Investigational AML drugs boosted remission rates

 

Two investigational drugs appear to be improving outcomes for patients with acute myeloid leukemia (AML), based on results reported in separate abstracts of studies that will be featured at press conferences to be held during the annual meeting of the American Society of Hematology.

In the first study, induction therapy with the investigational drug CPX-351 (Vyxeos), a liposomal formulation of cytarabine and daunorubicin, allowed a higher proportion of patients over age 60 with secondary AML to qualify for allogeneic hematopoietic cell transplants. Those patients went on to have improved survival, compared with patients who received standard 7+3 cytarabine and daunorubicin, Jeffrey E. Lancet, MD, of the H. Lee Moffitt Cancer Center and Research Institute, Tampa, and his colleagues reported in abstract 906.

In a second phase Ib study of patients under age 60 with newly diagnosed AML, adding the investigational drug vadastuximab talirine to standard 7+3 induction therapy led to a high remission rate within the first induction cycle, and the majority of remissions were negative for minimal residual disease (MRD), Harry P. Erba, MD, PhD, professor of medicine at the University of Alabama at Birmingham, and his colleagues reported in abstract 211. Vadastuximab talirine is a CD33-directed antibody conjugated to two molecules of a pyrrolobenzodiazepine (PBD) dimer. CD33, a cell surface antigen, is expressed in approximately 90% of AML cases.

The finding that CPX-351 may be an effective bridge to successful transplant for older patients with newly diagnosed secondary AML comes from an exploratory analysis of a phase III study comparing induction therapy with CPX-351 and standard cytarabine and daunorubicin. Initial data from the randomized open-label study, reported last June at the annual meeting of the American Society of Clinical Oncology, indicated CPX-351 significantly improved overall survival, event-free survival, and treatment response without an increase in 60-day mortality or in the frequency and severity of adverse events, compared with the standard 7+3 regimen of cytarabine and daunorubicin.

The data to be presented at ASH 2016 will examine the outcomes of 52 patients in the CPX-351 arm and 39 patients in the standard cytarabine and daunorubicin arm who underwent allogeneic hematopoietic cell transplantation (HCT) after induction. Data reported in the abstract indicate that 18 of the 52 patients in the CPX-351 arm and 26 of the 39 patients in the standard cytarabine and daunorubicin arm have died. The median survival time was 10.25 months with standard therapy; median survival has not yet been reached in the CPX-351 arm. The results indicate 53% fewer deaths occurred within 100 days of transplant in the CPX-351 group.

Newly diagnosed secondary AML was defined as having a history of prior cytotoxic treatment, antecedent myelodysplastic syndrome (MDS) with or without prior treatment with hypomethylating agents, or AML with World Health Organization–defined MDS-related cytogenetic abnormalities.

For the trial, conducted over 2 years at 39 U.S. and Canadian sites, 153 patients were randomized to the CPX-351 arm and 156 randomized to the standard therapy arm. Of 125 patients who had a complete response (CR) or a CR with incomplete (CRi) platelet or neutrophil recovery, 91 underwent allogeneic HCT: 52 (34%) from the CPX-351 arm and 39 (25%) from the standard therapy arm. Each arm had a similar percentage of patients who underwent transplant in CR/CRi status; however, the CPX-351 arm contained a higher percentage of patients age 70 and older (31% vs. 15%). Mortality at 100 days after transplant was 9.6% for patients in the CPX-351 arm and 20.5% for patients in the standard therapy arm. Deaths that occurred within 100 days after allogeneic HCT were due to refractory AML (CPX-351, 3.8%; standard therapy, 7.7%); graft vs. host disease (CPX-351, 3.8%; standard therapy, 2.6%); or renal, respiratory, or multiorgan failure, or septic shock (CPX-351, 0 for each; standard therapy, 2.6% for each), or the cause of death was unknown (CPX-351, 1.9%; standard therapy, 0).

For the 91 patients who had transplants, those in the CPX-351 arm had markedly better overall survival (hazard ratio, 0.46; P = .0046). The time-dependent Cox hazard ratio for overall survival in the CPX-351 arm vs. the 7+3 arm was 0.51 (95% confidence interval, 0.35–0.75; P = .0007).

In the phase Ib trial of vadastuximab talirine, 42 patients received the drug on days 1 and 4 of standard 7+3 cytarabine and daunorubicin induction therapy. Most patients had intermediate (40%) or adverse (43%) cytogenetic risk by Medical Research Council criteria, and 17% of patients had secondary AML. Response was assessed on days 15 and 28; MRD was assessed centrally by bone marrow examination using a multiparametric flow cytometric assay. The investigator chose whether to do a second induction regimen and any postremission therapies, which did not include additional administration of vadastuximab talirine.

Of the 40 patients who could be evaluated for efficacy, 24 (60%) had a CR and 7 (18%) had a CRi, and 4 (10%) reached a morphologic leukemia-free state. Nearly all (94%) of CR and CRi responses occurred after one cycle of induction therapy, and 23 of the 31 patients who reached CR or CRi achieved MRD-negative status.

Extramedullary adverse events, including hepatic toxicity, and induction mortality rates were similar to reported rates for 7+3 cytarabine and daunorubicin alone. All patients had grade 4 myelosuppression. In patients who achieved CR or CRi, the estimated median time to count recovery from day 1 of therapy was 33 days for neutrophils and 35 days for platelets. The 30- and 60-day mortality rates were 0% and 7%, respectively.

An alternative schedule of single-day dosing on day 1 is under investigation, and enrollment continues.

The CPX-351 (Vyxeos) study was supported by the drug’s maker, Celator Pharmaceuticals, which is a subsidiary of Jazz Pharmaceuticals. Dr. Lancet is a consultant to Celator as well as numerous other drug companies. Several of his colleagues disclosed a wide variety of relationships with drug companies, including Celator. Two of the study investigators disclosed employment by and equity ownership in Celator.

The vadastuximab talirine study was sponsored by the drug’s maker, Seattle Genetics. Dr. Erba disclosed a wide variety of relationships with drug companies, including research funding from Seattle Genetics. His colleagues had a similar wide variety of relationships, and two disclosed employment by and equity ownership in Seattle Genetics.
 

 

Abstract 906 Survival Following Allogeneic Hematopoietic Cell Transplantation in Older High-Risk Acute Myeloid Leukemia Patients Initially Treated With CPX-351 Liposome Injection Versus Standard Cytarabine and Daunorubicin: Subgroup Analysis of a Large Phase III Trial, will be presented in session 616 at 4:00 p.m. on Monday, Dec. 5.



Abstract 211 A Phase Ib Study of Vadastuximab Talirine in Combination With 7+3 Induction Therapy for Patients With Newly Diagnosed Acute Myeloid Leukemia (AML) will be presented in session 613 at 4:00 p.m. on Saturday, Dec. 3.

mdales@frontlinemedcom.com

On Twitter @maryjodales

 

Two investigational drugs appear to be improving outcomes for patients with acute myeloid leukemia (AML), based on results reported in separate abstracts of studies that will be featured at press conferences to be held during the annual meeting of the American Society of Hematology.

In the first study, induction therapy with the investigational drug CPX-351 (Vyxeos), a liposomal formulation of cytarabine and daunorubicin, allowed a higher proportion of patients over age 60 with secondary AML to qualify for allogeneic hematopoietic cell transplants. Those patients went on to have improved survival, compared with patients who received standard 7+3 cytarabine and daunorubicin, Jeffrey E. Lancet, MD, of the H. Lee Moffitt Cancer Center and Research Institute, Tampa, and his colleagues reported in abstract 906.

In a second phase Ib study of patients under age 60 with newly diagnosed AML, adding the investigational drug vadastuximab talirine to standard 7+3 induction therapy led to a high remission rate within the first induction cycle, and the majority of remissions were negative for minimal residual disease (MRD), Harry P. Erba, MD, PhD, professor of medicine at the University of Alabama at Birmingham, and his colleagues reported in abstract 211. Vadastuximab talirine is a CD33-directed antibody conjugated to two molecules of a pyrrolobenzodiazepine (PBD) dimer. CD33, a cell surface antigen, is expressed in approximately 90% of AML cases.

The finding that CPX-351 may be an effective bridge to successful transplant for older patients with newly diagnosed secondary AML comes from an exploratory analysis of a phase III study comparing induction therapy with CPX-351 and standard cytarabine and daunorubicin. Initial data from the randomized open-label study, reported last June at the annual meeting of the American Society of Clinical Oncology, indicated CPX-351 significantly improved overall survival, event-free survival, and treatment response without an increase in 60-day mortality or in the frequency and severity of adverse events, compared with the standard 7+3 regimen of cytarabine and daunorubicin.

The data to be presented at ASH 2016 will examine the outcomes of 52 patients in the CPX-351 arm and 39 patients in the standard cytarabine and daunorubicin arm who underwent allogeneic hematopoietic cell transplantation (HCT) after induction. Data reported in the abstract indicate that 18 of the 52 patients in the CPX-351 arm and 26 of the 39 patients in the standard cytarabine and daunorubicin arm have died. The median survival time was 10.25 months with standard therapy; median survival has not yet been reached in the CPX-351 arm. The results indicate 53% fewer deaths occurred within 100 days of transplant in the CPX-351 group.

Newly diagnosed secondary AML was defined as having a history of prior cytotoxic treatment, antecedent myelodysplastic syndrome (MDS) with or without prior treatment with hypomethylating agents, or AML with World Health Organization–defined MDS-related cytogenetic abnormalities.

For the trial, conducted over 2 years at 39 U.S. and Canadian sites, 153 patients were randomized to the CPX-351 arm and 156 randomized to the standard therapy arm. Of 125 patients who had a complete response (CR) or a CR with incomplete (CRi) platelet or neutrophil recovery, 91 underwent allogeneic HCT: 52 (34%) from the CPX-351 arm and 39 (25%) from the standard therapy arm. Each arm had a similar percentage of patients who underwent transplant in CR/CRi status; however, the CPX-351 arm contained a higher percentage of patients age 70 and older (31% vs. 15%). Mortality at 100 days after transplant was 9.6% for patients in the CPX-351 arm and 20.5% for patients in the standard therapy arm. Deaths that occurred within 100 days after allogeneic HCT were due to refractory AML (CPX-351, 3.8%; standard therapy, 7.7%); graft vs. host disease (CPX-351, 3.8%; standard therapy, 2.6%); or renal, respiratory, or multiorgan failure, or septic shock (CPX-351, 0 for each; standard therapy, 2.6% for each), or the cause of death was unknown (CPX-351, 1.9%; standard therapy, 0).

For the 91 patients who had transplants, those in the CPX-351 arm had markedly better overall survival (hazard ratio, 0.46; P = .0046). The time-dependent Cox hazard ratio for overall survival in the CPX-351 arm vs. the 7+3 arm was 0.51 (95% confidence interval, 0.35–0.75; P = .0007).

In the phase Ib trial of vadastuximab talirine, 42 patients received the drug on days 1 and 4 of standard 7+3 cytarabine and daunorubicin induction therapy. Most patients had intermediate (40%) or adverse (43%) cytogenetic risk by Medical Research Council criteria, and 17% of patients had secondary AML. Response was assessed on days 15 and 28; MRD was assessed centrally by bone marrow examination using a multiparametric flow cytometric assay. The investigator chose whether to do a second induction regimen and any postremission therapies, which did not include additional administration of vadastuximab talirine.

Of the 40 patients who could be evaluated for efficacy, 24 (60%) had a CR and 7 (18%) had a CRi, and 4 (10%) reached a morphologic leukemia-free state. Nearly all (94%) of CR and CRi responses occurred after one cycle of induction therapy, and 23 of the 31 patients who reached CR or CRi achieved MRD-negative status.

Extramedullary adverse events, including hepatic toxicity, and induction mortality rates were similar to reported rates for 7+3 cytarabine and daunorubicin alone. All patients had grade 4 myelosuppression. In patients who achieved CR or CRi, the estimated median time to count recovery from day 1 of therapy was 33 days for neutrophils and 35 days for platelets. The 30- and 60-day mortality rates were 0% and 7%, respectively.

An alternative schedule of single-day dosing on day 1 is under investigation, and enrollment continues.

The CPX-351 (Vyxeos) study was supported by the drug’s maker, Celator Pharmaceuticals, which is a subsidiary of Jazz Pharmaceuticals. Dr. Lancet is a consultant to Celator as well as numerous other drug companies. Several of his colleagues disclosed a wide variety of relationships with drug companies, including Celator. Two of the study investigators disclosed employment by and equity ownership in Celator.

The vadastuximab talirine study was sponsored by the drug’s maker, Seattle Genetics. Dr. Erba disclosed a wide variety of relationships with drug companies, including research funding from Seattle Genetics. His colleagues had a similar wide variety of relationships, and two disclosed employment by and equity ownership in Seattle Genetics.
 

 

Abstract 906 Survival Following Allogeneic Hematopoietic Cell Transplantation in Older High-Risk Acute Myeloid Leukemia Patients Initially Treated With CPX-351 Liposome Injection Versus Standard Cytarabine and Daunorubicin: Subgroup Analysis of a Large Phase III Trial, will be presented in session 616 at 4:00 p.m. on Monday, Dec. 5.



Abstract 211 A Phase Ib Study of Vadastuximab Talirine in Combination With 7+3 Induction Therapy for Patients With Newly Diagnosed Acute Myeloid Leukemia (AML) will be presented in session 613 at 4:00 p.m. on Saturday, Dec. 3.

mdales@frontlinemedcom.com

On Twitter @maryjodales

 

Two investigational drugs appear to be improving outcomes for patients with acute myeloid leukemia (AML), based on results reported in separate abstracts of studies that will be featured at press conferences to be held during the annual meeting of the American Society of Hematology.

In the first study, induction therapy with the investigational drug CPX-351 (Vyxeos), a liposomal formulation of cytarabine and daunorubicin, allowed a higher proportion of patients over age 60 with secondary AML to qualify for allogeneic hematopoietic cell transplants. Those patients went on to have improved survival, compared with patients who received standard 7+3 cytarabine and daunorubicin, Jeffrey E. Lancet, MD, of the H. Lee Moffitt Cancer Center and Research Institute, Tampa, and his colleagues reported in abstract 906.

In a second phase Ib study of patients under age 60 with newly diagnosed AML, adding the investigational drug vadastuximab talirine to standard 7+3 induction therapy led to a high remission rate within the first induction cycle, and the majority of remissions were negative for minimal residual disease (MRD), Harry P. Erba, MD, PhD, professor of medicine at the University of Alabama at Birmingham, and his colleagues reported in abstract 211. Vadastuximab talirine is a CD33-directed antibody conjugated to two molecules of a pyrrolobenzodiazepine (PBD) dimer. CD33, a cell surface antigen, is expressed in approximately 90% of AML cases.

The finding that CPX-351 may be an effective bridge to successful transplant for older patients with newly diagnosed secondary AML comes from an exploratory analysis of a phase III study comparing induction therapy with CPX-351 and standard cytarabine and daunorubicin. Initial data from the randomized open-label study, reported last June at the annual meeting of the American Society of Clinical Oncology, indicated CPX-351 significantly improved overall survival, event-free survival, and treatment response without an increase in 60-day mortality or in the frequency and severity of adverse events, compared with the standard 7+3 regimen of cytarabine and daunorubicin.

The data to be presented at ASH 2016 will examine the outcomes of 52 patients in the CPX-351 arm and 39 patients in the standard cytarabine and daunorubicin arm who underwent allogeneic hematopoietic cell transplantation (HCT) after induction. Data reported in the abstract indicate that 18 of the 52 patients in the CPX-351 arm and 26 of the 39 patients in the standard cytarabine and daunorubicin arm have died. The median survival time was 10.25 months with standard therapy; median survival has not yet been reached in the CPX-351 arm. The results indicate 53% fewer deaths occurred within 100 days of transplant in the CPX-351 group.

Newly diagnosed secondary AML was defined as having a history of prior cytotoxic treatment, antecedent myelodysplastic syndrome (MDS) with or without prior treatment with hypomethylating agents, or AML with World Health Organization–defined MDS-related cytogenetic abnormalities.

For the trial, conducted over 2 years at 39 U.S. and Canadian sites, 153 patients were randomized to the CPX-351 arm and 156 randomized to the standard therapy arm. Of 125 patients who had a complete response (CR) or a CR with incomplete (CRi) platelet or neutrophil recovery, 91 underwent allogeneic HCT: 52 (34%) from the CPX-351 arm and 39 (25%) from the standard therapy arm. Each arm had a similar percentage of patients who underwent transplant in CR/CRi status; however, the CPX-351 arm contained a higher percentage of patients age 70 and older (31% vs. 15%). Mortality at 100 days after transplant was 9.6% for patients in the CPX-351 arm and 20.5% for patients in the standard therapy arm. Deaths that occurred within 100 days after allogeneic HCT were due to refractory AML (CPX-351, 3.8%; standard therapy, 7.7%); graft vs. host disease (CPX-351, 3.8%; standard therapy, 2.6%); or renal, respiratory, or multiorgan failure, or septic shock (CPX-351, 0 for each; standard therapy, 2.6% for each), or the cause of death was unknown (CPX-351, 1.9%; standard therapy, 0).

For the 91 patients who had transplants, those in the CPX-351 arm had markedly better overall survival (hazard ratio, 0.46; P = .0046). The time-dependent Cox hazard ratio for overall survival in the CPX-351 arm vs. the 7+3 arm was 0.51 (95% confidence interval, 0.35–0.75; P = .0007).

In the phase Ib trial of vadastuximab talirine, 42 patients received the drug on days 1 and 4 of standard 7+3 cytarabine and daunorubicin induction therapy. Most patients had intermediate (40%) or adverse (43%) cytogenetic risk by Medical Research Council criteria, and 17% of patients had secondary AML. Response was assessed on days 15 and 28; MRD was assessed centrally by bone marrow examination using a multiparametric flow cytometric assay. The investigator chose whether to do a second induction regimen and any postremission therapies, which did not include additional administration of vadastuximab talirine.

Of the 40 patients who could be evaluated for efficacy, 24 (60%) had a CR and 7 (18%) had a CRi, and 4 (10%) reached a morphologic leukemia-free state. Nearly all (94%) of CR and CRi responses occurred after one cycle of induction therapy, and 23 of the 31 patients who reached CR or CRi achieved MRD-negative status.

Extramedullary adverse events, including hepatic toxicity, and induction mortality rates were similar to reported rates for 7+3 cytarabine and daunorubicin alone. All patients had grade 4 myelosuppression. In patients who achieved CR or CRi, the estimated median time to count recovery from day 1 of therapy was 33 days for neutrophils and 35 days for platelets. The 30- and 60-day mortality rates were 0% and 7%, respectively.

An alternative schedule of single-day dosing on day 1 is under investigation, and enrollment continues.

The CPX-351 (Vyxeos) study was supported by the drug’s maker, Celator Pharmaceuticals, which is a subsidiary of Jazz Pharmaceuticals. Dr. Lancet is a consultant to Celator as well as numerous other drug companies. Several of his colleagues disclosed a wide variety of relationships with drug companies, including Celator. Two of the study investigators disclosed employment by and equity ownership in Celator.

The vadastuximab talirine study was sponsored by the drug’s maker, Seattle Genetics. Dr. Erba disclosed a wide variety of relationships with drug companies, including research funding from Seattle Genetics. His colleagues had a similar wide variety of relationships, and two disclosed employment by and equity ownership in Seattle Genetics.
 

 

Abstract 906 Survival Following Allogeneic Hematopoietic Cell Transplantation in Older High-Risk Acute Myeloid Leukemia Patients Initially Treated With CPX-351 Liposome Injection Versus Standard Cytarabine and Daunorubicin: Subgroup Analysis of a Large Phase III Trial, will be presented in session 616 at 4:00 p.m. on Monday, Dec. 5.



Abstract 211 A Phase Ib Study of Vadastuximab Talirine in Combination With 7+3 Induction Therapy for Patients With Newly Diagnosed Acute Myeloid Leukemia (AML) will be presented in session 613 at 4:00 p.m. on Saturday, Dec. 3.

mdales@frontlinemedcom.com

On Twitter @maryjodales