Hematology Times

Photo by Rhoda Baer

The European Commission (EC) has granted marketing authorization for Sandoz’s pegfilgrastim product Ziextenzo®, a biosimilar of Amgen’s Neulasta.

Ziextenzo is approved for the same use as the reference medicine—to reduce the duration of neutropenia and the incidence of febrile neutropenia in adults receiving cytotoxic chemotherapy for malignancies except chronic myeloid leukemia and myelodysplastic syndromes.

The approval is valid in all countries of the European Union as well as Norway, Iceland, and Liechtenstein.

The EC’s approval was based on research suggesting Ziextenzo is comparable to Neulasta in terms of safety, efficacy, pharmacokinetics, and pharmacodynamics.^1,2,3,4

1. Blackwell K. et al. Pooled analysis of two randomized, double-blind trials comparing proposed biosimilar LA-EP2006 with reference pegfilgrastim in breast cancer. Ann Oncol 28, 2272-2277 (2017).

2. Nakov R. et al. Proposed biosimilar pegfilgrastim LA-EP2006 shows similarity in pharmacokinetics and pharmacodynamics to reference pegfilgrastim in healthy subjects. 2017 San Antonio Breast Cancer Symposium, abstract P3-14-10.

3. Blackwell K. et al. A Comparison of Proposed Biosimilar LA-EP2006 and Reference Pegfilgrastim for the Prevention of Neutropenia in Patients With Early-Stage Breast Cancer Receiving Myelosuppressive Adjuvant or Neoadjuvant Chemotherapy: Pegfilgrastim Randomized Oncology (Supportive Care) Trial to Evaluate Comparative Treatment (PROTECT-2), a Phase III, Randomized, Double-Blind Trial. Oncologist 21, 789-794 (2016).

4. Harbeck N. et al. Randomized, double-blind study comparing proposed biosimilar LA-EP2006 with reference pegfilgrastim in breast cancer. Future Oncol 12, 1359-1367 (2016).

Photo by Rhoda Baer

The European Commission (EC) has granted marketing authorization for Sandoz’s pegfilgrastim product Ziextenzo®, a biosimilar of Amgen’s Neulasta.

Ziextenzo is approved for the same use as the reference medicine—to reduce the duration of neutropenia and the incidence of febrile neutropenia in adults receiving cytotoxic chemotherapy for malignancies except chronic myeloid leukemia and myelodysplastic syndromes.

The approval is valid in all countries of the European Union as well as Norway, Iceland, and Liechtenstein.

The EC’s approval was based on research suggesting Ziextenzo is comparable to Neulasta in terms of safety, efficacy, pharmacokinetics, and pharmacodynamics.^1,2,3,4

1. Blackwell K. et al. Pooled analysis of two randomized, double-blind trials comparing proposed biosimilar LA-EP2006 with reference pegfilgrastim in breast cancer. Ann Oncol 28, 2272-2277 (2017).

2. Nakov R. et al. Proposed biosimilar pegfilgrastim LA-EP2006 shows similarity in pharmacokinetics and pharmacodynamics to reference pegfilgrastim in healthy subjects. 2017 San Antonio Breast Cancer Symposium, abstract P3-14-10.

3. Blackwell K. et al. A Comparison of Proposed Biosimilar LA-EP2006 and Reference Pegfilgrastim for the Prevention of Neutropenia in Patients With Early-Stage Breast Cancer Receiving Myelosuppressive Adjuvant or Neoadjuvant Chemotherapy: Pegfilgrastim Randomized Oncology (Supportive Care) Trial to Evaluate Comparative Treatment (PROTECT-2), a Phase III, Randomized, Double-Blind Trial. Oncologist 21, 789-794 (2016).

4. Harbeck N. et al. Randomized, double-blind study comparing proposed biosimilar LA-EP2006 with reference pegfilgrastim in breast cancer. Future Oncol 12, 1359-1367 (2016).

Photo by Rhoda Baer

The European Commission (EC) has granted marketing authorization for Sandoz’s pegfilgrastim product Ziextenzo®, a biosimilar of Amgen’s Neulasta.

Ziextenzo is approved for the same use as the reference medicine—to reduce the duration of neutropenia and the incidence of febrile neutropenia in adults receiving cytotoxic chemotherapy for malignancies except chronic myeloid leukemia and myelodysplastic syndromes.

The approval is valid in all countries of the European Union as well as Norway, Iceland, and Liechtenstein.

The EC’s approval was based on research suggesting Ziextenzo is comparable to Neulasta in terms of safety, efficacy, pharmacokinetics, and pharmacodynamics.^1,2,3,4

1. Blackwell K. et al. Pooled analysis of two randomized, double-blind trials comparing proposed biosimilar LA-EP2006 with reference pegfilgrastim in breast cancer. Ann Oncol 28, 2272-2277 (2017).

2. Nakov R. et al. Proposed biosimilar pegfilgrastim LA-EP2006 shows similarity in pharmacokinetics and pharmacodynamics to reference pegfilgrastim in healthy subjects. 2017 San Antonio Breast Cancer Symposium, abstract P3-14-10.

3. Blackwell K. et al. A Comparison of Proposed Biosimilar LA-EP2006 and Reference Pegfilgrastim for the Prevention of Neutropenia in Patients With Early-Stage Breast Cancer Receiving Myelosuppressive Adjuvant or Neoadjuvant Chemotherapy: Pegfilgrastim Randomized Oncology (Supportive Care) Trial to Evaluate Comparative Treatment (PROTECT-2), a Phase III, Randomized, Double-Blind Trial. Oncologist 21, 789-794 (2016).

4. Harbeck N. et al. Randomized, double-blind study comparing proposed biosimilar LA-EP2006 with reference pegfilgrastim in breast cancer. Future Oncol 12, 1359-1367 (2016).

Photo by Chad McNeeley

New research suggests older individuals with clonal hematopoiesis of indeterminate potential (CHIP) are a safe donor source for allogeneic hematopoietic stem cell transplant (HSCT).

Researchers found that transplants from older donors with CHIP resulted in similar survival as transplants from older donors without CHIP.

HSCT recipients with CHIP donors had a lower risk of relapse or progression but a higher risk of chronic graft-versus-host disease (GHVD), and they were more likely to develop donor-cell malignancies.

Frederik Damm, MD, of Charité – University Medical Center Berlin in Germany, and his colleagues reported these findings in the Journal of Clinical Oncology.

Little is known about the influence of donor CHIP in allogeneic HSCT, according to the researchers.

However, an increasing number of older patients are receiving donations from older, mostly sibling, donors who may have CHIP. CHIP increases with age and is associated with a greater risk of hematologic cancers, cardiovascular disease, and death from coronary heart disease.

With this in mind, Dr. Damm and his colleagues set out to determine how donor CHIP affects the outcome of HSCT.

Between 1993 and 2017, the researchers collected blood samples from 500 healthy, related HSCT donors, age 55 or older, at 10 transplant centers in Germany and France. The researchers sequenced the samples with a 66-gene panel.

The team also assessed overall survival (OS), non-relapse mortality (NRM), cumulative incidence of relapse/progression (CIR/P), cytomegalovirus (CMV) reactivation, and acute and chronic GVHD in the HSCT recipients.

Mutation analysis

The researchers identified 92 clonal mutations in 80 (16.0%) of the 500 donors. The variant allele frequency was 5.9% (range, 2% to 43%). In 20 patients, 25 variant alleles were present at a frequency of 10% or greater.

The researchers detected a single gene mutation in 70 donors, nine donors had two mutations, and one donor had four mutations. The most frequently mutated genes were DNMT3A (40/500, 8%), TET2 (11/500, 2.2%), and ASXL1 (7/500, 1.4%).

Baseline characteristics such as age, sex, or stem cells harvested per kilogram of body weight were similar between donors with and without CHIP.

Recipient characteristics were also evenly distributed regarding donor CHIP status and baseline characteristics.

However, the researchers noted that donor CHIP was present significantly more often in donors for recipients with myeloid compared to lymphoid neoplasms—19.2% and 6.3%, respectively (P≤0.001).

The prevalence of donor CHIP increased with age, from 10.3% (ages 60 to 64) to 20.3% (ages 65 to 69), 22.5% (ages 70 to 74), and 28.6% (ages 75 to 79).

The researchers observed no statistically significant association between CHIP and age, most likely, they wrote, “because 82% of all donors in our cohort were age 60 to 69 years.”

Transplant outcome

Donor CHIP led to slightly faster leukocyte engraftment, although it did not impact thrombocyte engraftment time.

The cumulative incidence of leukocyte engraftment after 15 days was 64.1% for HSCT recipients with CHIP donors and 51.4% for those with non-CHIP donors (P=0.023).

Chronic GVHD after HSCT was more likely for recipients with CHIP donors, with a 5-year cumulative incidence of 52.9%, compared to 35.7% for patients with non-CHIP donors (P=0.008).

Multivariate analysis showed donor CHIP to be an independent risk factor for chronic GVHD when adjusted for antithymocyte globulin application and donor age.

The researchers identified donor DNMT3A mutation as the predominant CHIP factor for developing chronic GVHD. The incidence of chronic GVHD was 58.5% in patients with DNMT3A-mutated donors and 36.6% in patients with wild-type donors (P=0.006).

The researchers noted that no other CHIP mutations or characteristics affected the development of chronic GVHD.

Donor CHIP status did not impact the incidence of acute GVHD or CMV reactivation.

Transplant recipients with CHIP donors had a lower CIR/P (P=0.027) than recipients with non-CHIP donors. Patients whose donors had CHIP with a DNMT3A mutation also had a lower CIR/P (P=0.029).

Donor CHIP had no effect on NRM.

Neither donor CHIP nor donor DNMT3A mutational status impacted CIR/P or NRM in patients who underwent HSCT while they were in complete response (CR).

However, patients not in CR at the time of HSCT had a lower CIR/P when the donor was CHIP-positive (hazard ratio [HR]=0.49; 95% confidence interval [CI], 0.27 to 0.88; P=0.019) or had a DNMT3A mutation (HR=0.34; 95% CI, 0.15 to 0.81; P=0.015).

Two of 82 patients with CHIP donors developed donor-cell malignancies, but there were no donor-cell malignancies in recipients with non-CHIP donors (P=0.026).

Survival

“To our knowledge, we showed, for the first time, that donor CHIP did not affect the survival of 500 HSCT recipients,” the researchers wrote.

At a median follow-up of 3.3 years, the median OS was 2 years, and the 5-year OS was 37.6%.

The researchers observed no survival differences in patients with CHIP donors or non-CHIP donors (HR=0.88; 95% CI, 0.65 to 1.321; P=0.434). And the same was true for DNMT3A mutation (HR=0.89; 95% CI, 0.58 to 1.35; P=0.573).

The researchers pointed out that patients with myelodysplastic syndromes or acute myeloid leukemia who were not in CR when they underwent HSCT had a survival benefit with donor CHIP (HR=0.49; 95% CI, 0.28 to 0.86; P=0.011).

“This finding could implicate an important clinical potential in this difficult-to-treat subgroup,” the researchers noted.

However, this was not the case for patients with myeloproliferative neoplasia, for whom donor CHIP tended to reduce survival (P=0.077).

The research team recommended future studies be conducted in younger and unrelated donors to confirm the results of this study.

The research was funded by numerous grants and fellowships, and the researchers reported no relevant conflicts of interest.

Photo by Chad McNeeley

New research suggests older individuals with clonal hematopoiesis of indeterminate potential (CHIP) are a safe donor source for allogeneic hematopoietic stem cell transplant (HSCT).

Researchers found that transplants from older donors with CHIP resulted in similar survival as transplants from older donors without CHIP.

HSCT recipients with CHIP donors had a lower risk of relapse or progression but a higher risk of chronic graft-versus-host disease (GHVD), and they were more likely to develop donor-cell malignancies.

Frederik Damm, MD, of Charité – University Medical Center Berlin in Germany, and his colleagues reported these findings in the Journal of Clinical Oncology.

Little is known about the influence of donor CHIP in allogeneic HSCT, according to the researchers.

However, an increasing number of older patients are receiving donations from older, mostly sibling, donors who may have CHIP. CHIP increases with age and is associated with a greater risk of hematologic cancers, cardiovascular disease, and death from coronary heart disease.

With this in mind, Dr. Damm and his colleagues set out to determine how donor CHIP affects the outcome of HSCT.

Between 1993 and 2017, the researchers collected blood samples from 500 healthy, related HSCT donors, age 55 or older, at 10 transplant centers in Germany and France. The researchers sequenced the samples with a 66-gene panel.

The team also assessed overall survival (OS), non-relapse mortality (NRM), cumulative incidence of relapse/progression (CIR/P), cytomegalovirus (CMV) reactivation, and acute and chronic GVHD in the HSCT recipients.

Mutation analysis

The researchers identified 92 clonal mutations in 80 (16.0%) of the 500 donors. The variant allele frequency was 5.9% (range, 2% to 43%). In 20 patients, 25 variant alleles were present at a frequency of 10% or greater.

The researchers detected a single gene mutation in 70 donors, nine donors had two mutations, and one donor had four mutations. The most frequently mutated genes were DNMT3A (40/500, 8%), TET2 (11/500, 2.2%), and ASXL1 (7/500, 1.4%).

Baseline characteristics such as age, sex, or stem cells harvested per kilogram of body weight were similar between donors with and without CHIP.

Recipient characteristics were also evenly distributed regarding donor CHIP status and baseline characteristics.

However, the researchers noted that donor CHIP was present significantly more often in donors for recipients with myeloid compared to lymphoid neoplasms—19.2% and 6.3%, respectively (P≤0.001).

The prevalence of donor CHIP increased with age, from 10.3% (ages 60 to 64) to 20.3% (ages 65 to 69), 22.5% (ages 70 to 74), and 28.6% (ages 75 to 79).

The researchers observed no statistically significant association between CHIP and age, most likely, they wrote, “because 82% of all donors in our cohort were age 60 to 69 years.”

Transplant outcome

Donor CHIP led to slightly faster leukocyte engraftment, although it did not impact thrombocyte engraftment time.

The cumulative incidence of leukocyte engraftment after 15 days was 64.1% for HSCT recipients with CHIP donors and 51.4% for those with non-CHIP donors (P=0.023).

Chronic GVHD after HSCT was more likely for recipients with CHIP donors, with a 5-year cumulative incidence of 52.9%, compared to 35.7% for patients with non-CHIP donors (P=0.008).

Multivariate analysis showed donor CHIP to be an independent risk factor for chronic GVHD when adjusted for antithymocyte globulin application and donor age.

The researchers identified donor DNMT3A mutation as the predominant CHIP factor for developing chronic GVHD. The incidence of chronic GVHD was 58.5% in patients with DNMT3A-mutated donors and 36.6% in patients with wild-type donors (P=0.006).

The researchers noted that no other CHIP mutations or characteristics affected the development of chronic GVHD.

Donor CHIP status did not impact the incidence of acute GVHD or CMV reactivation.

Transplant recipients with CHIP donors had a lower CIR/P (P=0.027) than recipients with non-CHIP donors. Patients whose donors had CHIP with a DNMT3A mutation also had a lower CIR/P (P=0.029).

Donor CHIP had no effect on NRM.

Neither donor CHIP nor donor DNMT3A mutational status impacted CIR/P or NRM in patients who underwent HSCT while they were in complete response (CR).

However, patients not in CR at the time of HSCT had a lower CIR/P when the donor was CHIP-positive (hazard ratio [HR]=0.49; 95% confidence interval [CI], 0.27 to 0.88; P=0.019) or had a DNMT3A mutation (HR=0.34; 95% CI, 0.15 to 0.81; P=0.015).

Two of 82 patients with CHIP donors developed donor-cell malignancies, but there were no donor-cell malignancies in recipients with non-CHIP donors (P=0.026).

Survival

“To our knowledge, we showed, for the first time, that donor CHIP did not affect the survival of 500 HSCT recipients,” the researchers wrote.

At a median follow-up of 3.3 years, the median OS was 2 years, and the 5-year OS was 37.6%.

The researchers observed no survival differences in patients with CHIP donors or non-CHIP donors (HR=0.88; 95% CI, 0.65 to 1.321; P=0.434). And the same was true for DNMT3A mutation (HR=0.89; 95% CI, 0.58 to 1.35; P=0.573).

The researchers pointed out that patients with myelodysplastic syndromes or acute myeloid leukemia who were not in CR when they underwent HSCT had a survival benefit with donor CHIP (HR=0.49; 95% CI, 0.28 to 0.86; P=0.011).

“This finding could implicate an important clinical potential in this difficult-to-treat subgroup,” the researchers noted.

However, this was not the case for patients with myeloproliferative neoplasia, for whom donor CHIP tended to reduce survival (P=0.077).

The research team recommended future studies be conducted in younger and unrelated donors to confirm the results of this study.

The research was funded by numerous grants and fellowships, and the researchers reported no relevant conflicts of interest.

Photo by Chad McNeeley

New research suggests older individuals with clonal hematopoiesis of indeterminate potential (CHIP) are a safe donor source for allogeneic hematopoietic stem cell transplant (HSCT).

Researchers found that transplants from older donors with CHIP resulted in similar survival as transplants from older donors without CHIP.

HSCT recipients with CHIP donors had a lower risk of relapse or progression but a higher risk of chronic graft-versus-host disease (GHVD), and they were more likely to develop donor-cell malignancies.

Frederik Damm, MD, of Charité – University Medical Center Berlin in Germany, and his colleagues reported these findings in the Journal of Clinical Oncology.

Little is known about the influence of donor CHIP in allogeneic HSCT, according to the researchers.

However, an increasing number of older patients are receiving donations from older, mostly sibling, donors who may have CHIP. CHIP increases with age and is associated with a greater risk of hematologic cancers, cardiovascular disease, and death from coronary heart disease.

With this in mind, Dr. Damm and his colleagues set out to determine how donor CHIP affects the outcome of HSCT.

Between 1993 and 2017, the researchers collected blood samples from 500 healthy, related HSCT donors, age 55 or older, at 10 transplant centers in Germany and France. The researchers sequenced the samples with a 66-gene panel.

The team also assessed overall survival (OS), non-relapse mortality (NRM), cumulative incidence of relapse/progression (CIR/P), cytomegalovirus (CMV) reactivation, and acute and chronic GVHD in the HSCT recipients.

Mutation analysis

The researchers identified 92 clonal mutations in 80 (16.0%) of the 500 donors. The variant allele frequency was 5.9% (range, 2% to 43%). In 20 patients, 25 variant alleles were present at a frequency of 10% or greater.

The researchers detected a single gene mutation in 70 donors, nine donors had two mutations, and one donor had four mutations. The most frequently mutated genes were DNMT3A (40/500, 8%), TET2 (11/500, 2.2%), and ASXL1 (7/500, 1.4%).

Baseline characteristics such as age, sex, or stem cells harvested per kilogram of body weight were similar between donors with and without CHIP.

Recipient characteristics were also evenly distributed regarding donor CHIP status and baseline characteristics.

However, the researchers noted that donor CHIP was present significantly more often in donors for recipients with myeloid compared to lymphoid neoplasms—19.2% and 6.3%, respectively (P≤0.001).

The prevalence of donor CHIP increased with age, from 10.3% (ages 60 to 64) to 20.3% (ages 65 to 69), 22.5% (ages 70 to 74), and 28.6% (ages 75 to 79).

The researchers observed no statistically significant association between CHIP and age, most likely, they wrote, “because 82% of all donors in our cohort were age 60 to 69 years.”

Transplant outcome

Donor CHIP led to slightly faster leukocyte engraftment, although it did not impact thrombocyte engraftment time.

The cumulative incidence of leukocyte engraftment after 15 days was 64.1% for HSCT recipients with CHIP donors and 51.4% for those with non-CHIP donors (P=0.023).

Chronic GVHD after HSCT was more likely for recipients with CHIP donors, with a 5-year cumulative incidence of 52.9%, compared to 35.7% for patients with non-CHIP donors (P=0.008).

Multivariate analysis showed donor CHIP to be an independent risk factor for chronic GVHD when adjusted for antithymocyte globulin application and donor age.

The researchers identified donor DNMT3A mutation as the predominant CHIP factor for developing chronic GVHD. The incidence of chronic GVHD was 58.5% in patients with DNMT3A-mutated donors and 36.6% in patients with wild-type donors (P=0.006).

The researchers noted that no other CHIP mutations or characteristics affected the development of chronic GVHD.

Donor CHIP status did not impact the incidence of acute GVHD or CMV reactivation.

Transplant recipients with CHIP donors had a lower CIR/P (P=0.027) than recipients with non-CHIP donors. Patients whose donors had CHIP with a DNMT3A mutation also had a lower CIR/P (P=0.029).

Donor CHIP had no effect on NRM.

Neither donor CHIP nor donor DNMT3A mutational status impacted CIR/P or NRM in patients who underwent HSCT while they were in complete response (CR).

However, patients not in CR at the time of HSCT had a lower CIR/P when the donor was CHIP-positive (hazard ratio [HR]=0.49; 95% confidence interval [CI], 0.27 to 0.88; P=0.019) or had a DNMT3A mutation (HR=0.34; 95% CI, 0.15 to 0.81; P=0.015).

Two of 82 patients with CHIP donors developed donor-cell malignancies, but there were no donor-cell malignancies in recipients with non-CHIP donors (P=0.026).

Survival

“To our knowledge, we showed, for the first time, that donor CHIP did not affect the survival of 500 HSCT recipients,” the researchers wrote.

At a median follow-up of 3.3 years, the median OS was 2 years, and the 5-year OS was 37.6%.

The researchers observed no survival differences in patients with CHIP donors or non-CHIP donors (HR=0.88; 95% CI, 0.65 to 1.321; P=0.434). And the same was true for DNMT3A mutation (HR=0.89; 95% CI, 0.58 to 1.35; P=0.573).

The researchers pointed out that patients with myelodysplastic syndromes or acute myeloid leukemia who were not in CR when they underwent HSCT had a survival benefit with donor CHIP (HR=0.49; 95% CI, 0.28 to 0.86; P=0.011).

“This finding could implicate an important clinical potential in this difficult-to-treat subgroup,” the researchers noted.

However, this was not the case for patients with myeloproliferative neoplasia, for whom donor CHIP tended to reduce survival (P=0.077).

The research team recommended future studies be conducted in younger and unrelated donors to confirm the results of this study.

The research was funded by numerous grants and fellowships, and the researchers reported no relevant conflicts of interest.

Photo by Rhoda Baer

The European Commission (EC) has approved Mundipharma’s pegfilgrastim product Pelmeg, a biosimilar of Amgen’s Neulasta.

Pelmeg is approved for use in reducing the duration of neutropenia and the incidence of febrile neutropenia in adults who receive cytotoxic chemotherapy for malignancies, with the exceptions of chronic myeloid leukemia and myelodysplastic syndromes.

The approval is valid in all countries of the European Union as well as Norway, Iceland, and Liechtenstein.

The EC’s approval of Pelmeg was supported by research showing pharmacokinetic comparability between Pelmeg and Neulasta at a dose of 6 mg, pharmacodynamic comparability at doses of 6 mg and 3 mg, and no clinically meaningful differences in the safety and immunogenicity profiles of Pelmeg and Neulasta.^1,2,3

1. Roth K. et al. Demonstration of pharmacokinetic and pharmacodynamic comparability in healthy volunteers for B12019, a proposed pegfilgrastim biosimilar. ECCO 2017, abstract 241.

2. Roth K. et al. Comparability of pharmacodynamics and immunogenicity of B12019, a proposed pegfilgrastim biosimilar to Neulasta®. ASH 2017, abstract 1002.

3. Roth K. et al. Pharmacokinetic and pharmacodynamic comparability of B12019, a proposed pegfilgrastim biosimilar. ESMO 2017, poster 1573.

Photo by Rhoda Baer

The European Commission (EC) has approved Mundipharma’s pegfilgrastim product Pelmeg, a biosimilar of Amgen’s Neulasta.

Pelmeg is approved for use in reducing the duration of neutropenia and the incidence of febrile neutropenia in adults who receive cytotoxic chemotherapy for malignancies, with the exceptions of chronic myeloid leukemia and myelodysplastic syndromes.

The approval is valid in all countries of the European Union as well as Norway, Iceland, and Liechtenstein.

The EC’s approval of Pelmeg was supported by research showing pharmacokinetic comparability between Pelmeg and Neulasta at a dose of 6 mg, pharmacodynamic comparability at doses of 6 mg and 3 mg, and no clinically meaningful differences in the safety and immunogenicity profiles of Pelmeg and Neulasta.^1,2,3

1. Roth K. et al. Demonstration of pharmacokinetic and pharmacodynamic comparability in healthy volunteers for B12019, a proposed pegfilgrastim biosimilar. ECCO 2017, abstract 241.

2. Roth K. et al. Comparability of pharmacodynamics and immunogenicity of B12019, a proposed pegfilgrastim biosimilar to Neulasta®. ASH 2017, abstract 1002.

3. Roth K. et al. Pharmacokinetic and pharmacodynamic comparability of B12019, a proposed pegfilgrastim biosimilar. ESMO 2017, poster 1573.

Photo by Rhoda Baer

The European Commission (EC) has approved Mundipharma’s pegfilgrastim product Pelmeg, a biosimilar of Amgen’s Neulasta.

Pelmeg is approved for use in reducing the duration of neutropenia and the incidence of febrile neutropenia in adults who receive cytotoxic chemotherapy for malignancies, with the exceptions of chronic myeloid leukemia and myelodysplastic syndromes.

The approval is valid in all countries of the European Union as well as Norway, Iceland, and Liechtenstein.

The EC’s approval of Pelmeg was supported by research showing pharmacokinetic comparability between Pelmeg and Neulasta at a dose of 6 mg, pharmacodynamic comparability at doses of 6 mg and 3 mg, and no clinically meaningful differences in the safety and immunogenicity profiles of Pelmeg and Neulasta.^1,2,3

1. Roth K. et al. Demonstration of pharmacokinetic and pharmacodynamic comparability in healthy volunteers for B12019, a proposed pegfilgrastim biosimilar. ECCO 2017, abstract 241.

2. Roth K. et al. Comparability of pharmacodynamics and immunogenicity of B12019, a proposed pegfilgrastim biosimilar to Neulasta®. ASH 2017, abstract 1002.

3. Roth K. et al. Pharmacokinetic and pharmacodynamic comparability of B12019, a proposed pegfilgrastim biosimilar. ESMO 2017, poster 1573.

Henrique Orlandi Mourao

The U.S. Food and Drug Administration (FDA) has accepted for priority review a new drug application (NDA) for the FLT3 inhibitor quizartinib.

With this NDA, Daiichi Sankyo is seeking approval for quizartinib to treat adults with relapsed/refractory FLT3-ITD acute myeloid leukemia (AML).

The FDA grants priority review to applications for products that are expected to provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.

The FDA aims to take action on a priority review application within 6 months rather than the standard 10 months.

The FDA is expected to make a decision on the quizartinib NDA by May 25, 2019.

In addition to priority review, quizartinib has breakthrough therapy designation and fast track designation from the FDA.

Trial results

The NDA for quizartinib is supported by results from the phase 3 QuANTUM-R study. Topline results from this study were presented at the 23rd Congress of the European Hematology Association in June, and new analyses are set to be presented at the 2018 ASH Annual Meeting in December (abstract 563).

QuANTUM-R enrolled adults with FLT3-ITD AML (at least 3% FLT3-ITD allelic ratio) who had refractory disease or had relapsed within 6 months of their first complete response (CR).

Patients were randomized to receive once-daily treatment with quizartinib (n=245) or a salvage chemotherapy regimen (n=122)—low-dose cytarabine (LoDAC, n=29); combination mitoxantrone, etoposide, and cytarabine (MEC, n=40); or combination fludarabine, cytarabine, and idarubicin (FLAG-IDA, n=53).

Patients who responded to treatment could proceed to hematopoietic stem cell transplant (HSCT), and those in the quizartinib arm could resume quizartinib after HSCT.

In all, 241 patients received quizartinib, and 94 received salvage chemotherapy—LoDAC (n=22), MEC (n=25), and FLAG-IDA (n=47). Of the 28 patients in the chemotherapy group who were not treated, most withdrew consent.

Thirty-two percent of quizartinib-treated patients and 12% of the chemotherapy group went on to HSCT.

Efficacy

The median follow-up was 23.5 months. The efficacy results include all randomized patients.

The overall response rate was 69% in the quizartinib arm and 30% in the chemotherapy arm. The composite CR rate was 48% in the quizartinib arm and 27% in the chemotherapy arm. This includes:

• The CR rate (4% and 1%, respectively)
• The rate of CR with incomplete platelet recovery (4% and 0%, respectively)
• The rate of CR with incomplete hematologic recovery (40% and 26%, respectively).

The median event-free survival was 6.0 weeks in the quizartinib arm and 3.7 weeks in the chemotherapy arm (hazard ratio=0.90, P=0.1071).

The median overall survival was 6.2 months in the quizartinib arm and 4.7 months in the chemotherapy arm (hazard ratio=0.76, P=0.0177). The 1-year overall survival rate was 27% and 20%, respectively.

Safety

The safety results include only patients who received their assigned treatment.

Grade 3 or higher hematologic treatment-emergent adverse events occurring in at least 5% of patients (in the quizartinib and chemotherapy groups, respectively) included:

• Thrombocytopenia (35% and 34%)
• Anemia (30% and 29%)
• Neutropenia (32% and 25%)
• Febrile neutropenia (31% and 21%)
• Leukopenia (17% and 16%).

Grade 3 or higher non-hematologic treatment-emergent adverse events occurring in at least 5% of patients (in the quizartinib and chemotherapy groups, respectively) included:

• Sepsis/septic shock (16% and 18%)
• Hypokalemia (12% and 9%)
• Pneumonia (12% and 9%)
• Fatigue (8% and 1%)
• Dyspnea (5% for both)
• Hypophosphatemia (5% for both).

Henrique Orlandi Mourao

The U.S. Food and Drug Administration (FDA) has accepted for priority review a new drug application (NDA) for the FLT3 inhibitor quizartinib.

With this NDA, Daiichi Sankyo is seeking approval for quizartinib to treat adults with relapsed/refractory FLT3-ITD acute myeloid leukemia (AML).

The FDA grants priority review to applications for products that are expected to provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.

The FDA aims to take action on a priority review application within 6 months rather than the standard 10 months.

The FDA is expected to make a decision on the quizartinib NDA by May 25, 2019.

In addition to priority review, quizartinib has breakthrough therapy designation and fast track designation from the FDA.

Trial results

The NDA for quizartinib is supported by results from the phase 3 QuANTUM-R study. Topline results from this study were presented at the 23rd Congress of the European Hematology Association in June, and new analyses are set to be presented at the 2018 ASH Annual Meeting in December (abstract 563).

QuANTUM-R enrolled adults with FLT3-ITD AML (at least 3% FLT3-ITD allelic ratio) who had refractory disease or had relapsed within 6 months of their first complete response (CR).

Patients were randomized to receive once-daily treatment with quizartinib (n=245) or a salvage chemotherapy regimen (n=122)—low-dose cytarabine (LoDAC, n=29); combination mitoxantrone, etoposide, and cytarabine (MEC, n=40); or combination fludarabine, cytarabine, and idarubicin (FLAG-IDA, n=53).

Patients who responded to treatment could proceed to hematopoietic stem cell transplant (HSCT), and those in the quizartinib arm could resume quizartinib after HSCT.

In all, 241 patients received quizartinib, and 94 received salvage chemotherapy—LoDAC (n=22), MEC (n=25), and FLAG-IDA (n=47). Of the 28 patients in the chemotherapy group who were not treated, most withdrew consent.

Thirty-two percent of quizartinib-treated patients and 12% of the chemotherapy group went on to HSCT.

Efficacy

The median follow-up was 23.5 months. The efficacy results include all randomized patients.

The overall response rate was 69% in the quizartinib arm and 30% in the chemotherapy arm. The composite CR rate was 48% in the quizartinib arm and 27% in the chemotherapy arm. This includes:

• The CR rate (4% and 1%, respectively)
• The rate of CR with incomplete platelet recovery (4% and 0%, respectively)
• The rate of CR with incomplete hematologic recovery (40% and 26%, respectively).

The median event-free survival was 6.0 weeks in the quizartinib arm and 3.7 weeks in the chemotherapy arm (hazard ratio=0.90, P=0.1071).

The median overall survival was 6.2 months in the quizartinib arm and 4.7 months in the chemotherapy arm (hazard ratio=0.76, P=0.0177). The 1-year overall survival rate was 27% and 20%, respectively.

Safety

The safety results include only patients who received their assigned treatment.

Grade 3 or higher hematologic treatment-emergent adverse events occurring in at least 5% of patients (in the quizartinib and chemotherapy groups, respectively) included:

• Thrombocytopenia (35% and 34%)
• Anemia (30% and 29%)
• Neutropenia (32% and 25%)
• Febrile neutropenia (31% and 21%)
• Leukopenia (17% and 16%).

Grade 3 or higher non-hematologic treatment-emergent adverse events occurring in at least 5% of patients (in the quizartinib and chemotherapy groups, respectively) included:

• Sepsis/septic shock (16% and 18%)
• Hypokalemia (12% and 9%)
• Pneumonia (12% and 9%)
• Fatigue (8% and 1%)
• Dyspnea (5% for both)
• Hypophosphatemia (5% for both).

Henrique Orlandi Mourao

The U.S. Food and Drug Administration (FDA) has accepted for priority review a new drug application (NDA) for the FLT3 inhibitor quizartinib.

With this NDA, Daiichi Sankyo is seeking approval for quizartinib to treat adults with relapsed/refractory FLT3-ITD acute myeloid leukemia (AML).

The FDA grants priority review to applications for products that are expected to provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.

The FDA aims to take action on a priority review application within 6 months rather than the standard 10 months.

The FDA is expected to make a decision on the quizartinib NDA by May 25, 2019.

In addition to priority review, quizartinib has breakthrough therapy designation and fast track designation from the FDA.

Trial results

The NDA for quizartinib is supported by results from the phase 3 QuANTUM-R study. Topline results from this study were presented at the 23rd Congress of the European Hematology Association in June, and new analyses are set to be presented at the 2018 ASH Annual Meeting in December (abstract 563).

QuANTUM-R enrolled adults with FLT3-ITD AML (at least 3% FLT3-ITD allelic ratio) who had refractory disease or had relapsed within 6 months of their first complete response (CR).

Patients were randomized to receive once-daily treatment with quizartinib (n=245) or a salvage chemotherapy regimen (n=122)—low-dose cytarabine (LoDAC, n=29); combination mitoxantrone, etoposide, and cytarabine (MEC, n=40); or combination fludarabine, cytarabine, and idarubicin (FLAG-IDA, n=53).

Patients who responded to treatment could proceed to hematopoietic stem cell transplant (HSCT), and those in the quizartinib arm could resume quizartinib after HSCT.

In all, 241 patients received quizartinib, and 94 received salvage chemotherapy—LoDAC (n=22), MEC (n=25), and FLAG-IDA (n=47). Of the 28 patients in the chemotherapy group who were not treated, most withdrew consent.

Thirty-two percent of quizartinib-treated patients and 12% of the chemotherapy group went on to HSCT.

Efficacy

The median follow-up was 23.5 months. The efficacy results include all randomized patients.

The overall response rate was 69% in the quizartinib arm and 30% in the chemotherapy arm. The composite CR rate was 48% in the quizartinib arm and 27% in the chemotherapy arm. This includes:

• The CR rate (4% and 1%, respectively)
• The rate of CR with incomplete platelet recovery (4% and 0%, respectively)
• The rate of CR with incomplete hematologic recovery (40% and 26%, respectively).

The median event-free survival was 6.0 weeks in the quizartinib arm and 3.7 weeks in the chemotherapy arm (hazard ratio=0.90, P=0.1071).

The median overall survival was 6.2 months in the quizartinib arm and 4.7 months in the chemotherapy arm (hazard ratio=0.76, P=0.0177). The 1-year overall survival rate was 27% and 20%, respectively.

Safety

The safety results include only patients who received their assigned treatment.

Grade 3 or higher hematologic treatment-emergent adverse events occurring in at least 5% of patients (in the quizartinib and chemotherapy groups, respectively) included:

• Thrombocytopenia (35% and 34%)
• Anemia (30% and 29%)
• Neutropenia (32% and 25%)
• Febrile neutropenia (31% and 21%)
• Leukopenia (17% and 16%).

Grade 3 or higher non-hematologic treatment-emergent adverse events occurring in at least 5% of patients (in the quizartinib and chemotherapy groups, respectively) included:

• Sepsis/septic shock (16% and 18%)
• Hypokalemia (12% and 9%)
• Pneumonia (12% and 9%)
• Fatigue (8% and 1%)
• Dyspnea (5% for both)
• Hypophosphatemia (5% for both).

© Todd Buchanan 2017

An additional presentation has been added to the late-breaking abstract session of the 2018 ASH Annual Meeting.

The session was expanded from six abstracts to seven this year because of a record number of “exciting” submissions, according to ASH Secretary Robert A. Brodsky, MD, of Johns Hopkins University in Baltimore, Maryland.

“We received 98 late-breaking abstracts, which is a record,” Dr. Brodsky said.

“They were so exciting this year that we added a seventh, and, quite frankly, we could have added several more, but we just didn’t have time in the meeting.”

Dr. Brodsky discussed this year’s late-breaking abstracts during a recent press briefing.

Abstract LBA-1 reports results of rivaroxaban thromboprophylaxis in cancer patients with an increased risk of venous thromboembolism (VTE). Compared to placebo, rivaroxaban significantly reduced VTE and VTE-related death during treatment but not over the entire study period.

Abstract LBA-2 describes a phase 3, randomized trial comparing daratumumab plus lenalidomide and dexamethasone to lenalidomide and dexamethasone in patients with newly diagnosed multiple myeloma who are ineligible for transplant. The addition of daratumumab reduced the risk of disease progression or death by 45%.

Abstract LBA-3 details results with HemoTypeSC, a test used to detect sickle cell trait and sickle cell disease. The test correctly identified all phenotypes in the 1,000 children studied.

Abstract LBA-4 describes a randomized, phase 3 study comparing ibrutinib plus rituximab to fludarabine, cyclophosphamide, and rituximab in younger patients with untreated chronic lymphocytic leukemia (CLL). Investigators found that ibrutinib plus rituximab provided significantly better progression-free and overall survival than the three-drug combination.

Abstract LBA-5 details a strategy for direct oral anticoagulant use in patients with atrial fibrillation undergoing surgery. Investigators say the strategy is likely to be “practice-changing” and incorporated into guidelines.

Abstract LBA-6 ­covers a trial of emapalumab in patients with primary hemophagocytic lymphohistiocytosis. Emapalumab, which was recently approved by the U.S. Food and Drug Administration, produced responses in most of the 34 patients studied and had a favorable safety profile, according to investigators.

Abstract LBA-7 reports the discovery of a recurrent mutation in BCL2 that confers resistance to venetoclax in patients with progressive CLL. Investigators say this mutation could be a biomarker of CLL relapse.

© Todd Buchanan 2017

An additional presentation has been added to the late-breaking abstract session of the 2018 ASH Annual Meeting.

The session was expanded from six abstracts to seven this year because of a record number of “exciting” submissions, according to ASH Secretary Robert A. Brodsky, MD, of Johns Hopkins University in Baltimore, Maryland.

“We received 98 late-breaking abstracts, which is a record,” Dr. Brodsky said.

“They were so exciting this year that we added a seventh, and, quite frankly, we could have added several more, but we just didn’t have time in the meeting.”

Dr. Brodsky discussed this year’s late-breaking abstracts during a recent press briefing.

Abstract LBA-1 reports results of rivaroxaban thromboprophylaxis in cancer patients with an increased risk of venous thromboembolism (VTE). Compared to placebo, rivaroxaban significantly reduced VTE and VTE-related death during treatment but not over the entire study period.

Abstract LBA-2 describes a phase 3, randomized trial comparing daratumumab plus lenalidomide and dexamethasone to lenalidomide and dexamethasone in patients with newly diagnosed multiple myeloma who are ineligible for transplant. The addition of daratumumab reduced the risk of disease progression or death by 45%.

Abstract LBA-3 details results with HemoTypeSC, a test used to detect sickle cell trait and sickle cell disease. The test correctly identified all phenotypes in the 1,000 children studied.

Abstract LBA-4 describes a randomized, phase 3 study comparing ibrutinib plus rituximab to fludarabine, cyclophosphamide, and rituximab in younger patients with untreated chronic lymphocytic leukemia (CLL). Investigators found that ibrutinib plus rituximab provided significantly better progression-free and overall survival than the three-drug combination.

Abstract LBA-5 details a strategy for direct oral anticoagulant use in patients with atrial fibrillation undergoing surgery. Investigators say the strategy is likely to be “practice-changing” and incorporated into guidelines.

Abstract LBA-6 ­covers a trial of emapalumab in patients with primary hemophagocytic lymphohistiocytosis. Emapalumab, which was recently approved by the U.S. Food and Drug Administration, produced responses in most of the 34 patients studied and had a favorable safety profile, according to investigators.

Abstract LBA-7 reports the discovery of a recurrent mutation in BCL2 that confers resistance to venetoclax in patients with progressive CLL. Investigators say this mutation could be a biomarker of CLL relapse.

© Todd Buchanan 2017

An additional presentation has been added to the late-breaking abstract session of the 2018 ASH Annual Meeting.

The session was expanded from six abstracts to seven this year because of a record number of “exciting” submissions, according to ASH Secretary Robert A. Brodsky, MD, of Johns Hopkins University in Baltimore, Maryland.

“We received 98 late-breaking abstracts, which is a record,” Dr. Brodsky said.

“They were so exciting this year that we added a seventh, and, quite frankly, we could have added several more, but we just didn’t have time in the meeting.”

Dr. Brodsky discussed this year’s late-breaking abstracts during a recent press briefing.

Abstract LBA-1 reports results of rivaroxaban thromboprophylaxis in cancer patients with an increased risk of venous thromboembolism (VTE). Compared to placebo, rivaroxaban significantly reduced VTE and VTE-related death during treatment but not over the entire study period.

Abstract LBA-2 describes a phase 3, randomized trial comparing daratumumab plus lenalidomide and dexamethasone to lenalidomide and dexamethasone in patients with newly diagnosed multiple myeloma who are ineligible for transplant. The addition of daratumumab reduced the risk of disease progression or death by 45%.

Abstract LBA-3 details results with HemoTypeSC, a test used to detect sickle cell trait and sickle cell disease. The test correctly identified all phenotypes in the 1,000 children studied.

Abstract LBA-4 describes a randomized, phase 3 study comparing ibrutinib plus rituximab to fludarabine, cyclophosphamide, and rituximab in younger patients with untreated chronic lymphocytic leukemia (CLL). Investigators found that ibrutinib plus rituximab provided significantly better progression-free and overall survival than the three-drug combination.

Abstract LBA-5 details a strategy for direct oral anticoagulant use in patients with atrial fibrillation undergoing surgery. Investigators say the strategy is likely to be “practice-changing” and incorporated into guidelines.

Abstract LBA-6 ­covers a trial of emapalumab in patients with primary hemophagocytic lymphohistiocytosis. Emapalumab, which was recently approved by the U.S. Food and Drug Administration, produced responses in most of the 34 patients studied and had a favorable safety profile, according to investigators.

Abstract LBA-7 reports the discovery of a recurrent mutation in BCL2 that confers resistance to venetoclax in patients with progressive CLL. Investigators say this mutation could be a biomarker of CLL relapse.

Photo from Penn Medicine

Several studies set to be presented at the 2018 ASH Annual Meeting provide new insights regarding chimeric antigen receptor (CAR) T-cell therapies.

One study suggests ibrutinib may enhance CAR T-cell therapy in patients with chronic lymphocytic leukemia (CLL), and another suggests checkpoint inhibitors can augment CAR T-cell therapy in certain patients with B-cell acute lymphoblastic leukemia (ALL).

Two additional studies indicate that responses to tisagenlecleucel are durable in both ALL and diffuse large B-cell lymphoma (DLBCL).

A fifth study suggests hematopoietic stem cell transplant (HSCT) may reduce the risk of relapse after CAR T-cell therapy.

ASH Secretary Robert A. Brodsky, MD, of Johns Hopkins University in Baltimore, Maryland, discussed these studies during a media briefing ahead of the ASH Annual Meeting.

Ibrutinib

In the ibrutinib study (abstract 299), patients received the BTK inhibitor starting 2 weeks prior to leukapheresis and continued until 3 months after treatment with JCAR014.

Data suggest this strategy may improve responses and decrease the incidence of severe cytokine release syndrome in patients with relapsed or refractory CLL.

Responses occurred in 88% of patients who received ibrutinib and 56% of those who did not.

Grade 3-5 cytokine release syndrome occurred in 5 of 19 patients (26%) in the no-ibrutinib cohort and 0 of 17 patients in the ibrutinib cohort.

These findings are “early and preliminary but very exciting” Dr. Brodsky said.

Checkpoint inhibitors

Early results of the checkpoint inhibitor study (abstract 556) suggest that pembrolizumab or nivolumab may augment CD19-directed CAR T-cell therapy.

The 14 patients studied had early CAR T-cell loss, partial response, or no response to CAR T-cell therapy. Thirteen patients had B-cell ALL, and one had B lymphoblastic lymphoma.

CD19-directed CAR T-cell therapy consisted of tisagenlecleucel in four patients and CTL119 in 10. Thirteen patients received pembrolizumab, and one received nivolumab.

Three of six patients who had early B-cell recovery re-established B-cell aplasia with the addition of a checkpoint inhibitor. In two patients, B-cell aplasia persists with ongoing pembrolizumab.

Four patients who did not respond to or relapsed after their initial CAR T-cell therapy had a partial (n=2) or complete response (n=2) with the addition of pembrolizumab.

There were additional partial responses in the remaining four patients. However, one of these patients (with CD19-dim/negative disease) progressed.

“The idea was if you can give pembrolizumab, you can take the brakes off, and maybe you can reinitiate the immune attack,” Dr. Brodsky said.

“[This is a] very small [study with] preliminary data but very exciting that it is safe to give checkpoint inhibitors with CAR T cells, and it may be efficacious at getting the immune response back.”

Tisagenlecleucel follow-up

One of the two tisagenlecleucel updates (abstract 895) consists of data from the ELIANA trial, which includes pediatric and young adult patients with relapsed/refractory ALL.

The overall response rate was 82% (65/79). Of the 65 responders, 29 were still in response at follow-up.

The probability of relapse-free survival was 66% at 12 months and 18 months.

“These are some very fast-growing tumors, and these are refractory, resistant patients, so, as we get further and further out, it’s more encouraging to see that there are durable responses,” Dr. Brodsky said.

The other tisagenlecleucel update (abstract 1684) is from the JULIET trial, which includes adults with relapsed or refractory DLBCL (n=99).

The overall response rate was 54%. The probability of relapse-free survival was 66% at 6 months and 64% at both 12 months and 18 months.

HSCT consolidation

Dr. Brodsky also discussed long-term follow-up from a phase 1/2 trial of SCRI-CAR19v1, a CD19-specific CAR T-cell product, in patients with relapsed/refractory ALL (abstract 967).

Of the 50 evaluable patients, 17 had no history of HSCT prior to CAR T-cell therapy.

Three of the 17 patients did not proceed to HSCT after CAR T-cell therapy, and two of these patients relapsed. Of the 14 patients who did undergo HSCT after CAR T-cell therapy, two relapsed.

There were 33 patients with a prior history of HSCT, and 10 of them had another HSCT after CAR T-cell therapy. Five of them are still alive and in remission.

Of the 23 patients who did not undergo another HSCT, eight are still in remission.

“This study is very small, and it’s retrospective, but it suggests that bone marrow transplant is a good way to consolidate the remission after CAR T-cell therapy,” Dr. Brodsky said.

Photo from Penn Medicine

Several studies set to be presented at the 2018 ASH Annual Meeting provide new insights regarding chimeric antigen receptor (CAR) T-cell therapies.

One study suggests ibrutinib may enhance CAR T-cell therapy in patients with chronic lymphocytic leukemia (CLL), and another suggests checkpoint inhibitors can augment CAR T-cell therapy in certain patients with B-cell acute lymphoblastic leukemia (ALL).

Two additional studies indicate that responses to tisagenlecleucel are durable in both ALL and diffuse large B-cell lymphoma (DLBCL).

A fifth study suggests hematopoietic stem cell transplant (HSCT) may reduce the risk of relapse after CAR T-cell therapy.

ASH Secretary Robert A. Brodsky, MD, of Johns Hopkins University in Baltimore, Maryland, discussed these studies during a media briefing ahead of the ASH Annual Meeting.

Ibrutinib

In the ibrutinib study (abstract 299), patients received the BTK inhibitor starting 2 weeks prior to leukapheresis and continued until 3 months after treatment with JCAR014.

Data suggest this strategy may improve responses and decrease the incidence of severe cytokine release syndrome in patients with relapsed or refractory CLL.

Responses occurred in 88% of patients who received ibrutinib and 56% of those who did not.

Grade 3-5 cytokine release syndrome occurred in 5 of 19 patients (26%) in the no-ibrutinib cohort and 0 of 17 patients in the ibrutinib cohort.

These findings are “early and preliminary but very exciting” Dr. Brodsky said.

Checkpoint inhibitors

Early results of the checkpoint inhibitor study (abstract 556) suggest that pembrolizumab or nivolumab may augment CD19-directed CAR T-cell therapy.

The 14 patients studied had early CAR T-cell loss, partial response, or no response to CAR T-cell therapy. Thirteen patients had B-cell ALL, and one had B lymphoblastic lymphoma.

CD19-directed CAR T-cell therapy consisted of tisagenlecleucel in four patients and CTL119 in 10. Thirteen patients received pembrolizumab, and one received nivolumab.

Three of six patients who had early B-cell recovery re-established B-cell aplasia with the addition of a checkpoint inhibitor. In two patients, B-cell aplasia persists with ongoing pembrolizumab.

Four patients who did not respond to or relapsed after their initial CAR T-cell therapy had a partial (n=2) or complete response (n=2) with the addition of pembrolizumab.

There were additional partial responses in the remaining four patients. However, one of these patients (with CD19-dim/negative disease) progressed.

“The idea was if you can give pembrolizumab, you can take the brakes off, and maybe you can reinitiate the immune attack,” Dr. Brodsky said.

“[This is a] very small [study with] preliminary data but very exciting that it is safe to give checkpoint inhibitors with CAR T cells, and it may be efficacious at getting the immune response back.”

Tisagenlecleucel follow-up

One of the two tisagenlecleucel updates (abstract 895) consists of data from the ELIANA trial, which includes pediatric and young adult patients with relapsed/refractory ALL.

The overall response rate was 82% (65/79). Of the 65 responders, 29 were still in response at follow-up.

The probability of relapse-free survival was 66% at 12 months and 18 months.

“These are some very fast-growing tumors, and these are refractory, resistant patients, so, as we get further and further out, it’s more encouraging to see that there are durable responses,” Dr. Brodsky said.

The other tisagenlecleucel update (abstract 1684) is from the JULIET trial, which includes adults with relapsed or refractory DLBCL (n=99).

The overall response rate was 54%. The probability of relapse-free survival was 66% at 6 months and 64% at both 12 months and 18 months.

HSCT consolidation

Dr. Brodsky also discussed long-term follow-up from a phase 1/2 trial of SCRI-CAR19v1, a CD19-specific CAR T-cell product, in patients with relapsed/refractory ALL (abstract 967).

Of the 50 evaluable patients, 17 had no history of HSCT prior to CAR T-cell therapy.

Three of the 17 patients did not proceed to HSCT after CAR T-cell therapy, and two of these patients relapsed. Of the 14 patients who did undergo HSCT after CAR T-cell therapy, two relapsed.

There were 33 patients with a prior history of HSCT, and 10 of them had another HSCT after CAR T-cell therapy. Five of them are still alive and in remission.

Of the 23 patients who did not undergo another HSCT, eight are still in remission.

“This study is very small, and it’s retrospective, but it suggests that bone marrow transplant is a good way to consolidate the remission after CAR T-cell therapy,” Dr. Brodsky said.

Photo from Penn Medicine

Several studies set to be presented at the 2018 ASH Annual Meeting provide new insights regarding chimeric antigen receptor (CAR) T-cell therapies.

One study suggests ibrutinib may enhance CAR T-cell therapy in patients with chronic lymphocytic leukemia (CLL), and another suggests checkpoint inhibitors can augment CAR T-cell therapy in certain patients with B-cell acute lymphoblastic leukemia (ALL).

Two additional studies indicate that responses to tisagenlecleucel are durable in both ALL and diffuse large B-cell lymphoma (DLBCL).

A fifth study suggests hematopoietic stem cell transplant (HSCT) may reduce the risk of relapse after CAR T-cell therapy.

ASH Secretary Robert A. Brodsky, MD, of Johns Hopkins University in Baltimore, Maryland, discussed these studies during a media briefing ahead of the ASH Annual Meeting.

Ibrutinib

In the ibrutinib study (abstract 299), patients received the BTK inhibitor starting 2 weeks prior to leukapheresis and continued until 3 months after treatment with JCAR014.

Data suggest this strategy may improve responses and decrease the incidence of severe cytokine release syndrome in patients with relapsed or refractory CLL.

Responses occurred in 88% of patients who received ibrutinib and 56% of those who did not.

Grade 3-5 cytokine release syndrome occurred in 5 of 19 patients (26%) in the no-ibrutinib cohort and 0 of 17 patients in the ibrutinib cohort.

These findings are “early and preliminary but very exciting” Dr. Brodsky said.

Checkpoint inhibitors

Early results of the checkpoint inhibitor study (abstract 556) suggest that pembrolizumab or nivolumab may augment CD19-directed CAR T-cell therapy.

The 14 patients studied had early CAR T-cell loss, partial response, or no response to CAR T-cell therapy. Thirteen patients had B-cell ALL, and one had B lymphoblastic lymphoma.

CD19-directed CAR T-cell therapy consisted of tisagenlecleucel in four patients and CTL119 in 10. Thirteen patients received pembrolizumab, and one received nivolumab.

Three of six patients who had early B-cell recovery re-established B-cell aplasia with the addition of a checkpoint inhibitor. In two patients, B-cell aplasia persists with ongoing pembrolizumab.

Four patients who did not respond to or relapsed after their initial CAR T-cell therapy had a partial (n=2) or complete response (n=2) with the addition of pembrolizumab.

There were additional partial responses in the remaining four patients. However, one of these patients (with CD19-dim/negative disease) progressed.

“The idea was if you can give pembrolizumab, you can take the brakes off, and maybe you can reinitiate the immune attack,” Dr. Brodsky said.

“[This is a] very small [study with] preliminary data but very exciting that it is safe to give checkpoint inhibitors with CAR T cells, and it may be efficacious at getting the immune response back.”

Tisagenlecleucel follow-up

One of the two tisagenlecleucel updates (abstract 895) consists of data from the ELIANA trial, which includes pediatric and young adult patients with relapsed/refractory ALL.

The overall response rate was 82% (65/79). Of the 65 responders, 29 were still in response at follow-up.

The probability of relapse-free survival was 66% at 12 months and 18 months.

“These are some very fast-growing tumors, and these are refractory, resistant patients, so, as we get further and further out, it’s more encouraging to see that there are durable responses,” Dr. Brodsky said.

The other tisagenlecleucel update (abstract 1684) is from the JULIET trial, which includes adults with relapsed or refractory DLBCL (n=99).

The overall response rate was 54%. The probability of relapse-free survival was 66% at 6 months and 64% at both 12 months and 18 months.

HSCT consolidation

Dr. Brodsky also discussed long-term follow-up from a phase 1/2 trial of SCRI-CAR19v1, a CD19-specific CAR T-cell product, in patients with relapsed/refractory ALL (abstract 967).

Of the 50 evaluable patients, 17 had no history of HSCT prior to CAR T-cell therapy.

Three of the 17 patients did not proceed to HSCT after CAR T-cell therapy, and two of these patients relapsed. Of the 14 patients who did undergo HSCT after CAR T-cell therapy, two relapsed.

There were 33 patients with a prior history of HSCT, and 10 of them had another HSCT after CAR T-cell therapy. Five of them are still alive and in remission.

Of the 23 patients who did not undergo another HSCT, eight are still in remission.

“This study is very small, and it’s retrospective, but it suggests that bone marrow transplant is a good way to consolidate the remission after CAR T-cell therapy,” Dr. Brodsky said.

Micrograph showing MM

A retrospective study suggests haploidentical hematopoietic stem cell transplant (haplo-HSCT) is feasible in patients with multiply relapsed or high-risk multiple myeloma (MM).

Investigators said haplo-HSCT produced an “acceptable” rate of non-relapse mortality (NRM)—21% at 1 year—in such patients.

“Our results demonstrate that [haplo-HSCT] can be safely performed in appropriate patients with MM who lack an HLA-matched sibling or unrelated donor,” the investigators wrote in Biology of Blood and Marrow Transplantation.

The research was conducted by Firoozeh Sahebi, MD, of City of Hope Medical Center in Duarte, California, and her colleagues.

The team analyzed data from 96 MM patients who had failed at least one previous autologous transplant and underwent haplo-HSCT between 2008 and 2016.

The patients had a median age of 54.9 (range, 36.6-73.3), and 65.6% were male. At baseline, 37.5% of patients were in very good partial response or better, 31.2% were in partial response, 13.5% had stable disease, and 17.7% had relapsed disease.

The median follow-up was 24 months. Almost all patients (97%) achieved neutrophil engraftment by day 28, and 75% had recovery of platelets by day 60.

Grade 2-4 acute graft-vs-host-disease occurred in 39% of patients by 100 days. Chronic graft-vs-host-disease was seen in 46% of patients at 2 years.

The rate of NRM was 21% at 1 year and 26% at 2 years. The cumulative risk of relapse and progression was 50% at 1 year and 56% at 2 years.

The 2-year progression-free survival (PFS) was 17%, and the 2-year overall survival (OS) was 48%.

In a univariate analysis, bone marrow transplant was associated with significantly better OS than peripheral blood transplant (P=0.001). However, there was no significant difference in PFS between the two.

NRM was lower with bone marrow transplant (P=0.016), and there was a trend toward a higher relapse rate with bone marrow (P=0.083).

The use of cyclophosphamide after transplant was associated with significantly better OS (P=0.009) but not PFS, NRM, or relapse.

Other factors—such as disease status and conditioning regimen—had no significant impact on survival, NRM, or relapse.

The investigators said they had no conflicts of interest related to this research.

Micrograph showing MM

A retrospective study suggests haploidentical hematopoietic stem cell transplant (haplo-HSCT) is feasible in patients with multiply relapsed or high-risk multiple myeloma (MM).

Investigators said haplo-HSCT produced an “acceptable” rate of non-relapse mortality (NRM)—21% at 1 year—in such patients.

“Our results demonstrate that [haplo-HSCT] can be safely performed in appropriate patients with MM who lack an HLA-matched sibling or unrelated donor,” the investigators wrote in Biology of Blood and Marrow Transplantation.

The research was conducted by Firoozeh Sahebi, MD, of City of Hope Medical Center in Duarte, California, and her colleagues.

The team analyzed data from 96 MM patients who had failed at least one previous autologous transplant and underwent haplo-HSCT between 2008 and 2016.

The patients had a median age of 54.9 (range, 36.6-73.3), and 65.6% were male. At baseline, 37.5% of patients were in very good partial response or better, 31.2% were in partial response, 13.5% had stable disease, and 17.7% had relapsed disease.

The median follow-up was 24 months. Almost all patients (97%) achieved neutrophil engraftment by day 28, and 75% had recovery of platelets by day 60.

Grade 2-4 acute graft-vs-host-disease occurred in 39% of patients by 100 days. Chronic graft-vs-host-disease was seen in 46% of patients at 2 years.

The rate of NRM was 21% at 1 year and 26% at 2 years. The cumulative risk of relapse and progression was 50% at 1 year and 56% at 2 years.

The 2-year progression-free survival (PFS) was 17%, and the 2-year overall survival (OS) was 48%.

In a univariate analysis, bone marrow transplant was associated with significantly better OS than peripheral blood transplant (P=0.001). However, there was no significant difference in PFS between the two.

NRM was lower with bone marrow transplant (P=0.016), and there was a trend toward a higher relapse rate with bone marrow (P=0.083).

The use of cyclophosphamide after transplant was associated with significantly better OS (P=0.009) but not PFS, NRM, or relapse.

Other factors—such as disease status and conditioning regimen—had no significant impact on survival, NRM, or relapse.

The investigators said they had no conflicts of interest related to this research.

Micrograph showing MM

A retrospective study suggests haploidentical hematopoietic stem cell transplant (haplo-HSCT) is feasible in patients with multiply relapsed or high-risk multiple myeloma (MM).

Investigators said haplo-HSCT produced an “acceptable” rate of non-relapse mortality (NRM)—21% at 1 year—in such patients.

“Our results demonstrate that [haplo-HSCT] can be safely performed in appropriate patients with MM who lack an HLA-matched sibling or unrelated donor,” the investigators wrote in Biology of Blood and Marrow Transplantation.

The research was conducted by Firoozeh Sahebi, MD, of City of Hope Medical Center in Duarte, California, and her colleagues.

The team analyzed data from 96 MM patients who had failed at least one previous autologous transplant and underwent haplo-HSCT between 2008 and 2016.

The patients had a median age of 54.9 (range, 36.6-73.3), and 65.6% were male. At baseline, 37.5% of patients were in very good partial response or better, 31.2% were in partial response, 13.5% had stable disease, and 17.7% had relapsed disease.

The median follow-up was 24 months. Almost all patients (97%) achieved neutrophil engraftment by day 28, and 75% had recovery of platelets by day 60.

Grade 2-4 acute graft-vs-host-disease occurred in 39% of patients by 100 days. Chronic graft-vs-host-disease was seen in 46% of patients at 2 years.

The rate of NRM was 21% at 1 year and 26% at 2 years. The cumulative risk of relapse and progression was 50% at 1 year and 56% at 2 years.

The 2-year progression-free survival (PFS) was 17%, and the 2-year overall survival (OS) was 48%.

In a univariate analysis, bone marrow transplant was associated with significantly better OS than peripheral blood transplant (P=0.001). However, there was no significant difference in PFS between the two.

NRM was lower with bone marrow transplant (P=0.016), and there was a trend toward a higher relapse rate with bone marrow (P=0.083).

The use of cyclophosphamide after transplant was associated with significantly better OS (P=0.009) but not PFS, NRM, or relapse.

Other factors—such as disease status and conditioning regimen—had no significant impact on survival, NRM, or relapse.

The investigators said they had no conflicts of interest related to this research.

Photo courtesy of Abbvie

The U.S. Food and Drug Administration (FDA) has granted accelerated approval to venetoclax (Venclexta®) for use in acute myeloid leukemia (AML).

The BCL-2 inhibitor is now approved for use in combination with azacitidine, decitabine, or low-dose cytarabine to treat adults with newly diagnosed AML who are age 75 and older or who are ineligible for intensive chemotherapy.

The FDA grants accelerated approval based on a surrogate or intermediate endpoint that is reasonably likely to predict clinical benefit.

Therefore, continued approval of venetoclax in AML may be contingent upon verification of clinical benefit in confirmatory trials.

The approval is based on data from two studies—the phase 1 b M14-358 trial (NCT02203773) and the phase 1/2 M14-387 trial (NCT02287233).

M14-358 trial

In M14-358, newly diagnosed AML patients received venetoclax in combination with azacitidine (n=84) or decitabine (n=31). There were 67 patients in the azacitidine arm and 13 in the decitabine arm who were 75 or older or were ineligible for intensive induction chemotherapy.

Patients received venetoclax via a daily ramp-up to a final dose of 400 mg once daily. They received prophylaxis for tumor lysis syndrome and were hospitalized for monitoring during the ramp-up.

They received azacitidine at 75 mg/m² on days 1-7 of each 28-day cycle or decitabine at 20 mg/m² on days 1-5 of each cycle. Patients continued treatment until disease progression or unacceptable toxicity.

The median follow-up was 7.9 months for the azacitidine arm and 11 months for the decitabine arm.

The complete response (CR) rate was 37% (25/67) in the azacitidine arm and 54% (7/13) in the decitabine arm. The rates of CR with partial hematologic recovery were 24% (16/67) and 7.7% (1/13), respectively.

The most common adverse events (AEs)—occurring in at least 30% of patients in both arms—were nausea, diarrhea, constipation, neutropenia, thrombocytopenia, hemorrhage, peripheral edema, vomiting, fatigue, febrile neutropenia, rash, and anemia.

The incidence of serious AEs was 75% overall. The most frequent serious AEs (occurring in at least 5% of patients) were febrile neutropenia, pneumonia (excluding fungal), sepsis (excluding fungal), respiratory failure, and multiple organ dysfunction syndrome.

The incidence of fatal AEs was 1.5% within 30 days of treatment initiation.

M14-387 trial

The M14-387 trial included 82 AML patients who received venetoclax plus low-dose cytarabine. Patients were newly diagnosed with AML, but some had previous exposure to a hypomethylating agent for an antecedent hematologic disorder.

There were 61 patients who were 75 or older or were ineligible for intensive induction chemotherapy.

Patients received venetoclax via daily ramp-up to a final dose of 600 mg once daily. They received prophylaxis for tumor lysis syndrome and were hospitalized for monitoring during the ramp-up.

Cytarabine was given at 20 mg/m² on days 1-10 of each 28-day cycle. Patients continued to receive treatment until disease progression or unacceptable toxicity.

At a median follow-up of 6.5 months, the CR rate was 21% (13/61), and the rate of CR with partial hematologic recovery was 21% (13/61).

The most common AEs (occurring in at least 30% of patients) were nausea, thrombocytopenia, hemorrhage, febrile neutropenia, neutropenia, diarrhea, fatigue, constipation, and dyspnea.

The incidence of serious AEs was 95%. The most frequent serious AEs (occurring in at least 5% of patients) were febrile neutropenia, sepsis (excluding fungal), hemorrhage, pneumonia (excluding fungal), and device-related infection.

The incidence of fatal AEs was 4.9% within 30 days of treatment initiation.

Additional details from the M14-358 and M14-387 trials are available in the prescribing information for venetoclax.

Venetoclax is being developed by AbbVie and Roche. It is jointly commercialized by AbbVie and Genentech, a member of the Roche Group, in the United States and by AbbVie elsewhere.

Photo courtesy of Abbvie

The U.S. Food and Drug Administration (FDA) has granted accelerated approval to venetoclax (Venclexta®) for use in acute myeloid leukemia (AML).

The BCL-2 inhibitor is now approved for use in combination with azacitidine, decitabine, or low-dose cytarabine to treat adults with newly diagnosed AML who are age 75 and older or who are ineligible for intensive chemotherapy.

The FDA grants accelerated approval based on a surrogate or intermediate endpoint that is reasonably likely to predict clinical benefit.

Therefore, continued approval of venetoclax in AML may be contingent upon verification of clinical benefit in confirmatory trials.

The approval is based on data from two studies—the phase 1 b M14-358 trial (NCT02203773) and the phase 1/2 M14-387 trial (NCT02287233).

M14-358 trial

In M14-358, newly diagnosed AML patients received venetoclax in combination with azacitidine (n=84) or decitabine (n=31). There were 67 patients in the azacitidine arm and 13 in the decitabine arm who were 75 or older or were ineligible for intensive induction chemotherapy.

Patients received venetoclax via a daily ramp-up to a final dose of 400 mg once daily. They received prophylaxis for tumor lysis syndrome and were hospitalized for monitoring during the ramp-up.

They received azacitidine at 75 mg/m² on days 1-7 of each 28-day cycle or decitabine at 20 mg/m² on days 1-5 of each cycle. Patients continued treatment until disease progression or unacceptable toxicity.

The median follow-up was 7.9 months for the azacitidine arm and 11 months for the decitabine arm.

The complete response (CR) rate was 37% (25/67) in the azacitidine arm and 54% (7/13) in the decitabine arm. The rates of CR with partial hematologic recovery were 24% (16/67) and 7.7% (1/13), respectively.

The most common adverse events (AEs)—occurring in at least 30% of patients in both arms—were nausea, diarrhea, constipation, neutropenia, thrombocytopenia, hemorrhage, peripheral edema, vomiting, fatigue, febrile neutropenia, rash, and anemia.

The incidence of serious AEs was 75% overall. The most frequent serious AEs (occurring in at least 5% of patients) were febrile neutropenia, pneumonia (excluding fungal), sepsis (excluding fungal), respiratory failure, and multiple organ dysfunction syndrome.

The incidence of fatal AEs was 1.5% within 30 days of treatment initiation.

M14-387 trial

The M14-387 trial included 82 AML patients who received venetoclax plus low-dose cytarabine. Patients were newly diagnosed with AML, but some had previous exposure to a hypomethylating agent for an antecedent hematologic disorder.

There were 61 patients who were 75 or older or were ineligible for intensive induction chemotherapy.

Patients received venetoclax via daily ramp-up to a final dose of 600 mg once daily. They received prophylaxis for tumor lysis syndrome and were hospitalized for monitoring during the ramp-up.

Cytarabine was given at 20 mg/m² on days 1-10 of each 28-day cycle. Patients continued to receive treatment until disease progression or unacceptable toxicity.

At a median follow-up of 6.5 months, the CR rate was 21% (13/61), and the rate of CR with partial hematologic recovery was 21% (13/61).

The most common AEs (occurring in at least 30% of patients) were nausea, thrombocytopenia, hemorrhage, febrile neutropenia, neutropenia, diarrhea, fatigue, constipation, and dyspnea.

The incidence of serious AEs was 95%. The most frequent serious AEs (occurring in at least 5% of patients) were febrile neutropenia, sepsis (excluding fungal), hemorrhage, pneumonia (excluding fungal), and device-related infection.

The incidence of fatal AEs was 4.9% within 30 days of treatment initiation.

Additional details from the M14-358 and M14-387 trials are available in the prescribing information for venetoclax.

Venetoclax is being developed by AbbVie and Roche. It is jointly commercialized by AbbVie and Genentech, a member of the Roche Group, in the United States and by AbbVie elsewhere.

Photo courtesy of Abbvie

The U.S. Food and Drug Administration (FDA) has granted accelerated approval to venetoclax (Venclexta®) for use in acute myeloid leukemia (AML).

The BCL-2 inhibitor is now approved for use in combination with azacitidine, decitabine, or low-dose cytarabine to treat adults with newly diagnosed AML who are age 75 and older or who are ineligible for intensive chemotherapy.

The FDA grants accelerated approval based on a surrogate or intermediate endpoint that is reasonably likely to predict clinical benefit.

Therefore, continued approval of venetoclax in AML may be contingent upon verification of clinical benefit in confirmatory trials.

The approval is based on data from two studies—the phase 1 b M14-358 trial (NCT02203773) and the phase 1/2 M14-387 trial (NCT02287233).

M14-358 trial

In M14-358, newly diagnosed AML patients received venetoclax in combination with azacitidine (n=84) or decitabine (n=31). There were 67 patients in the azacitidine arm and 13 in the decitabine arm who were 75 or older or were ineligible for intensive induction chemotherapy.

Patients received venetoclax via a daily ramp-up to a final dose of 400 mg once daily. They received prophylaxis for tumor lysis syndrome and were hospitalized for monitoring during the ramp-up.

They received azacitidine at 75 mg/m² on days 1-7 of each 28-day cycle or decitabine at 20 mg/m² on days 1-5 of each cycle. Patients continued treatment until disease progression or unacceptable toxicity.

The median follow-up was 7.9 months for the azacitidine arm and 11 months for the decitabine arm.

The complete response (CR) rate was 37% (25/67) in the azacitidine arm and 54% (7/13) in the decitabine arm. The rates of CR with partial hematologic recovery were 24% (16/67) and 7.7% (1/13), respectively.

The most common adverse events (AEs)—occurring in at least 30% of patients in both arms—were nausea, diarrhea, constipation, neutropenia, thrombocytopenia, hemorrhage, peripheral edema, vomiting, fatigue, febrile neutropenia, rash, and anemia.

The incidence of serious AEs was 75% overall. The most frequent serious AEs (occurring in at least 5% of patients) were febrile neutropenia, pneumonia (excluding fungal), sepsis (excluding fungal), respiratory failure, and multiple organ dysfunction syndrome.

The incidence of fatal AEs was 1.5% within 30 days of treatment initiation.

M14-387 trial

The M14-387 trial included 82 AML patients who received venetoclax plus low-dose cytarabine. Patients were newly diagnosed with AML, but some had previous exposure to a hypomethylating agent for an antecedent hematologic disorder.

There were 61 patients who were 75 or older or were ineligible for intensive induction chemotherapy.

Patients received venetoclax via daily ramp-up to a final dose of 600 mg once daily. They received prophylaxis for tumor lysis syndrome and were hospitalized for monitoring during the ramp-up.

Cytarabine was given at 20 mg/m² on days 1-10 of each 28-day cycle. Patients continued to receive treatment until disease progression or unacceptable toxicity.

At a median follow-up of 6.5 months, the CR rate was 21% (13/61), and the rate of CR with partial hematologic recovery was 21% (13/61).

The most common AEs (occurring in at least 30% of patients) were nausea, thrombocytopenia, hemorrhage, febrile neutropenia, neutropenia, diarrhea, fatigue, constipation, and dyspnea.

The incidence of serious AEs was 95%. The most frequent serious AEs (occurring in at least 5% of patients) were febrile neutropenia, sepsis (excluding fungal), hemorrhage, pneumonia (excluding fungal), and device-related infection.

The incidence of fatal AEs was 4.9% within 30 days of treatment initiation.

Additional details from the M14-358 and M14-387 trials are available in the prescribing information for venetoclax.

Venetoclax is being developed by AbbVie and Roche. It is jointly commercialized by AbbVie and Genentech, a member of the Roche Group, in the United States and by AbbVie elsewhere.

Image by Lance Liotta

The U.S. Food and Drug Administration (FDA) has approved the hedgehog pathway inhibitor glasdegib (Daurismo™) to treat certain patients with acute myeloid leukemia (AML).

Glasdegib is approved for use in combination with low-dose cytarabine (LDAC) to treat adults with newly diagnosed AML who are age 75 and older or who are ineligible for intensive chemotherapy.

Glasdegib was approved under priority review and also received orphan drug designation from the FDA.

The prescribing information for glasdegib includes a boxed warning detailing the risk of embryo-fetal death or severe birth defects associated with the drug.

The FDA’s approval of glasdegib is based on results from the phase 2 BRIGHT AML 1003 trial (NCT01546038).

This trial included 111 adults with newly diagnosed AML and 14 patients with other conditions.

The patients were randomized to receive glasdegib (at 100 mg daily) in combination with LDAC (n=84) or LDAC alone (n=41).

The complete response rate among the AML patients was 18.2% (14/77) in the glasdegib arm and 2.6% (1/38) in the LDAC arm.

The median overall survival was 8.3 months in the glasdegib arm and 4.3 months in the LDAC arm (hazard ratio=0.46; P=0.0002).

The most common adverse events (AEs) in the first 90 days of treatment—occurring in at least 30% of patients in either arm (glasdegib-LDAC and LDAC alone, respectively)—were:

• Anemia (43% and 42%)
• Fatigue (36% and 32%)
• Hemorrhage (36% and 42%)
• Febrile neutropenia (31% and 22%)
• Musculoskeletal pain (30% and 17%)
• Edema (30% and 20%)
• Thrombocytopenia (30% and 27%).

The incidence of serious AEs was 79% in the glasdegib arm. The most common serious AEs occurring in at least 5% of patients in this arm were febrile neutropenia (29%), pneumonia (23%), hemorrhage (12%), anemia (7%), and sepsis (7%).

Additional data from this trial are included in the prescribing information for glasdegib. Glasdegib is a product of Pfizer.

Image by Lance Liotta

The U.S. Food and Drug Administration (FDA) has approved the hedgehog pathway inhibitor glasdegib (Daurismo™) to treat certain patients with acute myeloid leukemia (AML).

Glasdegib is approved for use in combination with low-dose cytarabine (LDAC) to treat adults with newly diagnosed AML who are age 75 and older or who are ineligible for intensive chemotherapy.

Glasdegib was approved under priority review and also received orphan drug designation from the FDA.

The prescribing information for glasdegib includes a boxed warning detailing the risk of embryo-fetal death or severe birth defects associated with the drug.

The FDA’s approval of glasdegib is based on results from the phase 2 BRIGHT AML 1003 trial (NCT01546038).

This trial included 111 adults with newly diagnosed AML and 14 patients with other conditions.

The patients were randomized to receive glasdegib (at 100 mg daily) in combination with LDAC (n=84) or LDAC alone (n=41).

The complete response rate among the AML patients was 18.2% (14/77) in the glasdegib arm and 2.6% (1/38) in the LDAC arm.

The median overall survival was 8.3 months in the glasdegib arm and 4.3 months in the LDAC arm (hazard ratio=0.46; P=0.0002).

The most common adverse events (AEs) in the first 90 days of treatment—occurring in at least 30% of patients in either arm (glasdegib-LDAC and LDAC alone, respectively)—were:

• Anemia (43% and 42%)
• Fatigue (36% and 32%)
• Hemorrhage (36% and 42%)
• Febrile neutropenia (31% and 22%)
• Musculoskeletal pain (30% and 17%)
• Edema (30% and 20%)
• Thrombocytopenia (30% and 27%).

The incidence of serious AEs was 79% in the glasdegib arm. The most common serious AEs occurring in at least 5% of patients in this arm were febrile neutropenia (29%), pneumonia (23%), hemorrhage (12%), anemia (7%), and sepsis (7%).

Additional data from this trial are included in the prescribing information for glasdegib. Glasdegib is a product of Pfizer.

Image by Lance Liotta

The U.S. Food and Drug Administration (FDA) has approved the hedgehog pathway inhibitor glasdegib (Daurismo™) to treat certain patients with acute myeloid leukemia (AML).

Glasdegib is approved for use in combination with low-dose cytarabine (LDAC) to treat adults with newly diagnosed AML who are age 75 and older or who are ineligible for intensive chemotherapy.

Glasdegib was approved under priority review and also received orphan drug designation from the FDA.

The prescribing information for glasdegib includes a boxed warning detailing the risk of embryo-fetal death or severe birth defects associated with the drug.

The FDA’s approval of glasdegib is based on results from the phase 2 BRIGHT AML 1003 trial (NCT01546038).

This trial included 111 adults with newly diagnosed AML and 14 patients with other conditions.

The patients were randomized to receive glasdegib (at 100 mg daily) in combination with LDAC (n=84) or LDAC alone (n=41).

The complete response rate among the AML patients was 18.2% (14/77) in the glasdegib arm and 2.6% (1/38) in the LDAC arm.

The median overall survival was 8.3 months in the glasdegib arm and 4.3 months in the LDAC arm (hazard ratio=0.46; P=0.0002).

The most common adverse events (AEs) in the first 90 days of treatment—occurring in at least 30% of patients in either arm (glasdegib-LDAC and LDAC alone, respectively)—were:

• Anemia (43% and 42%)
• Fatigue (36% and 32%)
• Hemorrhage (36% and 42%)
• Febrile neutropenia (31% and 22%)
• Musculoskeletal pain (30% and 17%)
• Edema (30% and 20%)
• Thrombocytopenia (30% and 27%).

The incidence of serious AEs was 79% in the glasdegib arm. The most common serious AEs occurring in at least 5% of patients in this arm were febrile neutropenia (29%), pneumonia (23%), hemorrhage (12%), anemia (7%), and sepsis (7%).

Additional data from this trial are included in the prescribing information for glasdegib. Glasdegib is a product of Pfizer.

follicular lymphoma

Phase 3 results suggest the biosimilar product CT-P10 is equivalent to rituximab in patients with low-tumor-burden follicular lymphoma (FL).

Overall response rates were similar—both exceeding 80%—in patients who received CT-P10 and those who received rituximab.

In addition, adverse event (AE) profiles were comparable between the treatment arms.

Larry W. Kwak, MD, PhD, of City of Hope in Duarte, California, and his colleagues reported these results in The Lancet Haematology.

CT-P10 was approved by the European Commission in 2017 and was recommended for approval by the U.S. Food and Drug Administration’s Oncologic Drugs Advisory Committee last month.

The phase 3 trial of CT-P10 included 258 patients with stage II-IV low-tumor-burden FL. They were randomized to receive CT-P10 (n=130) or rituximab (n=128).

Patients received intravenous CT-P10 or rituximab weekly for 4 weeks as induction therapy. Patients experiencing disease control went on to a maintenance phase with their assigned treatment, given every 8 weeks for six cycles, followed by another year of maintenance therapy with CT-P10 for those still on study.

Efficacy

The overall response rate at 7 months was 83% in patients randomized to CT-P10 and 81% in those randomized to rituximab.

The complete response rates were 28% and 34%, respectively. The unconfirmed complete response rates were 5% and 2%, respectively. And the partial response rates were 51% and 46%, respectively.

The two treatments were deemed therapeutically equivalent, as the two-sided 90% confidence intervals for the difference in proportion of responders between CT-P10 and rituximab were within the prespecified equivalence margin of 17%.

Safety

Treatment-emergent AEs occurred in 71% of patients in the CT-P10 arm and 67% of those in the rituximab arm.

The most common treatment-emergent AEs (in the CT-P10 and rituximab arms, respectively) were:

• Infusion-related reactions (31% and 29%)
• Infections (27% and 21%)
• Worsening neutropenia (22% for both)
• Upper respiratory tract infection (12% and 11%)
• Worsening anemia (10% and 14%)
• Worsening thrombocytopenia (8% and 7%)
• Fatigue (7% and 9%)
• Diarrhea (5% for both)
• Nausea (5% for both)
• Urinary tract infection (4% and 5%)
• Headache (3% and 5%).

Serious AEs were reported in six patients in the CT-P10 arm and three patients in the rituximab arm.

Two serious AEs—myocardial infarction and constipation—in the CT-P10 arm were considered related to treatment. None of the serious AEs in the rituximab arm were considered treatment-related.

Two patients in the CT-P10 arm discontinued treatment due to AEs—one due to myocardial infarction and one due to dermatitis. There were no AE-related discontinuations in the rituximab arm.

There were two deaths in the CT-P10 arm as of the cutoff date (January 4, 2018). One was due to myocardial infarction, and one was due to respiratory failure. The myocardial infarction was considered possibly related to treatment.

This trial was sponsored by Celltrion, the company developing CT-P10. Three study authors are employees of the company.

Dr. Kwak and several other authors not employed by Celltrion reported disclosures related to the company. Authors also reported relationships with Novartis, Roche, AbbVie, Celgene, and Takeda, among other entities.

follicular lymphoma

Phase 3 results suggest the biosimilar product CT-P10 is equivalent to rituximab in patients with low-tumor-burden follicular lymphoma (FL).

Overall response rates were similar—both exceeding 80%—in patients who received CT-P10 and those who received rituximab.

In addition, adverse event (AE) profiles were comparable between the treatment arms.

Larry W. Kwak, MD, PhD, of City of Hope in Duarte, California, and his colleagues reported these results in The Lancet Haematology.

CT-P10 was approved by the European Commission in 2017 and was recommended for approval by the U.S. Food and Drug Administration’s Oncologic Drugs Advisory Committee last month.

The phase 3 trial of CT-P10 included 258 patients with stage II-IV low-tumor-burden FL. They were randomized to receive CT-P10 (n=130) or rituximab (n=128).

Patients received intravenous CT-P10 or rituximab weekly for 4 weeks as induction therapy. Patients experiencing disease control went on to a maintenance phase with their assigned treatment, given every 8 weeks for six cycles, followed by another year of maintenance therapy with CT-P10 for those still on study.

Efficacy

The overall response rate at 7 months was 83% in patients randomized to CT-P10 and 81% in those randomized to rituximab.

The complete response rates were 28% and 34%, respectively. The unconfirmed complete response rates were 5% and 2%, respectively. And the partial response rates were 51% and 46%, respectively.

The two treatments were deemed therapeutically equivalent, as the two-sided 90% confidence intervals for the difference in proportion of responders between CT-P10 and rituximab were within the prespecified equivalence margin of 17%.

Safety

Treatment-emergent AEs occurred in 71% of patients in the CT-P10 arm and 67% of those in the rituximab arm.

The most common treatment-emergent AEs (in the CT-P10 and rituximab arms, respectively) were:

• Infusion-related reactions (31% and 29%)
• Infections (27% and 21%)
• Worsening neutropenia (22% for both)
• Upper respiratory tract infection (12% and 11%)
• Worsening anemia (10% and 14%)
• Worsening thrombocytopenia (8% and 7%)
• Fatigue (7% and 9%)
• Diarrhea (5% for both)
• Nausea (5% for both)
• Urinary tract infection (4% and 5%)
• Headache (3% and 5%).

Serious AEs were reported in six patients in the CT-P10 arm and three patients in the rituximab arm.

Two serious AEs—myocardial infarction and constipation—in the CT-P10 arm were considered related to treatment. None of the serious AEs in the rituximab arm were considered treatment-related.

Two patients in the CT-P10 arm discontinued treatment due to AEs—one due to myocardial infarction and one due to dermatitis. There were no AE-related discontinuations in the rituximab arm.

There were two deaths in the CT-P10 arm as of the cutoff date (January 4, 2018). One was due to myocardial infarction, and one was due to respiratory failure. The myocardial infarction was considered possibly related to treatment.

This trial was sponsored by Celltrion, the company developing CT-P10. Three study authors are employees of the company.

Dr. Kwak and several other authors not employed by Celltrion reported disclosures related to the company. Authors also reported relationships with Novartis, Roche, AbbVie, Celgene, and Takeda, among other entities.

follicular lymphoma

Phase 3 results suggest the biosimilar product CT-P10 is equivalent to rituximab in patients with low-tumor-burden follicular lymphoma (FL).

Overall response rates were similar—both exceeding 80%—in patients who received CT-P10 and those who received rituximab.

In addition, adverse event (AE) profiles were comparable between the treatment arms.

Larry W. Kwak, MD, PhD, of City of Hope in Duarte, California, and his colleagues reported these results in The Lancet Haematology.

CT-P10 was approved by the European Commission in 2017 and was recommended for approval by the U.S. Food and Drug Administration’s Oncologic Drugs Advisory Committee last month.

The phase 3 trial of CT-P10 included 258 patients with stage II-IV low-tumor-burden FL. They were randomized to receive CT-P10 (n=130) or rituximab (n=128).

Patients received intravenous CT-P10 or rituximab weekly for 4 weeks as induction therapy. Patients experiencing disease control went on to a maintenance phase with their assigned treatment, given every 8 weeks for six cycles, followed by another year of maintenance therapy with CT-P10 for those still on study.

Efficacy

The overall response rate at 7 months was 83% in patients randomized to CT-P10 and 81% in those randomized to rituximab.

The complete response rates were 28% and 34%, respectively. The unconfirmed complete response rates were 5% and 2%, respectively. And the partial response rates were 51% and 46%, respectively.

The two treatments were deemed therapeutically equivalent, as the two-sided 90% confidence intervals for the difference in proportion of responders between CT-P10 and rituximab were within the prespecified equivalence margin of 17%.

Safety

Treatment-emergent AEs occurred in 71% of patients in the CT-P10 arm and 67% of those in the rituximab arm.

The most common treatment-emergent AEs (in the CT-P10 and rituximab arms, respectively) were:

• Infusion-related reactions (31% and 29%)
• Infections (27% and 21%)
• Worsening neutropenia (22% for both)
• Upper respiratory tract infection (12% and 11%)
• Worsening anemia (10% and 14%)
• Worsening thrombocytopenia (8% and 7%)
• Fatigue (7% and 9%)
• Diarrhea (5% for both)
• Nausea (5% for both)
• Urinary tract infection (4% and 5%)
• Headache (3% and 5%).

Serious AEs were reported in six patients in the CT-P10 arm and three patients in the rituximab arm.

Two serious AEs—myocardial infarction and constipation—in the CT-P10 arm were considered related to treatment. None of the serious AEs in the rituximab arm were considered treatment-related.

Two patients in the CT-P10 arm discontinued treatment due to AEs—one due to myocardial infarction and one due to dermatitis. There were no AE-related discontinuations in the rituximab arm.

There were two deaths in the CT-P10 arm as of the cutoff date (January 4, 2018). One was due to myocardial infarction, and one was due to respiratory failure. The myocardial infarction was considered possibly related to treatment.

This trial was sponsored by Celltrion, the company developing CT-P10. Three study authors are employees of the company.

Dr. Kwak and several other authors not employed by Celltrion reported disclosures related to the company. Authors also reported relationships with Novartis, Roche, AbbVie, Celgene, and Takeda, among other entities.