EHA Congress 2015

STOCKHOLM – A chemotherapy-free regimen of ibrutinib plus venetoclax was generally safe and showed promising early efficacy in patients with relapsed or refractory chronic lymphocytic leukemia, investigators reported.

A planned interim analysis performed after the first 15 patients who had received two cycles of ibrutinib plus one of ibrutinib and venetoclax showed no treatment-related deaths or treatment interruptions, and all patients had clinical responses, including 8 with complete clinical remission (CR), reported Carsten U. Niemann, MD, PhD, from Rigshospitalet in Copenhagen, and his colleagues.

Niemann_Carsten_DEN_web.jpg

The goal of the ongoing VISION/HOVEN 141 study is to evaluate whether minimal residual disease (MRD)–guided therapy with the Bruton tyrosine kinase inhibitor ibrutinib and the BCL2 inhibitor venetoclax could lead to MRD negativity and allow select patients to stop treatment, Dr. Niemann said in an interview at the annual congress of the European Hematology Association.

“It’s a 100% clinical response rate and 53% CR. Obviously these are clinical responses, so we don’t have the CT scans, we don’t have the bone marrow biopsies, but we’re very happy to see even in the relapsed/refractory setting such good response rates,” he said.

The investigators are enrolling patients with relapsed/refractory chronic lymphocytic leukemia or small lymphocytic leukemia requiring treatment and starting all patients on ibrutinib 420 mg daily for the first 2 cycles, with venetoclax added in a 5-week ramp-up from 20 mg beginning with cycle 3 to a final dose of 400 mg daily for 15 total treatment cycles.

At the end of the induction phase, patients who are determined to be MRD-negative by flow cytometry at cycles 12 and 15, and by bone marrow at cycle 15, are randomized on a 1:2 basis to ibrutinib maintenance until disease progression or intolerable toxicity, or to observation until progression or loss of MRD negativity, at which time they start maintenance with ibrutinib until progression or toxicity, plus 12 months of venetoclax.

All 15 patients who were followed for 3 months had clinical responses, including 8 CRs (53%), 6 partial remissions (40%), and 1 partial remission with lymphocytosis (7%).

Three patients had ibrutinib dose reductions and two had venetoclax dose reductions, but no patients stopped treatment. Three patients had grade 2 adverse events (AEs), three had grade 3 AEs, and two had grade 4 AEs. There were no grade 5 AEs.

Two patients had serious AEs during the first two cycles with ibrutinib alone, one of which was a case of febrile neutropenia and one which was an adenocarcinoma of the lung. There were no serious AEs reported during venetoclax ramp-up. To date, there have been no cases of tumor lysis syndrome, atrial fibrillation, or bleeding events reported.
[embed:render:related:node:167701]
The results suggest that treatment with ibrutinib and venetoclax ramp-up is manageable in this patient population, and the study is ongoing, with further results expected to be reported at either the 2018 annual meeting of the American Society of Hematology or the 2019 annual meeting of the American Society of Clinical Oncology, Dr. Niemann said.

The study is supported by AbbVie and Janssen, which supplied the drugs and had the right to comment on the presentation. Dr. Niemann has previously disclosed consultancy fees from those companies and others.

SOURCE: Niemann CU et al. EHA Congress, Abstract PF346.


 

STOCKHOLM – A chemotherapy-free regimen of ibrutinib plus venetoclax was generally safe and showed promising early efficacy in patients with relapsed or refractory chronic lymphocytic leukemia, investigators reported.

A planned interim analysis performed after the first 15 patients who had received two cycles of ibrutinib plus one of ibrutinib and venetoclax showed no treatment-related deaths or treatment interruptions, and all patients had clinical responses, including 8 with complete clinical remission (CR), reported Carsten U. Niemann, MD, PhD, from Rigshospitalet in Copenhagen, and his colleagues.

Niemann_Carsten_DEN_web.jpg

The goal of the ongoing VISION/HOVEN 141 study is to evaluate whether minimal residual disease (MRD)–guided therapy with the Bruton tyrosine kinase inhibitor ibrutinib and the BCL2 inhibitor venetoclax could lead to MRD negativity and allow select patients to stop treatment, Dr. Niemann said in an interview at the annual congress of the European Hematology Association.

“It’s a 100% clinical response rate and 53% CR. Obviously these are clinical responses, so we don’t have the CT scans, we don’t have the bone marrow biopsies, but we’re very happy to see even in the relapsed/refractory setting such good response rates,” he said.

The investigators are enrolling patients with relapsed/refractory chronic lymphocytic leukemia or small lymphocytic leukemia requiring treatment and starting all patients on ibrutinib 420 mg daily for the first 2 cycles, with venetoclax added in a 5-week ramp-up from 20 mg beginning with cycle 3 to a final dose of 400 mg daily for 15 total treatment cycles.

At the end of the induction phase, patients who are determined to be MRD-negative by flow cytometry at cycles 12 and 15, and by bone marrow at cycle 15, are randomized on a 1:2 basis to ibrutinib maintenance until disease progression or intolerable toxicity, or to observation until progression or loss of MRD negativity, at which time they start maintenance with ibrutinib until progression or toxicity, plus 12 months of venetoclax.

All 15 patients who were followed for 3 months had clinical responses, including 8 CRs (53%), 6 partial remissions (40%), and 1 partial remission with lymphocytosis (7%).

Three patients had ibrutinib dose reductions and two had venetoclax dose reductions, but no patients stopped treatment. Three patients had grade 2 adverse events (AEs), three had grade 3 AEs, and two had grade 4 AEs. There were no grade 5 AEs.

Two patients had serious AEs during the first two cycles with ibrutinib alone, one of which was a case of febrile neutropenia and one which was an adenocarcinoma of the lung. There were no serious AEs reported during venetoclax ramp-up. To date, there have been no cases of tumor lysis syndrome, atrial fibrillation, or bleeding events reported.
[embed:render:related:node:167701]
The results suggest that treatment with ibrutinib and venetoclax ramp-up is manageable in this patient population, and the study is ongoing, with further results expected to be reported at either the 2018 annual meeting of the American Society of Hematology or the 2019 annual meeting of the American Society of Clinical Oncology, Dr. Niemann said.

The study is supported by AbbVie and Janssen, which supplied the drugs and had the right to comment on the presentation. Dr. Niemann has previously disclosed consultancy fees from those companies and others.

SOURCE: Niemann CU et al. EHA Congress, Abstract PF346.


 

STOCKHOLM – A chemotherapy-free regimen of ibrutinib plus venetoclax was generally safe and showed promising early efficacy in patients with relapsed or refractory chronic lymphocytic leukemia, investigators reported.

A planned interim analysis performed after the first 15 patients who had received two cycles of ibrutinib plus one of ibrutinib and venetoclax showed no treatment-related deaths or treatment interruptions, and all patients had clinical responses, including 8 with complete clinical remission (CR), reported Carsten U. Niemann, MD, PhD, from Rigshospitalet in Copenhagen, and his colleagues.

Niemann_Carsten_DEN_web.jpg

The goal of the ongoing VISION/HOVEN 141 study is to evaluate whether minimal residual disease (MRD)–guided therapy with the Bruton tyrosine kinase inhibitor ibrutinib and the BCL2 inhibitor venetoclax could lead to MRD negativity and allow select patients to stop treatment, Dr. Niemann said in an interview at the annual congress of the European Hematology Association.

“It’s a 100% clinical response rate and 53% CR. Obviously these are clinical responses, so we don’t have the CT scans, we don’t have the bone marrow biopsies, but we’re very happy to see even in the relapsed/refractory setting such good response rates,” he said.

The investigators are enrolling patients with relapsed/refractory chronic lymphocytic leukemia or small lymphocytic leukemia requiring treatment and starting all patients on ibrutinib 420 mg daily for the first 2 cycles, with venetoclax added in a 5-week ramp-up from 20 mg beginning with cycle 3 to a final dose of 400 mg daily for 15 total treatment cycles.

At the end of the induction phase, patients who are determined to be MRD-negative by flow cytometry at cycles 12 and 15, and by bone marrow at cycle 15, are randomized on a 1:2 basis to ibrutinib maintenance until disease progression or intolerable toxicity, or to observation until progression or loss of MRD negativity, at which time they start maintenance with ibrutinib until progression or toxicity, plus 12 months of venetoclax.

All 15 patients who were followed for 3 months had clinical responses, including 8 CRs (53%), 6 partial remissions (40%), and 1 partial remission with lymphocytosis (7%).

Three patients had ibrutinib dose reductions and two had venetoclax dose reductions, but no patients stopped treatment. Three patients had grade 2 adverse events (AEs), three had grade 3 AEs, and two had grade 4 AEs. There were no grade 5 AEs.

Two patients had serious AEs during the first two cycles with ibrutinib alone, one of which was a case of febrile neutropenia and one which was an adenocarcinoma of the lung. There were no serious AEs reported during venetoclax ramp-up. To date, there have been no cases of tumor lysis syndrome, atrial fibrillation, or bleeding events reported.
[embed:render:related:node:167701]
The results suggest that treatment with ibrutinib and venetoclax ramp-up is manageable in this patient population, and the study is ongoing, with further results expected to be reported at either the 2018 annual meeting of the American Society of Hematology or the 2019 annual meeting of the American Society of Clinical Oncology, Dr. Niemann said.

The study is supported by AbbVie and Janssen, which supplied the drugs and had the right to comment on the presentation. Dr. Niemann has previously disclosed consultancy fees from those companies and others.

SOURCE: Niemann CU et al. EHA Congress, Abstract PF346.


 

COPENHAGEN – Nivolumab may be an effective salvage therapy option for adults with Hodgkin lymphoma whose disease has progressed despite transplant and treatment with brentuximab vedotin, investigators reported.

In a subcohort of patients from the Checkmate 205 phase II trial, 80 patients with Hodgkin lymphoma who had disease progression following autologous stem cell transplant (ASCT) and brentuximab vedotin (Adcetris), nivolumab (Opdivo) therapy was associated with a 53% objective response rate according to independent reviewers, reported Dr. Anas Younes, chief of the lymphoma service at Memorial Sloan Kettering Cancer Center, New York.

RTEmagicC_706f4d265e38fc20cb_Younes_Anas_NYC.jpg.jpg

“The PD-1 checkpoint inhibitor nivolumab is an important new treatment to address unmet needs in patients with classical Hodgkin lymphoma with progressive disease and limited treatment options, especially after autologous transplant,” he said at a briefing at the annual congress of the European Hematology Association.

Objective response rates as determined by both investigators and independent reviewers were “impressive,” and had “encouraging durability,” he added. The median duration of response at time of data cutoff was 7.8 months, and the majority of patients had ongoing responses at the time of the analysis, Dr. Younes said.

Nivolumab was recently approved by the Food and Drug Administration for the treatment of classical Hodgkin lymphoma that has relapsed or progressed after ASCT followed by brentuximab vedotin.

In the Checkmate 205 registrational trial, 80 patients (median age 37, range 18-72 years) were assigned to receive nivolumab 3 mg/kg intravenously every 2 weeks. Patients were evaluated for response by both an independent radiologic review committee (IRRC) and investigators, using 2007 International Working Group response criteria. After a median follow-up of 8.9 months, the IRRC-rated objective response rate, the primary endpoint, was 66%, including 8.8% complete remissions (CR), and 57.5% partial remissions (PR).

Dr. Younes showed a waterfall plot indicating that nearly all patients had some degree of tumor regression, and all but one patient among the responders had tumor reductions of 50% or greater from baseline.

Among 43 patients who had had no response to brentuximab vedotin, subsequent treatment with nivolumab was associated with an IRRC-rated objective response rate of 72%. As noted, the median duration of response was 7.8 months, and the median time to response was 2.1 months.

As of the last follow-up, 33 of the 53 patients with IRRC-rated responses had retained response. The IRRC-determined 6-month progression-free survival rate was 77%, and the overall survival rate was 99%.

In all, 72 patients (90%) had a treatment-related adverse event. The most common events occurring in 15% or more of patients were fatigue, infusion-related reactions, and rash. Most of the immune-mediated adverse events were of low grade and manageable, and there were no treatment-related deaths, Dr. Younes said.

Briefing moderator Dr. Anton Hagenbeek, professor of hematology at the University of Amsterdam, who was not involved in the study, asked whether nivolumab can be considered as a bridge to other therapies in this population.

Dr. Younes said that the “natural progression of a single-agent therapy that has efficacy is to combine it with other active agents, or use maybe in the adjuvant or maintenance setting in certain circumstances.”

“I don’t expect single-agent nivolumab to cure our patients,” he added.

A similarly designed clinical trial, MK-3457-087/KEYNOTE-087, is exploring the use of pembrolizumab (Keytruda). This trial is ongoing but does not have published data as yet.

Checkmate 205 is sponsored by Bristol-Myers Squibb. Dr. Younes has served as a consultant/advisor, received honoraria and/or research funding from Gilead Sciences, Curis, Incyte, Janssen, Seattle Genetics, Novartis, Celgene, Millennium, and Sanofi. Dr. Hagenbeek reported no relevant disclosures.

COPENHAGEN – Nivolumab may be an effective salvage therapy option for adults with Hodgkin lymphoma whose disease has progressed despite transplant and treatment with brentuximab vedotin, investigators reported.

In a subcohort of patients from the Checkmate 205 phase II trial, 80 patients with Hodgkin lymphoma who had disease progression following autologous stem cell transplant (ASCT) and brentuximab vedotin (Adcetris), nivolumab (Opdivo) therapy was associated with a 53% objective response rate according to independent reviewers, reported Dr. Anas Younes, chief of the lymphoma service at Memorial Sloan Kettering Cancer Center, New York.

RTEmagicC_706f4d265e38fc20cb_Younes_Anas_NYC.jpg.jpg

“The PD-1 checkpoint inhibitor nivolumab is an important new treatment to address unmet needs in patients with classical Hodgkin lymphoma with progressive disease and limited treatment options, especially after autologous transplant,” he said at a briefing at the annual congress of the European Hematology Association.

Objective response rates as determined by both investigators and independent reviewers were “impressive,” and had “encouraging durability,” he added. The median duration of response at time of data cutoff was 7.8 months, and the majority of patients had ongoing responses at the time of the analysis, Dr. Younes said.

Nivolumab was recently approved by the Food and Drug Administration for the treatment of classical Hodgkin lymphoma that has relapsed or progressed after ASCT followed by brentuximab vedotin.

In the Checkmate 205 registrational trial, 80 patients (median age 37, range 18-72 years) were assigned to receive nivolumab 3 mg/kg intravenously every 2 weeks. Patients were evaluated for response by both an independent radiologic review committee (IRRC) and investigators, using 2007 International Working Group response criteria. After a median follow-up of 8.9 months, the IRRC-rated objective response rate, the primary endpoint, was 66%, including 8.8% complete remissions (CR), and 57.5% partial remissions (PR).

Dr. Younes showed a waterfall plot indicating that nearly all patients had some degree of tumor regression, and all but one patient among the responders had tumor reductions of 50% or greater from baseline.

Among 43 patients who had had no response to brentuximab vedotin, subsequent treatment with nivolumab was associated with an IRRC-rated objective response rate of 72%. As noted, the median duration of response was 7.8 months, and the median time to response was 2.1 months.

As of the last follow-up, 33 of the 53 patients with IRRC-rated responses had retained response. The IRRC-determined 6-month progression-free survival rate was 77%, and the overall survival rate was 99%.

In all, 72 patients (90%) had a treatment-related adverse event. The most common events occurring in 15% or more of patients were fatigue, infusion-related reactions, and rash. Most of the immune-mediated adverse events were of low grade and manageable, and there were no treatment-related deaths, Dr. Younes said.

Briefing moderator Dr. Anton Hagenbeek, professor of hematology at the University of Amsterdam, who was not involved in the study, asked whether nivolumab can be considered as a bridge to other therapies in this population.

Dr. Younes said that the “natural progression of a single-agent therapy that has efficacy is to combine it with other active agents, or use maybe in the adjuvant or maintenance setting in certain circumstances.”

“I don’t expect single-agent nivolumab to cure our patients,” he added.

A similarly designed clinical trial, MK-3457-087/KEYNOTE-087, is exploring the use of pembrolizumab (Keytruda). This trial is ongoing but does not have published data as yet.

Checkmate 205 is sponsored by Bristol-Myers Squibb. Dr. Younes has served as a consultant/advisor, received honoraria and/or research funding from Gilead Sciences, Curis, Incyte, Janssen, Seattle Genetics, Novartis, Celgene, Millennium, and Sanofi. Dr. Hagenbeek reported no relevant disclosures.

COPENHAGEN – Nivolumab may be an effective salvage therapy option for adults with Hodgkin lymphoma whose disease has progressed despite transplant and treatment with brentuximab vedotin, investigators reported.

In a subcohort of patients from the Checkmate 205 phase II trial, 80 patients with Hodgkin lymphoma who had disease progression following autologous stem cell transplant (ASCT) and brentuximab vedotin (Adcetris), nivolumab (Opdivo) therapy was associated with a 53% objective response rate according to independent reviewers, reported Dr. Anas Younes, chief of the lymphoma service at Memorial Sloan Kettering Cancer Center, New York.

RTEmagicC_706f4d265e38fc20cb_Younes_Anas_NYC.jpg.jpg

“The PD-1 checkpoint inhibitor nivolumab is an important new treatment to address unmet needs in patients with classical Hodgkin lymphoma with progressive disease and limited treatment options, especially after autologous transplant,” he said at a briefing at the annual congress of the European Hematology Association.

Objective response rates as determined by both investigators and independent reviewers were “impressive,” and had “encouraging durability,” he added. The median duration of response at time of data cutoff was 7.8 months, and the majority of patients had ongoing responses at the time of the analysis, Dr. Younes said.

Nivolumab was recently approved by the Food and Drug Administration for the treatment of classical Hodgkin lymphoma that has relapsed or progressed after ASCT followed by brentuximab vedotin.

In the Checkmate 205 registrational trial, 80 patients (median age 37, range 18-72 years) were assigned to receive nivolumab 3 mg/kg intravenously every 2 weeks. Patients were evaluated for response by both an independent radiologic review committee (IRRC) and investigators, using 2007 International Working Group response criteria. After a median follow-up of 8.9 months, the IRRC-rated objective response rate, the primary endpoint, was 66%, including 8.8% complete remissions (CR), and 57.5% partial remissions (PR).

Dr. Younes showed a waterfall plot indicating that nearly all patients had some degree of tumor regression, and all but one patient among the responders had tumor reductions of 50% or greater from baseline.

Among 43 patients who had had no response to brentuximab vedotin, subsequent treatment with nivolumab was associated with an IRRC-rated objective response rate of 72%. As noted, the median duration of response was 7.8 months, and the median time to response was 2.1 months.

As of the last follow-up, 33 of the 53 patients with IRRC-rated responses had retained response. The IRRC-determined 6-month progression-free survival rate was 77%, and the overall survival rate was 99%.

In all, 72 patients (90%) had a treatment-related adverse event. The most common events occurring in 15% or more of patients were fatigue, infusion-related reactions, and rash. Most of the immune-mediated adverse events were of low grade and manageable, and there were no treatment-related deaths, Dr. Younes said.

Briefing moderator Dr. Anton Hagenbeek, professor of hematology at the University of Amsterdam, who was not involved in the study, asked whether nivolumab can be considered as a bridge to other therapies in this population.

Dr. Younes said that the “natural progression of a single-agent therapy that has efficacy is to combine it with other active agents, or use maybe in the adjuvant or maintenance setting in certain circumstances.”

“I don’t expect single-agent nivolumab to cure our patients,” he added.

A similarly designed clinical trial, MK-3457-087/KEYNOTE-087, is exploring the use of pembrolizumab (Keytruda). This trial is ongoing but does not have published data as yet.

Checkmate 205 is sponsored by Bristol-Myers Squibb. Dr. Younes has served as a consultant/advisor, received honoraria and/or research funding from Gilead Sciences, Curis, Incyte, Janssen, Seattle Genetics, Novartis, Celgene, Millennium, and Sanofi. Dr. Hagenbeek reported no relevant disclosures.

Copenhagen – The monoclonal antibody blinatumomab nearly doubled overall survival compared with standard chemotherapy among patients with relapsed or refractory B-cell precursor leukemia negative for the Philadelphia chromosome, investigators reported.

Among 405 patients enrolled in the TOWER study, a multicenter, open-label phase III trial, median overall survival for patients treated with blinatumomab (Blincyto) was 7.7 months, compared with 4.0 months for patients treated with one of four standard chemotherapy regimens (P = .012) reported Dr. Max S. Topp of Universitätsklinikum in Würzburg, Germany.

RTEmagicC_033e283a898289d75d_Topp_Max_S_GERMANY2.jpg.jpg

“Blinatumomab is the first immunotherapy agent to demonstrate an overall survival benefit when compared to chemotherapy in patients relapsing with adult acute lymphoblastic leukemia. It increases almost twofold the overall survival when compared to standard care. This was consistent in all subgroups that we were looking at, regardless of age, prior salvage therapy, or patients relapsing after an allo-transplantation,” he said at a briefing prior to his presentation of the data at the annual congress of the European Hematology Association.

The trial was halted early, after a preplanned interim analysis showed a clear survival benefit with blinatumomab.

Blinatumomab is a bispecific T-cell engager (BiTE) antibody designed to direct cytotoxic T cells to cancer cells expressing the CD19 receptor. As previously reported, it has induced high complete remission rates in patients with relapsed or refractory acute lymphoblastic leukemia (ALL).

In May 2015, the Food and Drug Administration granted blinatumomab accelerated approval for the treatment of adult patients with relapsed/refractory Philadelphia chromosome–negative B-cell precursor acute lymphoblastic leukemia (BCP-ALL).

In the TOWER trial, patients with relapsed/refractory BCP-ALL were randomly assigned on a 2:1 basis to receive either blinatumomab (271 patients) or standard chemotherapy (134), consisting of the investigator’s choice of one of four defined regimens (based on either anthracyclines, histone deacetylase inhibitors, high-dose methotrexate, or clofarabine).

The patients were further stratified by age, prior salvage therapy, and prior allogeneic stem cell transplant (alloSCT).

Patients assigned to receive blinatumomab received it in 6-week cycles consisting of continuous infusions of 9 mcg/day in week 1 of cycle 1, then 28 mcg/day for weeks 3-4, followed by 2 weeks off. Patients were pretreated with dexamethasone for prophylaxis against the cytokine release syndrome.

Patients whose disease was in remission following two induction cycles could be continued on therapy until relapse.

As noted, the trial was halted early, after 248 patients had died; the primary analysis had been planned to occur after 330 patients had died.

In addition to the superior survival rates, blinatumomab was associated with a higher rate of complete responses (39% vs. 19%, P less than .001) and combined complete responses, complete hematologic responses, and complete responses with incomplete recovery of counts (46% vs. 28%, P = .001).

In all, 19% of patients assigned to blinatumomab and 17% assigned to chemotherapy died on study. Grade 3 or greater adverse events included neutropenia (38% of patients and 58%, respectively), infections (34% and 52%), neurologic events (9% and 8%), and the cytokine release syndrome (5% vs. 0%).

Dr. Anton Hagenbeek, professor of hematology at the University of Amsterdam, who moderated the briefing, asked Dr. Topp whether there were plans to use blinatumomab earlier in the course of disease.

Dr. Topp agreed that it might be a valuable addition to upfront therapy, noting that blinatumomab has been shown in a small percentage of patients who are positive for minimal residual disease to convert to being negative for minimal residual disease, and that this conversion was associated with improved overall survival.

Copenhagen – The monoclonal antibody blinatumomab nearly doubled overall survival compared with standard chemotherapy among patients with relapsed or refractory B-cell precursor leukemia negative for the Philadelphia chromosome, investigators reported.

Among 405 patients enrolled in the TOWER study, a multicenter, open-label phase III trial, median overall survival for patients treated with blinatumomab (Blincyto) was 7.7 months, compared with 4.0 months for patients treated with one of four standard chemotherapy regimens (P = .012) reported Dr. Max S. Topp of Universitätsklinikum in Würzburg, Germany.

RTEmagicC_033e283a898289d75d_Topp_Max_S_GERMANY2.jpg.jpg

“Blinatumomab is the first immunotherapy agent to demonstrate an overall survival benefit when compared to chemotherapy in patients relapsing with adult acute lymphoblastic leukemia. It increases almost twofold the overall survival when compared to standard care. This was consistent in all subgroups that we were looking at, regardless of age, prior salvage therapy, or patients relapsing after an allo-transplantation,” he said at a briefing prior to his presentation of the data at the annual congress of the European Hematology Association.

The trial was halted early, after a preplanned interim analysis showed a clear survival benefit with blinatumomab.

Blinatumomab is a bispecific T-cell engager (BiTE) antibody designed to direct cytotoxic T cells to cancer cells expressing the CD19 receptor. As previously reported, it has induced high complete remission rates in patients with relapsed or refractory acute lymphoblastic leukemia (ALL).

In May 2015, the Food and Drug Administration granted blinatumomab accelerated approval for the treatment of adult patients with relapsed/refractory Philadelphia chromosome–negative B-cell precursor acute lymphoblastic leukemia (BCP-ALL).

In the TOWER trial, patients with relapsed/refractory BCP-ALL were randomly assigned on a 2:1 basis to receive either blinatumomab (271 patients) or standard chemotherapy (134), consisting of the investigator’s choice of one of four defined regimens (based on either anthracyclines, histone deacetylase inhibitors, high-dose methotrexate, or clofarabine).

The patients were further stratified by age, prior salvage therapy, and prior allogeneic stem cell transplant (alloSCT).

Patients assigned to receive blinatumomab received it in 6-week cycles consisting of continuous infusions of 9 mcg/day in week 1 of cycle 1, then 28 mcg/day for weeks 3-4, followed by 2 weeks off. Patients were pretreated with dexamethasone for prophylaxis against the cytokine release syndrome.

Patients whose disease was in remission following two induction cycles could be continued on therapy until relapse.

As noted, the trial was halted early, after 248 patients had died; the primary analysis had been planned to occur after 330 patients had died.

In addition to the superior survival rates, blinatumomab was associated with a higher rate of complete responses (39% vs. 19%, P less than .001) and combined complete responses, complete hematologic responses, and complete responses with incomplete recovery of counts (46% vs. 28%, P = .001).

In all, 19% of patients assigned to blinatumomab and 17% assigned to chemotherapy died on study. Grade 3 or greater adverse events included neutropenia (38% of patients and 58%, respectively), infections (34% and 52%), neurologic events (9% and 8%), and the cytokine release syndrome (5% vs. 0%).

Dr. Anton Hagenbeek, professor of hematology at the University of Amsterdam, who moderated the briefing, asked Dr. Topp whether there were plans to use blinatumomab earlier in the course of disease.

Dr. Topp agreed that it might be a valuable addition to upfront therapy, noting that blinatumomab has been shown in a small percentage of patients who are positive for minimal residual disease to convert to being negative for minimal residual disease, and that this conversion was associated with improved overall survival.

Copenhagen – The monoclonal antibody blinatumomab nearly doubled overall survival compared with standard chemotherapy among patients with relapsed or refractory B-cell precursor leukemia negative for the Philadelphia chromosome, investigators reported.

Among 405 patients enrolled in the TOWER study, a multicenter, open-label phase III trial, median overall survival for patients treated with blinatumomab (Blincyto) was 7.7 months, compared with 4.0 months for patients treated with one of four standard chemotherapy regimens (P = .012) reported Dr. Max S. Topp of Universitätsklinikum in Würzburg, Germany.

RTEmagicC_033e283a898289d75d_Topp_Max_S_GERMANY2.jpg.jpg

“Blinatumomab is the first immunotherapy agent to demonstrate an overall survival benefit when compared to chemotherapy in patients relapsing with adult acute lymphoblastic leukemia. It increases almost twofold the overall survival when compared to standard care. This was consistent in all subgroups that we were looking at, regardless of age, prior salvage therapy, or patients relapsing after an allo-transplantation,” he said at a briefing prior to his presentation of the data at the annual congress of the European Hematology Association.

The trial was halted early, after a preplanned interim analysis showed a clear survival benefit with blinatumomab.

Blinatumomab is a bispecific T-cell engager (BiTE) antibody designed to direct cytotoxic T cells to cancer cells expressing the CD19 receptor. As previously reported, it has induced high complete remission rates in patients with relapsed or refractory acute lymphoblastic leukemia (ALL).

In May 2015, the Food and Drug Administration granted blinatumomab accelerated approval for the treatment of adult patients with relapsed/refractory Philadelphia chromosome–negative B-cell precursor acute lymphoblastic leukemia (BCP-ALL).

In the TOWER trial, patients with relapsed/refractory BCP-ALL were randomly assigned on a 2:1 basis to receive either blinatumomab (271 patients) or standard chemotherapy (134), consisting of the investigator’s choice of one of four defined regimens (based on either anthracyclines, histone deacetylase inhibitors, high-dose methotrexate, or clofarabine).

The patients were further stratified by age, prior salvage therapy, and prior allogeneic stem cell transplant (alloSCT).

Patients assigned to receive blinatumomab received it in 6-week cycles consisting of continuous infusions of 9 mcg/day in week 1 of cycle 1, then 28 mcg/day for weeks 3-4, followed by 2 weeks off. Patients were pretreated with dexamethasone for prophylaxis against the cytokine release syndrome.

Patients whose disease was in remission following two induction cycles could be continued on therapy until relapse.

As noted, the trial was halted early, after 248 patients had died; the primary analysis had been planned to occur after 330 patients had died.

In addition to the superior survival rates, blinatumomab was associated with a higher rate of complete responses (39% vs. 19%, P less than .001) and combined complete responses, complete hematologic responses, and complete responses with incomplete recovery of counts (46% vs. 28%, P = .001).

In all, 19% of patients assigned to blinatumomab and 17% assigned to chemotherapy died on study. Grade 3 or greater adverse events included neutropenia (38% of patients and 58%, respectively), infections (34% and 52%), neurologic events (9% and 8%), and the cytokine release syndrome (5% vs. 0%).

Dr. Anton Hagenbeek, professor of hematology at the University of Amsterdam, who moderated the briefing, asked Dr. Topp whether there were plans to use blinatumomab earlier in the course of disease.

Dr. Topp agreed that it might be a valuable addition to upfront therapy, noting that blinatumomab has been shown in a small percentage of patients who are positive for minimal residual disease to convert to being negative for minimal residual disease, and that this conversion was associated with improved overall survival.

VIENNA – Patients with high-risk newly diagnosed acute promyelocytic leukemia derive the same survival benefit from a chemotherapy-free combination as an anthracycline-containing standard of care, according to results of the AML17 APL study.

The 4-year overall survival rates in high-risk patients (WBC > 10 x 10⁹/L) were 87% with arsenic trioxide plus all-trans retinoic acid and 84% with the standard all-trans retinoic acid and idarubicin schedule.

Relapse-free survival rates were superior with the chemotherapy-free combination (100% vs. 74%; P = .008), Dr. Alan Burnett reported at the annual congress of the European Hematology Association.

“One of our rationales for using arsenic as first-line (therapy) was to try and get at the early death that remains a major problem in this disease,” he said.

Arsenic trioxide and gemtuzumab ozogamicin are effective as single agents with the former approved for relapsed disease in patients with APL. The GIMEMA-AMLSG-SAL trial indicated that a daily schedule of arsenic trioxide plus all-trans retinoic acid was at least as effective and may be superior to all-trans retinoic acid plus chemotherapy in low to moderate risk APL patients (N. Engl. J. Med. 2013;369: 111-21).

The AML17 APL trial was designed by the U.K. National Cancer Research Institute with the aim of comparing all-trans retinoic acid and idarubicin with arsenic trioxide in an attenuated dosing schedule plus all-trans retinoic acid. Importantly, high-risk patients were included, with the option to receive a single dose of gemtuzumab ozogamicin (Mylotarg) 6 mg/m² within the first 4 days of induction, said Dr. Burnett, who performed the research as head of hematology at Cardiff University in Wales and is now global lead for myeloid diseases at CTI BioPharma in Seattle. In the United States, gemtuzumab was withdrawn from the market in 2010 because of safety concerns.

From May 2009 to October 2013, 235 patients with molecularly confirmed APL were randomized at 81 centers to all-trans retinoic acid 45 mg/m² as a divided daily oral dose to day 60 or complete remission plus arsenic trioxide 0.3 mg/kg on days 1-5 of week 1 and then 0.25 mg/kg twice per week for 7 weeks plus all-trans retinoic acid 45 mg/m² as a divided daily oral dose to day 60 or complete remission or to idarubicin 12 mg/m² on days 2, 4, 6, 8 plus all-trans retinoic acid 45 mg/m² as a divided daily oral dose to day 60.

In the arsenic trioxide plus all-trans retinoic acid arm, this was followed by all-trans retinoic acid 45 mg/m² as a divided daily dose 2 weeks on and 2 weeks off plus four consolidation courses of arsenic trioxide 0.3 mg/kg days 1-5 of week 1 and then 0.25 mg/kg twice per week for 3 weeks (total 63 days of arsenic trioxide).

Consolidation in the all-trans retinoic acid and idarubicin arm was all-trans retinoic acid 45 mg/m² as a divided daily dose on days 1-15 plus idarubicin 5 mg/m² days 1-4 in course 2, mitoxantrone 10mg/m² days 1-4 in course 3, and idarubicin 12 mg/m² day 1 in course 4.

No maintenance was given in either arm. The median patient age was 47 years, with about 20% of patients over age 60; over 20% of the patients were high-risk, and they were equally balanced in the two treatment groups.

At 4 years, the overall survival rate among all patients was comparable – 93% with arsenic trioxide plus all-trans retinoic acid and 89% with all-trans retinoic acid and idarubicin.

However, event-free survival was significantly better in the arsenic trioxide plus all-trans retinoic acid cohort (91% vs. 74%; hazard ratio, 0.36; P = .003), as were frank relapse-free survival (97% vs. 83%; HR, 0.24; P = .004) and molecular relapse-free survival (98% vs. 70%; HR, 0.17; P < .0001), Dr. Burnett said.

One patient on arsenic trioxide plus all-trans retinoic acid experienced frank relapse, compared with 13 on all-trans retinoic acid and idarubicin, plus a further 19 molecular relapses occurred on this arm (cumulative incidence of molecular and hematologic relapse 0% vs. 27%, HR, 0.12; P < .0001).

“Once a patient was in molecular remission there were no further relapses in patients on (arsenic trioxide plus all-trans retinoic acid),” he said.

Of the 30 high-risk patients allocated to the chemo-free arm, 28 received gemtuzumab ozogamicin as per protocol. The overall survival at 4 years for these patients was 89%. Of the two patients not treated with gemtuzumab ozogamicin, one died on day 12 due to causes unrelated to treatment.

Among the 49 patients older than 60 years, overall survival was 80% with arsenic trioxide plus all-trans retinoic acid and 74% with all-trans retinoic acid and idarubicin. Similarly, among good-risk patients, relapse-free survival was significantly improved (96% vs. 79%; HR, 0.33; P = .04). Also, overall survival was not inferior at 95% vs. 90%, “very much replicating the outcomes seen in the GIMEMA study,” Dr. Burnett said.

The benefits were also achieved with significantly less grade 3-4 liver toxicity than observed in the GIMEMA study (<10% vs 63%).

There was, however, an excess of cardiac toxicity in course 2 with arsenic trioxide plus all-trans retinoic acid, compared with all-trans retinoic acid and idarubicin (P = .001).

“We’re not totally sure what that’s all due to, but it doesn’t look to be due to a QC prolongation,” he said.

The arsenic trioxide plus all-trans retinoic acid regimen was associated with significant reductions in supportive care requirements including fewer blood and platelet transfusions, days on antibiotics, and days in hospital, with “many patients treated exclusively as outpatients,” he added.

The low risk of relapse with arsenic trioxide plus all-trans retinoic acid also negates the need for minimal residual disease monitoring.

Finally, compared with the GIMEMA study protocol, the attenuated arsenic dosing schedule in AML17 APL resulted in less frequent dosing of arsenic trioxide (63 doses vs. 140 doses) and less drug required (151 vials vs. 280 vials for a 70-kg patient). At an acquisition cost of £350 per vial, this represents a cost savings of £46,000 (nearly $72,000) per patient, not to mention the added convenience to patients, Dr. Burnett observed.

Cancer Research U.K. funded the study. Cephalon provided the arsenic trioxide. Dr. Burnett disclosed part-time employment with CTI LifeSciences and in the last 12 months serving on the advisory boards of Celgene, Agios, Pfizer, and Bristol-Myers Squibb.

pwendling@frontlinemedcom.com

VIENNA – Patients with high-risk newly diagnosed acute promyelocytic leukemia derive the same survival benefit from a chemotherapy-free combination as an anthracycline-containing standard of care, according to results of the AML17 APL study.

The 4-year overall survival rates in high-risk patients (WBC > 10 x 10⁹/L) were 87% with arsenic trioxide plus all-trans retinoic acid and 84% with the standard all-trans retinoic acid and idarubicin schedule.

Relapse-free survival rates were superior with the chemotherapy-free combination (100% vs. 74%; P = .008), Dr. Alan Burnett reported at the annual congress of the European Hematology Association.

“One of our rationales for using arsenic as first-line (therapy) was to try and get at the early death that remains a major problem in this disease,” he said.

Arsenic trioxide and gemtuzumab ozogamicin are effective as single agents with the former approved for relapsed disease in patients with APL. The GIMEMA-AMLSG-SAL trial indicated that a daily schedule of arsenic trioxide plus all-trans retinoic acid was at least as effective and may be superior to all-trans retinoic acid plus chemotherapy in low to moderate risk APL patients (N. Engl. J. Med. 2013;369: 111-21).

The AML17 APL trial was designed by the U.K. National Cancer Research Institute with the aim of comparing all-trans retinoic acid and idarubicin with arsenic trioxide in an attenuated dosing schedule plus all-trans retinoic acid. Importantly, high-risk patients were included, with the option to receive a single dose of gemtuzumab ozogamicin (Mylotarg) 6 mg/m² within the first 4 days of induction, said Dr. Burnett, who performed the research as head of hematology at Cardiff University in Wales and is now global lead for myeloid diseases at CTI BioPharma in Seattle. In the United States, gemtuzumab was withdrawn from the market in 2010 because of safety concerns.

From May 2009 to October 2013, 235 patients with molecularly confirmed APL were randomized at 81 centers to all-trans retinoic acid 45 mg/m² as a divided daily oral dose to day 60 or complete remission plus arsenic trioxide 0.3 mg/kg on days 1-5 of week 1 and then 0.25 mg/kg twice per week for 7 weeks plus all-trans retinoic acid 45 mg/m² as a divided daily oral dose to day 60 or complete remission or to idarubicin 12 mg/m² on days 2, 4, 6, 8 plus all-trans retinoic acid 45 mg/m² as a divided daily oral dose to day 60.

In the arsenic trioxide plus all-trans retinoic acid arm, this was followed by all-trans retinoic acid 45 mg/m² as a divided daily dose 2 weeks on and 2 weeks off plus four consolidation courses of arsenic trioxide 0.3 mg/kg days 1-5 of week 1 and then 0.25 mg/kg twice per week for 3 weeks (total 63 days of arsenic trioxide).

Consolidation in the all-trans retinoic acid and idarubicin arm was all-trans retinoic acid 45 mg/m² as a divided daily dose on days 1-15 plus idarubicin 5 mg/m² days 1-4 in course 2, mitoxantrone 10mg/m² days 1-4 in course 3, and idarubicin 12 mg/m² day 1 in course 4.

No maintenance was given in either arm. The median patient age was 47 years, with about 20% of patients over age 60; over 20% of the patients were high-risk, and they were equally balanced in the two treatment groups.

At 4 years, the overall survival rate among all patients was comparable – 93% with arsenic trioxide plus all-trans retinoic acid and 89% with all-trans retinoic acid and idarubicin.

However, event-free survival was significantly better in the arsenic trioxide plus all-trans retinoic acid cohort (91% vs. 74%; hazard ratio, 0.36; P = .003), as were frank relapse-free survival (97% vs. 83%; HR, 0.24; P = .004) and molecular relapse-free survival (98% vs. 70%; HR, 0.17; P < .0001), Dr. Burnett said.

One patient on arsenic trioxide plus all-trans retinoic acid experienced frank relapse, compared with 13 on all-trans retinoic acid and idarubicin, plus a further 19 molecular relapses occurred on this arm (cumulative incidence of molecular and hematologic relapse 0% vs. 27%, HR, 0.12; P < .0001).

“Once a patient was in molecular remission there were no further relapses in patients on (arsenic trioxide plus all-trans retinoic acid),” he said.

Of the 30 high-risk patients allocated to the chemo-free arm, 28 received gemtuzumab ozogamicin as per protocol. The overall survival at 4 years for these patients was 89%. Of the two patients not treated with gemtuzumab ozogamicin, one died on day 12 due to causes unrelated to treatment.

Among the 49 patients older than 60 years, overall survival was 80% with arsenic trioxide plus all-trans retinoic acid and 74% with all-trans retinoic acid and idarubicin. Similarly, among good-risk patients, relapse-free survival was significantly improved (96% vs. 79%; HR, 0.33; P = .04). Also, overall survival was not inferior at 95% vs. 90%, “very much replicating the outcomes seen in the GIMEMA study,” Dr. Burnett said.

The benefits were also achieved with significantly less grade 3-4 liver toxicity than observed in the GIMEMA study (<10% vs 63%).

There was, however, an excess of cardiac toxicity in course 2 with arsenic trioxide plus all-trans retinoic acid, compared with all-trans retinoic acid and idarubicin (P = .001).

“We’re not totally sure what that’s all due to, but it doesn’t look to be due to a QC prolongation,” he said.

The arsenic trioxide plus all-trans retinoic acid regimen was associated with significant reductions in supportive care requirements including fewer blood and platelet transfusions, days on antibiotics, and days in hospital, with “many patients treated exclusively as outpatients,” he added.

The low risk of relapse with arsenic trioxide plus all-trans retinoic acid also negates the need for minimal residual disease monitoring.

Finally, compared with the GIMEMA study protocol, the attenuated arsenic dosing schedule in AML17 APL resulted in less frequent dosing of arsenic trioxide (63 doses vs. 140 doses) and less drug required (151 vials vs. 280 vials for a 70-kg patient). At an acquisition cost of £350 per vial, this represents a cost savings of £46,000 (nearly $72,000) per patient, not to mention the added convenience to patients, Dr. Burnett observed.

Cancer Research U.K. funded the study. Cephalon provided the arsenic trioxide. Dr. Burnett disclosed part-time employment with CTI LifeSciences and in the last 12 months serving on the advisory boards of Celgene, Agios, Pfizer, and Bristol-Myers Squibb.

pwendling@frontlinemedcom.com

VIENNA – Patients with high-risk newly diagnosed acute promyelocytic leukemia derive the same survival benefit from a chemotherapy-free combination as an anthracycline-containing standard of care, according to results of the AML17 APL study.

The 4-year overall survival rates in high-risk patients (WBC > 10 x 10⁹/L) were 87% with arsenic trioxide plus all-trans retinoic acid and 84% with the standard all-trans retinoic acid and idarubicin schedule.

Relapse-free survival rates were superior with the chemotherapy-free combination (100% vs. 74%; P = .008), Dr. Alan Burnett reported at the annual congress of the European Hematology Association.

“One of our rationales for using arsenic as first-line (therapy) was to try and get at the early death that remains a major problem in this disease,” he said.

Arsenic trioxide and gemtuzumab ozogamicin are effective as single agents with the former approved for relapsed disease in patients with APL. The GIMEMA-AMLSG-SAL trial indicated that a daily schedule of arsenic trioxide plus all-trans retinoic acid was at least as effective and may be superior to all-trans retinoic acid plus chemotherapy in low to moderate risk APL patients (N. Engl. J. Med. 2013;369: 111-21).

The AML17 APL trial was designed by the U.K. National Cancer Research Institute with the aim of comparing all-trans retinoic acid and idarubicin with arsenic trioxide in an attenuated dosing schedule plus all-trans retinoic acid. Importantly, high-risk patients were included, with the option to receive a single dose of gemtuzumab ozogamicin (Mylotarg) 6 mg/m² within the first 4 days of induction, said Dr. Burnett, who performed the research as head of hematology at Cardiff University in Wales and is now global lead for myeloid diseases at CTI BioPharma in Seattle. In the United States, gemtuzumab was withdrawn from the market in 2010 because of safety concerns.

From May 2009 to October 2013, 235 patients with molecularly confirmed APL were randomized at 81 centers to all-trans retinoic acid 45 mg/m² as a divided daily oral dose to day 60 or complete remission plus arsenic trioxide 0.3 mg/kg on days 1-5 of week 1 and then 0.25 mg/kg twice per week for 7 weeks plus all-trans retinoic acid 45 mg/m² as a divided daily oral dose to day 60 or complete remission or to idarubicin 12 mg/m² on days 2, 4, 6, 8 plus all-trans retinoic acid 45 mg/m² as a divided daily oral dose to day 60.

In the arsenic trioxide plus all-trans retinoic acid arm, this was followed by all-trans retinoic acid 45 mg/m² as a divided daily dose 2 weeks on and 2 weeks off plus four consolidation courses of arsenic trioxide 0.3 mg/kg days 1-5 of week 1 and then 0.25 mg/kg twice per week for 3 weeks (total 63 days of arsenic trioxide).

Consolidation in the all-trans retinoic acid and idarubicin arm was all-trans retinoic acid 45 mg/m² as a divided daily dose on days 1-15 plus idarubicin 5 mg/m² days 1-4 in course 2, mitoxantrone 10mg/m² days 1-4 in course 3, and idarubicin 12 mg/m² day 1 in course 4.

No maintenance was given in either arm. The median patient age was 47 years, with about 20% of patients over age 60; over 20% of the patients were high-risk, and they were equally balanced in the two treatment groups.

At 4 years, the overall survival rate among all patients was comparable – 93% with arsenic trioxide plus all-trans retinoic acid and 89% with all-trans retinoic acid and idarubicin.

However, event-free survival was significantly better in the arsenic trioxide plus all-trans retinoic acid cohort (91% vs. 74%; hazard ratio, 0.36; P = .003), as were frank relapse-free survival (97% vs. 83%; HR, 0.24; P = .004) and molecular relapse-free survival (98% vs. 70%; HR, 0.17; P < .0001), Dr. Burnett said.

One patient on arsenic trioxide plus all-trans retinoic acid experienced frank relapse, compared with 13 on all-trans retinoic acid and idarubicin, plus a further 19 molecular relapses occurred on this arm (cumulative incidence of molecular and hematologic relapse 0% vs. 27%, HR, 0.12; P < .0001).

“Once a patient was in molecular remission there were no further relapses in patients on (arsenic trioxide plus all-trans retinoic acid),” he said.

Of the 30 high-risk patients allocated to the chemo-free arm, 28 received gemtuzumab ozogamicin as per protocol. The overall survival at 4 years for these patients was 89%. Of the two patients not treated with gemtuzumab ozogamicin, one died on day 12 due to causes unrelated to treatment.

Among the 49 patients older than 60 years, overall survival was 80% with arsenic trioxide plus all-trans retinoic acid and 74% with all-trans retinoic acid and idarubicin. Similarly, among good-risk patients, relapse-free survival was significantly improved (96% vs. 79%; HR, 0.33; P = .04). Also, overall survival was not inferior at 95% vs. 90%, “very much replicating the outcomes seen in the GIMEMA study,” Dr. Burnett said.

The benefits were also achieved with significantly less grade 3-4 liver toxicity than observed in the GIMEMA study (<10% vs 63%).

There was, however, an excess of cardiac toxicity in course 2 with arsenic trioxide plus all-trans retinoic acid, compared with all-trans retinoic acid and idarubicin (P = .001).

“We’re not totally sure what that’s all due to, but it doesn’t look to be due to a QC prolongation,” he said.

The arsenic trioxide plus all-trans retinoic acid regimen was associated with significant reductions in supportive care requirements including fewer blood and platelet transfusions, days on antibiotics, and days in hospital, with “many patients treated exclusively as outpatients,” he added.

The low risk of relapse with arsenic trioxide plus all-trans retinoic acid also negates the need for minimal residual disease monitoring.

Finally, compared with the GIMEMA study protocol, the attenuated arsenic dosing schedule in AML17 APL resulted in less frequent dosing of arsenic trioxide (63 doses vs. 140 doses) and less drug required (151 vials vs. 280 vials for a 70-kg patient). At an acquisition cost of £350 per vial, this represents a cost savings of £46,000 (nearly $72,000) per patient, not to mention the added convenience to patients, Dr. Burnett observed.

Cancer Research U.K. funded the study. Cephalon provided the arsenic trioxide. Dr. Burnett disclosed part-time employment with CTI LifeSciences and in the last 12 months serving on the advisory boards of Celgene, Agios, Pfizer, and Bristol-Myers Squibb.

pwendling@frontlinemedcom.com

VIENNA – The investigational dual HDAC and Pi3K inhibitor CUDC-907 was reasonably tolerated and clinically active in a phase I study of relapsed or refractory lymphomas and multiple myeloma.

Among 44 patients evaluable for response, 7 had objective responses (16%).

Two complete and four partial responses occurred in 10 evaluable patients with diffuse large B-cell lymphoma (DLBCL).

One partial response was reported in 12 evaluable patients with Hodgkin lymphoma.

Stable disease was the best response in 4 of 6 evaluable patients with multiple myeloma and 11 of 16 patients with other lymphomas, Dr. Yasuhiro Oki reported at the annual congress of the European Hematology Association.

The first-in-human trial enrolled 57 patients with lymphoma (DLBCL, Hodgkin, Burkitt, follicular, gray zone, lymphoplasmacytic, mantle cell, marginal zone, and small lymphocytic) or multiple myeloma that was refractory to or relapsed after at least two prior regimens.

The median number of prior regimens was 5 (range 2-10), including prior histone deacetylase (HDAC) inhibitors in 11% and prior phosphatidylinositol 3-kinase (Pi3K) inhibitors in 9%.

The 3+3 design tested three different once-daily dosing schedules for the oral small molecule: 30 mg and 60 mg, 5 days on and 2 days off (5/2) 60 mg, and intermittent twice- or thrice-weekly at 60 mg, 90 mg, 120 mg, and 150 mg. The safety and efficacy data are from the completed dose escalation and ongoing expansion stages of the phase I trial with CUDC-907 administered as monotherapy.

Median treatment duration in the DLBCL group was 3 months, with treatment ongoing in some patients beyond 2 years. Long-term responders have included three patients with transformed follicular lymphoma (t-FL)/DLBCL, one with so-called triple-hit status involving translocations/rearrangements of MYC, BCL-2, and BCL-6 genes, according to Dr. Oki of University of Texas MD Anderson Cancer Center in Houston.

The patient with Hodgkin lymphoma who responded had failed four prior therapies, but experienced a 42% reduction in tumor size on imaging by cycle two and a partial response to 60 mg 5/2 CUDC-907 by cycle six.

At least one adverse event (AE) occurred in 50 of the 57 patients, but AEs have been reversible with standard interventions, dose holds, or dose reductions, he added.

The most common grade 3/4 AEs reported in two or more patients were diarrhea, hyperglycemia, fatigue, thrombocytopenia, and decreased neutrophils.

Four dose-limiting toxicities occurred in three patients: grade 3 diarrhea in the 60-mg once-daily and 150-mg thrice-weekly dose groups and grade 4 hyperglycemia in the 60-mg once-daily and 150-mg twice-weekly dose groups.

“The 5/2 60-mg and thrice-weekly 120-mg dosing was found to be reasonably tolerated while still achieving objective responses,” Dr. Oki noted in the poster.

The ongoing expansion phase is evaluating CUDC-907 at the recommended phase II doses of 60 mg 5/2 and 120 mg thrice-weekly in patients with relapsed refractory DLBCL, Hodgkin lymphoma, and multiple myeloma.

The trial is currently enrolling patients with DLBCL for treatment with CUDC-907 monotherapy and in combination with standard-dose rituximab.

Phase II testing of CUDC-907 in combination with rituximab in relapsed/refractory DLBCL is projected to start at the earliest in fourth-quarter 2015, according to the authors.

CUDC-907 (60 mg 5/2 and 120 mg three times weekly) is also being evaluated in advanced or relapsed solid tumors in an ongoing phase I trial.

pwendling@frontlinemedcom.com

On Twitter@pwendl

VIENNA – The investigational dual HDAC and Pi3K inhibitor CUDC-907 was reasonably tolerated and clinically active in a phase I study of relapsed or refractory lymphomas and multiple myeloma.

Among 44 patients evaluable for response, 7 had objective responses (16%).

Two complete and four partial responses occurred in 10 evaluable patients with diffuse large B-cell lymphoma (DLBCL).

One partial response was reported in 12 evaluable patients with Hodgkin lymphoma.

Stable disease was the best response in 4 of 6 evaluable patients with multiple myeloma and 11 of 16 patients with other lymphomas, Dr. Yasuhiro Oki reported at the annual congress of the European Hematology Association.

The first-in-human trial enrolled 57 patients with lymphoma (DLBCL, Hodgkin, Burkitt, follicular, gray zone, lymphoplasmacytic, mantle cell, marginal zone, and small lymphocytic) or multiple myeloma that was refractory to or relapsed after at least two prior regimens.

The median number of prior regimens was 5 (range 2-10), including prior histone deacetylase (HDAC) inhibitors in 11% and prior phosphatidylinositol 3-kinase (Pi3K) inhibitors in 9%.

The 3+3 design tested three different once-daily dosing schedules for the oral small molecule: 30 mg and 60 mg, 5 days on and 2 days off (5/2) 60 mg, and intermittent twice- or thrice-weekly at 60 mg, 90 mg, 120 mg, and 150 mg. The safety and efficacy data are from the completed dose escalation and ongoing expansion stages of the phase I trial with CUDC-907 administered as monotherapy.

Median treatment duration in the DLBCL group was 3 months, with treatment ongoing in some patients beyond 2 years. Long-term responders have included three patients with transformed follicular lymphoma (t-FL)/DLBCL, one with so-called triple-hit status involving translocations/rearrangements of MYC, BCL-2, and BCL-6 genes, according to Dr. Oki of University of Texas MD Anderson Cancer Center in Houston.

The patient with Hodgkin lymphoma who responded had failed four prior therapies, but experienced a 42% reduction in tumor size on imaging by cycle two and a partial response to 60 mg 5/2 CUDC-907 by cycle six.

At least one adverse event (AE) occurred in 50 of the 57 patients, but AEs have been reversible with standard interventions, dose holds, or dose reductions, he added.

The most common grade 3/4 AEs reported in two or more patients were diarrhea, hyperglycemia, fatigue, thrombocytopenia, and decreased neutrophils.

Four dose-limiting toxicities occurred in three patients: grade 3 diarrhea in the 60-mg once-daily and 150-mg thrice-weekly dose groups and grade 4 hyperglycemia in the 60-mg once-daily and 150-mg twice-weekly dose groups.

“The 5/2 60-mg and thrice-weekly 120-mg dosing was found to be reasonably tolerated while still achieving objective responses,” Dr. Oki noted in the poster.

The ongoing expansion phase is evaluating CUDC-907 at the recommended phase II doses of 60 mg 5/2 and 120 mg thrice-weekly in patients with relapsed refractory DLBCL, Hodgkin lymphoma, and multiple myeloma.

The trial is currently enrolling patients with DLBCL for treatment with CUDC-907 monotherapy and in combination with standard-dose rituximab.

Phase II testing of CUDC-907 in combination with rituximab in relapsed/refractory DLBCL is projected to start at the earliest in fourth-quarter 2015, according to the authors.

CUDC-907 (60 mg 5/2 and 120 mg three times weekly) is also being evaluated in advanced or relapsed solid tumors in an ongoing phase I trial.

pwendling@frontlinemedcom.com

On Twitter@pwendl

VIENNA – The investigational dual HDAC and Pi3K inhibitor CUDC-907 was reasonably tolerated and clinically active in a phase I study of relapsed or refractory lymphomas and multiple myeloma.

Among 44 patients evaluable for response, 7 had objective responses (16%).

Two complete and four partial responses occurred in 10 evaluable patients with diffuse large B-cell lymphoma (DLBCL).

One partial response was reported in 12 evaluable patients with Hodgkin lymphoma.

Stable disease was the best response in 4 of 6 evaluable patients with multiple myeloma and 11 of 16 patients with other lymphomas, Dr. Yasuhiro Oki reported at the annual congress of the European Hematology Association.

The first-in-human trial enrolled 57 patients with lymphoma (DLBCL, Hodgkin, Burkitt, follicular, gray zone, lymphoplasmacytic, mantle cell, marginal zone, and small lymphocytic) or multiple myeloma that was refractory to or relapsed after at least two prior regimens.

The median number of prior regimens was 5 (range 2-10), including prior histone deacetylase (HDAC) inhibitors in 11% and prior phosphatidylinositol 3-kinase (Pi3K) inhibitors in 9%.

The 3+3 design tested three different once-daily dosing schedules for the oral small molecule: 30 mg and 60 mg, 5 days on and 2 days off (5/2) 60 mg, and intermittent twice- or thrice-weekly at 60 mg, 90 mg, 120 mg, and 150 mg. The safety and efficacy data are from the completed dose escalation and ongoing expansion stages of the phase I trial with CUDC-907 administered as monotherapy.

Median treatment duration in the DLBCL group was 3 months, with treatment ongoing in some patients beyond 2 years. Long-term responders have included three patients with transformed follicular lymphoma (t-FL)/DLBCL, one with so-called triple-hit status involving translocations/rearrangements of MYC, BCL-2, and BCL-6 genes, according to Dr. Oki of University of Texas MD Anderson Cancer Center in Houston.

The patient with Hodgkin lymphoma who responded had failed four prior therapies, but experienced a 42% reduction in tumor size on imaging by cycle two and a partial response to 60 mg 5/2 CUDC-907 by cycle six.

At least one adverse event (AE) occurred in 50 of the 57 patients, but AEs have been reversible with standard interventions, dose holds, or dose reductions, he added.

The most common grade 3/4 AEs reported in two or more patients were diarrhea, hyperglycemia, fatigue, thrombocytopenia, and decreased neutrophils.

Four dose-limiting toxicities occurred in three patients: grade 3 diarrhea in the 60-mg once-daily and 150-mg thrice-weekly dose groups and grade 4 hyperglycemia in the 60-mg once-daily and 150-mg twice-weekly dose groups.

“The 5/2 60-mg and thrice-weekly 120-mg dosing was found to be reasonably tolerated while still achieving objective responses,” Dr. Oki noted in the poster.

The ongoing expansion phase is evaluating CUDC-907 at the recommended phase II doses of 60 mg 5/2 and 120 mg thrice-weekly in patients with relapsed refractory DLBCL, Hodgkin lymphoma, and multiple myeloma.

The trial is currently enrolling patients with DLBCL for treatment with CUDC-907 monotherapy and in combination with standard-dose rituximab.

Phase II testing of CUDC-907 in combination with rituximab in relapsed/refractory DLBCL is projected to start at the earliest in fourth-quarter 2015, according to the authors.

CUDC-907 (60 mg 5/2 and 120 mg three times weekly) is also being evaluated in advanced or relapsed solid tumors in an ongoing phase I trial.

pwendling@frontlinemedcom.com

On Twitter@pwendl

HSCs_being_prepared_for_transplant_credit_Chad_McNeeley_230.jpg

HSCT preparation

Photo by Chad McNeeley

VIENNA—Outcomes of hematopoietic stem cell transplant (HSCT) are encouraging in myelofibrosis (MF) patients who respond well to JAK inhibitors, according to researchers.

The group found that patients with the best response to JAK inhibition had a 2-year survival probability of 91% after HSCT, compared to 32% for patients with

leukemic transformation while on a JAK inhibitor.

In addition, receiving a JAK inhibitor until HSCT could prevent the return of MF-related symptoms.

Mohamed Shanavas, MD, of Princess Margaret Cancer Centre in Toronto, Ontario, Canada, presented these findings at the 20th Congress of the European Hematology Association (abstract S450*).

The decision to undergo HSCT is a complex one in MF, particularly for those patients who are responding to JAK inhibitors. So Dr Shanavas and his colleagues undertook a retrospective, multicenter analysis to determine if there is an association between response to JAK inhibition and HSCT outcome.

The investigators analyzed the outcomes of 100 patients who had a first HSCT for primary MF, post-essential thrombocythemia MF, or post-polycythemia vera MF. Patients had to have exposure to a JAK inhibitor but no history of leukemic transformation prior to taking a JAK inhibitor.

Response criteria

The researchers stratified patients’ JAK1/2 response according to the following criteria:

• Group A: Clinical improvement: Fifty percent or greater reduction in palpable spleen length for spleen palpable by ≥ 10 cm, or complete resolution of splenomegaly for spleen < 10 cm
• Group B: Stable disease: Spleen response not meeting the criteria of clinical improvement
• Group C: A 10% to 19% increase in blasts, new onset of anemia requiring transfusions, or intolerance to treatment due to side effects
• Group D: Progressive disease: New splenomegaly > 5 cm, 100% increase in spleen 5-10 cm, or 50% increase in spleen > 10 cm
• Group E: Leukemic transformation: Bone marrow or circulating blasts ≥ 20%.

Patient and treatment characteristics

Patients were a median age of 59 (range, 32–72). Fifty-seven had primary MF, 21 had post-essential thrombocythemia MF, and 22 had post-polycythemia vera MF. Sixty-two patients had JAK2^V617F-mutated disease, 37 were wild-type, and 1 had unknown JAK status.

The majority of patients had intermediate-2 or high-risk disease according to their DIPSS scores, and 42 had a transplant comorbidity index score of 3 or greater.

Most patients (n=91) had ruxolitinib as their JAK inhibitor, 6 had momelotinib, and 3 had another inhibitor.

The median duration of JAK inhibitor therapy was 5 months (range, 1–36), and 66 patients were on treatment at the time of transplant. Thirty patients had previously discontinued JAK therapy, and the status of 4 was unknown.

In terms of their response to JAK inhibitors, 23 patients were in group A (clinical improvement), 31 in group B (stable disease), 15 in group C (increased blasts/transfusion need/intolerance), 18 in group D (progressive disease), and 13 in group E (leukemic transformation).

Fifty patients received a matched unrelated donor transplant, 36 had a matched sibling donor, and 14 had either a mismatched unrelated donor or a haploidentical transplant.

Fifty-six patients had a reduced-intensity conditioning regimen, and 44 had full intensity. Fifty percent of patients had T-cell depletion prior to transplant.

Outcomes

Patients who stopped JAK inhibitor therapy 6 or more days prior to transplant (n=20) experienced more “withdrawal symptoms”—the return of MF-related symptoms—than patients in whom the interval was less than 6 days (n=46). For the most part, withdrawal symptoms were non-severe in nature.

Two patients had fatal HSCT-related toxicity of venoocclusive disease, 4 had primary graft failure, and 4 had secondary graft failure. Forty-three percent of cytomegalovirus-seropositive patients had reactivation, 6 patients had Epstein-Barr virus reactivation, 6 had adenovirus or human polyomavirus BK infections, and 7 had invasive fungal infections.

Grade 2-4 acute graft-vs-host disease (GVHD) occurred in 37% of patients at day 100, and grade 3-4 occurred in 16%. Chronic GVHD of all grades occurred in 48% of patients, and extensive chronic GVHD occurred in 23%.

The cumulative incidence of relapse at 2 years was 17%, and non-relapse mortality was 28%. Overall survival (OS) was 61%.

“We analyzed this outcome based upon the response to JAK inhibitors,” Dr Shanavas said. “Patients who were deriving clinical improvement, group A, had a superior outcome, with a probability of survival of 91% at 2 years. Patients who had leukemic transformation, group E, had an inferior OS of 32% at 2 years.”

He noted that the outcomes appeared similar in the other 3 groups, so the researchers combined them for further analysis.

“As expected,” he said, “patients who had leukemic transformation had a significantly higher relapse rate than the other groups.”

The researchers then performed a multivariate analysis and found that response to JAK inhibitors, DIPSS score prior to JAK therapy, and donor type had a significant effect on OS.

The team concluded that prior exposure to JAK inhibitors does not have a negative effect on early HSCT outcomes. And actually, patients who undergo HSCT while responding to JAK inhibitors have encouraging outcomes.

ico_ht.gif

*Information in the abstract differs from that presented at the meeting.

HSCs_being_prepared_for_transplant_credit_Chad_McNeeley_230.jpg

HSCT preparation

Photo by Chad McNeeley

VIENNA—Outcomes of hematopoietic stem cell transplant (HSCT) are encouraging in myelofibrosis (MF) patients who respond well to JAK inhibitors, according to researchers.

The group found that patients with the best response to JAK inhibition had a 2-year survival probability of 91% after HSCT, compared to 32% for patients with

leukemic transformation while on a JAK inhibitor.

In addition, receiving a JAK inhibitor until HSCT could prevent the return of MF-related symptoms.

Mohamed Shanavas, MD, of Princess Margaret Cancer Centre in Toronto, Ontario, Canada, presented these findings at the 20th Congress of the European Hematology Association (abstract S450*).

The decision to undergo HSCT is a complex one in MF, particularly for those patients who are responding to JAK inhibitors. So Dr Shanavas and his colleagues undertook a retrospective, multicenter analysis to determine if there is an association between response to JAK inhibition and HSCT outcome.

The investigators analyzed the outcomes of 100 patients who had a first HSCT for primary MF, post-essential thrombocythemia MF, or post-polycythemia vera MF. Patients had to have exposure to a JAK inhibitor but no history of leukemic transformation prior to taking a JAK inhibitor.

Response criteria

The researchers stratified patients’ JAK1/2 response according to the following criteria:

• Group A: Clinical improvement: Fifty percent or greater reduction in palpable spleen length for spleen palpable by ≥ 10 cm, or complete resolution of splenomegaly for spleen < 10 cm
• Group B: Stable disease: Spleen response not meeting the criteria of clinical improvement
• Group C: A 10% to 19% increase in blasts, new onset of anemia requiring transfusions, or intolerance to treatment due to side effects
• Group D: Progressive disease: New splenomegaly > 5 cm, 100% increase in spleen 5-10 cm, or 50% increase in spleen > 10 cm
• Group E: Leukemic transformation: Bone marrow or circulating blasts ≥ 20%.

Patient and treatment characteristics

Patients were a median age of 59 (range, 32–72). Fifty-seven had primary MF, 21 had post-essential thrombocythemia MF, and 22 had post-polycythemia vera MF. Sixty-two patients had JAK2^V617F-mutated disease, 37 were wild-type, and 1 had unknown JAK status.

The majority of patients had intermediate-2 or high-risk disease according to their DIPSS scores, and 42 had a transplant comorbidity index score of 3 or greater.

Most patients (n=91) had ruxolitinib as their JAK inhibitor, 6 had momelotinib, and 3 had another inhibitor.

The median duration of JAK inhibitor therapy was 5 months (range, 1–36), and 66 patients were on treatment at the time of transplant. Thirty patients had previously discontinued JAK therapy, and the status of 4 was unknown.

In terms of their response to JAK inhibitors, 23 patients were in group A (clinical improvement), 31 in group B (stable disease), 15 in group C (increased blasts/transfusion need/intolerance), 18 in group D (progressive disease), and 13 in group E (leukemic transformation).

Fifty patients received a matched unrelated donor transplant, 36 had a matched sibling donor, and 14 had either a mismatched unrelated donor or a haploidentical transplant.

Fifty-six patients had a reduced-intensity conditioning regimen, and 44 had full intensity. Fifty percent of patients had T-cell depletion prior to transplant.

Outcomes

Patients who stopped JAK inhibitor therapy 6 or more days prior to transplant (n=20) experienced more “withdrawal symptoms”—the return of MF-related symptoms—than patients in whom the interval was less than 6 days (n=46). For the most part, withdrawal symptoms were non-severe in nature.

Two patients had fatal HSCT-related toxicity of venoocclusive disease, 4 had primary graft failure, and 4 had secondary graft failure. Forty-three percent of cytomegalovirus-seropositive patients had reactivation, 6 patients had Epstein-Barr virus reactivation, 6 had adenovirus or human polyomavirus BK infections, and 7 had invasive fungal infections.

Grade 2-4 acute graft-vs-host disease (GVHD) occurred in 37% of patients at day 100, and grade 3-4 occurred in 16%. Chronic GVHD of all grades occurred in 48% of patients, and extensive chronic GVHD occurred in 23%.

The cumulative incidence of relapse at 2 years was 17%, and non-relapse mortality was 28%. Overall survival (OS) was 61%.

“We analyzed this outcome based upon the response to JAK inhibitors,” Dr Shanavas said. “Patients who were deriving clinical improvement, group A, had a superior outcome, with a probability of survival of 91% at 2 years. Patients who had leukemic transformation, group E, had an inferior OS of 32% at 2 years.”

He noted that the outcomes appeared similar in the other 3 groups, so the researchers combined them for further analysis.

“As expected,” he said, “patients who had leukemic transformation had a significantly higher relapse rate than the other groups.”

The researchers then performed a multivariate analysis and found that response to JAK inhibitors, DIPSS score prior to JAK therapy, and donor type had a significant effect on OS.

The team concluded that prior exposure to JAK inhibitors does not have a negative effect on early HSCT outcomes. And actually, patients who undergo HSCT while responding to JAK inhibitors have encouraging outcomes.

ico_ht.gif

*Information in the abstract differs from that presented at the meeting.

HSCs_being_prepared_for_transplant_credit_Chad_McNeeley_230.jpg

HSCT preparation

Photo by Chad McNeeley

VIENNA—Outcomes of hematopoietic stem cell transplant (HSCT) are encouraging in myelofibrosis (MF) patients who respond well to JAK inhibitors, according to researchers.

The group found that patients with the best response to JAK inhibition had a 2-year survival probability of 91% after HSCT, compared to 32% for patients with

leukemic transformation while on a JAK inhibitor.

In addition, receiving a JAK inhibitor until HSCT could prevent the return of MF-related symptoms.

Mohamed Shanavas, MD, of Princess Margaret Cancer Centre in Toronto, Ontario, Canada, presented these findings at the 20th Congress of the European Hematology Association (abstract S450*).

The decision to undergo HSCT is a complex one in MF, particularly for those patients who are responding to JAK inhibitors. So Dr Shanavas and his colleagues undertook a retrospective, multicenter analysis to determine if there is an association between response to JAK inhibition and HSCT outcome.

The investigators analyzed the outcomes of 100 patients who had a first HSCT for primary MF, post-essential thrombocythemia MF, or post-polycythemia vera MF. Patients had to have exposure to a JAK inhibitor but no history of leukemic transformation prior to taking a JAK inhibitor.

Response criteria

The researchers stratified patients’ JAK1/2 response according to the following criteria:

• Group A: Clinical improvement: Fifty percent or greater reduction in palpable spleen length for spleen palpable by ≥ 10 cm, or complete resolution of splenomegaly for spleen < 10 cm
• Group B: Stable disease: Spleen response not meeting the criteria of clinical improvement
• Group C: A 10% to 19% increase in blasts, new onset of anemia requiring transfusions, or intolerance to treatment due to side effects
• Group D: Progressive disease: New splenomegaly > 5 cm, 100% increase in spleen 5-10 cm, or 50% increase in spleen > 10 cm
• Group E: Leukemic transformation: Bone marrow or circulating blasts ≥ 20%.

Patient and treatment characteristics

Patients were a median age of 59 (range, 32–72). Fifty-seven had primary MF, 21 had post-essential thrombocythemia MF, and 22 had post-polycythemia vera MF. Sixty-two patients had JAK2^V617F-mutated disease, 37 were wild-type, and 1 had unknown JAK status.

The majority of patients had intermediate-2 or high-risk disease according to their DIPSS scores, and 42 had a transplant comorbidity index score of 3 or greater.

Most patients (n=91) had ruxolitinib as their JAK inhibitor, 6 had momelotinib, and 3 had another inhibitor.

The median duration of JAK inhibitor therapy was 5 months (range, 1–36), and 66 patients were on treatment at the time of transplant. Thirty patients had previously discontinued JAK therapy, and the status of 4 was unknown.

In terms of their response to JAK inhibitors, 23 patients were in group A (clinical improvement), 31 in group B (stable disease), 15 in group C (increased blasts/transfusion need/intolerance), 18 in group D (progressive disease), and 13 in group E (leukemic transformation).

Fifty patients received a matched unrelated donor transplant, 36 had a matched sibling donor, and 14 had either a mismatched unrelated donor or a haploidentical transplant.

Fifty-six patients had a reduced-intensity conditioning regimen, and 44 had full intensity. Fifty percent of patients had T-cell depletion prior to transplant.

Outcomes

Patients who stopped JAK inhibitor therapy 6 or more days prior to transplant (n=20) experienced more “withdrawal symptoms”—the return of MF-related symptoms—than patients in whom the interval was less than 6 days (n=46). For the most part, withdrawal symptoms were non-severe in nature.

Two patients had fatal HSCT-related toxicity of venoocclusive disease, 4 had primary graft failure, and 4 had secondary graft failure. Forty-three percent of cytomegalovirus-seropositive patients had reactivation, 6 patients had Epstein-Barr virus reactivation, 6 had adenovirus or human polyomavirus BK infections, and 7 had invasive fungal infections.

Grade 2-4 acute graft-vs-host disease (GVHD) occurred in 37% of patients at day 100, and grade 3-4 occurred in 16%. Chronic GVHD of all grades occurred in 48% of patients, and extensive chronic GVHD occurred in 23%.

The cumulative incidence of relapse at 2 years was 17%, and non-relapse mortality was 28%. Overall survival (OS) was 61%.

“We analyzed this outcome based upon the response to JAK inhibitors,” Dr Shanavas said. “Patients who were deriving clinical improvement, group A, had a superior outcome, with a probability of survival of 91% at 2 years. Patients who had leukemic transformation, group E, had an inferior OS of 32% at 2 years.”

He noted that the outcomes appeared similar in the other 3 groups, so the researchers combined them for further analysis.

“As expected,” he said, “patients who had leukemic transformation had a significantly higher relapse rate than the other groups.”

The researchers then performed a multivariate analysis and found that response to JAK inhibitors, DIPSS score prior to JAK therapy, and donor type had a significant effect on OS.

The team concluded that prior exposure to JAK inhibitors does not have a negative effect on early HSCT outcomes. And actually, patients who undergo HSCT while responding to JAK inhibitors have encouraging outcomes.

ico_ht.gif

*Information in the abstract differs from that presented at the meeting.

CLL_BM.jpg

Micrograph showing CLL

VIENNA—New research indicates that duvelisib, a dual inhibitor of PI3Kδ and PI3Kγ, can generate rapid partial responses in treatment-naïve patients with chronic lymphocytic leukemia (CLL).

The 18 patients in the expansion cohort of a phase 1 study of duvelisib had a median time to response of 3.7 months, according to iwCLL response criteria.

And 47% of the responses occurred by the first assessment on day 1 of cycle 3.

“One thing that does seem to be different with this drug is that you’re getting your [partial responses] a bit faster than you see with some of the other drugs,” said Susan O’Brien, MD, of UC Irvine Health in Orange, California.

“[W]hat that means in the long run is not completely clear, but there’s no question that the responses are very rapid.”

Dr O’Brien presented these findings at the 20th Congress of the European Hematology Association (abstract S434*). The research was funded by Infinity Pharmaceuticals, Inc., the company developing duvelisib.

Older CLL patients with comorbidities and patients with high-risk genomic alterations, such as 17p deletion and TP53 mutations, often don’t fare well on the standard chemoimmunotherapy. Duvelisib is being developed as a potential alternative for these patients and others with hematologic malignancies.

In the dose-escalation portion of this phase 1 study, duvelisib at 25 mg twice daily was well-tolerated and exhibited clinical activity in relapsed/refractory CLL, even in those patients with TP53 mutations and 17p deletion.

So investigators conducted the expansion cohort with 18 patients who received duvelisib at the same dose in 28-day cycles. Duvelisib is given continuously until patients have an adverse event or lose their response.

Patient demographics

Dr O’Brien said there was nothing unusual about the demographics of the study population, except the risk factors: 83% of the patients were over 65, “which is very different from what you would see in a chemoimmunotherapy trial.”

She noted that the patients’ median age was 74, and 56% of patients had either a 17p deletion or TP53 mutation.

“And that’s very unusual because . . . the percentage of patients with that abnormality in frontline CLL is about 5% to 10%,” she added.

Patients were a median of 3 years (range, 0–9) from their initial diagnosis, 47% had Rai stage 3 or greater disease, 44% had splenomegaly, and 11% had grade 4 cytopenia.

Response

Patients stayed on treatment for a median of 14 months (range, 1–20). Eight (44%) discontinued treatment—6 (33%) due to an adverse event, 1 withdrew consent, and 1 discontinued for other reasons.

The best overall response rate was 88%, which consisted of 15 partial responses. Two patients (12%) had stable disease, and there were no complete responses or cases of progressive disease.

One patient with a TP53 mutation/17p deletion withdrew consent prior to the first efficacy assessment.

“There’s no upfront progression,” Dr O’Brien said, “and the response rate was identical for patients with high-risk disease or 17p deletion.”

The median progression-free survival was not yet reached, and the rate was 92% at 18 months. One patient progressed at cycle 13.

The median overall survival was also not reached, with a 94% survival rate at 18 months. One patient died of progressive disease approximately 5 months after the last dose.

Adverse events

The most frequent adverse events (AEs) occurring in more than 25% of patients were, in order of frequency, diarrhea, rash, cough, neutropenia, peripheral edema, fatigue, nausea, pyrexia, ALT/AST increase, anemia, and dizziness.

Grade 3 AEs included diarrhea (22%), ALT/AST increase (17%), rash (11%), neutropenia (6%), fatigue (6%), and anemia (6%). The only grade 4 AE was neutropenia (28%).

Serious AEs in more than 1 patient included diarrhea (n=3), colitis (n=2), dehydration (n=2), pneumonia (n=2), and pneumonitis (n=2).

The AEs leading to treatment discontinuation were increased ALT/AST, dehydration, and spinal stenosis (all in 1 patient), as well as arthritis, pneumonitis, colitis, diarrhea, and stomatitis.

“We tend to see the transaminitis and the pneumonitis earlier, and then the late toxicity tends to be the diarrhea and colitis,” Dr O’ Brien said. “The one toxicity where I would not be inclined to try and re-treat a patient is pneumonitis, but I do think colitis can be successfully re-treated.”

Pharmacodynamic studies show very rapid inhibition of phosphorylated AKT following treatment, which is sustained throughout the whole first cycle. And following 1 cycle of duvelisib, there is near-complete inhibition of CLL proliferation, as evidenced by the reduction in Ki67.

Given these data, the investigators recommended further development of duvelisib in treatment-naïve CLL.

ico_ht.gif

*Information in the abstract differs from that presented at the meeting.

CLL_BM.jpg

Micrograph showing CLL

VIENNA—New research indicates that duvelisib, a dual inhibitor of PI3Kδ and PI3Kγ, can generate rapid partial responses in treatment-naïve patients with chronic lymphocytic leukemia (CLL).

The 18 patients in the expansion cohort of a phase 1 study of duvelisib had a median time to response of 3.7 months, according to iwCLL response criteria.

And 47% of the responses occurred by the first assessment on day 1 of cycle 3.

“One thing that does seem to be different with this drug is that you’re getting your [partial responses] a bit faster than you see with some of the other drugs,” said Susan O’Brien, MD, of UC Irvine Health in Orange, California.

“[W]hat that means in the long run is not completely clear, but there’s no question that the responses are very rapid.”

Dr O’Brien presented these findings at the 20th Congress of the European Hematology Association (abstract S434*). The research was funded by Infinity Pharmaceuticals, Inc., the company developing duvelisib.

Older CLL patients with comorbidities and patients with high-risk genomic alterations, such as 17p deletion and TP53 mutations, often don’t fare well on the standard chemoimmunotherapy. Duvelisib is being developed as a potential alternative for these patients and others with hematologic malignancies.

In the dose-escalation portion of this phase 1 study, duvelisib at 25 mg twice daily was well-tolerated and exhibited clinical activity in relapsed/refractory CLL, even in those patients with TP53 mutations and 17p deletion.

So investigators conducted the expansion cohort with 18 patients who received duvelisib at the same dose in 28-day cycles. Duvelisib is given continuously until patients have an adverse event or lose their response.

Patient demographics

Dr O’Brien said there was nothing unusual about the demographics of the study population, except the risk factors: 83% of the patients were over 65, “which is very different from what you would see in a chemoimmunotherapy trial.”

She noted that the patients’ median age was 74, and 56% of patients had either a 17p deletion or TP53 mutation.

“And that’s very unusual because . . . the percentage of patients with that abnormality in frontline CLL is about 5% to 10%,” she added.

Patients were a median of 3 years (range, 0–9) from their initial diagnosis, 47% had Rai stage 3 or greater disease, 44% had splenomegaly, and 11% had grade 4 cytopenia.

Response

Patients stayed on treatment for a median of 14 months (range, 1–20). Eight (44%) discontinued treatment—6 (33%) due to an adverse event, 1 withdrew consent, and 1 discontinued for other reasons.

The best overall response rate was 88%, which consisted of 15 partial responses. Two patients (12%) had stable disease, and there were no complete responses or cases of progressive disease.

One patient with a TP53 mutation/17p deletion withdrew consent prior to the first efficacy assessment.

“There’s no upfront progression,” Dr O’Brien said, “and the response rate was identical for patients with high-risk disease or 17p deletion.”

The median progression-free survival was not yet reached, and the rate was 92% at 18 months. One patient progressed at cycle 13.

The median overall survival was also not reached, with a 94% survival rate at 18 months. One patient died of progressive disease approximately 5 months after the last dose.

Adverse events

The most frequent adverse events (AEs) occurring in more than 25% of patients were, in order of frequency, diarrhea, rash, cough, neutropenia, peripheral edema, fatigue, nausea, pyrexia, ALT/AST increase, anemia, and dizziness.

Grade 3 AEs included diarrhea (22%), ALT/AST increase (17%), rash (11%), neutropenia (6%), fatigue (6%), and anemia (6%). The only grade 4 AE was neutropenia (28%).

Serious AEs in more than 1 patient included diarrhea (n=3), colitis (n=2), dehydration (n=2), pneumonia (n=2), and pneumonitis (n=2).

The AEs leading to treatment discontinuation were increased ALT/AST, dehydration, and spinal stenosis (all in 1 patient), as well as arthritis, pneumonitis, colitis, diarrhea, and stomatitis.

“We tend to see the transaminitis and the pneumonitis earlier, and then the late toxicity tends to be the diarrhea and colitis,” Dr O’ Brien said. “The one toxicity where I would not be inclined to try and re-treat a patient is pneumonitis, but I do think colitis can be successfully re-treated.”

Pharmacodynamic studies show very rapid inhibition of phosphorylated AKT following treatment, which is sustained throughout the whole first cycle. And following 1 cycle of duvelisib, there is near-complete inhibition of CLL proliferation, as evidenced by the reduction in Ki67.

Given these data, the investigators recommended further development of duvelisib in treatment-naïve CLL.

ico_ht.gif

*Information in the abstract differs from that presented at the meeting.

CLL_BM.jpg

Micrograph showing CLL

VIENNA—New research indicates that duvelisib, a dual inhibitor of PI3Kδ and PI3Kγ, can generate rapid partial responses in treatment-naïve patients with chronic lymphocytic leukemia (CLL).

The 18 patients in the expansion cohort of a phase 1 study of duvelisib had a median time to response of 3.7 months, according to iwCLL response criteria.

And 47% of the responses occurred by the first assessment on day 1 of cycle 3.

“One thing that does seem to be different with this drug is that you’re getting your [partial responses] a bit faster than you see with some of the other drugs,” said Susan O’Brien, MD, of UC Irvine Health in Orange, California.

“[W]hat that means in the long run is not completely clear, but there’s no question that the responses are very rapid.”

Dr O’Brien presented these findings at the 20th Congress of the European Hematology Association (abstract S434*). The research was funded by Infinity Pharmaceuticals, Inc., the company developing duvelisib.

Older CLL patients with comorbidities and patients with high-risk genomic alterations, such as 17p deletion and TP53 mutations, often don’t fare well on the standard chemoimmunotherapy. Duvelisib is being developed as a potential alternative for these patients and others with hematologic malignancies.

In the dose-escalation portion of this phase 1 study, duvelisib at 25 mg twice daily was well-tolerated and exhibited clinical activity in relapsed/refractory CLL, even in those patients with TP53 mutations and 17p deletion.

So investigators conducted the expansion cohort with 18 patients who received duvelisib at the same dose in 28-day cycles. Duvelisib is given continuously until patients have an adverse event or lose their response.

Patient demographics

Dr O’Brien said there was nothing unusual about the demographics of the study population, except the risk factors: 83% of the patients were over 65, “which is very different from what you would see in a chemoimmunotherapy trial.”

She noted that the patients’ median age was 74, and 56% of patients had either a 17p deletion or TP53 mutation.

“And that’s very unusual because . . . the percentage of patients with that abnormality in frontline CLL is about 5% to 10%,” she added.

Patients were a median of 3 years (range, 0–9) from their initial diagnosis, 47% had Rai stage 3 or greater disease, 44% had splenomegaly, and 11% had grade 4 cytopenia.

Response

Patients stayed on treatment for a median of 14 months (range, 1–20). Eight (44%) discontinued treatment—6 (33%) due to an adverse event, 1 withdrew consent, and 1 discontinued for other reasons.

The best overall response rate was 88%, which consisted of 15 partial responses. Two patients (12%) had stable disease, and there were no complete responses or cases of progressive disease.

One patient with a TP53 mutation/17p deletion withdrew consent prior to the first efficacy assessment.

“There’s no upfront progression,” Dr O’Brien said, “and the response rate was identical for patients with high-risk disease or 17p deletion.”

The median progression-free survival was not yet reached, and the rate was 92% at 18 months. One patient progressed at cycle 13.

The median overall survival was also not reached, with a 94% survival rate at 18 months. One patient died of progressive disease approximately 5 months after the last dose.

Adverse events

The most frequent adverse events (AEs) occurring in more than 25% of patients were, in order of frequency, diarrhea, rash, cough, neutropenia, peripheral edema, fatigue, nausea, pyrexia, ALT/AST increase, anemia, and dizziness.

Grade 3 AEs included diarrhea (22%), ALT/AST increase (17%), rash (11%), neutropenia (6%), fatigue (6%), and anemia (6%). The only grade 4 AE was neutropenia (28%).

Serious AEs in more than 1 patient included diarrhea (n=3), colitis (n=2), dehydration (n=2), pneumonia (n=2), and pneumonitis (n=2).

The AEs leading to treatment discontinuation were increased ALT/AST, dehydration, and spinal stenosis (all in 1 patient), as well as arthritis, pneumonitis, colitis, diarrhea, and stomatitis.

“We tend to see the transaminitis and the pneumonitis earlier, and then the late toxicity tends to be the diarrhea and colitis,” Dr O’ Brien said. “The one toxicity where I would not be inclined to try and re-treat a patient is pneumonitis, but I do think colitis can be successfully re-treated.”

Pharmacodynamic studies show very rapid inhibition of phosphorylated AKT following treatment, which is sustained throughout the whole first cycle. And following 1 cycle of duvelisib, there is near-complete inhibition of CLL proliferation, as evidenced by the reduction in Ki67.

Given these data, the investigators recommended further development of duvelisib in treatment-naïve CLL.

ico_ht.gif

*Information in the abstract differs from that presented at the meeting.

EHA2015_Messe%20Wien-rev-240.jpg

Messe Wien, site of EHA 2015

VIENNA—The immunotherapeutic agent PRM-151, when given alone or in combination with ruxolitinib, can reduce bone marrow fibrosis and improve platelet counts in patients with myelofibrosis (MF), results of a phase 2 trial suggest.

Using a novel assessment technique known as computer-assisted image analysis (CIA), researchers found that PRM-151, with or without ruxolitinib, prompted fibrosis responses in nearly three-quarters of patients studied.

And nearly 60% of thrombocytopenic patients saw improvements in their platelet counts.

“Thrombocytopenia remains a significant problem for many patients with myelofibrosis, and a new treatment that is not myelosuppressive and actually increases platelet counts would be of great benefit to patients,” said Srdan Verstovsek, MD, PhD, of the University of Texas MD Anderson Cancer Center in Houston.

He and his colleagues presented this research—the first part of a 2-stage study—at the 20th Congress of the European Hematology Association (abstract P677*). The trial is sponsored by Promedior, the company developing PRM-151.

Stage 1 of the study included 27 patients with a median age of 67 (range, 51-85). They had been diagnosed with primary MF, post-polycythemia vera MF, or post-essential thrombocythemia MF.

The patients received PRM-151 at 10 mg/kg IV dosed weekly (n=8) or monthly (n=7), or ruxolitinib plus PRM-151 at 10 mg/kg IV dosed weekly (n=6) or monthly (n=6). The patients who received ruxolitinib were already taking the drug, and doses varied. The mean duration of ruxolitinib treatment was 1.6 years (range, 0.6-3 years).

Patients were set to receive study treatment for 24 weeks but could continue beyond that if they experienced clinical improvement.

Response assessment: Using CIA

Hematopathologists who were blinded to the patient, treatment, and time point performed morphologic analysis on bone marrow specimens taken at baseline and at 12, 24, and 36 weeks (if available).

The pathologists also performed CIA on whole-slide scans from specimens taken at the same time points. The idea to use CIA came after morphologic analyses revealed some surprising findings.

“[The pathologists] were really struck by the fact that, in the patients who had reductions in fibrosis, there were other elements in the bone marrow that showed improvements,” said Beth Trehu, MD, Chief Medical Officer at Promedior. “There were trends toward normalization of the red cells and of the megakaryocytes.”

“They also remarked that, whereas the baseline samples were totally homogeneous—a grade 3 was a grade 3 throughout the bone marrow—after treatment, the samples became very heterogeneous. There were areas of grade 3, grade 2, grade 1, and 0, all in one sample.”

To solve this problem, the pathologists decided that a sample’s WHO grade would be defined as whatever grade was present in at least 50% of the sample. But the team still thought these grades weren’t accurately quantifying the effects of PRM-151.

So they turned to CIA, which allowed them to quantify the volume of collagen or reticulin fibers in the bone marrow.

Fibrosis and platelet responses

According to CIA, 73% of evaluable patients (19/26) experienced reductions in bone marrow fibrosis at any time during the trial.

Of the 23 evaluable patients who had grade 2 or 3 fibrosis at baseline, 11 patients had a reduction of 1 grade or more during the study period, according to morphologic analysis. Nine patients had a fibrosis response by morphology at the last time point they were assessed.

Reductions in fibrosis correlated with increased platelet counts in thrombocytopenic patients. Fifty-seven percent of thrombocytopenic patients (8/14) saw an improvement in platelet counts after treatment.

Results across treatment groups were as follows:

“The responses we saw with single-agent PRM-151, in particular, give us a lot of confidence that this drug is absolutely reversing fibrosis in the bone marrow,” Dr Trehu said. “And that is very nicely correlated with improvements in platelets, which are much harder to see in patients who are getting ruxolitinib because it’s a myelosuppressive agent.”

Dr Trehu added that these data suggest a monthly dose of PRM-151 is sufficient to treat MF patients, and there is a path forward for PRM-151 both alone and in combination with ruxolitinib.

Hemoglobin and spleen responses

The researchers also observed some improvements in hemoglobin levels and spleen size after treatment.

Of the 15 patients who had hemoglobin levels below 100 g/L at baseline, 3 met criteria for hemoglobin improvement. This included becoming transfusion independent, having a 50% reduction in the need for transfusion, or experiencing a 2 g/L increase in hemoglobin.

“Other patients had a nice trend toward hemoglobin improvement,” Dr Trehu noted.

Of the 20 patients with palpable spleen at baseline, reductions occurred in all but 1 patient. Four patients had a 50% or greater reduction in spleen size, but this response did not last beyond 12 weeks.

Adverse events

Forty-eight percent of patients (13/27) had at least 1 treatment-related adverse event (AE). Grade 1 AEs included diarrhea (n=3), fatigue (n=2), bruising at the infusion site (n=2), oral herpes (n=1), joint swelling (n=2), and headache (n=2). One patient had grade 2 oral herpes.

There were 5 serious AEs that were possibly treatment-related. Three events, from which patients recovered, were abdominal pain, sialadenitis, and pneumonia. The other 2 serious AEs were gastroenteritis and pneumonia, which resulted in death in an 85-year-old patient.

There were 2 deaths unrelated to treatment. One was due to pneumonia, and the other was a result of multi-organ failure and cardiac arrest.

ico_ht.gif

*Information in the abstract differs from that presented at the meeting.

EHA2015_Messe%20Wien-rev-240.jpg

Messe Wien, site of EHA 2015

VIENNA—The immunotherapeutic agent PRM-151, when given alone or in combination with ruxolitinib, can reduce bone marrow fibrosis and improve platelet counts in patients with myelofibrosis (MF), results of a phase 2 trial suggest.

Using a novel assessment technique known as computer-assisted image analysis (CIA), researchers found that PRM-151, with or without ruxolitinib, prompted fibrosis responses in nearly three-quarters of patients studied.

And nearly 60% of thrombocytopenic patients saw improvements in their platelet counts.

“Thrombocytopenia remains a significant problem for many patients with myelofibrosis, and a new treatment that is not myelosuppressive and actually increases platelet counts would be of great benefit to patients,” said Srdan Verstovsek, MD, PhD, of the University of Texas MD Anderson Cancer Center in Houston.

He and his colleagues presented this research—the first part of a 2-stage study—at the 20th Congress of the European Hematology Association (abstract P677*). The trial is sponsored by Promedior, the company developing PRM-151.

Stage 1 of the study included 27 patients with a median age of 67 (range, 51-85). They had been diagnosed with primary MF, post-polycythemia vera MF, or post-essential thrombocythemia MF.

The patients received PRM-151 at 10 mg/kg IV dosed weekly (n=8) or monthly (n=7), or ruxolitinib plus PRM-151 at 10 mg/kg IV dosed weekly (n=6) or monthly (n=6). The patients who received ruxolitinib were already taking the drug, and doses varied. The mean duration of ruxolitinib treatment was 1.6 years (range, 0.6-3 years).

Patients were set to receive study treatment for 24 weeks but could continue beyond that if they experienced clinical improvement.

Response assessment: Using CIA

Hematopathologists who were blinded to the patient, treatment, and time point performed morphologic analysis on bone marrow specimens taken at baseline and at 12, 24, and 36 weeks (if available).

The pathologists also performed CIA on whole-slide scans from specimens taken at the same time points. The idea to use CIA came after morphologic analyses revealed some surprising findings.

“[The pathologists] were really struck by the fact that, in the patients who had reductions in fibrosis, there were other elements in the bone marrow that showed improvements,” said Beth Trehu, MD, Chief Medical Officer at Promedior. “There were trends toward normalization of the red cells and of the megakaryocytes.”

“They also remarked that, whereas the baseline samples were totally homogeneous—a grade 3 was a grade 3 throughout the bone marrow—after treatment, the samples became very heterogeneous. There were areas of grade 3, grade 2, grade 1, and 0, all in one sample.”

To solve this problem, the pathologists decided that a sample’s WHO grade would be defined as whatever grade was present in at least 50% of the sample. But the team still thought these grades weren’t accurately quantifying the effects of PRM-151.

So they turned to CIA, which allowed them to quantify the volume of collagen or reticulin fibers in the bone marrow.

Fibrosis and platelet responses

According to CIA, 73% of evaluable patients (19/26) experienced reductions in bone marrow fibrosis at any time during the trial.

Of the 23 evaluable patients who had grade 2 or 3 fibrosis at baseline, 11 patients had a reduction of 1 grade or more during the study period, according to morphologic analysis. Nine patients had a fibrosis response by morphology at the last time point they were assessed.

Reductions in fibrosis correlated with increased platelet counts in thrombocytopenic patients. Fifty-seven percent of thrombocytopenic patients (8/14) saw an improvement in platelet counts after treatment.

Results across treatment groups were as follows:

“The responses we saw with single-agent PRM-151, in particular, give us a lot of confidence that this drug is absolutely reversing fibrosis in the bone marrow,” Dr Trehu said. “And that is very nicely correlated with improvements in platelets, which are much harder to see in patients who are getting ruxolitinib because it’s a myelosuppressive agent.”

Dr Trehu added that these data suggest a monthly dose of PRM-151 is sufficient to treat MF patients, and there is a path forward for PRM-151 both alone and in combination with ruxolitinib.

Hemoglobin and spleen responses

The researchers also observed some improvements in hemoglobin levels and spleen size after treatment.

Of the 15 patients who had hemoglobin levels below 100 g/L at baseline, 3 met criteria for hemoglobin improvement. This included becoming transfusion independent, having a 50% reduction in the need for transfusion, or experiencing a 2 g/L increase in hemoglobin.

“Other patients had a nice trend toward hemoglobin improvement,” Dr Trehu noted.

Of the 20 patients with palpable spleen at baseline, reductions occurred in all but 1 patient. Four patients had a 50% or greater reduction in spleen size, but this response did not last beyond 12 weeks.

Adverse events

Forty-eight percent of patients (13/27) had at least 1 treatment-related adverse event (AE). Grade 1 AEs included diarrhea (n=3), fatigue (n=2), bruising at the infusion site (n=2), oral herpes (n=1), joint swelling (n=2), and headache (n=2). One patient had grade 2 oral herpes.

There were 5 serious AEs that were possibly treatment-related. Three events, from which patients recovered, were abdominal pain, sialadenitis, and pneumonia. The other 2 serious AEs were gastroenteritis and pneumonia, which resulted in death in an 85-year-old patient.

There were 2 deaths unrelated to treatment. One was due to pneumonia, and the other was a result of multi-organ failure and cardiac arrest.

ico_ht.gif

*Information in the abstract differs from that presented at the meeting.

EHA2015_Messe%20Wien-rev-240.jpg

Messe Wien, site of EHA 2015

VIENNA—The immunotherapeutic agent PRM-151, when given alone or in combination with ruxolitinib, can reduce bone marrow fibrosis and improve platelet counts in patients with myelofibrosis (MF), results of a phase 2 trial suggest.

Using a novel assessment technique known as computer-assisted image analysis (CIA), researchers found that PRM-151, with or without ruxolitinib, prompted fibrosis responses in nearly three-quarters of patients studied.

And nearly 60% of thrombocytopenic patients saw improvements in their platelet counts.

“Thrombocytopenia remains a significant problem for many patients with myelofibrosis, and a new treatment that is not myelosuppressive and actually increases platelet counts would be of great benefit to patients,” said Srdan Verstovsek, MD, PhD, of the University of Texas MD Anderson Cancer Center in Houston.

He and his colleagues presented this research—the first part of a 2-stage study—at the 20th Congress of the European Hematology Association (abstract P677*). The trial is sponsored by Promedior, the company developing PRM-151.

Stage 1 of the study included 27 patients with a median age of 67 (range, 51-85). They had been diagnosed with primary MF, post-polycythemia vera MF, or post-essential thrombocythemia MF.

The patients received PRM-151 at 10 mg/kg IV dosed weekly (n=8) or monthly (n=7), or ruxolitinib plus PRM-151 at 10 mg/kg IV dosed weekly (n=6) or monthly (n=6). The patients who received ruxolitinib were already taking the drug, and doses varied. The mean duration of ruxolitinib treatment was 1.6 years (range, 0.6-3 years).

Patients were set to receive study treatment for 24 weeks but could continue beyond that if they experienced clinical improvement.

Response assessment: Using CIA

Hematopathologists who were blinded to the patient, treatment, and time point performed morphologic analysis on bone marrow specimens taken at baseline and at 12, 24, and 36 weeks (if available).

The pathologists also performed CIA on whole-slide scans from specimens taken at the same time points. The idea to use CIA came after morphologic analyses revealed some surprising findings.

“[The pathologists] were really struck by the fact that, in the patients who had reductions in fibrosis, there were other elements in the bone marrow that showed improvements,” said Beth Trehu, MD, Chief Medical Officer at Promedior. “There were trends toward normalization of the red cells and of the megakaryocytes.”

“They also remarked that, whereas the baseline samples were totally homogeneous—a grade 3 was a grade 3 throughout the bone marrow—after treatment, the samples became very heterogeneous. There were areas of grade 3, grade 2, grade 1, and 0, all in one sample.”

To solve this problem, the pathologists decided that a sample’s WHO grade would be defined as whatever grade was present in at least 50% of the sample. But the team still thought these grades weren’t accurately quantifying the effects of PRM-151.

So they turned to CIA, which allowed them to quantify the volume of collagen or reticulin fibers in the bone marrow.

Fibrosis and platelet responses

According to CIA, 73% of evaluable patients (19/26) experienced reductions in bone marrow fibrosis at any time during the trial.

Of the 23 evaluable patients who had grade 2 or 3 fibrosis at baseline, 11 patients had a reduction of 1 grade or more during the study period, according to morphologic analysis. Nine patients had a fibrosis response by morphology at the last time point they were assessed.

Reductions in fibrosis correlated with increased platelet counts in thrombocytopenic patients. Fifty-seven percent of thrombocytopenic patients (8/14) saw an improvement in platelet counts after treatment.

Results across treatment groups were as follows:

“The responses we saw with single-agent PRM-151, in particular, give us a lot of confidence that this drug is absolutely reversing fibrosis in the bone marrow,” Dr Trehu said. “And that is very nicely correlated with improvements in platelets, which are much harder to see in patients who are getting ruxolitinib because it’s a myelosuppressive agent.”

Dr Trehu added that these data suggest a monthly dose of PRM-151 is sufficient to treat MF patients, and there is a path forward for PRM-151 both alone and in combination with ruxolitinib.

Hemoglobin and spleen responses

The researchers also observed some improvements in hemoglobin levels and spleen size after treatment.

Of the 15 patients who had hemoglobin levels below 100 g/L at baseline, 3 met criteria for hemoglobin improvement. This included becoming transfusion independent, having a 50% reduction in the need for transfusion, or experiencing a 2 g/L increase in hemoglobin.

“Other patients had a nice trend toward hemoglobin improvement,” Dr Trehu noted.

Of the 20 patients with palpable spleen at baseline, reductions occurred in all but 1 patient. Four patients had a 50% or greater reduction in spleen size, but this response did not last beyond 12 weeks.

Adverse events

Forty-eight percent of patients (13/27) had at least 1 treatment-related adverse event (AE). Grade 1 AEs included diarrhea (n=3), fatigue (n=2), bruising at the infusion site (n=2), oral herpes (n=1), joint swelling (n=2), and headache (n=2). One patient had grade 2 oral herpes.

There were 5 serious AEs that were possibly treatment-related. Three events, from which patients recovered, were abdominal pain, sialadenitis, and pneumonia. The other 2 serious AEs were gastroenteritis and pneumonia, which resulted in death in an 85-year-old patient.

There were 2 deaths unrelated to treatment. One was due to pneumonia, and the other was a result of multi-organ failure and cardiac arrest.

ico_ht.gif

*Information in the abstract differs from that presented at the meeting.