efficacy data in this small cohort that hasn’t been followed for too, too long,” Tara L. Lin, MD, of the University of Kansas Cancer Center, Kansas City, said during a poster discussion session.

“Most interesting is the fact that the combination seems to eliminate the leukemia stem cell population in those patients who respond,” she added.

The fact that 5F9 plus azacitidine eradicated leukemia stem cells in responding patients provides a mechanism for potential long-term durability of response, according to Dr. Sallman and his colleagues.

This first-in-class antibody targets CD47, a “do not eat me” macrophage checkpoint that is overexpressed on tumors, enabling immune invasion, they reported.

However, since CD47 is also expressed on older red blood cells, 5F9 is associated with transient anemia in the first cycle of treatment, Dr. Sallman told attendees at the poster discussion session.

“We do mitigate that with a priming dose of 5F9 that saturates these old red blood cells,” he said. “Over time, going along with the response, the patients have marked hemoglobin improvement, and we do not see worsening of other infection-related complications or cytopenias outside of anemia.”

Based on these results, expansion cohorts have been initiated in both AML and MDS, according to the investigators’ report.

When asked if 5F9 could be tolerable as part of more intensive regimens for fit patients, Dr. Sallman said there are a “whole host of combinations” that may possibly make sense.

“How chemotherapies and other novel agents impact these ‘eat me’ signals – I think some of that needs to be further investigated to come up with the most rational combination,” he said during a question and answer session.

Research funding for the study came from Forty Seven and the California Institute for Regenerative Medicine. Dr. Salman reported having no relationships to disclose. Study coauthors reported relationships with Abbvie, Agios, Celgene, Incyte, and Novartis, among other companies.

SOURCE: Sallman DA et al. ASCO 2019, Abstract 7009.

CHICAGO – Administering CPX-351 prior to a three-drug regimen produced a high response rate in pediatric patients with acute myeloid leukemia (AML) in first relapse.

Jennifer Smith/MDedge News

In a phase 1/2 trial, CPX-351 followed by fludarabine, cytarabine, and filgrastim (FLAG) produced an overall response rate of 81%, and 70% of responders had their best response while receiving CPX-351.

“This is the best response rate published in North America for those [pediatric AML patients] in first relapse,” said Todd Cooper, DO, of Seattle Children’s Hospital in Washington.

Dr. Cooper presented results from the phase 1/2 AAML1421 trial (NCT02642965) at the annual meeting of the American Society of Clinical Oncology.

The primary objective of phase 1 was to determine the recommended phase 2 dose and toxicities of CPX-351, a liposomal preparation of cytarabine and daunorubicin. The primary objective of phase 2 was to assess the best response in patients who received CPX-351 in cycle 1 and FLAG in cycle 2.

The trial enrolled 38 AML patients, 6 in the dose-finding phase and 32 in the efficacy phase. The patients’ median age at study entry was 11.91 years (range, 1.81-21.5). Most patients (88.9%) had CNS 1 disease, and most (73.7%) had not received a transplant.

Half of patients had a first complete response (CR) that lasted 180 to 365 days, 13.2% had a first CR lasting less than 180 days, and 36.8% had a first CR lasting more than 1 year.

Dosing and toxicity

During the dose-finding portion of the study, the first dose level of CPX-351 was 135 units/m² on days 1, 3, and 5. There was one dose-limiting toxicity — grade 3 decrease in ejection fraction — so 135 units/m² was deemed the recommended phase 2 dose.

The most common grade 3 or higher adverse events observed with CPX-351 in cycle 1 were infections and infestations (47.4%), febrile neutropenia (44.7%), maculopapular rash (39.5%), and prolonged QT interval (18.4%).

The most common grade 3 or higher adverse events observed with FLAG in cycle 2 were febrile neutropenia (23.1%), prolonged QT interval (23.1%), and infections and infestations (19.2%).

Response and survival

There were 37 patients evaluable for response. The overall response rate was defined as CR plus CR without platelet recovery (CRp) plus CR with incomplete hematologic recovery (CRi).

The overall response rate was 81.1% (n = 30), which included 20 CRs (54.1%), 5 CRps (13.5%), and 5 CRis (13.5%). Five patients had a partial response (13.5%), and two patients had treatment failure (5.4%).

During CPX-351 treatment (n = 37), the CR rate was 37.8% (n = 14), the CRp rate was 5.4% (n = 2), and the CRi rate was 32.4% (n = 12).

During FLAG treatment (n = 27), the CR rate was 48.1% (n = 13), the CRp rate was 25.9% (n = 7), and the CRi rate was 7.4% (n = 2).

Of the 25 patients who achieved a CR or CRp at any time, 21 (84%) were minimal residual disease negative by flow cytometry. Twelve patients were minimal residual disease negative after cycle 1.

Most patients who achieved a CRi or better (83.3%) went on to hematopoietic stem cell transplant.

The 2-year overall survival was 47% for all patients and 60% for responders. None of the non-responders were still alive 2 years after therapy.

“The results certainly warrant a phase 3 study of CPX-351,” Dr. Cooper said. “In fact, it is the lead molecule that’s going to be incorporated into the next COG phase 3 study.”

AAML1421 was sponsored by the Children’s Oncology Group in collaboration with the National Cancer Institute. Dr. Cooper disclosed relationships with Juno Therapeutics and Celgene.

[email protected]

SOURCE: Cooper TM et al. ASCO 2019. Abstract 10003.

CHICAGO – Administering CPX-351 prior to a three-drug regimen produced a high response rate in pediatric patients with acute myeloid leukemia (AML) in first relapse.

Jennifer Smith/MDedge News

In a phase 1/2 trial, CPX-351 followed by fludarabine, cytarabine, and filgrastim (FLAG) produced an overall response rate of 81%, and 70% of responders had their best response while receiving CPX-351.

“This is the best response rate published in North America for those [pediatric AML patients] in first relapse,” said Todd Cooper, DO, of Seattle Children’s Hospital in Washington.

Dr. Cooper presented results from the phase 1/2 AAML1421 trial (NCT02642965) at the annual meeting of the American Society of Clinical Oncology.

The primary objective of phase 1 was to determine the recommended phase 2 dose and toxicities of CPX-351, a liposomal preparation of cytarabine and daunorubicin. The primary objective of phase 2 was to assess the best response in patients who received CPX-351 in cycle 1 and FLAG in cycle 2.

The trial enrolled 38 AML patients, 6 in the dose-finding phase and 32 in the efficacy phase. The patients’ median age at study entry was 11.91 years (range, 1.81-21.5). Most patients (88.9%) had CNS 1 disease, and most (73.7%) had not received a transplant.

Half of patients had a first complete response (CR) that lasted 180 to 365 days, 13.2% had a first CR lasting less than 180 days, and 36.8% had a first CR lasting more than 1 year.

Dosing and toxicity

During the dose-finding portion of the study, the first dose level of CPX-351 was 135 units/m² on days 1, 3, and 5. There was one dose-limiting toxicity — grade 3 decrease in ejection fraction — so 135 units/m² was deemed the recommended phase 2 dose.

The most common grade 3 or higher adverse events observed with CPX-351 in cycle 1 were infections and infestations (47.4%), febrile neutropenia (44.7%), maculopapular rash (39.5%), and prolonged QT interval (18.4%).

The most common grade 3 or higher adverse events observed with FLAG in cycle 2 were febrile neutropenia (23.1%), prolonged QT interval (23.1%), and infections and infestations (19.2%).

Response and survival

There were 37 patients evaluable for response. The overall response rate was defined as CR plus CR without platelet recovery (CRp) plus CR with incomplete hematologic recovery (CRi).

The overall response rate was 81.1% (n = 30), which included 20 CRs (54.1%), 5 CRps (13.5%), and 5 CRis (13.5%). Five patients had a partial response (13.5%), and two patients had treatment failure (5.4%).

During CPX-351 treatment (n = 37), the CR rate was 37.8% (n = 14), the CRp rate was 5.4% (n = 2), and the CRi rate was 32.4% (n = 12).

During FLAG treatment (n = 27), the CR rate was 48.1% (n = 13), the CRp rate was 25.9% (n = 7), and the CRi rate was 7.4% (n = 2).

Of the 25 patients who achieved a CR or CRp at any time, 21 (84%) were minimal residual disease negative by flow cytometry. Twelve patients were minimal residual disease negative after cycle 1.

Most patients who achieved a CRi or better (83.3%) went on to hematopoietic stem cell transplant.

The 2-year overall survival was 47% for all patients and 60% for responders. None of the non-responders were still alive 2 years after therapy.

“The results certainly warrant a phase 3 study of CPX-351,” Dr. Cooper said. “In fact, it is the lead molecule that’s going to be incorporated into the next COG phase 3 study.”

AAML1421 was sponsored by the Children’s Oncology Group in collaboration with the National Cancer Institute. Dr. Cooper disclosed relationships with Juno Therapeutics and Celgene.

[email protected]

SOURCE: Cooper TM et al. ASCO 2019. Abstract 10003.

CHICAGO – Administering CPX-351 prior to a three-drug regimen produced a high response rate in pediatric patients with acute myeloid leukemia (AML) in first relapse.

Jennifer Smith/MDedge News

In a phase 1/2 trial, CPX-351 followed by fludarabine, cytarabine, and filgrastim (FLAG) produced an overall response rate of 81%, and 70% of responders had their best response while receiving CPX-351.

“This is the best response rate published in North America for those [pediatric AML patients] in first relapse,” said Todd Cooper, DO, of Seattle Children’s Hospital in Washington.

Dr. Cooper presented results from the phase 1/2 AAML1421 trial (NCT02642965) at the annual meeting of the American Society of Clinical Oncology.

The primary objective of phase 1 was to determine the recommended phase 2 dose and toxicities of CPX-351, a liposomal preparation of cytarabine and daunorubicin. The primary objective of phase 2 was to assess the best response in patients who received CPX-351 in cycle 1 and FLAG in cycle 2.

The trial enrolled 38 AML patients, 6 in the dose-finding phase and 32 in the efficacy phase. The patients’ median age at study entry was 11.91 years (range, 1.81-21.5). Most patients (88.9%) had CNS 1 disease, and most (73.7%) had not received a transplant.

Half of patients had a first complete response (CR) that lasted 180 to 365 days, 13.2% had a first CR lasting less than 180 days, and 36.8% had a first CR lasting more than 1 year.

Dosing and toxicity

During the dose-finding portion of the study, the first dose level of CPX-351 was 135 units/m² on days 1, 3, and 5. There was one dose-limiting toxicity — grade 3 decrease in ejection fraction — so 135 units/m² was deemed the recommended phase 2 dose.

The most common grade 3 or higher adverse events observed with CPX-351 in cycle 1 were infections and infestations (47.4%), febrile neutropenia (44.7%), maculopapular rash (39.5%), and prolonged QT interval (18.4%).

The most common grade 3 or higher adverse events observed with FLAG in cycle 2 were febrile neutropenia (23.1%), prolonged QT interval (23.1%), and infections and infestations (19.2%).

Response and survival

There were 37 patients evaluable for response. The overall response rate was defined as CR plus CR without platelet recovery (CRp) plus CR with incomplete hematologic recovery (CRi).

The overall response rate was 81.1% (n = 30), which included 20 CRs (54.1%), 5 CRps (13.5%), and 5 CRis (13.5%). Five patients had a partial response (13.5%), and two patients had treatment failure (5.4%).

During CPX-351 treatment (n = 37), the CR rate was 37.8% (n = 14), the CRp rate was 5.4% (n = 2), and the CRi rate was 32.4% (n = 12).

During FLAG treatment (n = 27), the CR rate was 48.1% (n = 13), the CRp rate was 25.9% (n = 7), and the CRi rate was 7.4% (n = 2).

Of the 25 patients who achieved a CR or CRp at any time, 21 (84%) were minimal residual disease negative by flow cytometry. Twelve patients were minimal residual disease negative after cycle 1.

Most patients who achieved a CRi or better (83.3%) went on to hematopoietic stem cell transplant.

The 2-year overall survival was 47% for all patients and 60% for responders. None of the non-responders were still alive 2 years after therapy.

“The results certainly warrant a phase 3 study of CPX-351,” Dr. Cooper said. “In fact, it is the lead molecule that’s going to be incorporated into the next COG phase 3 study.”

AAML1421 was sponsored by the Children’s Oncology Group in collaboration with the National Cancer Institute. Dr. Cooper disclosed relationships with Juno Therapeutics and Celgene.

[email protected]

SOURCE: Cooper TM et al. ASCO 2019. Abstract 10003.

SILVER SPRING, MD. – Daiichi Sankyo failed to make the case for approval of its investigational tyrosine kinase inhibitor quizartinib for patients with acute myeloid leukemia bearing the FLT3 internal tandem duplication (ITD) mutation.

Members of the Oncologic Drugs Advisory Committee (ODAC) of the Food and Drug Administration voted 8-3 not to recommend approval of the drug at this time, despite the prevailing sentiment among oncologists on the panel that, as one stated, “I need this drug. I want this drug.”

The prevailing majority of committee members agreed that the drug may have a place in the treatment of patients with FLT3-mutated AML, but that more robust data were needed to prove it.

Currently, only one agent, gilteritinib (Xospata) is approved by the FDA for the treatment of patients with relapsed or refractory FLT3-mutated AML.

QuANTUM-R

Daiichi Sankyo sought approval for quizartinib based on results of the phase 3 randomized QuANTUM-R trial. In this trial, single-agent therapy with quizartinib slightly but significantly prolonged survival – compared with salvage chemotherapy – of patients with relapsed/refractory FLT3-ITD positive AML.

Median overall survival (OS), the trial’s primary endpoint, was 6.2 months for 245 patients randomized to quizartinib, compared with 4.7 months for 122 patients assigned to salvage chemotherapy, a difference that translated into a hazard ratio (HR) for death of 0.76 (P = .0177).

The patients were randomly assigned on a 2:1 basis to receive either quizartinib or salvage chemotherapy. Quizartinib was dosed 30 mg per day for 15 days, which could be titrated upward to 60 mg daily if the corrected QT interval by Fredericia (QTcF) was 450 ms or less on day 16.

Chemotherapy was the investigator’s choice of one of three specified regimens: either low-dose cytarabine (LoDAC); mitoxantrone, etoposide, and intermediate-dose cytarabine (MEC); or fludarabine, cytarabine, and granulocyte-colony stimulating factor (G-CSF) with idarubicin (FLAG-IDA). Up to 2 cycles of MEC or FLAG-IDA were permitted; quizartinib and LoDAC were given until lack of benefit, unacceptable toxicity, or until the patient went on to hematopoietic stem cell transplant (HSCT).

Principal investigator Jorge Cortes, MD, from the University of Texas MD Anderson Cancer Center in Houston, speaking in support of the application, said that combined with the phase 2 study results, “these data support a clear and clinically meaningful benefit of quizartinib in this patient population.”

Mark Levis, MD. PhD, from the Johns Hopkins Sidney Kimmel Cancer Center in Baltimore, also spoke in support of the FLT3 inhibitor.

“I have studied both in the lab and in the clinic most FLT3 inhibitors that have been developed, including lestaurtinib, midostaurin, sorafenib and gilteritinib. Quizartinib is the most highly potent and selective FLT3 inhibitor I have ever worked with,” Dr. Levis said.

FDA: Data not up to snuff

But as FDA staff member Kunthel By, PhD, a statistical reviewer in the Office of Biostatistics, pointed out, the upper limit of the hazard ratio favoring quizartinib over chemotherapy was 0.99, and the difference in median overall survival was just 6.5 weeks.

Additionally, the trial data lacked internal consistency, showing no benefits for the drug in either event-free survival (EFS) or in complete response rates.

There were also imbalances in the number of patients with subsequent HSCT between the arms, with more patients on quizartinib undergoing HSCT despite not having a complete remission, than in the chemotherapy group. Also, there were differences in the number of patients who were randomized but not treated and in those censored early. And statistical stress tests indicated “a lack of robustness in the estimated treatment effect,” he said.

Safety issues raised in QuANTUM-R included slow potassium channel (IKs) blockade and related cardiac toxicitites, as well as the differentiation syndrome, acute febrile neutrophilic dermatosis, and cytopenias, said Aviva Krauss, MD, a clinical reviewer in the FDA’s Office of Hematology and Oncology Products.

“Quizartinib therapy is associated with significant and unique safety concerns in the [proposed population], including the risk of fatal cardiac events that cannot be predicted with certainty using routine QTc measurements,” she said.

She noted that the events occurred in QuANTUM-R despite dose modifications and concomitant medications guidelines in the study protocol.

Reviewers recommended that should the drug receive approval, the package labeling should include contraindication for use with other QT-prolonging agents, and a recommendation for prophylactic beta blockage, although the panelists in general felt that the latter recommendation was not necessary.

‘I believe in this drug’

The ODAC meeting was convened to answer questions about whether the overall survival results were credible based on a single clinical trial and outweighed the risks of treatment with quizartinib, and to assess risk strategies for reducing risks of potentially fatal cardiac toxicities, primarily prolongation of the QT interval.

A. Michael Lincoff, MD, a cardiologist at Case Western Reserve University and the Cleveland Clinic, both in Cleveland, Ohio, voted in favor of approval.

“I’m less concerned about the risk and I do think on the balance there is benefit,” he said.

But most committee members echoed the comments of Anthony D. Sung, MD, from the division of hematologic malignancies and cellular therapy at Duke University in Durham, N.C.

“My vote is based purely on the data I’m shown, and my vote is no,” he said. “But I want the FDA to know that I believe in this drug, and I think it should get approved, and I want to use it.”

The trial was sponsored by Daiichi Sankyo. Dr. Cortes reported research funding from Daiichi Sankyo, Pfizer, Arog, Astellas Pharma and Novartis, and consulting activities for all of the same companies except Arog. Dr. Levis is a paid consultant for Daiichi Sankyo. He and Dr. Cortes stated that they had no financial interests in the outcome of the ODAC meeting.

SILVER SPRING, MD. – Daiichi Sankyo failed to make the case for approval of its investigational tyrosine kinase inhibitor quizartinib for patients with acute myeloid leukemia bearing the FLT3 internal tandem duplication (ITD) mutation.

Members of the Oncologic Drugs Advisory Committee (ODAC) of the Food and Drug Administration voted 8-3 not to recommend approval of the drug at this time, despite the prevailing sentiment among oncologists on the panel that, as one stated, “I need this drug. I want this drug.”

The prevailing majority of committee members agreed that the drug may have a place in the treatment of patients with FLT3-mutated AML, but that more robust data were needed to prove it.

Currently, only one agent, gilteritinib (Xospata) is approved by the FDA for the treatment of patients with relapsed or refractory FLT3-mutated AML.

QuANTUM-R

Daiichi Sankyo sought approval for quizartinib based on results of the phase 3 randomized QuANTUM-R trial. In this trial, single-agent therapy with quizartinib slightly but significantly prolonged survival – compared with salvage chemotherapy – of patients with relapsed/refractory FLT3-ITD positive AML.

Median overall survival (OS), the trial’s primary endpoint, was 6.2 months for 245 patients randomized to quizartinib, compared with 4.7 months for 122 patients assigned to salvage chemotherapy, a difference that translated into a hazard ratio (HR) for death of 0.76 (P = .0177).

The patients were randomly assigned on a 2:1 basis to receive either quizartinib or salvage chemotherapy. Quizartinib was dosed 30 mg per day for 15 days, which could be titrated upward to 60 mg daily if the corrected QT interval by Fredericia (QTcF) was 450 ms or less on day 16.

Chemotherapy was the investigator’s choice of one of three specified regimens: either low-dose cytarabine (LoDAC); mitoxantrone, etoposide, and intermediate-dose cytarabine (MEC); or fludarabine, cytarabine, and granulocyte-colony stimulating factor (G-CSF) with idarubicin (FLAG-IDA). Up to 2 cycles of MEC or FLAG-IDA were permitted; quizartinib and LoDAC were given until lack of benefit, unacceptable toxicity, or until the patient went on to hematopoietic stem cell transplant (HSCT).

Principal investigator Jorge Cortes, MD, from the University of Texas MD Anderson Cancer Center in Houston, speaking in support of the application, said that combined with the phase 2 study results, “these data support a clear and clinically meaningful benefit of quizartinib in this patient population.”

Mark Levis, MD. PhD, from the Johns Hopkins Sidney Kimmel Cancer Center in Baltimore, also spoke in support of the FLT3 inhibitor.

“I have studied both in the lab and in the clinic most FLT3 inhibitors that have been developed, including lestaurtinib, midostaurin, sorafenib and gilteritinib. Quizartinib is the most highly potent and selective FLT3 inhibitor I have ever worked with,” Dr. Levis said.

FDA: Data not up to snuff

But as FDA staff member Kunthel By, PhD, a statistical reviewer in the Office of Biostatistics, pointed out, the upper limit of the hazard ratio favoring quizartinib over chemotherapy was 0.99, and the difference in median overall survival was just 6.5 weeks.

Additionally, the trial data lacked internal consistency, showing no benefits for the drug in either event-free survival (EFS) or in complete response rates.

There were also imbalances in the number of patients with subsequent HSCT between the arms, with more patients on quizartinib undergoing HSCT despite not having a complete remission, than in the chemotherapy group. Also, there were differences in the number of patients who were randomized but not treated and in those censored early. And statistical stress tests indicated “a lack of robustness in the estimated treatment effect,” he said.

Safety issues raised in QuANTUM-R included slow potassium channel (IKs) blockade and related cardiac toxicitites, as well as the differentiation syndrome, acute febrile neutrophilic dermatosis, and cytopenias, said Aviva Krauss, MD, a clinical reviewer in the FDA’s Office of Hematology and Oncology Products.

“Quizartinib therapy is associated with significant and unique safety concerns in the [proposed population], including the risk of fatal cardiac events that cannot be predicted with certainty using routine QTc measurements,” she said.

She noted that the events occurred in QuANTUM-R despite dose modifications and concomitant medications guidelines in the study protocol.

Reviewers recommended that should the drug receive approval, the package labeling should include contraindication for use with other QT-prolonging agents, and a recommendation for prophylactic beta blockage, although the panelists in general felt that the latter recommendation was not necessary.

‘I believe in this drug’

The ODAC meeting was convened to answer questions about whether the overall survival results were credible based on a single clinical trial and outweighed the risks of treatment with quizartinib, and to assess risk strategies for reducing risks of potentially fatal cardiac toxicities, primarily prolongation of the QT interval.

A. Michael Lincoff, MD, a cardiologist at Case Western Reserve University and the Cleveland Clinic, both in Cleveland, Ohio, voted in favor of approval.

“I’m less concerned about the risk and I do think on the balance there is benefit,” he said.

But most committee members echoed the comments of Anthony D. Sung, MD, from the division of hematologic malignancies and cellular therapy at Duke University in Durham, N.C.

“My vote is based purely on the data I’m shown, and my vote is no,” he said. “But I want the FDA to know that I believe in this drug, and I think it should get approved, and I want to use it.”

The trial was sponsored by Daiichi Sankyo. Dr. Cortes reported research funding from Daiichi Sankyo, Pfizer, Arog, Astellas Pharma and Novartis, and consulting activities for all of the same companies except Arog. Dr. Levis is a paid consultant for Daiichi Sankyo. He and Dr. Cortes stated that they had no financial interests in the outcome of the ODAC meeting.

SILVER SPRING, MD. – Daiichi Sankyo failed to make the case for approval of its investigational tyrosine kinase inhibitor quizartinib for patients with acute myeloid leukemia bearing the FLT3 internal tandem duplication (ITD) mutation.

Members of the Oncologic Drugs Advisory Committee (ODAC) of the Food and Drug Administration voted 8-3 not to recommend approval of the drug at this time, despite the prevailing sentiment among oncologists on the panel that, as one stated, “I need this drug. I want this drug.”

The prevailing majority of committee members agreed that the drug may have a place in the treatment of patients with FLT3-mutated AML, but that more robust data were needed to prove it.

Currently, only one agent, gilteritinib (Xospata) is approved by the FDA for the treatment of patients with relapsed or refractory FLT3-mutated AML.

QuANTUM-R

Daiichi Sankyo sought approval for quizartinib based on results of the phase 3 randomized QuANTUM-R trial. In this trial, single-agent therapy with quizartinib slightly but significantly prolonged survival – compared with salvage chemotherapy – of patients with relapsed/refractory FLT3-ITD positive AML.

Median overall survival (OS), the trial’s primary endpoint, was 6.2 months for 245 patients randomized to quizartinib, compared with 4.7 months for 122 patients assigned to salvage chemotherapy, a difference that translated into a hazard ratio (HR) for death of 0.76 (P = .0177).

The patients were randomly assigned on a 2:1 basis to receive either quizartinib or salvage chemotherapy. Quizartinib was dosed 30 mg per day for 15 days, which could be titrated upward to 60 mg daily if the corrected QT interval by Fredericia (QTcF) was 450 ms or less on day 16.

Chemotherapy was the investigator’s choice of one of three specified regimens: either low-dose cytarabine (LoDAC); mitoxantrone, etoposide, and intermediate-dose cytarabine (MEC); or fludarabine, cytarabine, and granulocyte-colony stimulating factor (G-CSF) with idarubicin (FLAG-IDA). Up to 2 cycles of MEC or FLAG-IDA were permitted; quizartinib and LoDAC were given until lack of benefit, unacceptable toxicity, or until the patient went on to hematopoietic stem cell transplant (HSCT).

Principal investigator Jorge Cortes, MD, from the University of Texas MD Anderson Cancer Center in Houston, speaking in support of the application, said that combined with the phase 2 study results, “these data support a clear and clinically meaningful benefit of quizartinib in this patient population.”

Mark Levis, MD. PhD, from the Johns Hopkins Sidney Kimmel Cancer Center in Baltimore, also spoke in support of the FLT3 inhibitor.

“I have studied both in the lab and in the clinic most FLT3 inhibitors that have been developed, including lestaurtinib, midostaurin, sorafenib and gilteritinib. Quizartinib is the most highly potent and selective FLT3 inhibitor I have ever worked with,” Dr. Levis said.

FDA: Data not up to snuff

But as FDA staff member Kunthel By, PhD, a statistical reviewer in the Office of Biostatistics, pointed out, the upper limit of the hazard ratio favoring quizartinib over chemotherapy was 0.99, and the difference in median overall survival was just 6.5 weeks.

Additionally, the trial data lacked internal consistency, showing no benefits for the drug in either event-free survival (EFS) or in complete response rates.

There were also imbalances in the number of patients with subsequent HSCT between the arms, with more patients on quizartinib undergoing HSCT despite not having a complete remission, than in the chemotherapy group. Also, there were differences in the number of patients who were randomized but not treated and in those censored early. And statistical stress tests indicated “a lack of robustness in the estimated treatment effect,” he said.

Safety issues raised in QuANTUM-R included slow potassium channel (IKs) blockade and related cardiac toxicitites, as well as the differentiation syndrome, acute febrile neutrophilic dermatosis, and cytopenias, said Aviva Krauss, MD, a clinical reviewer in the FDA’s Office of Hematology and Oncology Products.

“Quizartinib therapy is associated with significant and unique safety concerns in the [proposed population], including the risk of fatal cardiac events that cannot be predicted with certainty using routine QTc measurements,” she said.

She noted that the events occurred in QuANTUM-R despite dose modifications and concomitant medications guidelines in the study protocol.

Reviewers recommended that should the drug receive approval, the package labeling should include contraindication for use with other QT-prolonging agents, and a recommendation for prophylactic beta blockage, although the panelists in general felt that the latter recommendation was not necessary.

‘I believe in this drug’

The ODAC meeting was convened to answer questions about whether the overall survival results were credible based on a single clinical trial and outweighed the risks of treatment with quizartinib, and to assess risk strategies for reducing risks of potentially fatal cardiac toxicities, primarily prolongation of the QT interval.

A. Michael Lincoff, MD, a cardiologist at Case Western Reserve University and the Cleveland Clinic, both in Cleveland, Ohio, voted in favor of approval.

“I’m less concerned about the risk and I do think on the balance there is benefit,” he said.

But most committee members echoed the comments of Anthony D. Sung, MD, from the division of hematologic malignancies and cellular therapy at Duke University in Durham, N.C.

“My vote is based purely on the data I’m shown, and my vote is no,” he said. “But I want the FDA to know that I believe in this drug, and I think it should get approved, and I want to use it.”

The trial was sponsored by Daiichi Sankyo. Dr. Cortes reported research funding from Daiichi Sankyo, Pfizer, Arog, Astellas Pharma and Novartis, and consulting activities for all of the same companies except Arog. Dr. Levis is a paid consultant for Daiichi Sankyo. He and Dr. Cortes stated that they had no financial interests in the outcome of the ODAC meeting.

NEW ORLEANS – Researchers are organizing a master trial in an attempt to improve the treatment of pediatric acute myeloid leukemia (AML).

The Pediatric Acute Leukemia (PedAL) trial is an effort to collect data on all pediatric AML patients. The plan is to use these data to match patients to clinical trials, better understand pediatric AML, and bring new treatments to this population.

E. Anders Kolb, MD, of Nemours Center for Cancer and Blood Disorders in Wilmington, Del., described the initiative at the annual meeting of the American Society of Pediatric Hematology/Oncology.

Dr. Kolb noted that several drugs have been approved to treat adult AML in the last 2 years, but most of them are not approved for use in children.

“What we see in childhood AML is a lot different than what we see in adult AML, and this challenges the paradigm that we have traditionally followed where we use the adult as the 'preclinical model' for pediatric AML,” he said. “I think we are learning more and more that children have a unique disease, unique targets, and need unique therapies.”

The PedAL initiative is an attempt to address these unique needs. PedAL is part of the Leukemia & Lymphoma Society’s Children’s Initiative, and it involves researchers from academic centers and the Children’s Oncology Group.

The PedAL initiative includes preclinical, biomarker, and informatics research, as well as the master clinical trial. The main goal of the master trial is to collect genomic, proteomic, metabolomic, flow cytometry, and clinical data from all children with AML and use these data to match patients to clinical trials.

The PedAL trial will leverage Project:EveryChild, an effort by the Children’s Oncology Group to study every child with cancer. Each child enrolled in this program has an identification number that follows the child through all clinical interventions.

The goal is that Project:EveryChild will capture all pediatric AML patients at the time of diagnosis, although patients can join the project at any time. Then, sequencing, clinical, and other data will be collected from these patients and stored in a data commons.

If patients relapse after standard or other therapies, the GEARBOX algorithm (genomic eligibility algorithm at relapse for better outcomes) can be used to match the patient’s information to clinical trial eligibility criteria and provide a list of appropriate trials.

Dr. Kolb said this process should reduce logistical barriers and get relapsed patients to trials more quickly. Additionally, the data collected through PedAL should help researchers design better trials for pediatric patients with relapsed AML.

“Ultimately, we’ll create the largest data set that will give us a better understanding of all the risks and benefits associated with postrelapse AML,” Dr. Kolb said. “No matter what happens to the patient, no matter where that patient enrolls, we’re going to have the capacity to collect data and present that data to the community for analysis for improved understanding of outcomes.”

Dr. Kolb and his colleagues are already working with researchers in Europe and Japan to make this a global effort and create an international data commons. In addition, the researchers are planning to collaborate with the pharmaceutical industry to unite efforts in pediatric AML drug development.

“We can’t just test drugs in kids because they worked in adults,” Dr. Kolb said. “We really need to maintain the integrity of the science and ask relevant questions in children but do so with the intent to make sure these drugs are licensed for use in kids.”

Dr. Kolb reported having no conflicts of interest. The PedAL trial is sponsored by the Leukemia & Lymphoma Society.

[email protected]

NEW ORLEANS – Researchers are organizing a master trial in an attempt to improve the treatment of pediatric acute myeloid leukemia (AML).

The Pediatric Acute Leukemia (PedAL) trial is an effort to collect data on all pediatric AML patients. The plan is to use these data to match patients to clinical trials, better understand pediatric AML, and bring new treatments to this population.

E. Anders Kolb, MD, of Nemours Center for Cancer and Blood Disorders in Wilmington, Del., described the initiative at the annual meeting of the American Society of Pediatric Hematology/Oncology.

Dr. Kolb noted that several drugs have been approved to treat adult AML in the last 2 years, but most of them are not approved for use in children.

“What we see in childhood AML is a lot different than what we see in adult AML, and this challenges the paradigm that we have traditionally followed where we use the adult as the 'preclinical model' for pediatric AML,” he said. “I think we are learning more and more that children have a unique disease, unique targets, and need unique therapies.”

The PedAL initiative is an attempt to address these unique needs. PedAL is part of the Leukemia & Lymphoma Society’s Children’s Initiative, and it involves researchers from academic centers and the Children’s Oncology Group.

The PedAL initiative includes preclinical, biomarker, and informatics research, as well as the master clinical trial. The main goal of the master trial is to collect genomic, proteomic, metabolomic, flow cytometry, and clinical data from all children with AML and use these data to match patients to clinical trials.

The PedAL trial will leverage Project:EveryChild, an effort by the Children’s Oncology Group to study every child with cancer. Each child enrolled in this program has an identification number that follows the child through all clinical interventions.

The goal is that Project:EveryChild will capture all pediatric AML patients at the time of diagnosis, although patients can join the project at any time. Then, sequencing, clinical, and other data will be collected from these patients and stored in a data commons.

If patients relapse after standard or other therapies, the GEARBOX algorithm (genomic eligibility algorithm at relapse for better outcomes) can be used to match the patient’s information to clinical trial eligibility criteria and provide a list of appropriate trials.

Dr. Kolb said this process should reduce logistical barriers and get relapsed patients to trials more quickly. Additionally, the data collected through PedAL should help researchers design better trials for pediatric patients with relapsed AML.

“Ultimately, we’ll create the largest data set that will give us a better understanding of all the risks and benefits associated with postrelapse AML,” Dr. Kolb said. “No matter what happens to the patient, no matter where that patient enrolls, we’re going to have the capacity to collect data and present that data to the community for analysis for improved understanding of outcomes.”

Dr. Kolb and his colleagues are already working with researchers in Europe and Japan to make this a global effort and create an international data commons. In addition, the researchers are planning to collaborate with the pharmaceutical industry to unite efforts in pediatric AML drug development.

“We can’t just test drugs in kids because they worked in adults,” Dr. Kolb said. “We really need to maintain the integrity of the science and ask relevant questions in children but do so with the intent to make sure these drugs are licensed for use in kids.”

Dr. Kolb reported having no conflicts of interest. The PedAL trial is sponsored by the Leukemia & Lymphoma Society.

[email protected]

NEW ORLEANS – Researchers are organizing a master trial in an attempt to improve the treatment of pediatric acute myeloid leukemia (AML).

The Pediatric Acute Leukemia (PedAL) trial is an effort to collect data on all pediatric AML patients. The plan is to use these data to match patients to clinical trials, better understand pediatric AML, and bring new treatments to this population.

E. Anders Kolb, MD, of Nemours Center for Cancer and Blood Disorders in Wilmington, Del., described the initiative at the annual meeting of the American Society of Pediatric Hematology/Oncology.

Dr. Kolb noted that several drugs have been approved to treat adult AML in the last 2 years, but most of them are not approved for use in children.

“What we see in childhood AML is a lot different than what we see in adult AML, and this challenges the paradigm that we have traditionally followed where we use the adult as the 'preclinical model' for pediatric AML,” he said. “I think we are learning more and more that children have a unique disease, unique targets, and need unique therapies.”

The PedAL initiative is an attempt to address these unique needs. PedAL is part of the Leukemia & Lymphoma Society’s Children’s Initiative, and it involves researchers from academic centers and the Children’s Oncology Group.

The PedAL initiative includes preclinical, biomarker, and informatics research, as well as the master clinical trial. The main goal of the master trial is to collect genomic, proteomic, metabolomic, flow cytometry, and clinical data from all children with AML and use these data to match patients to clinical trials.

The PedAL trial will leverage Project:EveryChild, an effort by the Children’s Oncology Group to study every child with cancer. Each child enrolled in this program has an identification number that follows the child through all clinical interventions.

The goal is that Project:EveryChild will capture all pediatric AML patients at the time of diagnosis, although patients can join the project at any time. Then, sequencing, clinical, and other data will be collected from these patients and stored in a data commons.

If patients relapse after standard or other therapies, the GEARBOX algorithm (genomic eligibility algorithm at relapse for better outcomes) can be used to match the patient’s information to clinical trial eligibility criteria and provide a list of appropriate trials.

Dr. Kolb said this process should reduce logistical barriers and get relapsed patients to trials more quickly. Additionally, the data collected through PedAL should help researchers design better trials for pediatric patients with relapsed AML.

“Ultimately, we’ll create the largest data set that will give us a better understanding of all the risks and benefits associated with postrelapse AML,” Dr. Kolb said. “No matter what happens to the patient, no matter where that patient enrolls, we’re going to have the capacity to collect data and present that data to the community for analysis for improved understanding of outcomes.”

Dr. Kolb and his colleagues are already working with researchers in Europe and Japan to make this a global effort and create an international data commons. In addition, the researchers are planning to collaborate with the pharmaceutical industry to unite efforts in pediatric AML drug development.

“We can’t just test drugs in kids because they worked in adults,” Dr. Kolb said. “We really need to maintain the integrity of the science and ask relevant questions in children but do so with the intent to make sure these drugs are licensed for use in kids.”

Dr. Kolb reported having no conflicts of interest. The PedAL trial is sponsored by the Leukemia & Lymphoma Society.

[email protected]

NEWPORT BEACH, CALIF. – New research suggests patients with normal karyotype acute myeloid leukemia (NK-AML) can be divided into four risk groups associated with overall survival.

Investigators used machine learning algorithms to study the association between mutations and overall survival in 1,352 patients with NK-AML. The analysis revealed combinations of mutations that could be used to classify NK-AML patients into favorable, intermediate-1, intermediate-2, and unfavorable risk groups.

For example, patients who had NPM1 mutations but wild-type FLT3-ITD and DNMT3A, had a median overall survival of 99.1 months and could be classified as favorable risk. Conversely, patients who had NPM1, FLT3-ITD, and DNMT3A mutations, had a median overall survival of 13.4 months and could be classified as unfavorable risk.

Aziz Nazha, MD, of the Cleveland Clinic, and his colleagues conducted this research and presented the findings at the Acute Leukemia Forum of Hemedicus.

The investigators looked at genomic and clinical data from 1,352 patients with NK-AML. The patients were a median age of 55 years and had a median white blood cell count of 21.3 x 10⁹/L, a median hemoglobin of 9.1 g/dL, and a median platelet count of 61 x 10⁹/L. More than half of patients (57.3%) were male.

The patients were screened for 35 genes that are commonly mutated in AML and other myeloid malignancies. The investigators used machine learning algorithms, including random survival forest and recommender system algorithms, to study the association between mutations and overall survival in an “unbiased” way.

Dr. Nazha said there were a median of three mutations per patient sample, and “there are some competing interests between those mutations to impact the prognosis of the patient.”

The investigators used the mutations and their associations with overall survival to classify patients into the risk groups outlined in the table below.

[email protected]

NEWPORT BEACH, CALIF. – New research suggests patients with normal karyotype acute myeloid leukemia (NK-AML) can be divided into four risk groups associated with overall survival.

Investigators used machine learning algorithms to study the association between mutations and overall survival in 1,352 patients with NK-AML. The analysis revealed combinations of mutations that could be used to classify NK-AML patients into favorable, intermediate-1, intermediate-2, and unfavorable risk groups.

For example, patients who had NPM1 mutations but wild-type FLT3-ITD and DNMT3A, had a median overall survival of 99.1 months and could be classified as favorable risk. Conversely, patients who had NPM1, FLT3-ITD, and DNMT3A mutations, had a median overall survival of 13.4 months and could be classified as unfavorable risk.

Aziz Nazha, MD, of the Cleveland Clinic, and his colleagues conducted this research and presented the findings at the Acute Leukemia Forum of Hemedicus.

The investigators looked at genomic and clinical data from 1,352 patients with NK-AML. The patients were a median age of 55 years and had a median white blood cell count of 21.3 x 10⁹/L, a median hemoglobin of 9.1 g/dL, and a median platelet count of 61 x 10⁹/L. More than half of patients (57.3%) were male.

The patients were screened for 35 genes that are commonly mutated in AML and other myeloid malignancies. The investigators used machine learning algorithms, including random survival forest and recommender system algorithms, to study the association between mutations and overall survival in an “unbiased” way.

Dr. Nazha said there were a median of three mutations per patient sample, and “there are some competing interests between those mutations to impact the prognosis of the patient.”

The investigators used the mutations and their associations with overall survival to classify patients into the risk groups outlined in the table below.

[email protected]

NEWPORT BEACH, CALIF. – New research suggests patients with normal karyotype acute myeloid leukemia (NK-AML) can be divided into four risk groups associated with overall survival.

Investigators used machine learning algorithms to study the association between mutations and overall survival in 1,352 patients with NK-AML. The analysis revealed combinations of mutations that could be used to classify NK-AML patients into favorable, intermediate-1, intermediate-2, and unfavorable risk groups.

For example, patients who had NPM1 mutations but wild-type FLT3-ITD and DNMT3A, had a median overall survival of 99.1 months and could be classified as favorable risk. Conversely, patients who had NPM1, FLT3-ITD, and DNMT3A mutations, had a median overall survival of 13.4 months and could be classified as unfavorable risk.

Aziz Nazha, MD, of the Cleveland Clinic, and his colleagues conducted this research and presented the findings at the Acute Leukemia Forum of Hemedicus.

The investigators looked at genomic and clinical data from 1,352 patients with NK-AML. The patients were a median age of 55 years and had a median white blood cell count of 21.3 x 10⁹/L, a median hemoglobin of 9.1 g/dL, and a median platelet count of 61 x 10⁹/L. More than half of patients (57.3%) were male.

The patients were screened for 35 genes that are commonly mutated in AML and other myeloid malignancies. The investigators used machine learning algorithms, including random survival forest and recommender system algorithms, to study the association between mutations and overall survival in an “unbiased” way.

Dr. Nazha said there were a median of three mutations per patient sample, and “there are some competing interests between those mutations to impact the prognosis of the patient.”

The investigators used the mutations and their associations with overall survival to classify patients into the risk groups outlined in the table below.

[email protected]

NEWPORT BEACH, CALIF. – The combination of oral rigosertib and azacitidine is proceeding to a phase 3 trial in patients with myelodysplastic syndromes (MDS), but it isn’t clear if the combination will continue to be developed for acute myeloid leukemia (AML).

In a phase 1/2 trial, oral rigosertib plus azacitidine produced a 90% response rate in higher-risk MDS patients who were naive to hypomethylating agents (HMAs), a 54% response rate in higher-risk MDS patients who had failed HMA therapy, and a 50% response rate in patients with AML.

Genitourinary toxicities were initially a concern in this trial, but researchers found ways to mitigate the risk of these toxicities, according to Richard Woodman, MD, chief medical officer and senior vice president of research and development at Onconova Therapeutics, the company developing rigosertib.

Dr. Woodman and his colleagues presented results from the phase 1/2 trial in two posters at the Acute Leukemia Forum of Hemedicus.

Results in AML

The researchers reported phase 1 results in 17 patients with AML. Eleven patients had AML, according to investigator assessment, and six patients had refractory anemia with excess blasts in transformation, according to French American British criteria, as well as least 20% excess blasts at baseline.

The median age of the patients was 73 years, and 53% were men. Two patients had received no prior therapies, six patients had relapsed disease, and nine were refractory to their last therapy.

Patients received oral rigosertib at escalating doses twice daily on days 1-21 of a 28-day cycle. The recommended phase 2 dose was 840 mg daily (560 mg in the morning and 280 mg in the afternoon), but there were two expansion cohorts in which patients received 1,120 mg daily (560 mg twice a day or 840 mg in the morning and 280 mg in the afternoon). The patients also received azacitidine at 75 mg/m² per day subcutaneously or intravenously for 7 days starting on day 8.

Patients received a median of three treatment cycles. Fifteen of the 17 patients (88%) discontinued treatment, most because of progressive disease (n = 5), toxicity (n = 4), or death (n = 3).

Twelve patients were evaluable for response, and six (50%) responded. One patient achieved a morphologic complete remission (CR), three achieved a morphologic leukemia-free state, and two had a partial response.

The most common treatment-emergent adverse events (TEAEs) were fatigue (53%), diarrhea (53%), nausea (53%), constipation (47%), back pain (41%), pyrexia (41%), and pneumonia (35%). Grade 3 or higher TEAEs included pneumonia (35%) and anemia (24%).

These results haven’t provided a clear way forward for oral rigosertib and azacitidine in AML. Dr. Woodman said the researchers will have to review past studies and evaluate how AML patients (with at least 20% blasts) have responded to intravenous rigosertib, consult experts in the field, and then decide how they will move forward with oral rigosertib and azacitidine in AML.

Results in MDS

Dr. Woodman and his colleagues presented data on 74 patients with higher-risk MDS. The median age was 69 years, and 59% were men. Most patients were high risk (n = 23) or very high risk (n = 33), according to the Revised International Prognostic Scoring System.

The patients received oral rigosertib at a dose of 840 mg/day or higher on days 1-21 of a 28-day cycle. They also received azacitidine at 75 mg/m² per day subcutaneously or intravenously for 7 days starting on day 8.

The median duration of treatment was 7.8 months in patients who were HMA naive and 4.9 months in patients who failed HMA therapy. The most common reasons for treatment discontinuation in the HMA-naive patients were toxicity (n = 8), progression (n = 7), and patient request (n = 7). The most common reasons for discontinuation in patients who had failed HMA therapy were progression (n = 12), toxicity (n = 5), and investigator decision (n = 4).

In total, 55 patients were evaluable for response, 26 who had failed HMA therapy and 29 who were HMA naive.

“The best responses, not surprisingly, were in patients that were HMA naive,” Dr. Woodman said.

In the HMA-naive patients, the overall response rate was 90%. Ten patients had a CR, five had a marrow CR with hematologic improvement, three had hematologic improvement alone, eight had a marrow CR alone, and three patients had stable disease. None of the patients progressed.

In the patients who had failed HMA therapy, the overall response rate was 54%. One patient achieved a CR, one had a partial response, five had a marrow CR with hematologic improvement, two had hematologic improvement alone, five had a marrow CR alone, seven had stable disease, and five progressed.

The median duration of response was 10.8 months in patients who failed HMA therapy and 12.2 months in the HMA-naive patients.

The most common TEAEs in the entire MDS cohort were hematuria (45%), constipation (43%), diarrhea (42%), fatigue (42%), dysuria (38%), pyrexia (36%), nausea (35%), neutropenia (31%), and thrombocytopenia (30%).

Grade 3 or higher TEAEs were neutropenia (27%), thrombocytopenia (26%), hematuria (9%), dysuria (9%), diarrhea (5%), fatigue (4%), and pyrexia (1%).

Dr. Woodman said patients who were most likely to be at risk for genitourinary toxicities (hematuria and dysuria) were those who weren’t well hydrated, took rigosertib at night, and didn’t void their bladders before bedtime. He said the researchers’ hypothesis is that there is some local bladder irritation in that setting.

However, the researchers found ways to mitigate the risk of genitourinary toxicities, including:

• Requiring the second dose of rigosertib to be taken in the afternoon rather than evening (about 3 p.m.).
• Asking patients to consume at least 2 liters of fluid per day.
• Having patients empty their bladders before bedtime.
• Assessing urine pH roughly 2 hours after the morning dose of rigosertib and prescribing sodium bicarbonate if the pH is less than 7.5.

Dr. Woodman said the phase 2 results in MDS patients have prompted the development of a phase 3 trial in which researchers will compare oral rigosertib plus azacitidine to azacitidine plus placebo.

Dr. Woodman is employed by Onconova Therapeutics, which sponsored the phase 1/2 trial. The Acute Leukemia Forum is held by Hemedicus, which is owned by the same company as this news organization.

[email protected]

NEWPORT BEACH, CALIF. – The combination of oral rigosertib and azacitidine is proceeding to a phase 3 trial in patients with myelodysplastic syndromes (MDS), but it isn’t clear if the combination will continue to be developed for acute myeloid leukemia (AML).

In a phase 1/2 trial, oral rigosertib plus azacitidine produced a 90% response rate in higher-risk MDS patients who were naive to hypomethylating agents (HMAs), a 54% response rate in higher-risk MDS patients who had failed HMA therapy, and a 50% response rate in patients with AML.

Genitourinary toxicities were initially a concern in this trial, but researchers found ways to mitigate the risk of these toxicities, according to Richard Woodman, MD, chief medical officer and senior vice president of research and development at Onconova Therapeutics, the company developing rigosertib.

Dr. Woodman and his colleagues presented results from the phase 1/2 trial in two posters at the Acute Leukemia Forum of Hemedicus.

Results in AML

The researchers reported phase 1 results in 17 patients with AML. Eleven patients had AML, according to investigator assessment, and six patients had refractory anemia with excess blasts in transformation, according to French American British criteria, as well as least 20% excess blasts at baseline.

The median age of the patients was 73 years, and 53% were men. Two patients had received no prior therapies, six patients had relapsed disease, and nine were refractory to their last therapy.

Patients received oral rigosertib at escalating doses twice daily on days 1-21 of a 28-day cycle. The recommended phase 2 dose was 840 mg daily (560 mg in the morning and 280 mg in the afternoon), but there were two expansion cohorts in which patients received 1,120 mg daily (560 mg twice a day or 840 mg in the morning and 280 mg in the afternoon). The patients also received azacitidine at 75 mg/m² per day subcutaneously or intravenously for 7 days starting on day 8.

Patients received a median of three treatment cycles. Fifteen of the 17 patients (88%) discontinued treatment, most because of progressive disease (n = 5), toxicity (n = 4), or death (n = 3).

Twelve patients were evaluable for response, and six (50%) responded. One patient achieved a morphologic complete remission (CR), three achieved a morphologic leukemia-free state, and two had a partial response.

The most common treatment-emergent adverse events (TEAEs) were fatigue (53%), diarrhea (53%), nausea (53%), constipation (47%), back pain (41%), pyrexia (41%), and pneumonia (35%). Grade 3 or higher TEAEs included pneumonia (35%) and anemia (24%).

These results haven’t provided a clear way forward for oral rigosertib and azacitidine in AML. Dr. Woodman said the researchers will have to review past studies and evaluate how AML patients (with at least 20% blasts) have responded to intravenous rigosertib, consult experts in the field, and then decide how they will move forward with oral rigosertib and azacitidine in AML.

Results in MDS

Dr. Woodman and his colleagues presented data on 74 patients with higher-risk MDS. The median age was 69 years, and 59% were men. Most patients were high risk (n = 23) or very high risk (n = 33), according to the Revised International Prognostic Scoring System.

The patients received oral rigosertib at a dose of 840 mg/day or higher on days 1-21 of a 28-day cycle. They also received azacitidine at 75 mg/m² per day subcutaneously or intravenously for 7 days starting on day 8.

The median duration of treatment was 7.8 months in patients who were HMA naive and 4.9 months in patients who failed HMA therapy. The most common reasons for treatment discontinuation in the HMA-naive patients were toxicity (n = 8), progression (n = 7), and patient request (n = 7). The most common reasons for discontinuation in patients who had failed HMA therapy were progression (n = 12), toxicity (n = 5), and investigator decision (n = 4).

In total, 55 patients were evaluable for response, 26 who had failed HMA therapy and 29 who were HMA naive.

“The best responses, not surprisingly, were in patients that were HMA naive,” Dr. Woodman said.

In the HMA-naive patients, the overall response rate was 90%. Ten patients had a CR, five had a marrow CR with hematologic improvement, three had hematologic improvement alone, eight had a marrow CR alone, and three patients had stable disease. None of the patients progressed.

In the patients who had failed HMA therapy, the overall response rate was 54%. One patient achieved a CR, one had a partial response, five had a marrow CR with hematologic improvement, two had hematologic improvement alone, five had a marrow CR alone, seven had stable disease, and five progressed.

The median duration of response was 10.8 months in patients who failed HMA therapy and 12.2 months in the HMA-naive patients.

The most common TEAEs in the entire MDS cohort were hematuria (45%), constipation (43%), diarrhea (42%), fatigue (42%), dysuria (38%), pyrexia (36%), nausea (35%), neutropenia (31%), and thrombocytopenia (30%).

Grade 3 or higher TEAEs were neutropenia (27%), thrombocytopenia (26%), hematuria (9%), dysuria (9%), diarrhea (5%), fatigue (4%), and pyrexia (1%).

Dr. Woodman said patients who were most likely to be at risk for genitourinary toxicities (hematuria and dysuria) were those who weren’t well hydrated, took rigosertib at night, and didn’t void their bladders before bedtime. He said the researchers’ hypothesis is that there is some local bladder irritation in that setting.

However, the researchers found ways to mitigate the risk of genitourinary toxicities, including:

• Requiring the second dose of rigosertib to be taken in the afternoon rather than evening (about 3 p.m.).
• Asking patients to consume at least 2 liters of fluid per day.
• Having patients empty their bladders before bedtime.
• Assessing urine pH roughly 2 hours after the morning dose of rigosertib and prescribing sodium bicarbonate if the pH is less than 7.5.

Dr. Woodman said the phase 2 results in MDS patients have prompted the development of a phase 3 trial in which researchers will compare oral rigosertib plus azacitidine to azacitidine plus placebo.

Dr. Woodman is employed by Onconova Therapeutics, which sponsored the phase 1/2 trial. The Acute Leukemia Forum is held by Hemedicus, which is owned by the same company as this news organization.

[email protected]

NEWPORT BEACH, CALIF. – The combination of oral rigosertib and azacitidine is proceeding to a phase 3 trial in patients with myelodysplastic syndromes (MDS), but it isn’t clear if the combination will continue to be developed for acute myeloid leukemia (AML).

In a phase 1/2 trial, oral rigosertib plus azacitidine produced a 90% response rate in higher-risk MDS patients who were naive to hypomethylating agents (HMAs), a 54% response rate in higher-risk MDS patients who had failed HMA therapy, and a 50% response rate in patients with AML.

Genitourinary toxicities were initially a concern in this trial, but researchers found ways to mitigate the risk of these toxicities, according to Richard Woodman, MD, chief medical officer and senior vice president of research and development at Onconova Therapeutics, the company developing rigosertib.

Dr. Woodman and his colleagues presented results from the phase 1/2 trial in two posters at the Acute Leukemia Forum of Hemedicus.

Results in AML

The researchers reported phase 1 results in 17 patients with AML. Eleven patients had AML, according to investigator assessment, and six patients had refractory anemia with excess blasts in transformation, according to French American British criteria, as well as least 20% excess blasts at baseline.

The median age of the patients was 73 years, and 53% were men. Two patients had received no prior therapies, six patients had relapsed disease, and nine were refractory to their last therapy.

Patients received oral rigosertib at escalating doses twice daily on days 1-21 of a 28-day cycle. The recommended phase 2 dose was 840 mg daily (560 mg in the morning and 280 mg in the afternoon), but there were two expansion cohorts in which patients received 1,120 mg daily (560 mg twice a day or 840 mg in the morning and 280 mg in the afternoon). The patients also received azacitidine at 75 mg/m² per day subcutaneously or intravenously for 7 days starting on day 8.

Patients received a median of three treatment cycles. Fifteen of the 17 patients (88%) discontinued treatment, most because of progressive disease (n = 5), toxicity (n = 4), or death (n = 3).

Twelve patients were evaluable for response, and six (50%) responded. One patient achieved a morphologic complete remission (CR), three achieved a morphologic leukemia-free state, and two had a partial response.

The most common treatment-emergent adverse events (TEAEs) were fatigue (53%), diarrhea (53%), nausea (53%), constipation (47%), back pain (41%), pyrexia (41%), and pneumonia (35%). Grade 3 or higher TEAEs included pneumonia (35%) and anemia (24%).

These results haven’t provided a clear way forward for oral rigosertib and azacitidine in AML. Dr. Woodman said the researchers will have to review past studies and evaluate how AML patients (with at least 20% blasts) have responded to intravenous rigosertib, consult experts in the field, and then decide how they will move forward with oral rigosertib and azacitidine in AML.

Results in MDS

Dr. Woodman and his colleagues presented data on 74 patients with higher-risk MDS. The median age was 69 years, and 59% were men. Most patients were high risk (n = 23) or very high risk (n = 33), according to the Revised International Prognostic Scoring System.

The patients received oral rigosertib at a dose of 840 mg/day or higher on days 1-21 of a 28-day cycle. They also received azacitidine at 75 mg/m² per day subcutaneously or intravenously for 7 days starting on day 8.

The median duration of treatment was 7.8 months in patients who were HMA naive and 4.9 months in patients who failed HMA therapy. The most common reasons for treatment discontinuation in the HMA-naive patients were toxicity (n = 8), progression (n = 7), and patient request (n = 7). The most common reasons for discontinuation in patients who had failed HMA therapy were progression (n = 12), toxicity (n = 5), and investigator decision (n = 4).

In total, 55 patients were evaluable for response, 26 who had failed HMA therapy and 29 who were HMA naive.

“The best responses, not surprisingly, were in patients that were HMA naive,” Dr. Woodman said.

In the HMA-naive patients, the overall response rate was 90%. Ten patients had a CR, five had a marrow CR with hematologic improvement, three had hematologic improvement alone, eight had a marrow CR alone, and three patients had stable disease. None of the patients progressed.

In the patients who had failed HMA therapy, the overall response rate was 54%. One patient achieved a CR, one had a partial response, five had a marrow CR with hematologic improvement, two had hematologic improvement alone, five had a marrow CR alone, seven had stable disease, and five progressed.

The median duration of response was 10.8 months in patients who failed HMA therapy and 12.2 months in the HMA-naive patients.

The most common TEAEs in the entire MDS cohort were hematuria (45%), constipation (43%), diarrhea (42%), fatigue (42%), dysuria (38%), pyrexia (36%), nausea (35%), neutropenia (31%), and thrombocytopenia (30%).

Grade 3 or higher TEAEs were neutropenia (27%), thrombocytopenia (26%), hematuria (9%), dysuria (9%), diarrhea (5%), fatigue (4%), and pyrexia (1%).

Dr. Woodman said patients who were most likely to be at risk for genitourinary toxicities (hematuria and dysuria) were those who weren’t well hydrated, took rigosertib at night, and didn’t void their bladders before bedtime. He said the researchers’ hypothesis is that there is some local bladder irritation in that setting.

However, the researchers found ways to mitigate the risk of genitourinary toxicities, including:

• Requiring the second dose of rigosertib to be taken in the afternoon rather than evening (about 3 p.m.).
• Asking patients to consume at least 2 liters of fluid per day.
• Having patients empty their bladders before bedtime.
• Assessing urine pH roughly 2 hours after the morning dose of rigosertib and prescribing sodium bicarbonate if the pH is less than 7.5.

Dr. Woodman said the phase 2 results in MDS patients have prompted the development of a phase 3 trial in which researchers will compare oral rigosertib plus azacitidine to azacitidine plus placebo.

Dr. Woodman is employed by Onconova Therapeutics, which sponsored the phase 1/2 trial. The Acute Leukemia Forum is held by Hemedicus, which is owned by the same company as this news organization.

[email protected]

The Food and Drug Administration has approved ivosidenib (Tibsovo) for newly diagnosed acute myeloid leukemia (AML) with a susceptible IDH1 mutation in patients who are at least 75 years old or have comorbidities preventing the use of intensive induction chemotherapy.

Wikimedia Commons/FitzColinGerald/Creative Commons License

In July 2018, the FDA approved ivosidenib for adults with relapsed or refractory AML with a susceptible IDH1 mutation.

The latest approval was based on results from an open-label, single-arm, multicenter trial of patients with newly diagnosed AML with an IDH1 mutation. Patients were treated with 500 mg ivosidenib daily until disease progression, development of unacceptable toxicity, or hematopoietic stem cell transplantation; the median age of the 28 patients treated with ivosidenib was 77 years.

Of the 28 patients treated, 12 achieved complete remission or complete remission with partial hematologic recovery; 7 of the 17 transfusion-dependent patients achieved transfusion independence for at least 8 weeks.

The most common adverse events were diarrhea, fatigue, edema, decreased appetite, leukocytosis, nausea, arthralgia, abdominal pain, dyspnea, differentiation syndrome, and myalgia. The drug’s prescribing information includes a boxed warning on the risk of differentiation syndrome.

“The recommended ivosidenib dose is 500 mg orally once daily with or without food until disease progression or unacceptable toxicity. For patients without disease progression or unacceptable toxicity, treatment is recommended for a minimum of 6 months to allow time for clinical response,” the FDA noted.

Find the full press release on the FDA website.

[email protected]

The Food and Drug Administration has approved ivosidenib (Tibsovo) for newly diagnosed acute myeloid leukemia (AML) with a susceptible IDH1 mutation in patients who are at least 75 years old or have comorbidities preventing the use of intensive induction chemotherapy.

Wikimedia Commons/FitzColinGerald/Creative Commons License

In July 2018, the FDA approved ivosidenib for adults with relapsed or refractory AML with a susceptible IDH1 mutation.

The latest approval was based on results from an open-label, single-arm, multicenter trial of patients with newly diagnosed AML with an IDH1 mutation. Patients were treated with 500 mg ivosidenib daily until disease progression, development of unacceptable toxicity, or hematopoietic stem cell transplantation; the median age of the 28 patients treated with ivosidenib was 77 years.

Of the 28 patients treated, 12 achieved complete remission or complete remission with partial hematologic recovery; 7 of the 17 transfusion-dependent patients achieved transfusion independence for at least 8 weeks.

The most common adverse events were diarrhea, fatigue, edema, decreased appetite, leukocytosis, nausea, arthralgia, abdominal pain, dyspnea, differentiation syndrome, and myalgia. The drug’s prescribing information includes a boxed warning on the risk of differentiation syndrome.

“The recommended ivosidenib dose is 500 mg orally once daily with or without food until disease progression or unacceptable toxicity. For patients without disease progression or unacceptable toxicity, treatment is recommended for a minimum of 6 months to allow time for clinical response,” the FDA noted.

Find the full press release on the FDA website.

[email protected]

The Food and Drug Administration has approved ivosidenib (Tibsovo) for newly diagnosed acute myeloid leukemia (AML) with a susceptible IDH1 mutation in patients who are at least 75 years old or have comorbidities preventing the use of intensive induction chemotherapy.

Wikimedia Commons/FitzColinGerald/Creative Commons License

In July 2018, the FDA approved ivosidenib for adults with relapsed or refractory AML with a susceptible IDH1 mutation.

The latest approval was based on results from an open-label, single-arm, multicenter trial of patients with newly diagnosed AML with an IDH1 mutation. Patients were treated with 500 mg ivosidenib daily until disease progression, development of unacceptable toxicity, or hematopoietic stem cell transplantation; the median age of the 28 patients treated with ivosidenib was 77 years.

Of the 28 patients treated, 12 achieved complete remission or complete remission with partial hematologic recovery; 7 of the 17 transfusion-dependent patients achieved transfusion independence for at least 8 weeks.

The most common adverse events were diarrhea, fatigue, edema, decreased appetite, leukocytosis, nausea, arthralgia, abdominal pain, dyspnea, differentiation syndrome, and myalgia. The drug’s prescribing information includes a boxed warning on the risk of differentiation syndrome.

“The recommended ivosidenib dose is 500 mg orally once daily with or without food until disease progression or unacceptable toxicity. For patients without disease progression or unacceptable toxicity, treatment is recommended for a minimum of 6 months to allow time for clinical response,” the FDA noted.

Find the full press release on the FDA website.

[email protected]

NEWPORT BEACH, CALIF. – A five-drug regimen was deemed safe in patients with newly diagnosed acute myeloid leukemia (AML) or high-risk myelodysplastic syndromes (MDS), and it appeared to be effective regardless of patients’ FLT3 status.

Researchers tested this regimen – sorafenib plus granulocyte colony–stimulating factor (G-CSF), cladribine, high-dose cytarabine, and mitoxantrone (GCLAM) – in a phase 1 trial.

Kelsey-Leigh Garcia, a clinical research coordinator at Seattle Cancer Care Alliance, and her colleagues presented the results at the Acute Leukemia Forum of Hemedicus.

“The background for doing this study was our institutional results of GCLAM [Leukemia. 2018 Nov;32(11):2352-62] that showed a higher minimal residual disease–negative complete response rate than 7+3 [cytarabine continuously for 7 days, along with short infusions of an anthracycline on each of the first 3 days] and an international study by Röllig that showed the addition of sorafenib to 7+3 increased event-free survival versus [7+3 and] placebo [Lancet Oncol. 2015 Dec;16(16):1691-9],” Ms. Garcia said.

“GCLAM is the standard backbone at our institution, and we wanted to ask the question, ‘If we add sorafenib, can this improve upon the results of GCLAM?’ ” said Anna Halpern, MD, a hematologist-oncologist at the University of Washington, Seattle and principal investigator of the phase 1 trial.

The trial (NCT02728050) included 47 patients, 39 with AML and 8 with MDS. Patients were aged 60 years or younger and had a median age of 48. They had a median treatment-related mortality score of 1.76 (range, 0.19-12.26). A total of 11 patients (23%) had FLT3-ITD, and 4 (9%) had FLT3-TKD.

Treatment and toxicity

For induction, patients received G-CSF at 5 mcg/kg on days 0-5, cladribine at 5 mg/m² on days 1-5, and cytarabine at 2 g/m² on days 1-5. Mitoxantrone was given at 10 mg/m², 12 mg/m², 15 mg/m², or 18 mg/m² on days 1-3. Sorafenib was given at 200 mg twice daily, 400 mg in the morning and 200 mg in the afternoon, or 400 mg b.i.d. on days 10-19.

For consolidation, patients could receive up to four cycles of G-CSF, cladribine, and cytarabine plus sorafenib on days 8-27. Patients who did not proceed to transplant could receive 12 months of sorafenib as maintenance therapy.

There were four dose-limiting toxicities.

• Grade 4 intracranial hemorrhage with mitoxantrone at 12 mg/m² and sorafenib at 200 mg b.i.d.
• Grade 4 prolonged count recovery with mitoxantrone at 15 mg/m² and sorafenib at 200 mg b.i.d.
• Grade 4 sepsis, Sweet syndrome, and Bell’s palsy with mitoxantrone at 18 mg/m² and sorafenib at 200 mg b.i.d.
• Grade 3 cardiomyopathy and acute pericarditis with mitoxantrone at 18 mg/m² and sorafenib at 400 mg b.i.d.

However, these toxicities did not define the maximum-tolerated dose. Therefore, the recommended phase 2 dose of mitoxantrone is 18 mg/m², and the recommended phase 2 dose of sorafenib is 400 mg b.i.d.

There were no grade 5 treatment-related adverse events. Grade 3 events included febrile neutropenia (90%), maculopapular rash (20%), infections (10%), hand-foot syndrome (2%), and diarrhea (1%). Grade 4 events included sepsis, intracranial hemorrhage, and oral mucositis (all 1%).

Response and survival

Among the 46 evaluable patients, 83% achieved a complete response, 78% had a minimal residual disease–negative complete response, and 4% had a minimal residual disease–negative complete response with incomplete count recovery. A morphological leukemia-free state was achieved by 4% of patients, and 8% had resistant disease.

Fifty-nine percent of patients went on to transplant. The median overall survival had not been reached at a median follow-up of 10 months.

The researchers compared outcomes in this trial with outcomes in a cohort of patients who had received GCLAM alone, and there were no significant differences in overall survival or event-free survival.

“The trial wasn’t powered, necessarily, for efficacy, but we compared these results to our historical cohort of medically matched and age-matched patients treated with GCLAM alone and, so far, found no differences in survival between the two groups,” Dr. Halpern said.

She noted, however, that follow-up was short in the sorafenib trial, and it included patients treated with all dose levels of sorafenib and mitoxantrone.

A phase 2 study of sorafenib plus GCLAM in newly diagnosed AML or high-risk MDS is now underway.

Dr. Halpern and Ms. Garcia reported that they had no conflicts of interest. The phase 1 trial was sponsored by the University of Washington in collaboration with the National Cancer Institute, and funding was provided by Bayer.

The Acute Leukemia Forum is held by Hemedicus, which is owned by the same company as this news organization.

[email protected]

NEWPORT BEACH, CALIF. – A five-drug regimen was deemed safe in patients with newly diagnosed acute myeloid leukemia (AML) or high-risk myelodysplastic syndromes (MDS), and it appeared to be effective regardless of patients’ FLT3 status.

Researchers tested this regimen – sorafenib plus granulocyte colony–stimulating factor (G-CSF), cladribine, high-dose cytarabine, and mitoxantrone (GCLAM) – in a phase 1 trial.

Kelsey-Leigh Garcia, a clinical research coordinator at Seattle Cancer Care Alliance, and her colleagues presented the results at the Acute Leukemia Forum of Hemedicus.

“The background for doing this study was our institutional results of GCLAM [Leukemia. 2018 Nov;32(11):2352-62] that showed a higher minimal residual disease–negative complete response rate than 7+3 [cytarabine continuously for 7 days, along with short infusions of an anthracycline on each of the first 3 days] and an international study by Röllig that showed the addition of sorafenib to 7+3 increased event-free survival versus [7+3 and] placebo [Lancet Oncol. 2015 Dec;16(16):1691-9],” Ms. Garcia said.

“GCLAM is the standard backbone at our institution, and we wanted to ask the question, ‘If we add sorafenib, can this improve upon the results of GCLAM?’ ” said Anna Halpern, MD, a hematologist-oncologist at the University of Washington, Seattle and principal investigator of the phase 1 trial.

The trial (NCT02728050) included 47 patients, 39 with AML and 8 with MDS. Patients were aged 60 years or younger and had a median age of 48. They had a median treatment-related mortality score of 1.76 (range, 0.19-12.26). A total of 11 patients (23%) had FLT3-ITD, and 4 (9%) had FLT3-TKD.

Treatment and toxicity

For induction, patients received G-CSF at 5 mcg/kg on days 0-5, cladribine at 5 mg/m² on days 1-5, and cytarabine at 2 g/m² on days 1-5. Mitoxantrone was given at 10 mg/m², 12 mg/m², 15 mg/m², or 18 mg/m² on days 1-3. Sorafenib was given at 200 mg twice daily, 400 mg in the morning and 200 mg in the afternoon, or 400 mg b.i.d. on days 10-19.

For consolidation, patients could receive up to four cycles of G-CSF, cladribine, and cytarabine plus sorafenib on days 8-27. Patients who did not proceed to transplant could receive 12 months of sorafenib as maintenance therapy.

There were four dose-limiting toxicities.

• Grade 4 intracranial hemorrhage with mitoxantrone at 12 mg/m² and sorafenib at 200 mg b.i.d.
• Grade 4 prolonged count recovery with mitoxantrone at 15 mg/m² and sorafenib at 200 mg b.i.d.
• Grade 4 sepsis, Sweet syndrome, and Bell’s palsy with mitoxantrone at 18 mg/m² and sorafenib at 200 mg b.i.d.
• Grade 3 cardiomyopathy and acute pericarditis with mitoxantrone at 18 mg/m² and sorafenib at 400 mg b.i.d.

However, these toxicities did not define the maximum-tolerated dose. Therefore, the recommended phase 2 dose of mitoxantrone is 18 mg/m², and the recommended phase 2 dose of sorafenib is 400 mg b.i.d.

There were no grade 5 treatment-related adverse events. Grade 3 events included febrile neutropenia (90%), maculopapular rash (20%), infections (10%), hand-foot syndrome (2%), and diarrhea (1%). Grade 4 events included sepsis, intracranial hemorrhage, and oral mucositis (all 1%).

Response and survival

Among the 46 evaluable patients, 83% achieved a complete response, 78% had a minimal residual disease–negative complete response, and 4% had a minimal residual disease–negative complete response with incomplete count recovery. A morphological leukemia-free state was achieved by 4% of patients, and 8% had resistant disease.

Fifty-nine percent of patients went on to transplant. The median overall survival had not been reached at a median follow-up of 10 months.

The researchers compared outcomes in this trial with outcomes in a cohort of patients who had received GCLAM alone, and there were no significant differences in overall survival or event-free survival.

“The trial wasn’t powered, necessarily, for efficacy, but we compared these results to our historical cohort of medically matched and age-matched patients treated with GCLAM alone and, so far, found no differences in survival between the two groups,” Dr. Halpern said.

She noted, however, that follow-up was short in the sorafenib trial, and it included patients treated with all dose levels of sorafenib and mitoxantrone.

A phase 2 study of sorafenib plus GCLAM in newly diagnosed AML or high-risk MDS is now underway.

Dr. Halpern and Ms. Garcia reported that they had no conflicts of interest. The phase 1 trial was sponsored by the University of Washington in collaboration with the National Cancer Institute, and funding was provided by Bayer.

The Acute Leukemia Forum is held by Hemedicus, which is owned by the same company as this news organization.

[email protected]

NEWPORT BEACH, CALIF. – A five-drug regimen was deemed safe in patients with newly diagnosed acute myeloid leukemia (AML) or high-risk myelodysplastic syndromes (MDS), and it appeared to be effective regardless of patients’ FLT3 status.

Researchers tested this regimen – sorafenib plus granulocyte colony–stimulating factor (G-CSF), cladribine, high-dose cytarabine, and mitoxantrone (GCLAM) – in a phase 1 trial.

Kelsey-Leigh Garcia, a clinical research coordinator at Seattle Cancer Care Alliance, and her colleagues presented the results at the Acute Leukemia Forum of Hemedicus.

“The background for doing this study was our institutional results of GCLAM [Leukemia. 2018 Nov;32(11):2352-62] that showed a higher minimal residual disease–negative complete response rate than 7+3 [cytarabine continuously for 7 days, along with short infusions of an anthracycline on each of the first 3 days] and an international study by Röllig that showed the addition of sorafenib to 7+3 increased event-free survival versus [7+3 and] placebo [Lancet Oncol. 2015 Dec;16(16):1691-9],” Ms. Garcia said.

“GCLAM is the standard backbone at our institution, and we wanted to ask the question, ‘If we add sorafenib, can this improve upon the results of GCLAM?’ ” said Anna Halpern, MD, a hematologist-oncologist at the University of Washington, Seattle and principal investigator of the phase 1 trial.

The trial (NCT02728050) included 47 patients, 39 with AML and 8 with MDS. Patients were aged 60 years or younger and had a median age of 48. They had a median treatment-related mortality score of 1.76 (range, 0.19-12.26). A total of 11 patients (23%) had FLT3-ITD, and 4 (9%) had FLT3-TKD.

Treatment and toxicity

For induction, patients received G-CSF at 5 mcg/kg on days 0-5, cladribine at 5 mg/m² on days 1-5, and cytarabine at 2 g/m² on days 1-5. Mitoxantrone was given at 10 mg/m², 12 mg/m², 15 mg/m², or 18 mg/m² on days 1-3. Sorafenib was given at 200 mg twice daily, 400 mg in the morning and 200 mg in the afternoon, or 400 mg b.i.d. on days 10-19.

For consolidation, patients could receive up to four cycles of G-CSF, cladribine, and cytarabine plus sorafenib on days 8-27. Patients who did not proceed to transplant could receive 12 months of sorafenib as maintenance therapy.

There were four dose-limiting toxicities.

• Grade 4 intracranial hemorrhage with mitoxantrone at 12 mg/m² and sorafenib at 200 mg b.i.d.
• Grade 4 prolonged count recovery with mitoxantrone at 15 mg/m² and sorafenib at 200 mg b.i.d.
• Grade 4 sepsis, Sweet syndrome, and Bell’s palsy with mitoxantrone at 18 mg/m² and sorafenib at 200 mg b.i.d.
• Grade 3 cardiomyopathy and acute pericarditis with mitoxantrone at 18 mg/m² and sorafenib at 400 mg b.i.d.

However, these toxicities did not define the maximum-tolerated dose. Therefore, the recommended phase 2 dose of mitoxantrone is 18 mg/m², and the recommended phase 2 dose of sorafenib is 400 mg b.i.d.

There were no grade 5 treatment-related adverse events. Grade 3 events included febrile neutropenia (90%), maculopapular rash (20%), infections (10%), hand-foot syndrome (2%), and diarrhea (1%). Grade 4 events included sepsis, intracranial hemorrhage, and oral mucositis (all 1%).

Response and survival

Among the 46 evaluable patients, 83% achieved a complete response, 78% had a minimal residual disease–negative complete response, and 4% had a minimal residual disease–negative complete response with incomplete count recovery. A morphological leukemia-free state was achieved by 4% of patients, and 8% had resistant disease.

Fifty-nine percent of patients went on to transplant. The median overall survival had not been reached at a median follow-up of 10 months.

The researchers compared outcomes in this trial with outcomes in a cohort of patients who had received GCLAM alone, and there were no significant differences in overall survival or event-free survival.

“The trial wasn’t powered, necessarily, for efficacy, but we compared these results to our historical cohort of medically matched and age-matched patients treated with GCLAM alone and, so far, found no differences in survival between the two groups,” Dr. Halpern said.

She noted, however, that follow-up was short in the sorafenib trial, and it included patients treated with all dose levels of sorafenib and mitoxantrone.

A phase 2 study of sorafenib plus GCLAM in newly diagnosed AML or high-risk MDS is now underway.

Dr. Halpern and Ms. Garcia reported that they had no conflicts of interest. The phase 1 trial was sponsored by the University of Washington in collaboration with the National Cancer Institute, and funding was provided by Bayer.

The Acute Leukemia Forum is held by Hemedicus, which is owned by the same company as this news organization.

[email protected]