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Combined checkpoint blockade promising in HL
© Todd Buchanan 2016
SAN DIEGO—Immune checkpoint blockade with nivolumab plus ipilimumab has shown promise in treating hematologic malignancies, particularly classical Hodgkin lymphoma (HL), based on results of the combination cohort of the phase 1 CheckMate 039 study.
Thirty-one heavily pre-treated HL patients achieved an overall response rate (ORR) of 74%, including 6 complete responses.
And in transplant-naïve HL patients, the combination produced an ORR of 67%.
“Most in the room would be familiar with the excellent results that we have seen with monotherapy with nivolumab,” Stephen Ansell, MD, PhD, of the Mayo Clinic in Rochester, Minnesota, said at the 2016 ASH Annual Meeting.
“In classical Hodgkin lymphoma, we’ve seen meaningful and clinically quite stellar results and durable responses.”
“Our plan was, as part of this trial [CheckMate 039], to then move to see whether adding a further checkpoint, ipilimumab, could enhance the results seen with nivolumab.”
Dr Ansell presented the findings for the checkpoint combination as abstract 183. He disclosed research funding from Bristol-Myers Squibb, the company that funded the study.
Checkpoint inhibitors
Nivolumab and ipilimumab are both fully human monoclonal antibodies, but ipilimumab “works in a slightly different fashion from nivolumab,” Dr Ansell said.
Nivolumab targets the programmed death receptor-1 (PD-1) and disrupts PD-1 pathway signaling and restores anti-tumor T-cell function.
Ipilimumab targets cytotoxic T-lymphocyte antigen 4 (CTLA-4) and induces anti-tumor immunity.
The combination has shown superior efficacy, compared to either agent alone, in preclinical studies and a phase 1 trial of patients with advanced melanoma.
So the investigators added a combination cohort to CheckMate 039.
Combination cohort study design
Patients were eligible to enroll if they had relapsed or refractory HL, B-cell non-Hodgkin lymphoma (NHL, including follicular or diffuse large B-cell lymphoma), T-cell NHL (including cutaneous or peripheral T-cell lymphoma), or multiple myeloma (MM).
Patients could not have had prior organ or allogeneic stem cell transplant and no prior immune checkpoint blockade therapy.
Treatment consisted of nivolumab at 3 mg/kg IV plus ipilimumab at 1 mg/kg IV every 3 weeks for 4 doses. The combination phase was followed by nivolumab monotherapy at the same dose every 2 weeks for 2 years.
The primary endpoint was safety and tolerability. Secondary endpoints included investigator-assessed best overall response, duration of response, progression-free survival (PFS), and biomarker analyses.
Patient characteristics
The investigators enrolled 31 HL, 15 B-cell NHL, 11 T-cell NHL, and 7 MM patients. Most patients, Dr Ansell noted, were heavily pretreated.
HL patients were 42% male, 52% had an ECOG status of 1, and they had a median of 4 (range, 2 to 10) prior systemic therapies. Forty-two percent had prior autologous stem cell transplant (ASCT).
“Interestingly, in the Hodgkin cohort, a number of patients had not proceeded to an autologous transplant, but predominantly because these were chemo-refractory or chemo-resistant patients not eligible for a transplant,” Dr Ansell pointed out.
Of the HL patients, 18 were transplant-naïve, 13 were chemo-resistant, 3 were ineligible for ASCT, and 2 declined the procedure.
B-cell NHL patients were 73% male, and 80% had an ECOG status of 1. They had a median of 3 (range, 1 to 16) prior systemic therapies. Seven percent had a prior ASCT.
T-cell NHL patients were 55% male, 73% had an ECOG status of 1, and they had a median of 4 (range, 1 to 11) prior systemic therapies. None had a prior ASCT.
MM patients were 86% male, 71% had an ECOG status of 1, and they had a median of 5 (range, 2 to 20) prior systemic therapies. More than half had a prior ASCT.
Patient disposition
With follow-up approaching a year, more patients with HL are still on treatment (39%) compared with B-cell NHL (13%), T-cell NHL (18%), and MM (0%) patients.
“Of note, however, is that the reasons for going off treatment were predominantly disease progression,” Dr Ansell said.
“The vast majority of patients who came off treatment came off treatment because their disease progressed, and the numbers that came off because of toxicity were relatively low.”
Seven HL patients went off treatment due to disease progression and 2 due to study drug toxicity.
Eleven B-cell NHL patients went off treatment due to disease progression and 2 withdrew due to unrelated adverse events (AEs).
Five T-cell NHL patients went off treatment due to disease progression and 2 due to study drug toxicity.
And 4 MM patients withdrew due to disease progression, 1 due to study drug toxicity, and 1 due to AEs unrelated to the study drug.
About two-thirds of HL patients, over 90% of B-cell NHL patients, about 80% of T-cell NHL patients, and about 70% of MM patients received 90% or more of the intended dose of each drug.
Safety
One patient with primary mediastinal B-cell lymphoma was included in the safety analysis, for a total of 65 patients treated.
“The majority of patients had some degree of adverse event,” Dr Ansell explained. “But if one looks at the grade 3 and 4 adverse events, those were seen in a more modest number of patients, in a minority of patients. And most importantly, if one looks at the adverse events that led to discontinuation, one can see that this was in a significant minority of patients.”
Five patients discontinued due to treatment-related AEs, which were pneumonitis (n=3), pneumonia and pneumonitis (n=1), and diabetic ketoacidosis (n=1).
Overall, 51 patients (78%) experienced an AE; 19 (29%) had a grade 3–4 AE, 14 (22%) had a serious AE, and 5 (8%) discontinued due to an AE.
Of 31 HL patients, 28 (90%) had an AE, 8 (26%) had a grade 3–4 AE, 6 (19%) had a serious AE, and 2 (6%) discontinued due to an AE.
All 11 T-cell NHL patients experienced an AE, 5 patients (45%) a grade 3-4 AE, 4 patients (36%) had a serious AE, and 2 patients (18%) discontinued because of an AE.
About half of B-cell NHL and MM patients experienced an AE, with 1 MM patient discontinuing as a result of it and no B-cell NHL patient discontinuing due to an AE.
“I would highlight that most of the adverse events were, as expected, immunological in nature . . . . ,” Dr Ansell said. “A very modest number of patients had grade 3 and 4 toxicities.”
The most common drug-related AEs of any grade were fatigue (n=17; 26%), pyrexia (n=15; 23%), rash (n=7; 11%), diarrhea (n=12; 18%), and nausea, pneumonitis, cough, and infusion-related reactions, with 9 patients each (14%).
Efficacy
Twenty-three HL patients (74%) achieved an overall response, including 6 patients (19%) with a complete response and 17 (55%) with a partial response. Three patients (10%) had stable disease, and 3 (10%) had relapsed or progressive disease. Response was not reported for 2 patients (6%).
“Most of these responses are durable, and, very encouraging, you can see patients out approaching a year continuing on therapy,” Dr Ansell said.
The ORR in the 18 transplant-naive patients was 67% (n=67).
The median duration of response for HL patients was not reached and ranged from 0.0 to 13.4 months.
B-cell NHL patients had an ORR of 20% (n=3). There were no complete responses and 3 (20%) partial responses. One patient (7%) had stable disease, and 8 (53%) had relapsed or progressive disase. The median duration of partial response was not reached and ranged from 11.0 to 12.7 months.
T-cell NHL patients had an ORR of 9% (n=1). There were no complete responses and 1 (9%) partial response. Four patients (36%) had stable disease, and 3 (27%) had relapsed or progressive disease. The median duration of partial response was not reached and was 3.9 months.
Except for 1 patient with stable disease, MM patients did not respond to therapy.
Biomarker analysis
All 19 HL patients with a known PD-L1 status at baseline saw their tumor burden decrease to below baseline levels. This may be because HL is characterized by high PD-L1 expression and high responsiveness to checkpoint blockade.
Patients with NHL, on the other hand, have a diverse group of tumors characterized by variable PD-L1 expression. Eight of 13 patients with known expression saw their tumor burden decrease with treatment to below baseline.
Encouraged by the results, the investigators believe further investigation of the combination is in order, as the combination, with limited follow-up, achieved a high and durable ORR in HL patients, including those who were transplant-naïve. 
© Todd Buchanan 2016
SAN DIEGO—Immune checkpoint blockade with nivolumab plus ipilimumab has shown promise in treating hematologic malignancies, particularly classical Hodgkin lymphoma (HL), based on results of the combination cohort of the phase 1 CheckMate 039 study.
Thirty-one heavily pre-treated HL patients achieved an overall response rate (ORR) of 74%, including 6 complete responses.
And in transplant-naïve HL patients, the combination produced an ORR of 67%.
“Most in the room would be familiar with the excellent results that we have seen with monotherapy with nivolumab,” Stephen Ansell, MD, PhD, of the Mayo Clinic in Rochester, Minnesota, said at the 2016 ASH Annual Meeting.
“In classical Hodgkin lymphoma, we’ve seen meaningful and clinically quite stellar results and durable responses.”
“Our plan was, as part of this trial [CheckMate 039], to then move to see whether adding a further checkpoint, ipilimumab, could enhance the results seen with nivolumab.”
Dr Ansell presented the findings for the checkpoint combination as abstract 183. He disclosed research funding from Bristol-Myers Squibb, the company that funded the study.
Checkpoint inhibitors
Nivolumab and ipilimumab are both fully human monoclonal antibodies, but ipilimumab “works in a slightly different fashion from nivolumab,” Dr Ansell said.
Nivolumab targets the programmed death receptor-1 (PD-1) and disrupts PD-1 pathway signaling and restores anti-tumor T-cell function.
Ipilimumab targets cytotoxic T-lymphocyte antigen 4 (CTLA-4) and induces anti-tumor immunity.
The combination has shown superior efficacy, compared to either agent alone, in preclinical studies and a phase 1 trial of patients with advanced melanoma.
So the investigators added a combination cohort to CheckMate 039.
Combination cohort study design
Patients were eligible to enroll if they had relapsed or refractory HL, B-cell non-Hodgkin lymphoma (NHL, including follicular or diffuse large B-cell lymphoma), T-cell NHL (including cutaneous or peripheral T-cell lymphoma), or multiple myeloma (MM).
Patients could not have had prior organ or allogeneic stem cell transplant and no prior immune checkpoint blockade therapy.
Treatment consisted of nivolumab at 3 mg/kg IV plus ipilimumab at 1 mg/kg IV every 3 weeks for 4 doses. The combination phase was followed by nivolumab monotherapy at the same dose every 2 weeks for 2 years.
The primary endpoint was safety and tolerability. Secondary endpoints included investigator-assessed best overall response, duration of response, progression-free survival (PFS), and biomarker analyses.
Patient characteristics
The investigators enrolled 31 HL, 15 B-cell NHL, 11 T-cell NHL, and 7 MM patients. Most patients, Dr Ansell noted, were heavily pretreated.
HL patients were 42% male, 52% had an ECOG status of 1, and they had a median of 4 (range, 2 to 10) prior systemic therapies. Forty-two percent had prior autologous stem cell transplant (ASCT).
“Interestingly, in the Hodgkin cohort, a number of patients had not proceeded to an autologous transplant, but predominantly because these were chemo-refractory or chemo-resistant patients not eligible for a transplant,” Dr Ansell pointed out.
Of the HL patients, 18 were transplant-naïve, 13 were chemo-resistant, 3 were ineligible for ASCT, and 2 declined the procedure.
B-cell NHL patients were 73% male, and 80% had an ECOG status of 1. They had a median of 3 (range, 1 to 16) prior systemic therapies. Seven percent had a prior ASCT.
T-cell NHL patients were 55% male, 73% had an ECOG status of 1, and they had a median of 4 (range, 1 to 11) prior systemic therapies. None had a prior ASCT.
MM patients were 86% male, 71% had an ECOG status of 1, and they had a median of 5 (range, 2 to 20) prior systemic therapies. More than half had a prior ASCT.
Patient disposition
With follow-up approaching a year, more patients with HL are still on treatment (39%) compared with B-cell NHL (13%), T-cell NHL (18%), and MM (0%) patients.
“Of note, however, is that the reasons for going off treatment were predominantly disease progression,” Dr Ansell said.
“The vast majority of patients who came off treatment came off treatment because their disease progressed, and the numbers that came off because of toxicity were relatively low.”
Seven HL patients went off treatment due to disease progression and 2 due to study drug toxicity.
Eleven B-cell NHL patients went off treatment due to disease progression and 2 withdrew due to unrelated adverse events (AEs).
Five T-cell NHL patients went off treatment due to disease progression and 2 due to study drug toxicity.
And 4 MM patients withdrew due to disease progression, 1 due to study drug toxicity, and 1 due to AEs unrelated to the study drug.
About two-thirds of HL patients, over 90% of B-cell NHL patients, about 80% of T-cell NHL patients, and about 70% of MM patients received 90% or more of the intended dose of each drug.
Safety
One patient with primary mediastinal B-cell lymphoma was included in the safety analysis, for a total of 65 patients treated.
“The majority of patients had some degree of adverse event,” Dr Ansell explained. “But if one looks at the grade 3 and 4 adverse events, those were seen in a more modest number of patients, in a minority of patients. And most importantly, if one looks at the adverse events that led to discontinuation, one can see that this was in a significant minority of patients.”
Five patients discontinued due to treatment-related AEs, which were pneumonitis (n=3), pneumonia and pneumonitis (n=1), and diabetic ketoacidosis (n=1).
Overall, 51 patients (78%) experienced an AE; 19 (29%) had a grade 3–4 AE, 14 (22%) had a serious AE, and 5 (8%) discontinued due to an AE.
Of 31 HL patients, 28 (90%) had an AE, 8 (26%) had a grade 3–4 AE, 6 (19%) had a serious AE, and 2 (6%) discontinued due to an AE.
All 11 T-cell NHL patients experienced an AE, 5 patients (45%) a grade 3-4 AE, 4 patients (36%) had a serious AE, and 2 patients (18%) discontinued because of an AE.
About half of B-cell NHL and MM patients experienced an AE, with 1 MM patient discontinuing as a result of it and no B-cell NHL patient discontinuing due to an AE.
“I would highlight that most of the adverse events were, as expected, immunological in nature . . . . ,” Dr Ansell said. “A very modest number of patients had grade 3 and 4 toxicities.”
The most common drug-related AEs of any grade were fatigue (n=17; 26%), pyrexia (n=15; 23%), rash (n=7; 11%), diarrhea (n=12; 18%), and nausea, pneumonitis, cough, and infusion-related reactions, with 9 patients each (14%).
Efficacy
Twenty-three HL patients (74%) achieved an overall response, including 6 patients (19%) with a complete response and 17 (55%) with a partial response. Three patients (10%) had stable disease, and 3 (10%) had relapsed or progressive disease. Response was not reported for 2 patients (6%).
“Most of these responses are durable, and, very encouraging, you can see patients out approaching a year continuing on therapy,” Dr Ansell said.
The ORR in the 18 transplant-naive patients was 67% (n=67).
The median duration of response for HL patients was not reached and ranged from 0.0 to 13.4 months.
B-cell NHL patients had an ORR of 20% (n=3). There were no complete responses and 3 (20%) partial responses. One patient (7%) had stable disease, and 8 (53%) had relapsed or progressive disase. The median duration of partial response was not reached and ranged from 11.0 to 12.7 months.
T-cell NHL patients had an ORR of 9% (n=1). There were no complete responses and 1 (9%) partial response. Four patients (36%) had stable disease, and 3 (27%) had relapsed or progressive disease. The median duration of partial response was not reached and was 3.9 months.
Except for 1 patient with stable disease, MM patients did not respond to therapy.
Biomarker analysis
All 19 HL patients with a known PD-L1 status at baseline saw their tumor burden decrease to below baseline levels. This may be because HL is characterized by high PD-L1 expression and high responsiveness to checkpoint blockade.
Patients with NHL, on the other hand, have a diverse group of tumors characterized by variable PD-L1 expression. Eight of 13 patients with known expression saw their tumor burden decrease with treatment to below baseline.
Encouraged by the results, the investigators believe further investigation of the combination is in order, as the combination, with limited follow-up, achieved a high and durable ORR in HL patients, including those who were transplant-naïve.
© Todd Buchanan 2016
SAN DIEGO—Immune checkpoint blockade with nivolumab plus ipilimumab has shown promise in treating hematologic malignancies, particularly classical Hodgkin lymphoma (HL), based on results of the combination cohort of the phase 1 CheckMate 039 study.
Thirty-one heavily pre-treated HL patients achieved an overall response rate (ORR) of 74%, including 6 complete responses.
And in transplant-naïve HL patients, the combination produced an ORR of 67%.
“Most in the room would be familiar with the excellent results that we have seen with monotherapy with nivolumab,” Stephen Ansell, MD, PhD, of the Mayo Clinic in Rochester, Minnesota, said at the 2016 ASH Annual Meeting.
“In classical Hodgkin lymphoma, we’ve seen meaningful and clinically quite stellar results and durable responses.”
“Our plan was, as part of this trial [CheckMate 039], to then move to see whether adding a further checkpoint, ipilimumab, could enhance the results seen with nivolumab.”
Dr Ansell presented the findings for the checkpoint combination as abstract 183. He disclosed research funding from Bristol-Myers Squibb, the company that funded the study.
Checkpoint inhibitors
Nivolumab and ipilimumab are both fully human monoclonal antibodies, but ipilimumab “works in a slightly different fashion from nivolumab,” Dr Ansell said.
Nivolumab targets the programmed death receptor-1 (PD-1) and disrupts PD-1 pathway signaling and restores anti-tumor T-cell function.
Ipilimumab targets cytotoxic T-lymphocyte antigen 4 (CTLA-4) and induces anti-tumor immunity.
The combination has shown superior efficacy, compared to either agent alone, in preclinical studies and a phase 1 trial of patients with advanced melanoma.
So the investigators added a combination cohort to CheckMate 039.
Combination cohort study design
Patients were eligible to enroll if they had relapsed or refractory HL, B-cell non-Hodgkin lymphoma (NHL, including follicular or diffuse large B-cell lymphoma), T-cell NHL (including cutaneous or peripheral T-cell lymphoma), or multiple myeloma (MM).
Patients could not have had prior organ or allogeneic stem cell transplant and no prior immune checkpoint blockade therapy.
Treatment consisted of nivolumab at 3 mg/kg IV plus ipilimumab at 1 mg/kg IV every 3 weeks for 4 doses. The combination phase was followed by nivolumab monotherapy at the same dose every 2 weeks for 2 years.
The primary endpoint was safety and tolerability. Secondary endpoints included investigator-assessed best overall response, duration of response, progression-free survival (PFS), and biomarker analyses.
Patient characteristics
The investigators enrolled 31 HL, 15 B-cell NHL, 11 T-cell NHL, and 7 MM patients. Most patients, Dr Ansell noted, were heavily pretreated.
HL patients were 42% male, 52% had an ECOG status of 1, and they had a median of 4 (range, 2 to 10) prior systemic therapies. Forty-two percent had prior autologous stem cell transplant (ASCT).
“Interestingly, in the Hodgkin cohort, a number of patients had not proceeded to an autologous transplant, but predominantly because these were chemo-refractory or chemo-resistant patients not eligible for a transplant,” Dr Ansell pointed out.
Of the HL patients, 18 were transplant-naïve, 13 were chemo-resistant, 3 were ineligible for ASCT, and 2 declined the procedure.
B-cell NHL patients were 73% male, and 80% had an ECOG status of 1. They had a median of 3 (range, 1 to 16) prior systemic therapies. Seven percent had a prior ASCT.
T-cell NHL patients were 55% male, 73% had an ECOG status of 1, and they had a median of 4 (range, 1 to 11) prior systemic therapies. None had a prior ASCT.
MM patients were 86% male, 71% had an ECOG status of 1, and they had a median of 5 (range, 2 to 20) prior systemic therapies. More than half had a prior ASCT.
Patient disposition
With follow-up approaching a year, more patients with HL are still on treatment (39%) compared with B-cell NHL (13%), T-cell NHL (18%), and MM (0%) patients.
“Of note, however, is that the reasons for going off treatment were predominantly disease progression,” Dr Ansell said.
“The vast majority of patients who came off treatment came off treatment because their disease progressed, and the numbers that came off because of toxicity were relatively low.”
Seven HL patients went off treatment due to disease progression and 2 due to study drug toxicity.
Eleven B-cell NHL patients went off treatment due to disease progression and 2 withdrew due to unrelated adverse events (AEs).
Five T-cell NHL patients went off treatment due to disease progression and 2 due to study drug toxicity.
And 4 MM patients withdrew due to disease progression, 1 due to study drug toxicity, and 1 due to AEs unrelated to the study drug.
About two-thirds of HL patients, over 90% of B-cell NHL patients, about 80% of T-cell NHL patients, and about 70% of MM patients received 90% or more of the intended dose of each drug.
Safety
One patient with primary mediastinal B-cell lymphoma was included in the safety analysis, for a total of 65 patients treated.
“The majority of patients had some degree of adverse event,” Dr Ansell explained. “But if one looks at the grade 3 and 4 adverse events, those were seen in a more modest number of patients, in a minority of patients. And most importantly, if one looks at the adverse events that led to discontinuation, one can see that this was in a significant minority of patients.”
Five patients discontinued due to treatment-related AEs, which were pneumonitis (n=3), pneumonia and pneumonitis (n=1), and diabetic ketoacidosis (n=1).
Overall, 51 patients (78%) experienced an AE; 19 (29%) had a grade 3–4 AE, 14 (22%) had a serious AE, and 5 (8%) discontinued due to an AE.
Of 31 HL patients, 28 (90%) had an AE, 8 (26%) had a grade 3–4 AE, 6 (19%) had a serious AE, and 2 (6%) discontinued due to an AE.
All 11 T-cell NHL patients experienced an AE, 5 patients (45%) a grade 3-4 AE, 4 patients (36%) had a serious AE, and 2 patients (18%) discontinued because of an AE.
About half of B-cell NHL and MM patients experienced an AE, with 1 MM patient discontinuing as a result of it and no B-cell NHL patient discontinuing due to an AE.
“I would highlight that most of the adverse events were, as expected, immunological in nature . . . . ,” Dr Ansell said. “A very modest number of patients had grade 3 and 4 toxicities.”
The most common drug-related AEs of any grade were fatigue (n=17; 26%), pyrexia (n=15; 23%), rash (n=7; 11%), diarrhea (n=12; 18%), and nausea, pneumonitis, cough, and infusion-related reactions, with 9 patients each (14%).
Efficacy
Twenty-three HL patients (74%) achieved an overall response, including 6 patients (19%) with a complete response and 17 (55%) with a partial response. Three patients (10%) had stable disease, and 3 (10%) had relapsed or progressive disease. Response was not reported for 2 patients (6%).
“Most of these responses are durable, and, very encouraging, you can see patients out approaching a year continuing on therapy,” Dr Ansell said.
The ORR in the 18 transplant-naive patients was 67% (n=67).
The median duration of response for HL patients was not reached and ranged from 0.0 to 13.4 months.
B-cell NHL patients had an ORR of 20% (n=3). There were no complete responses and 3 (20%) partial responses. One patient (7%) had stable disease, and 8 (53%) had relapsed or progressive disase. The median duration of partial response was not reached and ranged from 11.0 to 12.7 months.
T-cell NHL patients had an ORR of 9% (n=1). There were no complete responses and 1 (9%) partial response. Four patients (36%) had stable disease, and 3 (27%) had relapsed or progressive disease. The median duration of partial response was not reached and was 3.9 months.
Except for 1 patient with stable disease, MM patients did not respond to therapy.
Biomarker analysis
All 19 HL patients with a known PD-L1 status at baseline saw their tumor burden decrease to below baseline levels. This may be because HL is characterized by high PD-L1 expression and high responsiveness to checkpoint blockade.
Patients with NHL, on the other hand, have a diverse group of tumors characterized by variable PD-L1 expression. Eight of 13 patients with known expression saw their tumor burden decrease with treatment to below baseline.
Encouraged by the results, the investigators believe further investigation of the combination is in order, as the combination, with limited follow-up, achieved a high and durable ORR in HL patients, including those who were transplant-naïve.
Ruxolitinib may prevent CRS after CAR T-cell therapy
Photo courtesy of NCI
SAN DIEGO—A novel xenograft model of acute myeloid leukemia (AML) demonstrated that the JAK/STAT inhibitor ruxolitinib can prevent severe cytokine release syndrome (CRS) without impairing the anti-tumor effect of chimeric antigen receptor (CAR) T cells, according to research presented at the 2016 ASH Annual Meeting.
Almost all patients responding to CART-cell therapy develop CRS, and up to 60% develop severe CRS.
The research team believes the mouse model and findings with ruxolitinib will provide an important platform for studying CRS prevention and treatment.
At ASH, Saad Kenderian, MD, of the Mayo Clinic in Rochester, Minnesota, explained that CRS produces very high levels of the inflammatory protein IL-6.
Treatment with ruxolitinib in clinical studies has reduced human inflammatory cytokines. Therefore, it made sense to the investigators to study ruxolitinib as a means to prevent CRS after CAR T-cell therapy.
Tocilizumab has been used to treat grade 3 and 4 CRS, but physicians are concerned that earlier introduction during the course of CRS may impair CAR T-cell function.
At present, no relevant preclinical model for CRS after CAR T-cell therapy exists, “which is limiting the development of CRS preventative modalities that could, in turn, enhance the feasibility of CAR T-cell therapy,” Dr Kenderian said.
And so the investigators decided to create an animal model.
Dr Kenderian described the work at the meeting as abstract 652.
Mouse model for human CRS
Using NSG-S mice (non-obese diabetic, SCID ɣ -/- mice additionally transgenic for human stem cell factor, IL-3, and GM-CSF), investigators injected them with blasts from AML patients. After 3 to 4 weeks, investigators treated the mice with 1 x 106 CD123-directed CAR T cells.
Dr Kenderian noted this dose of CART123 was 10 times higher than doses previously used in primary AML xenograft models.
The mice became weak, emaciated, developed hunched bodies, became withdrawn, had poor motor responses, and died in 7 to 10 days. The illness started within 1 week of CAR T-cell injection and correlated with significant expansion of T cells in the peripheral blood of these mice.
The team studied the serum from these mice 7 days after CART123 injection. They found extreme elevation of human IL-6, interferon-γ, tumor necrosis factor-α, and other inflammatory cytokines. This response resembled human CRS after CAR T-cell therapy.
Ruxolitinib treatment
The investigators first studied ruxolitinib activity in vitro with CART123 cells and found that ruxolitinib did not impair CAR T-cell effector functions.
“And also, ruxolitinib was not directly toxic to CAR T cells,” Dr Kenderian added.
But ruxolitinib did slow CAR T-cell proliferation in vitro.
They next tested ruxolitinib and CART123 in the mouse model.
Once the mice experienced high-burden disease, investigators treated them with CART123. That same day, investigators began treating the mice with ruxolitinib for 1 week. The mice were randomized to 30, 60, 90 mg/kg, or vehicle twice a day.
Twenty-nine days after AML injection, the mice treated with CART123 plus 90 mg or 60 mg of ruxolitinib experienced less weight loss than those treated with CART123 plus 30 mg of ruxolitinib or CART123-only.
“And more importantly, all mice had eradication of their disease,” Dr Kenderian said.
Mice treated with CART123 plus 90 mg, 60 mg, or 30 mg of ruxolitinib or CART123 alone had fewer AML blasts at day 28 than mice treated with 60 mg of ruxolitinib alone.
The investigators then analyzed the effect of ruxolitinib on the anti-tumor effect of CART123 and found that ruxolitinib did not impair it.
The attenuation of inflammatory cytokines translated to a survival advantage for mice treated with CART123 and ruxolitinib.
The investigators believe the addition of ruxolitinib to CAR T-cell therapy is a modality that should be investigated in patients at high-risk of developing CRS.
Dr Kenderian disclosed patents, royalties, and research funding from Novartis.
Photo courtesy of NCI
SAN DIEGO—A novel xenograft model of acute myeloid leukemia (AML) demonstrated that the JAK/STAT inhibitor ruxolitinib can prevent severe cytokine release syndrome (CRS) without impairing the anti-tumor effect of chimeric antigen receptor (CAR) T cells, according to research presented at the 2016 ASH Annual Meeting.
Almost all patients responding to CART-cell therapy develop CRS, and up to 60% develop severe CRS.
The research team believes the mouse model and findings with ruxolitinib will provide an important platform for studying CRS prevention and treatment.
At ASH, Saad Kenderian, MD, of the Mayo Clinic in Rochester, Minnesota, explained that CRS produces very high levels of the inflammatory protein IL-6.
Treatment with ruxolitinib in clinical studies has reduced human inflammatory cytokines. Therefore, it made sense to the investigators to study ruxolitinib as a means to prevent CRS after CAR T-cell therapy.
Tocilizumab has been used to treat grade 3 and 4 CRS, but physicians are concerned that earlier introduction during the course of CRS may impair CAR T-cell function.
At present, no relevant preclinical model for CRS after CAR T-cell therapy exists, “which is limiting the development of CRS preventative modalities that could, in turn, enhance the feasibility of CAR T-cell therapy,” Dr Kenderian said.
And so the investigators decided to create an animal model.
Dr Kenderian described the work at the meeting as abstract 652.
Mouse model for human CRS
Using NSG-S mice (non-obese diabetic, SCID ɣ -/- mice additionally transgenic for human stem cell factor, IL-3, and GM-CSF), investigators injected them with blasts from AML patients. After 3 to 4 weeks, investigators treated the mice with 1 x 106 CD123-directed CAR T cells.
Dr Kenderian noted this dose of CART123 was 10 times higher than doses previously used in primary AML xenograft models.
The mice became weak, emaciated, developed hunched bodies, became withdrawn, had poor motor responses, and died in 7 to 10 days. The illness started within 1 week of CAR T-cell injection and correlated with significant expansion of T cells in the peripheral blood of these mice.
The team studied the serum from these mice 7 days after CART123 injection. They found extreme elevation of human IL-6, interferon-γ, tumor necrosis factor-α, and other inflammatory cytokines. This response resembled human CRS after CAR T-cell therapy.
Ruxolitinib treatment
The investigators first studied ruxolitinib activity in vitro with CART123 cells and found that ruxolitinib did not impair CAR T-cell effector functions.
“And also, ruxolitinib was not directly toxic to CAR T cells,” Dr Kenderian added.
But ruxolitinib did slow CAR T-cell proliferation in vitro.
They next tested ruxolitinib and CART123 in the mouse model.
Once the mice experienced high-burden disease, investigators treated them with CART123. That same day, investigators began treating the mice with ruxolitinib for 1 week. The mice were randomized to 30, 60, 90 mg/kg, or vehicle twice a day.
Twenty-nine days after AML injection, the mice treated with CART123 plus 90 mg or 60 mg of ruxolitinib experienced less weight loss than those treated with CART123 plus 30 mg of ruxolitinib or CART123-only.
“And more importantly, all mice had eradication of their disease,” Dr Kenderian said.
Mice treated with CART123 plus 90 mg, 60 mg, or 30 mg of ruxolitinib or CART123 alone had fewer AML blasts at day 28 than mice treated with 60 mg of ruxolitinib alone.
The investigators then analyzed the effect of ruxolitinib on the anti-tumor effect of CART123 and found that ruxolitinib did not impair it.
The attenuation of inflammatory cytokines translated to a survival advantage for mice treated with CART123 and ruxolitinib.
The investigators believe the addition of ruxolitinib to CAR T-cell therapy is a modality that should be investigated in patients at high-risk of developing CRS.
Dr Kenderian disclosed patents, royalties, and research funding from Novartis.
Photo courtesy of NCI
SAN DIEGO—A novel xenograft model of acute myeloid leukemia (AML) demonstrated that the JAK/STAT inhibitor ruxolitinib can prevent severe cytokine release syndrome (CRS) without impairing the anti-tumor effect of chimeric antigen receptor (CAR) T cells, according to research presented at the 2016 ASH Annual Meeting.
Almost all patients responding to CART-cell therapy develop CRS, and up to 60% develop severe CRS.
The research team believes the mouse model and findings with ruxolitinib will provide an important platform for studying CRS prevention and treatment.
At ASH, Saad Kenderian, MD, of the Mayo Clinic in Rochester, Minnesota, explained that CRS produces very high levels of the inflammatory protein IL-6.
Treatment with ruxolitinib in clinical studies has reduced human inflammatory cytokines. Therefore, it made sense to the investigators to study ruxolitinib as a means to prevent CRS after CAR T-cell therapy.
Tocilizumab has been used to treat grade 3 and 4 CRS, but physicians are concerned that earlier introduction during the course of CRS may impair CAR T-cell function.
At present, no relevant preclinical model for CRS after CAR T-cell therapy exists, “which is limiting the development of CRS preventative modalities that could, in turn, enhance the feasibility of CAR T-cell therapy,” Dr Kenderian said.
And so the investigators decided to create an animal model.
Dr Kenderian described the work at the meeting as abstract 652.
Mouse model for human CRS
Using NSG-S mice (non-obese diabetic, SCID ɣ -/- mice additionally transgenic for human stem cell factor, IL-3, and GM-CSF), investigators injected them with blasts from AML patients. After 3 to 4 weeks, investigators treated the mice with 1 x 106 CD123-directed CAR T cells.
Dr Kenderian noted this dose of CART123 was 10 times higher than doses previously used in primary AML xenograft models.
The mice became weak, emaciated, developed hunched bodies, became withdrawn, had poor motor responses, and died in 7 to 10 days. The illness started within 1 week of CAR T-cell injection and correlated with significant expansion of T cells in the peripheral blood of these mice.
The team studied the serum from these mice 7 days after CART123 injection. They found extreme elevation of human IL-6, interferon-γ, tumor necrosis factor-α, and other inflammatory cytokines. This response resembled human CRS after CAR T-cell therapy.
Ruxolitinib treatment
The investigators first studied ruxolitinib activity in vitro with CART123 cells and found that ruxolitinib did not impair CAR T-cell effector functions.
“And also, ruxolitinib was not directly toxic to CAR T cells,” Dr Kenderian added.
But ruxolitinib did slow CAR T-cell proliferation in vitro.
They next tested ruxolitinib and CART123 in the mouse model.
Once the mice experienced high-burden disease, investigators treated them with CART123. That same day, investigators began treating the mice with ruxolitinib for 1 week. The mice were randomized to 30, 60, 90 mg/kg, or vehicle twice a day.
Twenty-nine days after AML injection, the mice treated with CART123 plus 90 mg or 60 mg of ruxolitinib experienced less weight loss than those treated with CART123 plus 30 mg of ruxolitinib or CART123-only.
“And more importantly, all mice had eradication of their disease,” Dr Kenderian said.
Mice treated with CART123 plus 90 mg, 60 mg, or 30 mg of ruxolitinib or CART123 alone had fewer AML blasts at day 28 than mice treated with 60 mg of ruxolitinib alone.
The investigators then analyzed the effect of ruxolitinib on the anti-tumor effect of CART123 and found that ruxolitinib did not impair it.
The attenuation of inflammatory cytokines translated to a survival advantage for mice treated with CART123 and ruxolitinib.
The investigators believe the addition of ruxolitinib to CAR T-cell therapy is a modality that should be investigated in patients at high-risk of developing CRS.
Dr Kenderian disclosed patents, royalties, and research funding from Novartis.
MDS patients with mutated IDH2 benefit from enasidenib
Photo courtesy of ASH
SAN DIEGO—Daily treatment with enasidenib monotherapy in patients with mutated IDH2-positive myelodysplastic syndromes (MDS) induced responses in the majority of patients treated, according to a presentation at the 2016 ASH Annual Meeting.
The study was a portion of a larger phase 1/2 trial of the agent in patients with acute myeloid leukemia (AML) and other hematologic malignancies, so the subset was relatively small, numbering 17 patients.
Nevertheless, enasidenib was well tolerated and induced responses in these predominantly higher-risk patients.
Enasidenib (AG-221/CC-9007) is a selective, oral, potent inhibitor of mutant IDH2 (mIDH2), which produces 2-HG and thus alters DNA methylation and blocks cellular differentiation of hematopoietic progenitor cells.
Approximately 15% of AML patients and 5% of MDS patients have mIDH2. So investigators undertook the study to evaluate the safety and efficacy of enasidenib monotherapy in these diseases.
Eytan Stein, MD, of Memorial Sloan Kettering Cancer Center in New York, New York, presented the analysis of enasidenib in mIDH2-positive MDS patients as abstract 343.*
Study design
MDS patients were allowed to enroll during the dose-escalation and expansion phase of the study, Dr Stein explained.
Patients had to be 18 or older and have an advanced hematologic malignancy with mutated IDH2—relapsed or refractory AML, relapsed or refractory MDS, untreated AML, or other hematologic malignancy with mIDH2.
MDS patients could not be candidates for other therapies, had to be IPSS-R high risk, and had to have relapsed or refractory RAEB-1/RAEB-2 disease.
Investigators also performed co-molecular profiling using next-generation sequencing with a FoundationOne® Heme Panel.
All patients received daily oral enasidenib at 100 mg daily in 28-day cycles.
Patient characteristics
The study accrued a total of 239 patients—176 with relapsed or refractory AML, 37 with untreated AML, 9 with another hematologic malignancy, and 17 with MDS.
The median age of the MDS patients was 67 (range, 45-78), and 71% were male. All had the IDH2 mutation, 88% had R140 mutations, and 12% had R172.
Thirteen patients (76%) had an ECOG performance status of 0-1, and 4 (24%) had a performance status of 2.
A little more than a third (35%) of patients had 2 or more prior anti-cancer regimens.
Two patients (12%) received prior lenalidomide therapy, 8 (47%) received other treatments, including sorafenib (n=2) and vosaroxin, epoetin alfa, pracinostat, cytarabine plus clofarabine, ruxolitinib, and rigosertib (n=1 each). Four patients (24%) were untreated.
“I want to make the point,” Dr Stein said, “that, of those patients, three quarters of them, 76% [n=13], had received a prior hypomethylating agent, really understanding that this is a very poor-risk group of patients that we are studying here.”
About half of patients (47%) had intermediate-2/high IPSS risk status, good MDS cytogenetic risk, and high/very high IPSS-R risk status.
Adverse events
Grade 3-4 treatment-emergent adverse events (AEs) occurring in 2 or more patients were hyperbilirubinemia (n=5), pneumonia (n=4), thrombocytopenia (n=4), anemia (n=3), hypokalemia (n=3), dyspnea (n=2), and tumor lysis syndrome (n=2).
“As I’ve said in a number of meetings where I’ve talked about IDH2 inhibitors, and specifically enasidenib, the hyperbilirubinemia that is seen with this drug is an indirect hyperbilirubinemia,” Dr Stein said.
“A known off-target effect of this drug is inhibition of the UGT1a1 enzyme, which conjugates bilirubin, and this indirect hyperbilirubinemia, which is typically relatively mild [and] does not appear to have any clinical sequelae.”
Investigators considered 9 of the AEs reported for 6 patients to be drug-related.
Four serious enasidenib-related AEs included tumor lysis syndrome (n=2), increased blood bilirubin (n=1), and transaminitis (n=1).
There were no treatment-related deaths.
Response and survival
Ten of 17 patients (59%) achieved an overall response, defined as complete response (CR) plus partial response, plus marrow CR, plus hematologic improvement (HI).
One patient achieved CR, 1 had a partial response, 3 had marrow CR, and 5 had HI.
Dr Stein noted that, of the 13 patients who had received prior hypomethylating agent therapy, 7 (54%) had a response with enasidenib.
Of the patients who attained HI, 2 had trilineage and 2 had bilineage improvement.
The median time to response was 21 days (range, 10-87), and the median number of treatment cycles was 3.0.
Patients remained on study for up to 24 months. Four patients in hematologic remission are still on study, and 3 patients proceeded to stem cell or bone marrow transplant, Dr Stein said.
Two patients discontinued because of investigator decision, and 8 discontinued therapy due to death or disease progression.
The limitation of the study regarding overall survival, Dr Stein said, is that the number is very small.
At a median follow-up of 7.5 months, the median overall survival was not reached.
“So I’m not arguing that this is the end word of this,” he said. “This is going to be dynamic as more patients come on these studies. But I think it’s a nice indication that this treatment appears to be well-tolerated and doing good for a large subset of patients.”
Co-occurring mutations
The investigators also analyzed co-occurring mutations in 13 MDS patients.
The small patient population prevented the investigators from making definitive conclusions regarding potential correlations between response and co-mutations.
Nevertheless, Dr Stein said the analysis revealed something “very, very intriguing.”
He noted that 7 patients had ASXL1 mutations, and “those are typically patients who are bad actors.”
“Five of those 7 patients had a response,” Dr Stein said. “And of those 5, 3 of them had received a prior hypomethylating agent. I think it’s at least food for thought that you can salvage a patient who has failed a hypomethylating agent, with poor risk disease. I think this is very, very exciting.”
Celgene Corporation and its collaborator, Agios Pharmaceuticals, sponsored the trial.
*Information in the abstract differs from the presentation.
Photo courtesy of ASH
SAN DIEGO—Daily treatment with enasidenib monotherapy in patients with mutated IDH2-positive myelodysplastic syndromes (MDS) induced responses in the majority of patients treated, according to a presentation at the 2016 ASH Annual Meeting.
The study was a portion of a larger phase 1/2 trial of the agent in patients with acute myeloid leukemia (AML) and other hematologic malignancies, so the subset was relatively small, numbering 17 patients.
Nevertheless, enasidenib was well tolerated and induced responses in these predominantly higher-risk patients.
Enasidenib (AG-221/CC-9007) is a selective, oral, potent inhibitor of mutant IDH2 (mIDH2), which produces 2-HG and thus alters DNA methylation and blocks cellular differentiation of hematopoietic progenitor cells.
Approximately 15% of AML patients and 5% of MDS patients have mIDH2. So investigators undertook the study to evaluate the safety and efficacy of enasidenib monotherapy in these diseases.
Eytan Stein, MD, of Memorial Sloan Kettering Cancer Center in New York, New York, presented the analysis of enasidenib in mIDH2-positive MDS patients as abstract 343.*
Study design
MDS patients were allowed to enroll during the dose-escalation and expansion phase of the study, Dr Stein explained.
Patients had to be 18 or older and have an advanced hematologic malignancy with mutated IDH2—relapsed or refractory AML, relapsed or refractory MDS, untreated AML, or other hematologic malignancy with mIDH2.
MDS patients could not be candidates for other therapies, had to be IPSS-R high risk, and had to have relapsed or refractory RAEB-1/RAEB-2 disease.
Investigators also performed co-molecular profiling using next-generation sequencing with a FoundationOne® Heme Panel.
All patients received daily oral enasidenib at 100 mg daily in 28-day cycles.
Patient characteristics
The study accrued a total of 239 patients—176 with relapsed or refractory AML, 37 with untreated AML, 9 with another hematologic malignancy, and 17 with MDS.
The median age of the MDS patients was 67 (range, 45-78), and 71% were male. All had the IDH2 mutation, 88% had R140 mutations, and 12% had R172.
Thirteen patients (76%) had an ECOG performance status of 0-1, and 4 (24%) had a performance status of 2.
A little more than a third (35%) of patients had 2 or more prior anti-cancer regimens.
Two patients (12%) received prior lenalidomide therapy, 8 (47%) received other treatments, including sorafenib (n=2) and vosaroxin, epoetin alfa, pracinostat, cytarabine plus clofarabine, ruxolitinib, and rigosertib (n=1 each). Four patients (24%) were untreated.
“I want to make the point,” Dr Stein said, “that, of those patients, three quarters of them, 76% [n=13], had received a prior hypomethylating agent, really understanding that this is a very poor-risk group of patients that we are studying here.”
About half of patients (47%) had intermediate-2/high IPSS risk status, good MDS cytogenetic risk, and high/very high IPSS-R risk status.
Adverse events
Grade 3-4 treatment-emergent adverse events (AEs) occurring in 2 or more patients were hyperbilirubinemia (n=5), pneumonia (n=4), thrombocytopenia (n=4), anemia (n=3), hypokalemia (n=3), dyspnea (n=2), and tumor lysis syndrome (n=2).
“As I’ve said in a number of meetings where I’ve talked about IDH2 inhibitors, and specifically enasidenib, the hyperbilirubinemia that is seen with this drug is an indirect hyperbilirubinemia,” Dr Stein said.
“A known off-target effect of this drug is inhibition of the UGT1a1 enzyme, which conjugates bilirubin, and this indirect hyperbilirubinemia, which is typically relatively mild [and] does not appear to have any clinical sequelae.”
Investigators considered 9 of the AEs reported for 6 patients to be drug-related.
Four serious enasidenib-related AEs included tumor lysis syndrome (n=2), increased blood bilirubin (n=1), and transaminitis (n=1).
There were no treatment-related deaths.
Response and survival
Ten of 17 patients (59%) achieved an overall response, defined as complete response (CR) plus partial response, plus marrow CR, plus hematologic improvement (HI).
One patient achieved CR, 1 had a partial response, 3 had marrow CR, and 5 had HI.
Dr Stein noted that, of the 13 patients who had received prior hypomethylating agent therapy, 7 (54%) had a response with enasidenib.
Of the patients who attained HI, 2 had trilineage and 2 had bilineage improvement.
The median time to response was 21 days (range, 10-87), and the median number of treatment cycles was 3.0.
Patients remained on study for up to 24 months. Four patients in hematologic remission are still on study, and 3 patients proceeded to stem cell or bone marrow transplant, Dr Stein said.
Two patients discontinued because of investigator decision, and 8 discontinued therapy due to death or disease progression.
The limitation of the study regarding overall survival, Dr Stein said, is that the number is very small.
At a median follow-up of 7.5 months, the median overall survival was not reached.
“So I’m not arguing that this is the end word of this,” he said. “This is going to be dynamic as more patients come on these studies. But I think it’s a nice indication that this treatment appears to be well-tolerated and doing good for a large subset of patients.”
Co-occurring mutations
The investigators also analyzed co-occurring mutations in 13 MDS patients.
The small patient population prevented the investigators from making definitive conclusions regarding potential correlations between response and co-mutations.
Nevertheless, Dr Stein said the analysis revealed something “very, very intriguing.”
He noted that 7 patients had ASXL1 mutations, and “those are typically patients who are bad actors.”
“Five of those 7 patients had a response,” Dr Stein said. “And of those 5, 3 of them had received a prior hypomethylating agent. I think it’s at least food for thought that you can salvage a patient who has failed a hypomethylating agent, with poor risk disease. I think this is very, very exciting.”
Celgene Corporation and its collaborator, Agios Pharmaceuticals, sponsored the trial.
*Information in the abstract differs from the presentation.
Photo courtesy of ASH
SAN DIEGO—Daily treatment with enasidenib monotherapy in patients with mutated IDH2-positive myelodysplastic syndromes (MDS) induced responses in the majority of patients treated, according to a presentation at the 2016 ASH Annual Meeting.
The study was a portion of a larger phase 1/2 trial of the agent in patients with acute myeloid leukemia (AML) and other hematologic malignancies, so the subset was relatively small, numbering 17 patients.
Nevertheless, enasidenib was well tolerated and induced responses in these predominantly higher-risk patients.
Enasidenib (AG-221/CC-9007) is a selective, oral, potent inhibitor of mutant IDH2 (mIDH2), which produces 2-HG and thus alters DNA methylation and blocks cellular differentiation of hematopoietic progenitor cells.
Approximately 15% of AML patients and 5% of MDS patients have mIDH2. So investigators undertook the study to evaluate the safety and efficacy of enasidenib monotherapy in these diseases.
Eytan Stein, MD, of Memorial Sloan Kettering Cancer Center in New York, New York, presented the analysis of enasidenib in mIDH2-positive MDS patients as abstract 343.*
Study design
MDS patients were allowed to enroll during the dose-escalation and expansion phase of the study, Dr Stein explained.
Patients had to be 18 or older and have an advanced hematologic malignancy with mutated IDH2—relapsed or refractory AML, relapsed or refractory MDS, untreated AML, or other hematologic malignancy with mIDH2.
MDS patients could not be candidates for other therapies, had to be IPSS-R high risk, and had to have relapsed or refractory RAEB-1/RAEB-2 disease.
Investigators also performed co-molecular profiling using next-generation sequencing with a FoundationOne® Heme Panel.
All patients received daily oral enasidenib at 100 mg daily in 28-day cycles.
Patient characteristics
The study accrued a total of 239 patients—176 with relapsed or refractory AML, 37 with untreated AML, 9 with another hematologic malignancy, and 17 with MDS.
The median age of the MDS patients was 67 (range, 45-78), and 71% were male. All had the IDH2 mutation, 88% had R140 mutations, and 12% had R172.
Thirteen patients (76%) had an ECOG performance status of 0-1, and 4 (24%) had a performance status of 2.
A little more than a third (35%) of patients had 2 or more prior anti-cancer regimens.
Two patients (12%) received prior lenalidomide therapy, 8 (47%) received other treatments, including sorafenib (n=2) and vosaroxin, epoetin alfa, pracinostat, cytarabine plus clofarabine, ruxolitinib, and rigosertib (n=1 each). Four patients (24%) were untreated.
“I want to make the point,” Dr Stein said, “that, of those patients, three quarters of them, 76% [n=13], had received a prior hypomethylating agent, really understanding that this is a very poor-risk group of patients that we are studying here.”
About half of patients (47%) had intermediate-2/high IPSS risk status, good MDS cytogenetic risk, and high/very high IPSS-R risk status.
Adverse events
Grade 3-4 treatment-emergent adverse events (AEs) occurring in 2 or more patients were hyperbilirubinemia (n=5), pneumonia (n=4), thrombocytopenia (n=4), anemia (n=3), hypokalemia (n=3), dyspnea (n=2), and tumor lysis syndrome (n=2).
“As I’ve said in a number of meetings where I’ve talked about IDH2 inhibitors, and specifically enasidenib, the hyperbilirubinemia that is seen with this drug is an indirect hyperbilirubinemia,” Dr Stein said.
“A known off-target effect of this drug is inhibition of the UGT1a1 enzyme, which conjugates bilirubin, and this indirect hyperbilirubinemia, which is typically relatively mild [and] does not appear to have any clinical sequelae.”
Investigators considered 9 of the AEs reported for 6 patients to be drug-related.
Four serious enasidenib-related AEs included tumor lysis syndrome (n=2), increased blood bilirubin (n=1), and transaminitis (n=1).
There were no treatment-related deaths.
Response and survival
Ten of 17 patients (59%) achieved an overall response, defined as complete response (CR) plus partial response, plus marrow CR, plus hematologic improvement (HI).
One patient achieved CR, 1 had a partial response, 3 had marrow CR, and 5 had HI.
Dr Stein noted that, of the 13 patients who had received prior hypomethylating agent therapy, 7 (54%) had a response with enasidenib.
Of the patients who attained HI, 2 had trilineage and 2 had bilineage improvement.
The median time to response was 21 days (range, 10-87), and the median number of treatment cycles was 3.0.
Patients remained on study for up to 24 months. Four patients in hematologic remission are still on study, and 3 patients proceeded to stem cell or bone marrow transplant, Dr Stein said.
Two patients discontinued because of investigator decision, and 8 discontinued therapy due to death or disease progression.
The limitation of the study regarding overall survival, Dr Stein said, is that the number is very small.
At a median follow-up of 7.5 months, the median overall survival was not reached.
“So I’m not arguing that this is the end word of this,” he said. “This is going to be dynamic as more patients come on these studies. But I think it’s a nice indication that this treatment appears to be well-tolerated and doing good for a large subset of patients.”
Co-occurring mutations
The investigators also analyzed co-occurring mutations in 13 MDS patients.
The small patient population prevented the investigators from making definitive conclusions regarding potential correlations between response and co-mutations.
Nevertheless, Dr Stein said the analysis revealed something “very, very intriguing.”
He noted that 7 patients had ASXL1 mutations, and “those are typically patients who are bad actors.”
“Five of those 7 patients had a response,” Dr Stein said. “And of those 5, 3 of them had received a prior hypomethylating agent. I think it’s at least food for thought that you can salvage a patient who has failed a hypomethylating agent, with poor risk disease. I think this is very, very exciting.”
Celgene Corporation and its collaborator, Agios Pharmaceuticals, sponsored the trial.
*Information in the abstract differs from the presentation.
CAR met primary endpoint at interim analysis in DLBCL
2016 ASH Annual Meeting
SAN DIEGO—The chimeric antigen receptor (CAR) T-cell therapy KTE-C19 has met its primary endpoint at the pre-specified interim analysis of the phase 2 ZUMA-1 trial in diffuse large B-cell lymphoma (DLBCL), according to data presented at the 2016 ASH Annual Meeting.
DLBCL patients had an overall response rate (ORR) of 76% and a complete response (CR) rate of 47% (P<0.0001) after 3 months or more of follow-up. And most responses were evident by day 30, the researchers report.
ZUMA-1 is the first multicenter trial of an anti-CD19 CAR T-cell therapy in refractory, aggressive non-Hodgkin lymphoma (NHL).
A second NHL cohort of primary mediastinal B-cell lymphoma or transformed follicular lymphoma (PMBCL/TFL) patients were also treated. Together, the cohorts achieved an ORR of 79% and a CR rate of 52%.
Sattva Neelapu, MD, of The University of Texas MD Anderson Cancer Center in Houston, Texas, presented the results as a late-breaking abstract (LBA-6*).
Detailed results of the PMBCL/TFL cohort were presented separately (abstract 998) at the meeting.
Earlier data from the phase 2 study have been reported in Hematology Times.
Phase 2 interim analysis
The study enrolled 111 patients, all of whom underwent leukapheresis. Seven of these patients were not treated, 5 due to serious adverse events (SAEs), 1 due to unavailable product, and 2 due to non-measurable disease.
“Importantly, there was no bridging therapy allowed on the study,” Dr Neelapu pointed out.
Patients then received a conditioning regimen of cyclophosphamide (500 mg/m2) and fludarabine (30 mg/m2) for 3 days. Two patients experienced SAEs after the conditioning regimen, making it a total of 10 patients who could not be treated.
Two days after the conditioning regimen was completed, investigators dosed 101 patients with KTE-C19 at a target dose of 2 × 106 anti-CD19 CAR T cells/kg.
“The majority of patients that were enrolled on the study were treated,” Dr Neelapu emphasized. “In fact, 91% of the 111 patients enrolled were treated and received the target dose of KTE-C19.”
Dr Neelapu noted that the success rate for manufacturing the CAR T cells was 99%, and the average turnaround time from apheresis to delivery to the clinical site was 17 days.
The study called for a pre-specified interim efficacy analysis when 50 patients in cohort 1—DLBCL patients—had at least 3 months of follow-up. This occurred on August 24, 2016, and the data was analyzed as of that date.
The primary endpoint was ORR of P<0.0001 using an exact binomial test comparing observed ORR to a historical control assumption of 20%. Key secondary endpoints included duration of response, overall survival, safety, and levels of CAR T cells and cytokines.
At the time of the pre-specified interim analysis, 93 patients had at least 1 month of follow-up. Fifty-one patients with DLBCL and 11 patients with PMBCL/TFL had at least 3 months of follow-up.
Patient characteristics
Dr Neelapu reported data on 73 DLBCL patients (cohort 1) and 20 PMBCL/TFL patients (cohort 2) evaluable with at least 1 month of follow-up at the time of the presentation.
The median age of all 93 patients was 59 (range, 25-76), and about half were 60 years or older.
Two-thirds of patients in cohort 1 and three-quarters in cohort 2 were male. Sixty-six percent of cohort 1 and 40% of cohort 2 had an ECOG performance status of 1.
Cohort 1 had a median of 3 prior therapies (range, 1-7), and 44% had an International Prognostic Index (IPI) risk score of 3-4. Cohort 2 had a median of 4 prior therapies (range, 2-12), and 45% had an IPI risk score of 3-4.
Fifty-six DLBCL patients (77%) were refractory to their second or later line of therapy, and 15 (21%) had relapsed after autologous stem cell transplant.
Sixteen PMBCL/TFL patients (80%) were refractory to their second or later line of therapy, and 4 (20%) relapsed after autologous stem cell transplant.
Results
Dr Neelapu indicated that patients responded rapidly to treatment, and most responses were evident at the first tumor assessment.
At 3 months’ follow-up or longer, the ORR was 76% and the CR rate 47% for the 51 DLBCL patients in cohort 1. This was a 6-fold higher CR rate compared with historical outcomes.
For the 11 PMBCL/TFL patients in cohort 2, the ORR was 91% and the CR rate was 73% at 3 months or longer.
Both cohorts combined yielded an ORR of 79% and a CR rate of 52%.
The treatment effect was consistent across key covariates—refractory patients, disease stage, IPI risk score, CD4/CD8 ratio, and steroid and tocilizumab use.
Dr Neelapu described the case of a 62-year-old male with refractory DLBCL who had 4 prior rituximab-based therapies. He had no response to his last 3 therapies combining rituximab with GDP (gemcitabine, cisplatin, and dexamethasone), ICE (ifosfamide, carboplatin, and etoposide), or lenalidomide.
After KTE-C19 therapy, the patient has an ongoing CR that has lasted more than 9 months.
Adverse events
Sixty-eight DLBCL patients (93%) experienced grade 3 or higher adverse events (AEs). These included 10 patients (14%) with cytokine release syndrome (CRS) and 18 (25%) with neurologic events.
Eighteen PMBCL/TFL patients (90%) experienced grade 3 or higher AEs, 2 (10%) with grade 3 or higher CRS and 9 (45%) with grade 3 or higher neurologic events.
CRS and neurological events were generally reversible, Dr Neelapu said. All CRS events resolved except 1 in the PMBCL/TFL cohort.
In both cohorts combined, 38% of patients received tocilizumab, 17% received corticosteroids, and 17% received both.
Three neurological events were ongoing at the data cut-off—grade 1 memory impairment, grade 1 tremor, and grade 2 tremor.
There were no cases of cerebral edema.
Three patients died from causes other than progressive disease—1 DLBCL patient and 2 in the PMBCL/TFL cohort.
Investigators considered the DLBCL patient death (due to hemophagocytic lymphohistiocytosis) and 1 death in the PMBCL/TFL arm (due to cardiac arrest) to be treatment-related.
Investigators did not consider the other death in the PMBCL/TFL arm (due to pulmonary embolism) to be treatment-related.
The most frequent grade 3 or higher treatment-emergent AEs in both arms combined included neutropenia (63%), anemia (42%), leukopenia (40%), febrile neutropenia (29%), thrombocytopenia (26%), encephalopathy (19%), hypophosphatemia (17%), and decreased lymphocyte count (17%).
Peak CAR T-cell expansion occurred between 7 and 14 days and was associated with ongoing CRs and grade 3 or greater neurological events, but not with CRS.
AEs were managed effectively across the 22 study sites, Dr Neelapu added, and most sites had no prior CAR T-cell therapy experience.
Dr Neelapu noted that the ZUMA-1 results are consistent with earlier KTE-C19 trials in aggressive NHL.
The primary analysis for this phase 2 study is expected to occur when all treated patients have 6 months of follow-up in the first quarter of 2017.
The study is sponsored by Kite Pharma but is also funded, in part, by the Leukemia and Lymphoma Society Therapy Acceleration Program.
*Information in the abstract differs from that presented at the meeting.
2016 ASH Annual Meeting
SAN DIEGO—The chimeric antigen receptor (CAR) T-cell therapy KTE-C19 has met its primary endpoint at the pre-specified interim analysis of the phase 2 ZUMA-1 trial in diffuse large B-cell lymphoma (DLBCL), according to data presented at the 2016 ASH Annual Meeting.
DLBCL patients had an overall response rate (ORR) of 76% and a complete response (CR) rate of 47% (P<0.0001) after 3 months or more of follow-up. And most responses were evident by day 30, the researchers report.
ZUMA-1 is the first multicenter trial of an anti-CD19 CAR T-cell therapy in refractory, aggressive non-Hodgkin lymphoma (NHL).
A second NHL cohort of primary mediastinal B-cell lymphoma or transformed follicular lymphoma (PMBCL/TFL) patients were also treated. Together, the cohorts achieved an ORR of 79% and a CR rate of 52%.
Sattva Neelapu, MD, of The University of Texas MD Anderson Cancer Center in Houston, Texas, presented the results as a late-breaking abstract (LBA-6*).
Detailed results of the PMBCL/TFL cohort were presented separately (abstract 998) at the meeting.
Earlier data from the phase 2 study have been reported in Hematology Times.
Phase 2 interim analysis
The study enrolled 111 patients, all of whom underwent leukapheresis. Seven of these patients were not treated, 5 due to serious adverse events (SAEs), 1 due to unavailable product, and 2 due to non-measurable disease.
“Importantly, there was no bridging therapy allowed on the study,” Dr Neelapu pointed out.
Patients then received a conditioning regimen of cyclophosphamide (500 mg/m2) and fludarabine (30 mg/m2) for 3 days. Two patients experienced SAEs after the conditioning regimen, making it a total of 10 patients who could not be treated.
Two days after the conditioning regimen was completed, investigators dosed 101 patients with KTE-C19 at a target dose of 2 × 106 anti-CD19 CAR T cells/kg.
“The majority of patients that were enrolled on the study were treated,” Dr Neelapu emphasized. “In fact, 91% of the 111 patients enrolled were treated and received the target dose of KTE-C19.”
Dr Neelapu noted that the success rate for manufacturing the CAR T cells was 99%, and the average turnaround time from apheresis to delivery to the clinical site was 17 days.
The study called for a pre-specified interim efficacy analysis when 50 patients in cohort 1—DLBCL patients—had at least 3 months of follow-up. This occurred on August 24, 2016, and the data was analyzed as of that date.
The primary endpoint was ORR of P<0.0001 using an exact binomial test comparing observed ORR to a historical control assumption of 20%. Key secondary endpoints included duration of response, overall survival, safety, and levels of CAR T cells and cytokines.
At the time of the pre-specified interim analysis, 93 patients had at least 1 month of follow-up. Fifty-one patients with DLBCL and 11 patients with PMBCL/TFL had at least 3 months of follow-up.
Patient characteristics
Dr Neelapu reported data on 73 DLBCL patients (cohort 1) and 20 PMBCL/TFL patients (cohort 2) evaluable with at least 1 month of follow-up at the time of the presentation.
The median age of all 93 patients was 59 (range, 25-76), and about half were 60 years or older.
Two-thirds of patients in cohort 1 and three-quarters in cohort 2 were male. Sixty-six percent of cohort 1 and 40% of cohort 2 had an ECOG performance status of 1.
Cohort 1 had a median of 3 prior therapies (range, 1-7), and 44% had an International Prognostic Index (IPI) risk score of 3-4. Cohort 2 had a median of 4 prior therapies (range, 2-12), and 45% had an IPI risk score of 3-4.
Fifty-six DLBCL patients (77%) were refractory to their second or later line of therapy, and 15 (21%) had relapsed after autologous stem cell transplant.
Sixteen PMBCL/TFL patients (80%) were refractory to their second or later line of therapy, and 4 (20%) relapsed after autologous stem cell transplant.
Results
Dr Neelapu indicated that patients responded rapidly to treatment, and most responses were evident at the first tumor assessment.
At 3 months’ follow-up or longer, the ORR was 76% and the CR rate 47% for the 51 DLBCL patients in cohort 1. This was a 6-fold higher CR rate compared with historical outcomes.
For the 11 PMBCL/TFL patients in cohort 2, the ORR was 91% and the CR rate was 73% at 3 months or longer.
Both cohorts combined yielded an ORR of 79% and a CR rate of 52%.
The treatment effect was consistent across key covariates—refractory patients, disease stage, IPI risk score, CD4/CD8 ratio, and steroid and tocilizumab use.
Dr Neelapu described the case of a 62-year-old male with refractory DLBCL who had 4 prior rituximab-based therapies. He had no response to his last 3 therapies combining rituximab with GDP (gemcitabine, cisplatin, and dexamethasone), ICE (ifosfamide, carboplatin, and etoposide), or lenalidomide.
After KTE-C19 therapy, the patient has an ongoing CR that has lasted more than 9 months.
Adverse events
Sixty-eight DLBCL patients (93%) experienced grade 3 or higher adverse events (AEs). These included 10 patients (14%) with cytokine release syndrome (CRS) and 18 (25%) with neurologic events.
Eighteen PMBCL/TFL patients (90%) experienced grade 3 or higher AEs, 2 (10%) with grade 3 or higher CRS and 9 (45%) with grade 3 or higher neurologic events.
CRS and neurological events were generally reversible, Dr Neelapu said. All CRS events resolved except 1 in the PMBCL/TFL cohort.
In both cohorts combined, 38% of patients received tocilizumab, 17% received corticosteroids, and 17% received both.
Three neurological events were ongoing at the data cut-off—grade 1 memory impairment, grade 1 tremor, and grade 2 tremor.
There were no cases of cerebral edema.
Three patients died from causes other than progressive disease—1 DLBCL patient and 2 in the PMBCL/TFL cohort.
Investigators considered the DLBCL patient death (due to hemophagocytic lymphohistiocytosis) and 1 death in the PMBCL/TFL arm (due to cardiac arrest) to be treatment-related.
Investigators did not consider the other death in the PMBCL/TFL arm (due to pulmonary embolism) to be treatment-related.
The most frequent grade 3 or higher treatment-emergent AEs in both arms combined included neutropenia (63%), anemia (42%), leukopenia (40%), febrile neutropenia (29%), thrombocytopenia (26%), encephalopathy (19%), hypophosphatemia (17%), and decreased lymphocyte count (17%).
Peak CAR T-cell expansion occurred between 7 and 14 days and was associated with ongoing CRs and grade 3 or greater neurological events, but not with CRS.
AEs were managed effectively across the 22 study sites, Dr Neelapu added, and most sites had no prior CAR T-cell therapy experience.
Dr Neelapu noted that the ZUMA-1 results are consistent with earlier KTE-C19 trials in aggressive NHL.
The primary analysis for this phase 2 study is expected to occur when all treated patients have 6 months of follow-up in the first quarter of 2017.
The study is sponsored by Kite Pharma but is also funded, in part, by the Leukemia and Lymphoma Society Therapy Acceleration Program.
*Information in the abstract differs from that presented at the meeting.
2016 ASH Annual Meeting
SAN DIEGO—The chimeric antigen receptor (CAR) T-cell therapy KTE-C19 has met its primary endpoint at the pre-specified interim analysis of the phase 2 ZUMA-1 trial in diffuse large B-cell lymphoma (DLBCL), according to data presented at the 2016 ASH Annual Meeting.
DLBCL patients had an overall response rate (ORR) of 76% and a complete response (CR) rate of 47% (P<0.0001) after 3 months or more of follow-up. And most responses were evident by day 30, the researchers report.
ZUMA-1 is the first multicenter trial of an anti-CD19 CAR T-cell therapy in refractory, aggressive non-Hodgkin lymphoma (NHL).
A second NHL cohort of primary mediastinal B-cell lymphoma or transformed follicular lymphoma (PMBCL/TFL) patients were also treated. Together, the cohorts achieved an ORR of 79% and a CR rate of 52%.
Sattva Neelapu, MD, of The University of Texas MD Anderson Cancer Center in Houston, Texas, presented the results as a late-breaking abstract (LBA-6*).
Detailed results of the PMBCL/TFL cohort were presented separately (abstract 998) at the meeting.
Earlier data from the phase 2 study have been reported in Hematology Times.
Phase 2 interim analysis
The study enrolled 111 patients, all of whom underwent leukapheresis. Seven of these patients were not treated, 5 due to serious adverse events (SAEs), 1 due to unavailable product, and 2 due to non-measurable disease.
“Importantly, there was no bridging therapy allowed on the study,” Dr Neelapu pointed out.
Patients then received a conditioning regimen of cyclophosphamide (500 mg/m2) and fludarabine (30 mg/m2) for 3 days. Two patients experienced SAEs after the conditioning regimen, making it a total of 10 patients who could not be treated.
Two days after the conditioning regimen was completed, investigators dosed 101 patients with KTE-C19 at a target dose of 2 × 106 anti-CD19 CAR T cells/kg.
“The majority of patients that were enrolled on the study were treated,” Dr Neelapu emphasized. “In fact, 91% of the 111 patients enrolled were treated and received the target dose of KTE-C19.”
Dr Neelapu noted that the success rate for manufacturing the CAR T cells was 99%, and the average turnaround time from apheresis to delivery to the clinical site was 17 days.
The study called for a pre-specified interim efficacy analysis when 50 patients in cohort 1—DLBCL patients—had at least 3 months of follow-up. This occurred on August 24, 2016, and the data was analyzed as of that date.
The primary endpoint was ORR of P<0.0001 using an exact binomial test comparing observed ORR to a historical control assumption of 20%. Key secondary endpoints included duration of response, overall survival, safety, and levels of CAR T cells and cytokines.
At the time of the pre-specified interim analysis, 93 patients had at least 1 month of follow-up. Fifty-one patients with DLBCL and 11 patients with PMBCL/TFL had at least 3 months of follow-up.
Patient characteristics
Dr Neelapu reported data on 73 DLBCL patients (cohort 1) and 20 PMBCL/TFL patients (cohort 2) evaluable with at least 1 month of follow-up at the time of the presentation.
The median age of all 93 patients was 59 (range, 25-76), and about half were 60 years or older.
Two-thirds of patients in cohort 1 and three-quarters in cohort 2 were male. Sixty-six percent of cohort 1 and 40% of cohort 2 had an ECOG performance status of 1.
Cohort 1 had a median of 3 prior therapies (range, 1-7), and 44% had an International Prognostic Index (IPI) risk score of 3-4. Cohort 2 had a median of 4 prior therapies (range, 2-12), and 45% had an IPI risk score of 3-4.
Fifty-six DLBCL patients (77%) were refractory to their second or later line of therapy, and 15 (21%) had relapsed after autologous stem cell transplant.
Sixteen PMBCL/TFL patients (80%) were refractory to their second or later line of therapy, and 4 (20%) relapsed after autologous stem cell transplant.
Results
Dr Neelapu indicated that patients responded rapidly to treatment, and most responses were evident at the first tumor assessment.
At 3 months’ follow-up or longer, the ORR was 76% and the CR rate 47% for the 51 DLBCL patients in cohort 1. This was a 6-fold higher CR rate compared with historical outcomes.
For the 11 PMBCL/TFL patients in cohort 2, the ORR was 91% and the CR rate was 73% at 3 months or longer.
Both cohorts combined yielded an ORR of 79% and a CR rate of 52%.
The treatment effect was consistent across key covariates—refractory patients, disease stage, IPI risk score, CD4/CD8 ratio, and steroid and tocilizumab use.
Dr Neelapu described the case of a 62-year-old male with refractory DLBCL who had 4 prior rituximab-based therapies. He had no response to his last 3 therapies combining rituximab with GDP (gemcitabine, cisplatin, and dexamethasone), ICE (ifosfamide, carboplatin, and etoposide), or lenalidomide.
After KTE-C19 therapy, the patient has an ongoing CR that has lasted more than 9 months.
Adverse events
Sixty-eight DLBCL patients (93%) experienced grade 3 or higher adverse events (AEs). These included 10 patients (14%) with cytokine release syndrome (CRS) and 18 (25%) with neurologic events.
Eighteen PMBCL/TFL patients (90%) experienced grade 3 or higher AEs, 2 (10%) with grade 3 or higher CRS and 9 (45%) with grade 3 or higher neurologic events.
CRS and neurological events were generally reversible, Dr Neelapu said. All CRS events resolved except 1 in the PMBCL/TFL cohort.
In both cohorts combined, 38% of patients received tocilizumab, 17% received corticosteroids, and 17% received both.
Three neurological events were ongoing at the data cut-off—grade 1 memory impairment, grade 1 tremor, and grade 2 tremor.
There were no cases of cerebral edema.
Three patients died from causes other than progressive disease—1 DLBCL patient and 2 in the PMBCL/TFL cohort.
Investigators considered the DLBCL patient death (due to hemophagocytic lymphohistiocytosis) and 1 death in the PMBCL/TFL arm (due to cardiac arrest) to be treatment-related.
Investigators did not consider the other death in the PMBCL/TFL arm (due to pulmonary embolism) to be treatment-related.
The most frequent grade 3 or higher treatment-emergent AEs in both arms combined included neutropenia (63%), anemia (42%), leukopenia (40%), febrile neutropenia (29%), thrombocytopenia (26%), encephalopathy (19%), hypophosphatemia (17%), and decreased lymphocyte count (17%).
Peak CAR T-cell expansion occurred between 7 and 14 days and was associated with ongoing CRs and grade 3 or greater neurological events, but not with CRS.
AEs were managed effectively across the 22 study sites, Dr Neelapu added, and most sites had no prior CAR T-cell therapy experience.
Dr Neelapu noted that the ZUMA-1 results are consistent with earlier KTE-C19 trials in aggressive NHL.
The primary analysis for this phase 2 study is expected to occur when all treated patients have 6 months of follow-up in the first quarter of 2017.
The study is sponsored by Kite Pharma but is also funded, in part, by the Leukemia and Lymphoma Society Therapy Acceleration Program.
*Information in the abstract differs from that presented at the meeting.
‘Unprecedented’ MRD negativity with daratumumab in MM
© Todd Buchanan 2016
SAN DIEGO—Daratumumab added to standard of care regimens drives deep clinical responses beyond complete response (CR), a magnitude that is “unprecedented” in the relapsed/refractory multiple myeloma (MM) setting, according to a speaker at the 2016 ASH Annual Meeting.
Investigators added daratumumab to lenalidomide/dexamethasone in the POLLUX trial and to bortezomib/dexamethasone in the CASTOR trial.
In both phase 3 trials, the addition of daratumumab resulted in significant improvements in progression-free survival (PFS), overall response rate, and minimal residual disease (MRD) negativity when compared to control groups.
“The magnitude of daratumumab-induced MRD negativity in the relapsed setting is unprecedented and, for me, was not expected,” said Hervé Avet-Loiseau, MD, of Centre Hospitalier Universitaire Rangueil, Unité de Genomique du Myelome in Toulouse, France.
Dr Avet-Loiseau presented the MRD findings from CASTOR and POLLUX at the ASH Annual Meeting as abstract 246.*
He noted that, based on these studies, daratumumab received US Food and Drug Administration approvals for use in combination with standard of care regimens for MM patients who had received 1 or more prior lines of treatment.
Daratumumab had been previously approved as monotherapy for relapsed or refractory MM.
Study designs and findings from the POLLUX and CASTOR trials have been described earlier in Hematology Times.
Dr Avet-Loiseau provided updated PFS figures for the 2 studies.
At 18 months’ follow-up in the POLLUX study, the PFS rate for patients treated with daratumumab/lenalidomide/dexamethasone was 76%, compared to 49% in the lenalidomide/dexamethasone arm (P<0.0001).
At 12 months’ follow-up in the CASTOR study, the PFS with daratumumab was 60%, compared to 22% for bortezomib/dexamethasone (P<0.0001).
MRD criteria
In both studies, MRD assessments were conducted at suspected complete response (CR). Assessments were also conducted at 3 months and 6 months after CR in the POLLUX study and at 6 months and 12 months after the first study dose in the CASTOR study.
For the assessment of MRD, investigators used bone marrow aspirate samples and the ClonoSEQTM NGS-based assay.
Investigators evaluated MRD at 3 sensitivity thresholds: 10-4, 10-5, and 10-6.
And they used a stringent, unbiased evaluation, Dr Avet-Loiseau said. Any patient in the intent-to-treat population who was not assessed to be MRD negative was scored as MRD positive.
And the minimum cell input equivalent to the sensitivity threshold was required to determine MRD negativity.
MRD results
In the POLLUX study, 24.8% of patients achieved MRD negativity at the 10-5 cutoff, and 11.9% achieved MRD negativity at the 10-6 cutoff with the daratumumab combination.
This compared to 5.7% and 2.5% MRD negativity at the 10-5 and 10-6 cutoffs, respectively, without daratumumab (P<0.0001).
In the CASTOR study, the daratumumab-treated patients achieved 10.4% and 4.4% MRD negativity at the 10-5 and 10-6 cutoffs, respectively.
This compared to 2.4% and 0.8% MRD negativity in the control arm at the 10-5 and 10-6 cutoffs (P<0.005 and P<0.05), respectively.
“So, definitely, the addition of daratumumab improved the MRD negativity rate in both studies,” Dr Avet-Loiseau said.
“If you just look at the patients who did achieve CR in the POLLUX study, almost 50% of the patients [treated with daratumumab] achieved CR, and half of them were MRD negative at the cutoff of 10-5.”
In the CASTOR study, 25% of the patients treated with daratumumab achieved a CR. The MRD negativity rate was one-third in these patients.
“So again, we have consistently higher MRD negative rates in patients who achieve CR when they were treated in the daratumumab arms,” Dr Avet-Loiseau said.
“What is interesting, I think, is that the achievement of molecular CR was very rapid. [A]t 3 months, some patients did already achieve MRD negativity, and so we continued to see an improvement. [W]e still continue to see some achievement of MRD negativity.”
Investigators continue to follow the patients annually.
The investigators also analyzed MRD at 10-5 by cytogenetic risk and did not observe any MRD negativity in the control arm in either the POLLUX or CASTOR study.
“In contrast, we did observe some significant MRD negativity in the experimental arm with daratumumab—18% (POLLUX) and 14% (CASTOR) in high-risk patients,” Dr Avet-Loiseau said. “The most important prognostic factor is to achieve MRD negativity.”
However, even for patients who did not achieve MRD negativity, the PFS was much better in the experimental arms than in the control arms, he added.
This study, presented as a “Best of ASH” abstract, was funded by Janssen Research & Development, LLC.
*Information in the abstract differs from that presented at the meeting.
© Todd Buchanan 2016
SAN DIEGO—Daratumumab added to standard of care regimens drives deep clinical responses beyond complete response (CR), a magnitude that is “unprecedented” in the relapsed/refractory multiple myeloma (MM) setting, according to a speaker at the 2016 ASH Annual Meeting.
Investigators added daratumumab to lenalidomide/dexamethasone in the POLLUX trial and to bortezomib/dexamethasone in the CASTOR trial.
In both phase 3 trials, the addition of daratumumab resulted in significant improvements in progression-free survival (PFS), overall response rate, and minimal residual disease (MRD) negativity when compared to control groups.
“The magnitude of daratumumab-induced MRD negativity in the relapsed setting is unprecedented and, for me, was not expected,” said Hervé Avet-Loiseau, MD, of Centre Hospitalier Universitaire Rangueil, Unité de Genomique du Myelome in Toulouse, France.
Dr Avet-Loiseau presented the MRD findings from CASTOR and POLLUX at the ASH Annual Meeting as abstract 246.*
He noted that, based on these studies, daratumumab received US Food and Drug Administration approvals for use in combination with standard of care regimens for MM patients who had received 1 or more prior lines of treatment.
Daratumumab had been previously approved as monotherapy for relapsed or refractory MM.
Study designs and findings from the POLLUX and CASTOR trials have been described earlier in Hematology Times.
Dr Avet-Loiseau provided updated PFS figures for the 2 studies.
At 18 months’ follow-up in the POLLUX study, the PFS rate for patients treated with daratumumab/lenalidomide/dexamethasone was 76%, compared to 49% in the lenalidomide/dexamethasone arm (P<0.0001).
At 12 months’ follow-up in the CASTOR study, the PFS with daratumumab was 60%, compared to 22% for bortezomib/dexamethasone (P<0.0001).
MRD criteria
In both studies, MRD assessments were conducted at suspected complete response (CR). Assessments were also conducted at 3 months and 6 months after CR in the POLLUX study and at 6 months and 12 months after the first study dose in the CASTOR study.
For the assessment of MRD, investigators used bone marrow aspirate samples and the ClonoSEQTM NGS-based assay.
Investigators evaluated MRD at 3 sensitivity thresholds: 10-4, 10-5, and 10-6.
And they used a stringent, unbiased evaluation, Dr Avet-Loiseau said. Any patient in the intent-to-treat population who was not assessed to be MRD negative was scored as MRD positive.
And the minimum cell input equivalent to the sensitivity threshold was required to determine MRD negativity.
MRD results
In the POLLUX study, 24.8% of patients achieved MRD negativity at the 10-5 cutoff, and 11.9% achieved MRD negativity at the 10-6 cutoff with the daratumumab combination.
This compared to 5.7% and 2.5% MRD negativity at the 10-5 and 10-6 cutoffs, respectively, without daratumumab (P<0.0001).
In the CASTOR study, the daratumumab-treated patients achieved 10.4% and 4.4% MRD negativity at the 10-5 and 10-6 cutoffs, respectively.
This compared to 2.4% and 0.8% MRD negativity in the control arm at the 10-5 and 10-6 cutoffs (P<0.005 and P<0.05), respectively.
“So, definitely, the addition of daratumumab improved the MRD negativity rate in both studies,” Dr Avet-Loiseau said.
“If you just look at the patients who did achieve CR in the POLLUX study, almost 50% of the patients [treated with daratumumab] achieved CR, and half of them were MRD negative at the cutoff of 10-5.”
In the CASTOR study, 25% of the patients treated with daratumumab achieved a CR. The MRD negativity rate was one-third in these patients.
“So again, we have consistently higher MRD negative rates in patients who achieve CR when they were treated in the daratumumab arms,” Dr Avet-Loiseau said.
“What is interesting, I think, is that the achievement of molecular CR was very rapid. [A]t 3 months, some patients did already achieve MRD negativity, and so we continued to see an improvement. [W]e still continue to see some achievement of MRD negativity.”
Investigators continue to follow the patients annually.
The investigators also analyzed MRD at 10-5 by cytogenetic risk and did not observe any MRD negativity in the control arm in either the POLLUX or CASTOR study.
“In contrast, we did observe some significant MRD negativity in the experimental arm with daratumumab—18% (POLLUX) and 14% (CASTOR) in high-risk patients,” Dr Avet-Loiseau said. “The most important prognostic factor is to achieve MRD negativity.”
However, even for patients who did not achieve MRD negativity, the PFS was much better in the experimental arms than in the control arms, he added.
This study, presented as a “Best of ASH” abstract, was funded by Janssen Research & Development, LLC.
*Information in the abstract differs from that presented at the meeting.
© Todd Buchanan 2016
SAN DIEGO—Daratumumab added to standard of care regimens drives deep clinical responses beyond complete response (CR), a magnitude that is “unprecedented” in the relapsed/refractory multiple myeloma (MM) setting, according to a speaker at the 2016 ASH Annual Meeting.
Investigators added daratumumab to lenalidomide/dexamethasone in the POLLUX trial and to bortezomib/dexamethasone in the CASTOR trial.
In both phase 3 trials, the addition of daratumumab resulted in significant improvements in progression-free survival (PFS), overall response rate, and minimal residual disease (MRD) negativity when compared to control groups.
“The magnitude of daratumumab-induced MRD negativity in the relapsed setting is unprecedented and, for me, was not expected,” said Hervé Avet-Loiseau, MD, of Centre Hospitalier Universitaire Rangueil, Unité de Genomique du Myelome in Toulouse, France.
Dr Avet-Loiseau presented the MRD findings from CASTOR and POLLUX at the ASH Annual Meeting as abstract 246.*
He noted that, based on these studies, daratumumab received US Food and Drug Administration approvals for use in combination with standard of care regimens for MM patients who had received 1 or more prior lines of treatment.
Daratumumab had been previously approved as monotherapy for relapsed or refractory MM.
Study designs and findings from the POLLUX and CASTOR trials have been described earlier in Hematology Times.
Dr Avet-Loiseau provided updated PFS figures for the 2 studies.
At 18 months’ follow-up in the POLLUX study, the PFS rate for patients treated with daratumumab/lenalidomide/dexamethasone was 76%, compared to 49% in the lenalidomide/dexamethasone arm (P<0.0001).
At 12 months’ follow-up in the CASTOR study, the PFS with daratumumab was 60%, compared to 22% for bortezomib/dexamethasone (P<0.0001).
MRD criteria
In both studies, MRD assessments were conducted at suspected complete response (CR). Assessments were also conducted at 3 months and 6 months after CR in the POLLUX study and at 6 months and 12 months after the first study dose in the CASTOR study.
For the assessment of MRD, investigators used bone marrow aspirate samples and the ClonoSEQTM NGS-based assay.
Investigators evaluated MRD at 3 sensitivity thresholds: 10-4, 10-5, and 10-6.
And they used a stringent, unbiased evaluation, Dr Avet-Loiseau said. Any patient in the intent-to-treat population who was not assessed to be MRD negative was scored as MRD positive.
And the minimum cell input equivalent to the sensitivity threshold was required to determine MRD negativity.
MRD results
In the POLLUX study, 24.8% of patients achieved MRD negativity at the 10-5 cutoff, and 11.9% achieved MRD negativity at the 10-6 cutoff with the daratumumab combination.
This compared to 5.7% and 2.5% MRD negativity at the 10-5 and 10-6 cutoffs, respectively, without daratumumab (P<0.0001).
In the CASTOR study, the daratumumab-treated patients achieved 10.4% and 4.4% MRD negativity at the 10-5 and 10-6 cutoffs, respectively.
This compared to 2.4% and 0.8% MRD negativity in the control arm at the 10-5 and 10-6 cutoffs (P<0.005 and P<0.05), respectively.
“So, definitely, the addition of daratumumab improved the MRD negativity rate in both studies,” Dr Avet-Loiseau said.
“If you just look at the patients who did achieve CR in the POLLUX study, almost 50% of the patients [treated with daratumumab] achieved CR, and half of them were MRD negative at the cutoff of 10-5.”
In the CASTOR study, 25% of the patients treated with daratumumab achieved a CR. The MRD negativity rate was one-third in these patients.
“So again, we have consistently higher MRD negative rates in patients who achieve CR when they were treated in the daratumumab arms,” Dr Avet-Loiseau said.
“What is interesting, I think, is that the achievement of molecular CR was very rapid. [A]t 3 months, some patients did already achieve MRD negativity, and so we continued to see an improvement. [W]e still continue to see some achievement of MRD negativity.”
Investigators continue to follow the patients annually.
The investigators also analyzed MRD at 10-5 by cytogenetic risk and did not observe any MRD negativity in the control arm in either the POLLUX or CASTOR study.
“In contrast, we did observe some significant MRD negativity in the experimental arm with daratumumab—18% (POLLUX) and 14% (CASTOR) in high-risk patients,” Dr Avet-Loiseau said. “The most important prognostic factor is to achieve MRD negativity.”
However, even for patients who did not achieve MRD negativity, the PFS was much better in the experimental arms than in the control arms, he added.
This study, presented as a “Best of ASH” abstract, was funded by Janssen Research & Development, LLC.
*Information in the abstract differs from that presented at the meeting.
How old is too old to be on a kids’ protocol for ALL?
Photo by Bill Branson
SAN DIEGO—In recent years, pediatric or pediatric-inspired protocols have become the preferred treatment approach for younger adults with acute lymphoblastic leukemia (ALL).
These protocols include higher doses of steroids, vincristine, methotrexate, and L-asparaginase.
However, the upper age limit for this strategy has not been defined.
With the GRAALL-2005 study, investigators set out to determine how old is too old to be treated on pediatric protocols.
Their results suggest 55 is likely the upper age limit for patients with Ph-negative ALL.
The investigators also evaluated a hyper-fractionated (hyper-C) versus standard dose (standard-C) of cyclophosphamide during induction and late intensification.
They found that hyper-C did not provide an event-free survival (EFS) benefit in the overall study population, but patients age 55 and older did appear to benefit from hyper-C.
Françoise Huguet, MD, of the Institut Universitaire du Cancer de Toulouse in Toulouse, France, presented these findings at the 2016 ASH Annual Meeting (abstract 762).
GRAALL investigators had previously evaluated a pediatric-inspired protocol for adult patients in the GRAALL-2003 study, which validated the approach.
Study design
Patients with newly diagnosed, Ph-negative ALL were eligible to enroll if they were 18 to 59 years of age.
Treatment comprised a steroid pre-phase, a 5-drug induction, two 3-block dose-dense consolidation phases, a late intensification, a third consolidation phase, CNS irradiation, and a 2-year maintenance phase.
Patients could proceed to allogeneic transplant in first complete remission (CR) if eligible.
During induction and late intensification, patients received cyclophosphamide at 750 mg/m2 on day 1 and were then randomized to hyper-C (300 mg/m2/every 12 hours on days 15 to 17) or standard-C (750 mg/m2 on day 15).
The primary endpoint was EFS.
Patient population
Investigators randomized 787 evaluable patients—398 in the standard-C arm and 389 in the hyper-C arm.
Their median age was 36 years, 67% of patients had B-cell precursor ALL, and 33% had T-ALL.
Most had high-risk ALL, 72% of them receiving standard-C and 66% receiving hyper-C.
About a third of the patients in each arm proceeded to allogeneic stem cell transplant in first CR.
Results
The CR rate after induction therapy was 90.2% in the standard-C arm and 93.6% in the hyper-C arm, for an overall CR rate of 92%.
Most patients—87.5% in the standard-C arm and 91.8% in the hyper-C arm—achieved a response in 1 course of therapy.
Sixty percent of patients tested in the standard-C arm and 66% of those tested in the hyper-C arm were minimal residual disease negative at less than 10-4.
There were 26 (6.5%) deaths in the standard-C arm and 18 (4.6%) in the hyper-C arm.
The 5-year EFS rate was 52% overall, and hyper-C treatment had no impact on EFS (hazard ratio=0.89 [range, 0.7-1.1]; P=0.26).
Impact of age
Investigators conducted a post-hoc subgroup analysis of 5 age groups—18-24 years (n=200), 25-34 (n=172), 35-44 (n=171), 45-54 (n=151), and 55+ (n=93).
Overall, the CR rate tended to decrease with age. The rates were 98.5% (18-24), 95.3% (25-34), 87.7% (35-44), 89.4% (45-54), and 79.6% (55+).
Induction death rates increased from 0.5% in the youngest group to 18.3% in the oldest, but the rate of cumulative incidences of failure at 5 years was similar among all the age groups.
The cumulative incidence of treatment-related mortality, without censoring for transplant, ranged from 7.6% in the youngest group to 39.7% in the oldest.
And the 5-year EFS for the youngest patients was 60%, while, for the oldest, it was 26%.
“Above 50 years, the increase in age became highly significant,” Dr Huguet emphasized. “There were fewer CRs and lower survival.”
Treatment compliance
In terms of treatment compliance and median dose received in the induction course, patients aged 55-59 received significantly less L-asparaginase than those aged 18-54 (P<0.001).
During all 3 consolidation phases, patients aged 55-59 received significantly lower median doses of all medications—cytarabine, methotrexate, cyclophosphamide—than patients aged 18-54.
And in late intensification, patients aged 55-59 received significantly lower median doses of vincristine, prednisone, daunorubicin, and hyper-C than all other patients. The median doses of L-asparaginase and standard-C received were lower in the older patients but not significantly so.
EFS by age and randomization
The 5-year EFS for patients aged 18-54 was 57% with hyper-C, compared with 55% in the standard-C arm (P=0.66).
However, for older patients, there was a significant advantage for those receiving hyper-C. The 5-year EFS was 38% with hyper-C, compared to 12% with standard-C (P=0.007).
Dr Huguet explained that inferior compliance in patients 55 and older “might explain why a benefit associated with early hyper-C reinforcement became apparent in these older patients only.”
Dr Huguet concluded that the results “suggest that 55 years is likely to be the upper age limit to tolerate a pediatric-like therapy for younger adults with Ph-negative ALL.”
She added that patients over 54 might benefit from alternative front-line strategies.
Accordingly, investigators are planning to use new agents, such as blinatumomab or inotuzumab ozogamicin, in the next European Working Group on Adult ALL studies.
Photo by Bill Branson
SAN DIEGO—In recent years, pediatric or pediatric-inspired protocols have become the preferred treatment approach for younger adults with acute lymphoblastic leukemia (ALL).
These protocols include higher doses of steroids, vincristine, methotrexate, and L-asparaginase.
However, the upper age limit for this strategy has not been defined.
With the GRAALL-2005 study, investigators set out to determine how old is too old to be treated on pediatric protocols.
Their results suggest 55 is likely the upper age limit for patients with Ph-negative ALL.
The investigators also evaluated a hyper-fractionated (hyper-C) versus standard dose (standard-C) of cyclophosphamide during induction and late intensification.
They found that hyper-C did not provide an event-free survival (EFS) benefit in the overall study population, but patients age 55 and older did appear to benefit from hyper-C.
Françoise Huguet, MD, of the Institut Universitaire du Cancer de Toulouse in Toulouse, France, presented these findings at the 2016 ASH Annual Meeting (abstract 762).
GRAALL investigators had previously evaluated a pediatric-inspired protocol for adult patients in the GRAALL-2003 study, which validated the approach.
Study design
Patients with newly diagnosed, Ph-negative ALL were eligible to enroll if they were 18 to 59 years of age.
Treatment comprised a steroid pre-phase, a 5-drug induction, two 3-block dose-dense consolidation phases, a late intensification, a third consolidation phase, CNS irradiation, and a 2-year maintenance phase.
Patients could proceed to allogeneic transplant in first complete remission (CR) if eligible.
During induction and late intensification, patients received cyclophosphamide at 750 mg/m2 on day 1 and were then randomized to hyper-C (300 mg/m2/every 12 hours on days 15 to 17) or standard-C (750 mg/m2 on day 15).
The primary endpoint was EFS.
Patient population
Investigators randomized 787 evaluable patients—398 in the standard-C arm and 389 in the hyper-C arm.
Their median age was 36 years, 67% of patients had B-cell precursor ALL, and 33% had T-ALL.
Most had high-risk ALL, 72% of them receiving standard-C and 66% receiving hyper-C.
About a third of the patients in each arm proceeded to allogeneic stem cell transplant in first CR.
Results
The CR rate after induction therapy was 90.2% in the standard-C arm and 93.6% in the hyper-C arm, for an overall CR rate of 92%.
Most patients—87.5% in the standard-C arm and 91.8% in the hyper-C arm—achieved a response in 1 course of therapy.
Sixty percent of patients tested in the standard-C arm and 66% of those tested in the hyper-C arm were minimal residual disease negative at less than 10-4.
There were 26 (6.5%) deaths in the standard-C arm and 18 (4.6%) in the hyper-C arm.
The 5-year EFS rate was 52% overall, and hyper-C treatment had no impact on EFS (hazard ratio=0.89 [range, 0.7-1.1]; P=0.26).
Impact of age
Investigators conducted a post-hoc subgroup analysis of 5 age groups—18-24 years (n=200), 25-34 (n=172), 35-44 (n=171), 45-54 (n=151), and 55+ (n=93).
Overall, the CR rate tended to decrease with age. The rates were 98.5% (18-24), 95.3% (25-34), 87.7% (35-44), 89.4% (45-54), and 79.6% (55+).
Induction death rates increased from 0.5% in the youngest group to 18.3% in the oldest, but the rate of cumulative incidences of failure at 5 years was similar among all the age groups.
The cumulative incidence of treatment-related mortality, without censoring for transplant, ranged from 7.6% in the youngest group to 39.7% in the oldest.
And the 5-year EFS for the youngest patients was 60%, while, for the oldest, it was 26%.
“Above 50 years, the increase in age became highly significant,” Dr Huguet emphasized. “There were fewer CRs and lower survival.”
Treatment compliance
In terms of treatment compliance and median dose received in the induction course, patients aged 55-59 received significantly less L-asparaginase than those aged 18-54 (P<0.001).
During all 3 consolidation phases, patients aged 55-59 received significantly lower median doses of all medications—cytarabine, methotrexate, cyclophosphamide—than patients aged 18-54.
And in late intensification, patients aged 55-59 received significantly lower median doses of vincristine, prednisone, daunorubicin, and hyper-C than all other patients. The median doses of L-asparaginase and standard-C received were lower in the older patients but not significantly so.
EFS by age and randomization
The 5-year EFS for patients aged 18-54 was 57% with hyper-C, compared with 55% in the standard-C arm (P=0.66).
However, for older patients, there was a significant advantage for those receiving hyper-C. The 5-year EFS was 38% with hyper-C, compared to 12% with standard-C (P=0.007).
Dr Huguet explained that inferior compliance in patients 55 and older “might explain why a benefit associated with early hyper-C reinforcement became apparent in these older patients only.”
Dr Huguet concluded that the results “suggest that 55 years is likely to be the upper age limit to tolerate a pediatric-like therapy for younger adults with Ph-negative ALL.”
She added that patients over 54 might benefit from alternative front-line strategies.
Accordingly, investigators are planning to use new agents, such as blinatumomab or inotuzumab ozogamicin, in the next European Working Group on Adult ALL studies.
Photo by Bill Branson
SAN DIEGO—In recent years, pediatric or pediatric-inspired protocols have become the preferred treatment approach for younger adults with acute lymphoblastic leukemia (ALL).
These protocols include higher doses of steroids, vincristine, methotrexate, and L-asparaginase.
However, the upper age limit for this strategy has not been defined.
With the GRAALL-2005 study, investigators set out to determine how old is too old to be treated on pediatric protocols.
Their results suggest 55 is likely the upper age limit for patients with Ph-negative ALL.
The investigators also evaluated a hyper-fractionated (hyper-C) versus standard dose (standard-C) of cyclophosphamide during induction and late intensification.
They found that hyper-C did not provide an event-free survival (EFS) benefit in the overall study population, but patients age 55 and older did appear to benefit from hyper-C.
Françoise Huguet, MD, of the Institut Universitaire du Cancer de Toulouse in Toulouse, France, presented these findings at the 2016 ASH Annual Meeting (abstract 762).
GRAALL investigators had previously evaluated a pediatric-inspired protocol for adult patients in the GRAALL-2003 study, which validated the approach.
Study design
Patients with newly diagnosed, Ph-negative ALL were eligible to enroll if they were 18 to 59 years of age.
Treatment comprised a steroid pre-phase, a 5-drug induction, two 3-block dose-dense consolidation phases, a late intensification, a third consolidation phase, CNS irradiation, and a 2-year maintenance phase.
Patients could proceed to allogeneic transplant in first complete remission (CR) if eligible.
During induction and late intensification, patients received cyclophosphamide at 750 mg/m2 on day 1 and were then randomized to hyper-C (300 mg/m2/every 12 hours on days 15 to 17) or standard-C (750 mg/m2 on day 15).
The primary endpoint was EFS.
Patient population
Investigators randomized 787 evaluable patients—398 in the standard-C arm and 389 in the hyper-C arm.
Their median age was 36 years, 67% of patients had B-cell precursor ALL, and 33% had T-ALL.
Most had high-risk ALL, 72% of them receiving standard-C and 66% receiving hyper-C.
About a third of the patients in each arm proceeded to allogeneic stem cell transplant in first CR.
Results
The CR rate after induction therapy was 90.2% in the standard-C arm and 93.6% in the hyper-C arm, for an overall CR rate of 92%.
Most patients—87.5% in the standard-C arm and 91.8% in the hyper-C arm—achieved a response in 1 course of therapy.
Sixty percent of patients tested in the standard-C arm and 66% of those tested in the hyper-C arm were minimal residual disease negative at less than 10-4.
There were 26 (6.5%) deaths in the standard-C arm and 18 (4.6%) in the hyper-C arm.
The 5-year EFS rate was 52% overall, and hyper-C treatment had no impact on EFS (hazard ratio=0.89 [range, 0.7-1.1]; P=0.26).
Impact of age
Investigators conducted a post-hoc subgroup analysis of 5 age groups—18-24 years (n=200), 25-34 (n=172), 35-44 (n=171), 45-54 (n=151), and 55+ (n=93).
Overall, the CR rate tended to decrease with age. The rates were 98.5% (18-24), 95.3% (25-34), 87.7% (35-44), 89.4% (45-54), and 79.6% (55+).
Induction death rates increased from 0.5% in the youngest group to 18.3% in the oldest, but the rate of cumulative incidences of failure at 5 years was similar among all the age groups.
The cumulative incidence of treatment-related mortality, without censoring for transplant, ranged from 7.6% in the youngest group to 39.7% in the oldest.
And the 5-year EFS for the youngest patients was 60%, while, for the oldest, it was 26%.
“Above 50 years, the increase in age became highly significant,” Dr Huguet emphasized. “There were fewer CRs and lower survival.”
Treatment compliance
In terms of treatment compliance and median dose received in the induction course, patients aged 55-59 received significantly less L-asparaginase than those aged 18-54 (P<0.001).
During all 3 consolidation phases, patients aged 55-59 received significantly lower median doses of all medications—cytarabine, methotrexate, cyclophosphamide—than patients aged 18-54.
And in late intensification, patients aged 55-59 received significantly lower median doses of vincristine, prednisone, daunorubicin, and hyper-C than all other patients. The median doses of L-asparaginase and standard-C received were lower in the older patients but not significantly so.
EFS by age and randomization
The 5-year EFS for patients aged 18-54 was 57% with hyper-C, compared with 55% in the standard-C arm (P=0.66).
However, for older patients, there was a significant advantage for those receiving hyper-C. The 5-year EFS was 38% with hyper-C, compared to 12% with standard-C (P=0.007).
Dr Huguet explained that inferior compliance in patients 55 and older “might explain why a benefit associated with early hyper-C reinforcement became apparent in these older patients only.”
Dr Huguet concluded that the results “suggest that 55 years is likely to be the upper age limit to tolerate a pediatric-like therapy for younger adults with Ph-negative ALL.”
She added that patients over 54 might benefit from alternative front-line strategies.
Accordingly, investigators are planning to use new agents, such as blinatumomab or inotuzumab ozogamicin, in the next European Working Group on Adult ALL studies.
Another treatment on the horizon for SCD
Photo courtesy of ASH
SAN DIEGO—The first-in-class humanized anti-P-selectin antibody SelG1, also known as crizanlizumab, significantly reduced sickle cell pain crises (SCPC) when compared to placebo in the phase 2 SUSTAIN trial.
The higher dose of SelG1 tested reduced the annual rate of SCPC by 45% (P=0.01) and the annual rate of uncomplicated SCPC by 63% (P=0.015).
Acute painful crises are the primary cause for patients with sickle cell disease (SCD) to seek medical attention.
Kenneth I. Ataga, MD, of the University of North Carolina at Chapel Hill, explained that upregulation of P-selectin on endothelial cells and platelets contributes to the cell-cell interaction involved in the pathogenesis of SCPC. SelG1 binds to P-selectin and inhibits its interaction with P-selectin glycoprotein ligand 1.
Dr Ataga presented results from the SUSTAIN study during the plenary session of the 2016 ASH Annual Meeting (abstract 1).
The study was also published in NEJM. The research was sponsored by Selexys Pharmaceuticals Corporation, which was recently acquired by Novartis.
Patient population
A total of 198 patients were randomized, 67 to high-dose SelG1 (5.0 mg/kg), 66 to low-dose SelG1 (2.5 mg/kg), and 65 to placebo.
They received a loading dose in the first 2 weeks of treatment, followed by monthly dosing for a year.
Patients had to have a diagnosis of SCD, including genotypes HbSS, HbSC, HbSb0-thalassemia, or HbSB+-thalassemia.
They had to have at least 2 but not more than 10 acute sickle-related pain events within 12 months of study entry.
Patients ranged in age from 16 to 57 years, about 70% had HbSS, and 60% were on concomitant hydroxyurea therapy.
Patients not already receiving hydroxyurea were not permitted to start it during the study. And patients could not be on chronic transfusion therapy.
Study endpoints
The primary endpoint was the annual rate of adjudicated SCPC.
“Painful crisis was defined as an active episode of pain, and it was felt to be related to sickle cell disease-specific events and no other medically defined causes,” Dr Ataga explained.
The pain episodes also had to result in a visit to a medical facility and require treatment with parenteral or oral narcotics or parenteral nonsteroidal anti-inflammatory drugs.
The definition of SCPC included not only typical painful episodes but also acute chest syndrome (ACS), hepatic or splenic sequestration, and priapism.
Secondary endpoints included the annual rate of days hospitalized, time to first and second SCPC, the annual rate of uncomplicated pain crises, and the annual rate of ACS, among others.
Efficacy
The median annual rate of SCPC was 1.63 in the high-dose arm, 2.01 in the low-dose arm, and 2.98 in the placebo arm, amounting to a significant 45.3% reduction with the higher dose of SelG1 compared to placebo. The low dose resulted in a reduction of 32.6% compared to placebo, but this was not significant.
Twenty-four patients in the high-dose arm had an SCPC rate of 0, compared with 12 in the low-dose arm and 11 on placebo.
SCD genotype or concomitant hydroxyurea use did not impact these results.
Patients in the high-dose arm had a median annual rate of 4 hospitalization days, compared with 6.87 in both the low-dose and placebo groups. The difference was not significant, although the reduction in the high-dose arm was 41.8%.
The median annual rate of uncomplicated SCPC was 1.08 in the high-dose arm, 2.00 in the low-dose arm, and 2.91 in the placebo arm. Uncomplicated SCPC excluded ACS, splenic or hepatic sequestration, and priapism.
The reduction in the high-dose arm compared to placebo was significant, at 62.9% (P=0.015).
“The rate of ACS was pretty rare,” Dr Ataga said, “so the median rate across the various groups was 0.”
And time to the first SCPC was 4.1 months (P=0.001) in the high-dose group, 2.2 months (P=0.136) in the low-dose group, and 1.4 months in the placebo group.
“The curves separated pretty early,” Dr Ataga noted, “and were maintained throughout the course of the treatment phase, suggesting that the beneficial effect of SelG1 manifested pretty early following initiation of treatment.”
The time to second event was also significant in the high-dose arm compared to placebo, at 10.3 months and 5.1 months, respectively (P=0.022).
Safety
One or more adverse events occurred in over 85% of patients in each group.
Adverse events that occurred in at least 10% of SelG1-treated patients and amounted to at least double the number in the placebo group were arthralgia, diarrhea, pruritus, vomiting, and chest pain.
Five patients died while on study, but none of these deaths were related to the study drug.
Despite the adverse events, Dr Ataga said the drug was, overall, well-tolerated among the patients who received treatment.
Photo courtesy of ASH
SAN DIEGO—The first-in-class humanized anti-P-selectin antibody SelG1, also known as crizanlizumab, significantly reduced sickle cell pain crises (SCPC) when compared to placebo in the phase 2 SUSTAIN trial.
The higher dose of SelG1 tested reduced the annual rate of SCPC by 45% (P=0.01) and the annual rate of uncomplicated SCPC by 63% (P=0.015).
Acute painful crises are the primary cause for patients with sickle cell disease (SCD) to seek medical attention.
Kenneth I. Ataga, MD, of the University of North Carolina at Chapel Hill, explained that upregulation of P-selectin on endothelial cells and platelets contributes to the cell-cell interaction involved in the pathogenesis of SCPC. SelG1 binds to P-selectin and inhibits its interaction with P-selectin glycoprotein ligand 1.
Dr Ataga presented results from the SUSTAIN study during the plenary session of the 2016 ASH Annual Meeting (abstract 1).
The study was also published in NEJM. The research was sponsored by Selexys Pharmaceuticals Corporation, which was recently acquired by Novartis.
Patient population
A total of 198 patients were randomized, 67 to high-dose SelG1 (5.0 mg/kg), 66 to low-dose SelG1 (2.5 mg/kg), and 65 to placebo.
They received a loading dose in the first 2 weeks of treatment, followed by monthly dosing for a year.
Patients had to have a diagnosis of SCD, including genotypes HbSS, HbSC, HbSb0-thalassemia, or HbSB+-thalassemia.
They had to have at least 2 but not more than 10 acute sickle-related pain events within 12 months of study entry.
Patients ranged in age from 16 to 57 years, about 70% had HbSS, and 60% were on concomitant hydroxyurea therapy.
Patients not already receiving hydroxyurea were not permitted to start it during the study. And patients could not be on chronic transfusion therapy.
Study endpoints
The primary endpoint was the annual rate of adjudicated SCPC.
“Painful crisis was defined as an active episode of pain, and it was felt to be related to sickle cell disease-specific events and no other medically defined causes,” Dr Ataga explained.
The pain episodes also had to result in a visit to a medical facility and require treatment with parenteral or oral narcotics or parenteral nonsteroidal anti-inflammatory drugs.
The definition of SCPC included not only typical painful episodes but also acute chest syndrome (ACS), hepatic or splenic sequestration, and priapism.
Secondary endpoints included the annual rate of days hospitalized, time to first and second SCPC, the annual rate of uncomplicated pain crises, and the annual rate of ACS, among others.
Efficacy
The median annual rate of SCPC was 1.63 in the high-dose arm, 2.01 in the low-dose arm, and 2.98 in the placebo arm, amounting to a significant 45.3% reduction with the higher dose of SelG1 compared to placebo. The low dose resulted in a reduction of 32.6% compared to placebo, but this was not significant.
Twenty-four patients in the high-dose arm had an SCPC rate of 0, compared with 12 in the low-dose arm and 11 on placebo.
SCD genotype or concomitant hydroxyurea use did not impact these results.
Patients in the high-dose arm had a median annual rate of 4 hospitalization days, compared with 6.87 in both the low-dose and placebo groups. The difference was not significant, although the reduction in the high-dose arm was 41.8%.
The median annual rate of uncomplicated SCPC was 1.08 in the high-dose arm, 2.00 in the low-dose arm, and 2.91 in the placebo arm. Uncomplicated SCPC excluded ACS, splenic or hepatic sequestration, and priapism.
The reduction in the high-dose arm compared to placebo was significant, at 62.9% (P=0.015).
“The rate of ACS was pretty rare,” Dr Ataga said, “so the median rate across the various groups was 0.”
And time to the first SCPC was 4.1 months (P=0.001) in the high-dose group, 2.2 months (P=0.136) in the low-dose group, and 1.4 months in the placebo group.
“The curves separated pretty early,” Dr Ataga noted, “and were maintained throughout the course of the treatment phase, suggesting that the beneficial effect of SelG1 manifested pretty early following initiation of treatment.”
The time to second event was also significant in the high-dose arm compared to placebo, at 10.3 months and 5.1 months, respectively (P=0.022).
Safety
One or more adverse events occurred in over 85% of patients in each group.
Adverse events that occurred in at least 10% of SelG1-treated patients and amounted to at least double the number in the placebo group were arthralgia, diarrhea, pruritus, vomiting, and chest pain.
Five patients died while on study, but none of these deaths were related to the study drug.
Despite the adverse events, Dr Ataga said the drug was, overall, well-tolerated among the patients who received treatment.
Photo courtesy of ASH
SAN DIEGO—The first-in-class humanized anti-P-selectin antibody SelG1, also known as crizanlizumab, significantly reduced sickle cell pain crises (SCPC) when compared to placebo in the phase 2 SUSTAIN trial.
The higher dose of SelG1 tested reduced the annual rate of SCPC by 45% (P=0.01) and the annual rate of uncomplicated SCPC by 63% (P=0.015).
Acute painful crises are the primary cause for patients with sickle cell disease (SCD) to seek medical attention.
Kenneth I. Ataga, MD, of the University of North Carolina at Chapel Hill, explained that upregulation of P-selectin on endothelial cells and platelets contributes to the cell-cell interaction involved in the pathogenesis of SCPC. SelG1 binds to P-selectin and inhibits its interaction with P-selectin glycoprotein ligand 1.
Dr Ataga presented results from the SUSTAIN study during the plenary session of the 2016 ASH Annual Meeting (abstract 1).
The study was also published in NEJM. The research was sponsored by Selexys Pharmaceuticals Corporation, which was recently acquired by Novartis.
Patient population
A total of 198 patients were randomized, 67 to high-dose SelG1 (5.0 mg/kg), 66 to low-dose SelG1 (2.5 mg/kg), and 65 to placebo.
They received a loading dose in the first 2 weeks of treatment, followed by monthly dosing for a year.
Patients had to have a diagnosis of SCD, including genotypes HbSS, HbSC, HbSb0-thalassemia, or HbSB+-thalassemia.
They had to have at least 2 but not more than 10 acute sickle-related pain events within 12 months of study entry.
Patients ranged in age from 16 to 57 years, about 70% had HbSS, and 60% were on concomitant hydroxyurea therapy.
Patients not already receiving hydroxyurea were not permitted to start it during the study. And patients could not be on chronic transfusion therapy.
Study endpoints
The primary endpoint was the annual rate of adjudicated SCPC.
“Painful crisis was defined as an active episode of pain, and it was felt to be related to sickle cell disease-specific events and no other medically defined causes,” Dr Ataga explained.
The pain episodes also had to result in a visit to a medical facility and require treatment with parenteral or oral narcotics or parenteral nonsteroidal anti-inflammatory drugs.
The definition of SCPC included not only typical painful episodes but also acute chest syndrome (ACS), hepatic or splenic sequestration, and priapism.
Secondary endpoints included the annual rate of days hospitalized, time to first and second SCPC, the annual rate of uncomplicated pain crises, and the annual rate of ACS, among others.
Efficacy
The median annual rate of SCPC was 1.63 in the high-dose arm, 2.01 in the low-dose arm, and 2.98 in the placebo arm, amounting to a significant 45.3% reduction with the higher dose of SelG1 compared to placebo. The low dose resulted in a reduction of 32.6% compared to placebo, but this was not significant.
Twenty-four patients in the high-dose arm had an SCPC rate of 0, compared with 12 in the low-dose arm and 11 on placebo.
SCD genotype or concomitant hydroxyurea use did not impact these results.
Patients in the high-dose arm had a median annual rate of 4 hospitalization days, compared with 6.87 in both the low-dose and placebo groups. The difference was not significant, although the reduction in the high-dose arm was 41.8%.
The median annual rate of uncomplicated SCPC was 1.08 in the high-dose arm, 2.00 in the low-dose arm, and 2.91 in the placebo arm. Uncomplicated SCPC excluded ACS, splenic or hepatic sequestration, and priapism.
The reduction in the high-dose arm compared to placebo was significant, at 62.9% (P=0.015).
“The rate of ACS was pretty rare,” Dr Ataga said, “so the median rate across the various groups was 0.”
And time to the first SCPC was 4.1 months (P=0.001) in the high-dose group, 2.2 months (P=0.136) in the low-dose group, and 1.4 months in the placebo group.
“The curves separated pretty early,” Dr Ataga noted, “and were maintained throughout the course of the treatment phase, suggesting that the beneficial effect of SelG1 manifested pretty early following initiation of treatment.”
The time to second event was also significant in the high-dose arm compared to placebo, at 10.3 months and 5.1 months, respectively (P=0.022).
Safety
One or more adverse events occurred in over 85% of patients in each group.
Adverse events that occurred in at least 10% of SelG1-treated patients and amounted to at least double the number in the placebo group were arthralgia, diarrhea, pruritus, vomiting, and chest pain.
Five patients died while on study, but none of these deaths were related to the study drug.
Despite the adverse events, Dr Ataga said the drug was, overall, well-tolerated among the patients who received treatment.
Potential treatment for cGVHD after steroid failure
2016 ASH Annual Meeting
SAN DIEGO—Ibrutinib, a Bruton’s tyrosine kinase inhibitor approved to treat chronic lymphocytic leukemia and other hematologic diseases, appears to provide relief for patients suffering from chronic graft-versus-host disease (cGVHD) after failing corticosteroid therapy.
At present, no approved therapy exists for these patients. Ibrutinib reduced the severity of cGVHD in preclinical models and has been used successfully in the post-allogeneic transplant setting.
The US Food and Drug Administration granted ibrutinib breakthrough therapy and orphan drug designations as a potential treatment for cGVHD.
David Miklos, MD, of Stanford University in California, explained at the 2016 ASH Annual Meeting that, in cGVHD, healthy B cells have been corrupted to produce self-reactive antibody complexes, and the T cells are killing healthy tissues and cells.
This destructive process involves the Bruton’s tyrosine kinase molecule, which can be inhibited and thereby block some of the downstream cGVHD pathogenesis.
“And to this aim, we went about testing the benefits of ibrutinib in the treatment of steroid-refractory chronic graft-versus-host disease,” Dr Miklos said.
In phase 1 of the study, investigators tested the 420 mg oral once-daily dose. They found no dose-limiting toxicities.
“So this dose was carried forward into the phase 2 study,” Dr Miklos said.
He presented results of the phase 2 study at the meeting as a late-breaking abstract (LBA-3).
Study design
Patients were eligible for the study if they had steroid-dependent or -refractory cGVHD. They had to have 3 or fewer prior treatments, and they could continue other systemic immunosuppression if they were using it.
They had to have erythematous rash on more than 25% of their body surface or a total mouth score of more than 4 as defined by National Institutes of Health (NIH) criteria.
Patients with cGVHD had to have failed frontline therapy.
They were treated with the phase 1 dose until progression of cGVHD or unacceptable toxicity.
The primary endpoint was cGVHD response per NIH 2005 response criteria.
Secondary endpoints included rate of sustained response, change in Lee cGVHD symptom scale, changes in corticosteroid requirement over time, and safety endpoints.
Investigators enrolled 42 patients, the first of whom was dosed in July 2014.
Patient demographics
Patients were a median age of 56 (range, 19–74), and 52% were male.
The median time from allogeneic transplant to the diagnosis of cGVHD was 7.6 months (range, 1.5–76.0), and the median time from initial cGVHD diagnosis to start of ibrutinib therapy was 13.7 months (range, 1.1–63.2).
Most patients had mouth (86%), skin (81%), or gastrointestinal (33%) cGVHD involvement.
And most patients had received matched (88%), unrelated (60%), nonmyeloablative (57%) peripheral blood stem cell (88%) transplants.
“This was a heavily treated patient population,” Dr Miklos said.
They had received a median of 2 (range, 1–3) prior regimens, with a median prednisone dose at enrollment of 0.3 mg/kg/day.
Prior cGVHD therapies included corticosteroids (100%), tacrolimus (50%), extracorporeal photopheresis (33%), rituximab (26%), mycophenolate mofetil (24%), cyclosporine (19%), sirolimus (17%), and other immunosuppressants (5%).
Results
The overall response rate was 67%, including 9 complete responses and 19 partial responses. Seventy-nine percent responded by the first assessment, and 71% of the 28 responders had a sustained cGVHD response of at least 5 months.
Investigators observed responses across multiple organs. Eighty percent (20/25) of patients with at least 2 involved organs at baseline responded in at least 2 organs, and 56% (5/9) of patients with 3 or more involved organs at baseline responded in at least 3 organs.
“These responses seen across all organs and in multiple organs suggest that the ibrutinib is actually targeting the underlying process of chronic GVHD and not simply masking the symptoms of chronic GVHD,” Dr Miklos noted.
Median corticosteroid use decreased throughout the ibrutinib treatment period. Twenty-six patients (62%) reduced steroid doses to less than 0.15/mg/kg/day while on ibrutinib.
Five responders discontinued all corticosteroid treatment.
Dr Miklos pointed out that baseline steroid dose did not vary between those patients who had responses and those who did not.
And ibrutinib produced clinically meaning improvement in the Lee symptom scale score among patients who responded.
Discontinuation and toxicity
At a median follow-up of 14 months, 12 patients were still on ibrutinib therapy.
“Only 5 patients discontinued for the progression of chronic GVHD,” Dr Miklos noted.
Other reasons for discontinuation included adverse events (AEs, n=14), patient decision (n=6), investigator decision (n=2), recurrence or progression of original malignancy (n=2), and noncompliance with study drug (n=1).
“The AE profile largely reflects what has been seen with ibrutinib use in the patients being treated for malignancies,” Dr Miklos said. “They also reflect adverse events that we see in patients receiving corticosteroids for the treatment of chronic GVHD.”
Treatment-emergent AEs occurring in more than 15% of patients included fatigue, diarrhea, muscle spasms, nausea, bruising, upper respiratory tract infection, pneumonia, pyrexia, headache, and fall.
Serious AEs occurred in 22 patients (52%), including pneumonia (n=6), septic shock (n=2), and pyrexia (n=2).
Two patients died while on study due to multilobular pneumonia and bronchopulmonary aspergillosis.
Exploratory endpoints
Investigators measured plasma levels of various factors following ibrutinib therapy through the first 90 days. Proinflammatory, chemotactic, and fibrotic factors decreased significantly while patients were on ibrutinib.
“This indicates that the cellular inflammation, the immune recruitment, and the fibrosis at the root of chronic GVHD was improving,” Dr Mikos said.
These factors included IFNγ, TNFα, IP-10, and CXCL9—biomarkers associated with cGVHD.
“We believe the efficacy of ibrutinib in this population supports further study in frontline treatment of chronic GVHD in a randomized, double-blinded study,” Dr Miklos concluded.
The current study was sponsored by Pharmacyclics, Inc.
2016 ASH Annual Meeting
SAN DIEGO—Ibrutinib, a Bruton’s tyrosine kinase inhibitor approved to treat chronic lymphocytic leukemia and other hematologic diseases, appears to provide relief for patients suffering from chronic graft-versus-host disease (cGVHD) after failing corticosteroid therapy.
At present, no approved therapy exists for these patients. Ibrutinib reduced the severity of cGVHD in preclinical models and has been used successfully in the post-allogeneic transplant setting.
The US Food and Drug Administration granted ibrutinib breakthrough therapy and orphan drug designations as a potential treatment for cGVHD.
David Miklos, MD, of Stanford University in California, explained at the 2016 ASH Annual Meeting that, in cGVHD, healthy B cells have been corrupted to produce self-reactive antibody complexes, and the T cells are killing healthy tissues and cells.
This destructive process involves the Bruton’s tyrosine kinase molecule, which can be inhibited and thereby block some of the downstream cGVHD pathogenesis.
“And to this aim, we went about testing the benefits of ibrutinib in the treatment of steroid-refractory chronic graft-versus-host disease,” Dr Miklos said.
In phase 1 of the study, investigators tested the 420 mg oral once-daily dose. They found no dose-limiting toxicities.
“So this dose was carried forward into the phase 2 study,” Dr Miklos said.
He presented results of the phase 2 study at the meeting as a late-breaking abstract (LBA-3).
Study design
Patients were eligible for the study if they had steroid-dependent or -refractory cGVHD. They had to have 3 or fewer prior treatments, and they could continue other systemic immunosuppression if they were using it.
They had to have erythematous rash on more than 25% of their body surface or a total mouth score of more than 4 as defined by National Institutes of Health (NIH) criteria.
Patients with cGVHD had to have failed frontline therapy.
They were treated with the phase 1 dose until progression of cGVHD or unacceptable toxicity.
The primary endpoint was cGVHD response per NIH 2005 response criteria.
Secondary endpoints included rate of sustained response, change in Lee cGVHD symptom scale, changes in corticosteroid requirement over time, and safety endpoints.
Investigators enrolled 42 patients, the first of whom was dosed in July 2014.
Patient demographics
Patients were a median age of 56 (range, 19–74), and 52% were male.
The median time from allogeneic transplant to the diagnosis of cGVHD was 7.6 months (range, 1.5–76.0), and the median time from initial cGVHD diagnosis to start of ibrutinib therapy was 13.7 months (range, 1.1–63.2).
Most patients had mouth (86%), skin (81%), or gastrointestinal (33%) cGVHD involvement.
And most patients had received matched (88%), unrelated (60%), nonmyeloablative (57%) peripheral blood stem cell (88%) transplants.
“This was a heavily treated patient population,” Dr Miklos said.
They had received a median of 2 (range, 1–3) prior regimens, with a median prednisone dose at enrollment of 0.3 mg/kg/day.
Prior cGVHD therapies included corticosteroids (100%), tacrolimus (50%), extracorporeal photopheresis (33%), rituximab (26%), mycophenolate mofetil (24%), cyclosporine (19%), sirolimus (17%), and other immunosuppressants (5%).
Results
The overall response rate was 67%, including 9 complete responses and 19 partial responses. Seventy-nine percent responded by the first assessment, and 71% of the 28 responders had a sustained cGVHD response of at least 5 months.
Investigators observed responses across multiple organs. Eighty percent (20/25) of patients with at least 2 involved organs at baseline responded in at least 2 organs, and 56% (5/9) of patients with 3 or more involved organs at baseline responded in at least 3 organs.
“These responses seen across all organs and in multiple organs suggest that the ibrutinib is actually targeting the underlying process of chronic GVHD and not simply masking the symptoms of chronic GVHD,” Dr Miklos noted.
Median corticosteroid use decreased throughout the ibrutinib treatment period. Twenty-six patients (62%) reduced steroid doses to less than 0.15/mg/kg/day while on ibrutinib.
Five responders discontinued all corticosteroid treatment.
Dr Miklos pointed out that baseline steroid dose did not vary between those patients who had responses and those who did not.
And ibrutinib produced clinically meaning improvement in the Lee symptom scale score among patients who responded.
Discontinuation and toxicity
At a median follow-up of 14 months, 12 patients were still on ibrutinib therapy.
“Only 5 patients discontinued for the progression of chronic GVHD,” Dr Miklos noted.
Other reasons for discontinuation included adverse events (AEs, n=14), patient decision (n=6), investigator decision (n=2), recurrence or progression of original malignancy (n=2), and noncompliance with study drug (n=1).
“The AE profile largely reflects what has been seen with ibrutinib use in the patients being treated for malignancies,” Dr Miklos said. “They also reflect adverse events that we see in patients receiving corticosteroids for the treatment of chronic GVHD.”
Treatment-emergent AEs occurring in more than 15% of patients included fatigue, diarrhea, muscle spasms, nausea, bruising, upper respiratory tract infection, pneumonia, pyrexia, headache, and fall.
Serious AEs occurred in 22 patients (52%), including pneumonia (n=6), septic shock (n=2), and pyrexia (n=2).
Two patients died while on study due to multilobular pneumonia and bronchopulmonary aspergillosis.
Exploratory endpoints
Investigators measured plasma levels of various factors following ibrutinib therapy through the first 90 days. Proinflammatory, chemotactic, and fibrotic factors decreased significantly while patients were on ibrutinib.
“This indicates that the cellular inflammation, the immune recruitment, and the fibrosis at the root of chronic GVHD was improving,” Dr Mikos said.
These factors included IFNγ, TNFα, IP-10, and CXCL9—biomarkers associated with cGVHD.
“We believe the efficacy of ibrutinib in this population supports further study in frontline treatment of chronic GVHD in a randomized, double-blinded study,” Dr Miklos concluded.
The current study was sponsored by Pharmacyclics, Inc.
2016 ASH Annual Meeting
SAN DIEGO—Ibrutinib, a Bruton’s tyrosine kinase inhibitor approved to treat chronic lymphocytic leukemia and other hematologic diseases, appears to provide relief for patients suffering from chronic graft-versus-host disease (cGVHD) after failing corticosteroid therapy.
At present, no approved therapy exists for these patients. Ibrutinib reduced the severity of cGVHD in preclinical models and has been used successfully in the post-allogeneic transplant setting.
The US Food and Drug Administration granted ibrutinib breakthrough therapy and orphan drug designations as a potential treatment for cGVHD.
David Miklos, MD, of Stanford University in California, explained at the 2016 ASH Annual Meeting that, in cGVHD, healthy B cells have been corrupted to produce self-reactive antibody complexes, and the T cells are killing healthy tissues and cells.
This destructive process involves the Bruton’s tyrosine kinase molecule, which can be inhibited and thereby block some of the downstream cGVHD pathogenesis.
“And to this aim, we went about testing the benefits of ibrutinib in the treatment of steroid-refractory chronic graft-versus-host disease,” Dr Miklos said.
In phase 1 of the study, investigators tested the 420 mg oral once-daily dose. They found no dose-limiting toxicities.
“So this dose was carried forward into the phase 2 study,” Dr Miklos said.
He presented results of the phase 2 study at the meeting as a late-breaking abstract (LBA-3).
Study design
Patients were eligible for the study if they had steroid-dependent or -refractory cGVHD. They had to have 3 or fewer prior treatments, and they could continue other systemic immunosuppression if they were using it.
They had to have erythematous rash on more than 25% of their body surface or a total mouth score of more than 4 as defined by National Institutes of Health (NIH) criteria.
Patients with cGVHD had to have failed frontline therapy.
They were treated with the phase 1 dose until progression of cGVHD or unacceptable toxicity.
The primary endpoint was cGVHD response per NIH 2005 response criteria.
Secondary endpoints included rate of sustained response, change in Lee cGVHD symptom scale, changes in corticosteroid requirement over time, and safety endpoints.
Investigators enrolled 42 patients, the first of whom was dosed in July 2014.
Patient demographics
Patients were a median age of 56 (range, 19–74), and 52% were male.
The median time from allogeneic transplant to the diagnosis of cGVHD was 7.6 months (range, 1.5–76.0), and the median time from initial cGVHD diagnosis to start of ibrutinib therapy was 13.7 months (range, 1.1–63.2).
Most patients had mouth (86%), skin (81%), or gastrointestinal (33%) cGVHD involvement.
And most patients had received matched (88%), unrelated (60%), nonmyeloablative (57%) peripheral blood stem cell (88%) transplants.
“This was a heavily treated patient population,” Dr Miklos said.
They had received a median of 2 (range, 1–3) prior regimens, with a median prednisone dose at enrollment of 0.3 mg/kg/day.
Prior cGVHD therapies included corticosteroids (100%), tacrolimus (50%), extracorporeal photopheresis (33%), rituximab (26%), mycophenolate mofetil (24%), cyclosporine (19%), sirolimus (17%), and other immunosuppressants (5%).
Results
The overall response rate was 67%, including 9 complete responses and 19 partial responses. Seventy-nine percent responded by the first assessment, and 71% of the 28 responders had a sustained cGVHD response of at least 5 months.
Investigators observed responses across multiple organs. Eighty percent (20/25) of patients with at least 2 involved organs at baseline responded in at least 2 organs, and 56% (5/9) of patients with 3 or more involved organs at baseline responded in at least 3 organs.
“These responses seen across all organs and in multiple organs suggest that the ibrutinib is actually targeting the underlying process of chronic GVHD and not simply masking the symptoms of chronic GVHD,” Dr Miklos noted.
Median corticosteroid use decreased throughout the ibrutinib treatment period. Twenty-six patients (62%) reduced steroid doses to less than 0.15/mg/kg/day while on ibrutinib.
Five responders discontinued all corticosteroid treatment.
Dr Miklos pointed out that baseline steroid dose did not vary between those patients who had responses and those who did not.
And ibrutinib produced clinically meaning improvement in the Lee symptom scale score among patients who responded.
Discontinuation and toxicity
At a median follow-up of 14 months, 12 patients were still on ibrutinib therapy.
“Only 5 patients discontinued for the progression of chronic GVHD,” Dr Miklos noted.
Other reasons for discontinuation included adverse events (AEs, n=14), patient decision (n=6), investigator decision (n=2), recurrence or progression of original malignancy (n=2), and noncompliance with study drug (n=1).
“The AE profile largely reflects what has been seen with ibrutinib use in the patients being treated for malignancies,” Dr Miklos said. “They also reflect adverse events that we see in patients receiving corticosteroids for the treatment of chronic GVHD.”
Treatment-emergent AEs occurring in more than 15% of patients included fatigue, diarrhea, muscle spasms, nausea, bruising, upper respiratory tract infection, pneumonia, pyrexia, headache, and fall.
Serious AEs occurred in 22 patients (52%), including pneumonia (n=6), septic shock (n=2), and pyrexia (n=2).
Two patients died while on study due to multilobular pneumonia and bronchopulmonary aspergillosis.
Exploratory endpoints
Investigators measured plasma levels of various factors following ibrutinib therapy through the first 90 days. Proinflammatory, chemotactic, and fibrotic factors decreased significantly while patients were on ibrutinib.
“This indicates that the cellular inflammation, the immune recruitment, and the fibrosis at the root of chronic GVHD was improving,” Dr Mikos said.
These factors included IFNγ, TNFα, IP-10, and CXCL9—biomarkers associated with cGVHD.
“We believe the efficacy of ibrutinib in this population supports further study in frontline treatment of chronic GVHD in a randomized, double-blinded study,” Dr Miklos concluded.
The current study was sponsored by Pharmacyclics, Inc.
Pacritinib bests BAT despite study truncation
SAN DIEGO—The JAK2/FLT3 inhibitor pacritinib significantly reduces spleen volume and symptoms in patients with myelofibrosis and low platelet counts,
compared to best available therapy (BAT), according to results of the PERSIST-2 trial.
In this phase 3 trial, BAT included the JAK1/2 inhibitor ruxolitinib. And pacritinib demonstrated benefits over BAT despite a truncated trial.
The US Food and Drug Administration (FDA) placed PERSIST-2 on clinical hold in February 2016 due to concerns over interim survival results, bleeding, and cardiovascular events.
Patients randomized at least 22 weeks prior to the clinical hold contributed data to the week 24 endpoint, the results of which were presented at the 2016 ASH Annual Meeting.
John Mascarenhas, MD, of Icahn School of Medicine at Mount Sinai in New York, New York, delivered the results as a late-breaking abstract (LBA-5).
Ruxolitinib is FDA-approved to treat myelofibrosis, but it is associated with dose-limiting cytopenias and is not indicated for patients with platelet counts less than 50,000/μL.
The earlier PERSIST-1 trial demonstrated sustained spleen volume reduction (SVR) and symptom control with pacritinib therapy regardless of baseline platelet count, but it did not include ruxolitinib in the BAT arm.
PERSIST-2 study design
Patients were randomized on a 1:1:1 basis to pacritinib at 400 mg once daily (PAC QD), pacritinib at 200 mg twice daily (PAC BID), or BAT, including ruxolitinib.
Patients had to have primary or secondary myelofibrosis and platelet counts of 100,000/μL or less. Patients were allowed to have had prior JAK2 inhibitors.
Crossover from BAT was allowed after progression at any time or at week 24.
The study had 2 primary endpoints: percent of patients achieving a 35% or greater SVR and the percent of patients achieving a 50% or more reduction in total symptom score (TSS) by MPN-SAF TSS 2.0.
The primary study objective was the efficacy of pooled QD and BID pacritinib compared to BAT. The secondary objective was the efficacy of QD or BD separately compared to BAT.
Patient demographics
The study randomized 311 patients, and 221 were included in the intent-to-treat efficacy population.
The efficacy population consisted of all patients randomized prior to September 7, 2015, which allowed their data to be included in the week 24 endpoint analysis prior to the clinical hold.
The PAC QD arm consisted of 75 patients with a median age of 69 (range, 39-85). Seventy-one percent were 65 or older, and about half were male.
About three-quarters had an ECOG performance status of 0-1, 61% had primary myelofibrosis, 21% had primary polycythemia vera (PPV), and 17% had primary essential thrombocythemia (PET). About half were DIPSS Intermediate-2 risk, 80% were JAK2V617F positive, and 51% had a platelet count less than 50,000/μL.
The PAC BID arm consisted of 74 patients with a median age of 67 (range, 39-85). Sixty-two percent were 65 or older, and 65% were male.
Eighty-eight percent had an ECOG performance status of 0-1, 74% had primary myelofibrosis, 19% had PPV, and 7% had PET. About half were DIPSS Intermediate-2 risk, 80% were JAK2V617F positive, and 42% had a platelet count less than 50,000/μL.
The BAT arm consisted of 72 patients with a median age of 69 (range, 32-83). Seventy-one percent were 65 or older, and about half were male.
Three-quarters had an ECOG performance status of 0-1, 60% had primary myelofibrosis, 22% had PPV, and 18% had PET. About half were DIPSS Intermediate-2 risk, 71% were JAK2V617F positive, and 44% had a platelet count less than 50,000/µL.
Prior ruxolitinib therapy was consistent across the arms—41.3% (PAC QD), 42% (PAC BID), and 46% (BAT).
“Now, it’s important to note,” Dr Mascarenhas said, “that the most common BAT was ruxolitinib, 45%, and hydroxyurea, 19%. And 19% of BAT patients actually had no treatment, watch and wait. This highlights the fact that this is an area where there is really no other viable therapeutic option for these patients.”
Efficacy
Pacritinib-treated patients had significantly greater spleen reduction from baseline to week 24 than BAT-treated patients, with 18% (QD+BID), 15% (QD), and 22% (BID) achieving 35% or more SVR compared to 3% in the BAT arm.
Pacritinib-treated patients also experienced greater TSS reduction, with 25% (QD+BID), 17% (QD), and 32% (BID) reporting 50% or more reduction in TSS compared to 14% in the BAT arm. However, only the PAC BID arm was significantly different from BAT.
SVR in all subgroups—age, gender, JAK2 mutation status, prior treatment, platelet count, hemoglobin, peripheral blasts, and white blood cell count—demonstrated superiority for pacritinib.
Median changes in individual symptom scores were also better in the pacritinib arms than in the BAT arm in almost every category—tiredness, early satiety, abdominal discomfort, inactivity, night sweats, bone pain, and pain under ribs on the left side.
Pruritus was the only category in which BAT was superior, and that was compared to the QD arm and not the BID arm.
The majority of patients who stopped pacritinib therapy were taken off due to the clinical hold.
There were no significant differences between the groups in overall survival. Hazard ratios for overall survival (95% confidence intervals) were 0.68 (0.30, 1.53) for PAC BID vs BAT, 1.18 (0.57, 2.44) for PAC QD vs BAT, and 0.61 (0.27, 1.35) for PAC BID vs QD.
PAC BID maintained this survival advantage compared with BAT across nearly all demographic and myelofibrosis-associated risk factors.
Patients who were red blood cell transfusion-dependent at baseline experienced a statistically significant decrease in transfusion frequency from baseline to week 24 in both the QD and BID pacritinib arms compared with BAT.
And thrombocytopenia was not a significant factor for patients who were receiving pacritinib and had platelet counts less than 50,000/μL.
Toxicity
The most common treatment-emergent adverse events (AEs) associated with pacritinib were diarrhea, nausea, vomiting, anemia, and thrombocytopenia. They were generally less frequent for BID compared with QD administration.
The most common serious adverse events (SAEs)—occurring in 5% of patients or more in any arms—were anemia (5%, 8%, and 3%), thrombocytopenia (2%, 6%, and 2%), pneumonia (5%, 6%, and 4%), and acute renal failure (5%, 2%, and 2%) in the QD, BID, and BAT arms, respectively.
SAEs of interest included congestive heart failure, atrial fibrillation, cardiac arrest, epistaxis, and subdural hematoma, which occurred in 3% or fewer patients in any arm.
“They [the SAEs] were relatively infrequent, and there was not a clear signal of toxicity,” Dr Mascarenhas said.
Deaths
Deaths in the intent-to-treat evaluable population were censored at the time of full clinical hold.
For the entire enrolled population, 15/104 deaths occurred in the QD arm, 10/107 in the BID arm, and 14/100 in the BAT arm.
After the full clinical hold, 7, 10, and 6 deaths occurred in the QD, BID, and BAT arms, respectively.
Seven of 20 patients died after crossover to pacritinib. Five were due to AEs—3 cardiac, 1 bleeding, and 1 other.
“It’s important to note that progression of disease was the leading cause of death in the PAC BID arm,” Dr Mascarenhas noted. “This is after the patients stopped the drug [when the trial was on clinical hold].”
Conclusions
Despite study truncation, pacritinib (QD+BID) was significantly more effective than BAT for SVR (P=0.001) and trended toward improved TSS (P=0.079).
Pacritinib BID appeared more effective than QD versus BAT for SVR and TSS, and pacritinib BID appeared to have a better benefit/risk profile than BAT.
“This is a well-tolerated drug in many respects,” Dr Mascarenhas said. “This is a patient population that is quite ill, low platelets, poor outcome, and they did pretty well.”
When asked about the future of pacritinib, Dr Mascarenhas said he believes the benefit-to-risk ratio is in favor of the drug.
“Pacritinib offers patients in this vulnerable situation an opportunity for symptom relief, basically spleen and symptoms,” he said. “So I think this is a drug that will hopefully move forward.”
Dr Mascarenhas disclosed research funding from CTI Biopharma, the sponsor of the trial.
SAN DIEGO—The JAK2/FLT3 inhibitor pacritinib significantly reduces spleen volume and symptoms in patients with myelofibrosis and low platelet counts,
compared to best available therapy (BAT), according to results of the PERSIST-2 trial.
In this phase 3 trial, BAT included the JAK1/2 inhibitor ruxolitinib. And pacritinib demonstrated benefits over BAT despite a truncated trial.
The US Food and Drug Administration (FDA) placed PERSIST-2 on clinical hold in February 2016 due to concerns over interim survival results, bleeding, and cardiovascular events.
Patients randomized at least 22 weeks prior to the clinical hold contributed data to the week 24 endpoint, the results of which were presented at the 2016 ASH Annual Meeting.
John Mascarenhas, MD, of Icahn School of Medicine at Mount Sinai in New York, New York, delivered the results as a late-breaking abstract (LBA-5).
Ruxolitinib is FDA-approved to treat myelofibrosis, but it is associated with dose-limiting cytopenias and is not indicated for patients with platelet counts less than 50,000/μL.
The earlier PERSIST-1 trial demonstrated sustained spleen volume reduction (SVR) and symptom control with pacritinib therapy regardless of baseline platelet count, but it did not include ruxolitinib in the BAT arm.
PERSIST-2 study design
Patients were randomized on a 1:1:1 basis to pacritinib at 400 mg once daily (PAC QD), pacritinib at 200 mg twice daily (PAC BID), or BAT, including ruxolitinib.
Patients had to have primary or secondary myelofibrosis and platelet counts of 100,000/μL or less. Patients were allowed to have had prior JAK2 inhibitors.
Crossover from BAT was allowed after progression at any time or at week 24.
The study had 2 primary endpoints: percent of patients achieving a 35% or greater SVR and the percent of patients achieving a 50% or more reduction in total symptom score (TSS) by MPN-SAF TSS 2.0.
The primary study objective was the efficacy of pooled QD and BID pacritinib compared to BAT. The secondary objective was the efficacy of QD or BD separately compared to BAT.
Patient demographics
The study randomized 311 patients, and 221 were included in the intent-to-treat efficacy population.
The efficacy population consisted of all patients randomized prior to September 7, 2015, which allowed their data to be included in the week 24 endpoint analysis prior to the clinical hold.
The PAC QD arm consisted of 75 patients with a median age of 69 (range, 39-85). Seventy-one percent were 65 or older, and about half were male.
About three-quarters had an ECOG performance status of 0-1, 61% had primary myelofibrosis, 21% had primary polycythemia vera (PPV), and 17% had primary essential thrombocythemia (PET). About half were DIPSS Intermediate-2 risk, 80% were JAK2V617F positive, and 51% had a platelet count less than 50,000/μL.
The PAC BID arm consisted of 74 patients with a median age of 67 (range, 39-85). Sixty-two percent were 65 or older, and 65% were male.
Eighty-eight percent had an ECOG performance status of 0-1, 74% had primary myelofibrosis, 19% had PPV, and 7% had PET. About half were DIPSS Intermediate-2 risk, 80% were JAK2V617F positive, and 42% had a platelet count less than 50,000/μL.
The BAT arm consisted of 72 patients with a median age of 69 (range, 32-83). Seventy-one percent were 65 or older, and about half were male.
Three-quarters had an ECOG performance status of 0-1, 60% had primary myelofibrosis, 22% had PPV, and 18% had PET. About half were DIPSS Intermediate-2 risk, 71% were JAK2V617F positive, and 44% had a platelet count less than 50,000/µL.
Prior ruxolitinib therapy was consistent across the arms—41.3% (PAC QD), 42% (PAC BID), and 46% (BAT).
“Now, it’s important to note,” Dr Mascarenhas said, “that the most common BAT was ruxolitinib, 45%, and hydroxyurea, 19%. And 19% of BAT patients actually had no treatment, watch and wait. This highlights the fact that this is an area where there is really no other viable therapeutic option for these patients.”
Efficacy
Pacritinib-treated patients had significantly greater spleen reduction from baseline to week 24 than BAT-treated patients, with 18% (QD+BID), 15% (QD), and 22% (BID) achieving 35% or more SVR compared to 3% in the BAT arm.
Pacritinib-treated patients also experienced greater TSS reduction, with 25% (QD+BID), 17% (QD), and 32% (BID) reporting 50% or more reduction in TSS compared to 14% in the BAT arm. However, only the PAC BID arm was significantly different from BAT.
SVR in all subgroups—age, gender, JAK2 mutation status, prior treatment, platelet count, hemoglobin, peripheral blasts, and white blood cell count—demonstrated superiority for pacritinib.
Median changes in individual symptom scores were also better in the pacritinib arms than in the BAT arm in almost every category—tiredness, early satiety, abdominal discomfort, inactivity, night sweats, bone pain, and pain under ribs on the left side.
Pruritus was the only category in which BAT was superior, and that was compared to the QD arm and not the BID arm.
The majority of patients who stopped pacritinib therapy were taken off due to the clinical hold.
There were no significant differences between the groups in overall survival. Hazard ratios for overall survival (95% confidence intervals) were 0.68 (0.30, 1.53) for PAC BID vs BAT, 1.18 (0.57, 2.44) for PAC QD vs BAT, and 0.61 (0.27, 1.35) for PAC BID vs QD.
PAC BID maintained this survival advantage compared with BAT across nearly all demographic and myelofibrosis-associated risk factors.
Patients who were red blood cell transfusion-dependent at baseline experienced a statistically significant decrease in transfusion frequency from baseline to week 24 in both the QD and BID pacritinib arms compared with BAT.
And thrombocytopenia was not a significant factor for patients who were receiving pacritinib and had platelet counts less than 50,000/μL.
Toxicity
The most common treatment-emergent adverse events (AEs) associated with pacritinib were diarrhea, nausea, vomiting, anemia, and thrombocytopenia. They were generally less frequent for BID compared with QD administration.
The most common serious adverse events (SAEs)—occurring in 5% of patients or more in any arms—were anemia (5%, 8%, and 3%), thrombocytopenia (2%, 6%, and 2%), pneumonia (5%, 6%, and 4%), and acute renal failure (5%, 2%, and 2%) in the QD, BID, and BAT arms, respectively.
SAEs of interest included congestive heart failure, atrial fibrillation, cardiac arrest, epistaxis, and subdural hematoma, which occurred in 3% or fewer patients in any arm.
“They [the SAEs] were relatively infrequent, and there was not a clear signal of toxicity,” Dr Mascarenhas said.
Deaths
Deaths in the intent-to-treat evaluable population were censored at the time of full clinical hold.
For the entire enrolled population, 15/104 deaths occurred in the QD arm, 10/107 in the BID arm, and 14/100 in the BAT arm.
After the full clinical hold, 7, 10, and 6 deaths occurred in the QD, BID, and BAT arms, respectively.
Seven of 20 patients died after crossover to pacritinib. Five were due to AEs—3 cardiac, 1 bleeding, and 1 other.
“It’s important to note that progression of disease was the leading cause of death in the PAC BID arm,” Dr Mascarenhas noted. “This is after the patients stopped the drug [when the trial was on clinical hold].”
Conclusions
Despite study truncation, pacritinib (QD+BID) was significantly more effective than BAT for SVR (P=0.001) and trended toward improved TSS (P=0.079).
Pacritinib BID appeared more effective than QD versus BAT for SVR and TSS, and pacritinib BID appeared to have a better benefit/risk profile than BAT.
“This is a well-tolerated drug in many respects,” Dr Mascarenhas said. “This is a patient population that is quite ill, low platelets, poor outcome, and they did pretty well.”
When asked about the future of pacritinib, Dr Mascarenhas said he believes the benefit-to-risk ratio is in favor of the drug.
“Pacritinib offers patients in this vulnerable situation an opportunity for symptom relief, basically spleen and symptoms,” he said. “So I think this is a drug that will hopefully move forward.”
Dr Mascarenhas disclosed research funding from CTI Biopharma, the sponsor of the trial.
SAN DIEGO—The JAK2/FLT3 inhibitor pacritinib significantly reduces spleen volume and symptoms in patients with myelofibrosis and low platelet counts,
compared to best available therapy (BAT), according to results of the PERSIST-2 trial.
In this phase 3 trial, BAT included the JAK1/2 inhibitor ruxolitinib. And pacritinib demonstrated benefits over BAT despite a truncated trial.
The US Food and Drug Administration (FDA) placed PERSIST-2 on clinical hold in February 2016 due to concerns over interim survival results, bleeding, and cardiovascular events.
Patients randomized at least 22 weeks prior to the clinical hold contributed data to the week 24 endpoint, the results of which were presented at the 2016 ASH Annual Meeting.
John Mascarenhas, MD, of Icahn School of Medicine at Mount Sinai in New York, New York, delivered the results as a late-breaking abstract (LBA-5).
Ruxolitinib is FDA-approved to treat myelofibrosis, but it is associated with dose-limiting cytopenias and is not indicated for patients with platelet counts less than 50,000/μL.
The earlier PERSIST-1 trial demonstrated sustained spleen volume reduction (SVR) and symptom control with pacritinib therapy regardless of baseline platelet count, but it did not include ruxolitinib in the BAT arm.
PERSIST-2 study design
Patients were randomized on a 1:1:1 basis to pacritinib at 400 mg once daily (PAC QD), pacritinib at 200 mg twice daily (PAC BID), or BAT, including ruxolitinib.
Patients had to have primary or secondary myelofibrosis and platelet counts of 100,000/μL or less. Patients were allowed to have had prior JAK2 inhibitors.
Crossover from BAT was allowed after progression at any time or at week 24.
The study had 2 primary endpoints: percent of patients achieving a 35% or greater SVR and the percent of patients achieving a 50% or more reduction in total symptom score (TSS) by MPN-SAF TSS 2.0.
The primary study objective was the efficacy of pooled QD and BID pacritinib compared to BAT. The secondary objective was the efficacy of QD or BD separately compared to BAT.
Patient demographics
The study randomized 311 patients, and 221 were included in the intent-to-treat efficacy population.
The efficacy population consisted of all patients randomized prior to September 7, 2015, which allowed their data to be included in the week 24 endpoint analysis prior to the clinical hold.
The PAC QD arm consisted of 75 patients with a median age of 69 (range, 39-85). Seventy-one percent were 65 or older, and about half were male.
About three-quarters had an ECOG performance status of 0-1, 61% had primary myelofibrosis, 21% had primary polycythemia vera (PPV), and 17% had primary essential thrombocythemia (PET). About half were DIPSS Intermediate-2 risk, 80% were JAK2V617F positive, and 51% had a platelet count less than 50,000/μL.
The PAC BID arm consisted of 74 patients with a median age of 67 (range, 39-85). Sixty-two percent were 65 or older, and 65% were male.
Eighty-eight percent had an ECOG performance status of 0-1, 74% had primary myelofibrosis, 19% had PPV, and 7% had PET. About half were DIPSS Intermediate-2 risk, 80% were JAK2V617F positive, and 42% had a platelet count less than 50,000/μL.
The BAT arm consisted of 72 patients with a median age of 69 (range, 32-83). Seventy-one percent were 65 or older, and about half were male.
Three-quarters had an ECOG performance status of 0-1, 60% had primary myelofibrosis, 22% had PPV, and 18% had PET. About half were DIPSS Intermediate-2 risk, 71% were JAK2V617F positive, and 44% had a platelet count less than 50,000/µL.
Prior ruxolitinib therapy was consistent across the arms—41.3% (PAC QD), 42% (PAC BID), and 46% (BAT).
“Now, it’s important to note,” Dr Mascarenhas said, “that the most common BAT was ruxolitinib, 45%, and hydroxyurea, 19%. And 19% of BAT patients actually had no treatment, watch and wait. This highlights the fact that this is an area where there is really no other viable therapeutic option for these patients.”
Efficacy
Pacritinib-treated patients had significantly greater spleen reduction from baseline to week 24 than BAT-treated patients, with 18% (QD+BID), 15% (QD), and 22% (BID) achieving 35% or more SVR compared to 3% in the BAT arm.
Pacritinib-treated patients also experienced greater TSS reduction, with 25% (QD+BID), 17% (QD), and 32% (BID) reporting 50% or more reduction in TSS compared to 14% in the BAT arm. However, only the PAC BID arm was significantly different from BAT.
SVR in all subgroups—age, gender, JAK2 mutation status, prior treatment, platelet count, hemoglobin, peripheral blasts, and white blood cell count—demonstrated superiority for pacritinib.
Median changes in individual symptom scores were also better in the pacritinib arms than in the BAT arm in almost every category—tiredness, early satiety, abdominal discomfort, inactivity, night sweats, bone pain, and pain under ribs on the left side.
Pruritus was the only category in which BAT was superior, and that was compared to the QD arm and not the BID arm.
The majority of patients who stopped pacritinib therapy were taken off due to the clinical hold.
There were no significant differences between the groups in overall survival. Hazard ratios for overall survival (95% confidence intervals) were 0.68 (0.30, 1.53) for PAC BID vs BAT, 1.18 (0.57, 2.44) for PAC QD vs BAT, and 0.61 (0.27, 1.35) for PAC BID vs QD.
PAC BID maintained this survival advantage compared with BAT across nearly all demographic and myelofibrosis-associated risk factors.
Patients who were red blood cell transfusion-dependent at baseline experienced a statistically significant decrease in transfusion frequency from baseline to week 24 in both the QD and BID pacritinib arms compared with BAT.
And thrombocytopenia was not a significant factor for patients who were receiving pacritinib and had platelet counts less than 50,000/μL.
Toxicity
The most common treatment-emergent adverse events (AEs) associated with pacritinib were diarrhea, nausea, vomiting, anemia, and thrombocytopenia. They were generally less frequent for BID compared with QD administration.
The most common serious adverse events (SAEs)—occurring in 5% of patients or more in any arms—were anemia (5%, 8%, and 3%), thrombocytopenia (2%, 6%, and 2%), pneumonia (5%, 6%, and 4%), and acute renal failure (5%, 2%, and 2%) in the QD, BID, and BAT arms, respectively.
SAEs of interest included congestive heart failure, atrial fibrillation, cardiac arrest, epistaxis, and subdural hematoma, which occurred in 3% or fewer patients in any arm.
“They [the SAEs] were relatively infrequent, and there was not a clear signal of toxicity,” Dr Mascarenhas said.
Deaths
Deaths in the intent-to-treat evaluable population were censored at the time of full clinical hold.
For the entire enrolled population, 15/104 deaths occurred in the QD arm, 10/107 in the BID arm, and 14/100 in the BAT arm.
After the full clinical hold, 7, 10, and 6 deaths occurred in the QD, BID, and BAT arms, respectively.
Seven of 20 patients died after crossover to pacritinib. Five were due to AEs—3 cardiac, 1 bleeding, and 1 other.
“It’s important to note that progression of disease was the leading cause of death in the PAC BID arm,” Dr Mascarenhas noted. “This is after the patients stopped the drug [when the trial was on clinical hold].”
Conclusions
Despite study truncation, pacritinib (QD+BID) was significantly more effective than BAT for SVR (P=0.001) and trended toward improved TSS (P=0.079).
Pacritinib BID appeared more effective than QD versus BAT for SVR and TSS, and pacritinib BID appeared to have a better benefit/risk profile than BAT.
“This is a well-tolerated drug in many respects,” Dr Mascarenhas said. “This is a patient population that is quite ill, low platelets, poor outcome, and they did pretty well.”
When asked about the future of pacritinib, Dr Mascarenhas said he believes the benefit-to-risk ratio is in favor of the drug.
“Pacritinib offers patients in this vulnerable situation an opportunity for symptom relief, basically spleen and symptoms,” he said. “So I think this is a drug that will hopefully move forward.”
Dr Mascarenhas disclosed research funding from CTI Biopharma, the sponsor of the trial.
Gene transfer for hemophilia B shows progress
SAN DIEGO—Researchers say they have optimized the SPK-9001 adeno-associated viral (AAV) vector
so that a “simple infusion” has significantly reduced bleeding events and the need for regular factor IX (FIX) infusions in 9 hemophilia B patients.
Eight of the patients were able to stop receiving FIX infusions and achieved an annualized bleeding rate (ABR) of 0. One patient had an ABR of 2 and required on-demand FIX therapy.
Lindsey George, MD, of the University of Pennsylvania in Philadelphia, presented these data, updating the interim results from the phase 1/2 trial of SPK-9001, during the plenary session of the 2016 ASH Annual Meeting (abstract 3*).
The trial is sponsored by Spark Therapeutics in collaboration with Pfizer.
Dr George explained that the bulk of hemophilia gene transfer efforts have coalesced around the use of in vitro, liver-directed, recombinant AAV vectors.
Earlier data showed sustained FIX activity at approximately 5% with AAV-serotype 8 (AAV8) vectors at 2 x 1012 vg/kg. However, levels of FIX:C at 12% are necessary to avoid bleeding into the joints, and higher doses elicit a capsid immune response.
Therefore, the team hypothesized that a highly efficient vector capsid and expression cassette, administered at low doses, would increase FIX expression to therapeutic levels and minimize the risk of a capsid immune response.
They developed an AAV capsid (Spark100) with a liver promoter and an expression cassette consisting of a codon-optimized, single-strand transgene encoding FIX-Padua.
In a prior AAV liver-directed gene transfer clinical trial, no patient developed inhibitors.
So the team conducted a phase 1/2 trial in males age 18 and older who had FIX:C levels of 2% or less.
The patients had to have less than 1:5 neutralizing antibodies to Spark100, more than 50 factor exposure days, no prior history of FIX inhibitors, no active hepatitis B or C virus, and liver fibrosis of stage 2 or less. They had to have a negative HIV viral load with CD4 levels of 200/mm3 or more.
At baseline, patients had to be on prophylaxis or be receiving on-demand therapy and have 4 or more bleeding events the year prior to infusion or a history of hemophilic arthropathy.
Results
The researchers enrolled 9 participants, ages 18 to 52. Six patients were on prophylaxis, and 3 had on-demand therapy at baseline.
They received a 1-hour, outpatient, intravenous infusion of SPK-9001 at 5 x 1011 vg/kg and were followed up for 52 weeks, with a long-term follow-up of 14 years.
Five patients had a history of HCV, and 1 had a history of HIV and was maintained on antiretroviral therapy.
One patient had neutralizing antibody titers to Spark100 capsid at a 1:1 ratio.
Prior to receiving SPK-9001, the patients required an annual number of infusions ranging from 0 to 159. Three patients had ABRs of 0, but the remaining patients had ABRs of 1, 2, 4, 10, 12, and 49.
After receiving SPK-9001, 8 of the patients were able to stop receiving FIX infusions and
achieved an ABR of 0. One patient had an ABR of 2 and required on-demand FIX therapy.
Dr George described one patient, a 23-year-old male who had severe hemophilia B and was maintained on weekly rFIX-Fc prophylaxis. He had no history of HCV or HIV.
Prior to receiving SPK-9001, he had 98 infusions and 4 breakthrough bleeds. After SPK-9001, he had a FIX activity level of 33% of normal at 52 weeks, no bleeding episodes, and required no rescue factor.
He had no vector-related adverse events, required no immunosuppression, and was safely off prophylaxis.
“Clinically, what this has meant for this man is he is now off his prophylaxis, he has no longer had breakthrough bleeding events, and he has not required factor for any reason,” Dr George said.
Capsid immune responses
Seven patients had less than 1:1 Spark100 neutralizing antibody at baseline and did not require steroids.
Their mean steady-state FIX activity was 31.9 + 7.4% at a follow-up of 12 to 52 weeks. Their liver function tests remained less than 1.5 times the upper limit of normal.
Two patients had capsid immune responses requiring steroid treatment.
One patient, a 45-year-old male, had a FIX:C of 1.9%, experienced 49 bleeding events prior to receiving SPK-9001, and was treated on-demand.
After SPK-9001, he had no vector-related adverse events, received a course of prednisone, and, at 20 weeks follow-up, had experienced no bleeding events and did not require factor use.
The second patient who had a capsid immune response was 36 years of age and on FIX prophylaxis. He had a history of HCV and no history of HIV.
After SPK-9001, he experienced no bleeding and required no factor use. He had grade 1 transaminase toxicity, which returned to within normal limits.
He is taking 40 mg prednisone daily and has stable FIX:C activity at 49 days after vector infusion.
Overall transgene-derived FIX activity
At a follow-up of 7 to 52 weeks, for a cumulative 238 weeks for all patients, their mean steady-state FIX activity was 28.3 + 10.0% of normal.
They had no vector or procedure-related unexpected adverse events, although 1 patient had transient grade 1 transaminase toxicity.
No patient developed FIX alloinhibitory antibodies.
One patient had FIX:C activity of 68% of normal at 7 weeks, and the first patient infused had 33% FIX:C activity at 52 weeks.
The transgene-derived FIX activity resulted in a significant reduction in bleeding events (P<0.05) and factor use (P<0.05). All patients stopped their prophylaxis.
The researchers recommend a larger cohort and continued observation to confirm these results.
Dr George noted that SPK-9001 has received breakthrough therapy designation from the US Food and Drug Administration.
*Information presented at the meeting differs from the abstract.
SAN DIEGO—Researchers say they have optimized the SPK-9001 adeno-associated viral (AAV) vector
so that a “simple infusion” has significantly reduced bleeding events and the need for regular factor IX (FIX) infusions in 9 hemophilia B patients.
Eight of the patients were able to stop receiving FIX infusions and achieved an annualized bleeding rate (ABR) of 0. One patient had an ABR of 2 and required on-demand FIX therapy.
Lindsey George, MD, of the University of Pennsylvania in Philadelphia, presented these data, updating the interim results from the phase 1/2 trial of SPK-9001, during the plenary session of the 2016 ASH Annual Meeting (abstract 3*).
The trial is sponsored by Spark Therapeutics in collaboration with Pfizer.
Dr George explained that the bulk of hemophilia gene transfer efforts have coalesced around the use of in vitro, liver-directed, recombinant AAV vectors.
Earlier data showed sustained FIX activity at approximately 5% with AAV-serotype 8 (AAV8) vectors at 2 x 1012 vg/kg. However, levels of FIX:C at 12% are necessary to avoid bleeding into the joints, and higher doses elicit a capsid immune response.
Therefore, the team hypothesized that a highly efficient vector capsid and expression cassette, administered at low doses, would increase FIX expression to therapeutic levels and minimize the risk of a capsid immune response.
They developed an AAV capsid (Spark100) with a liver promoter and an expression cassette consisting of a codon-optimized, single-strand transgene encoding FIX-Padua.
In a prior AAV liver-directed gene transfer clinical trial, no patient developed inhibitors.
So the team conducted a phase 1/2 trial in males age 18 and older who had FIX:C levels of 2% or less.
The patients had to have less than 1:5 neutralizing antibodies to Spark100, more than 50 factor exposure days, no prior history of FIX inhibitors, no active hepatitis B or C virus, and liver fibrosis of stage 2 or less. They had to have a negative HIV viral load with CD4 levels of 200/mm3 or more.
At baseline, patients had to be on prophylaxis or be receiving on-demand therapy and have 4 or more bleeding events the year prior to infusion or a history of hemophilic arthropathy.
Results
The researchers enrolled 9 participants, ages 18 to 52. Six patients were on prophylaxis, and 3 had on-demand therapy at baseline.
They received a 1-hour, outpatient, intravenous infusion of SPK-9001 at 5 x 1011 vg/kg and were followed up for 52 weeks, with a long-term follow-up of 14 years.
Five patients had a history of HCV, and 1 had a history of HIV and was maintained on antiretroviral therapy.
One patient had neutralizing antibody titers to Spark100 capsid at a 1:1 ratio.
Prior to receiving SPK-9001, the patients required an annual number of infusions ranging from 0 to 159. Three patients had ABRs of 0, but the remaining patients had ABRs of 1, 2, 4, 10, 12, and 49.
After receiving SPK-9001, 8 of the patients were able to stop receiving FIX infusions and
achieved an ABR of 0. One patient had an ABR of 2 and required on-demand FIX therapy.
Dr George described one patient, a 23-year-old male who had severe hemophilia B and was maintained on weekly rFIX-Fc prophylaxis. He had no history of HCV or HIV.
Prior to receiving SPK-9001, he had 98 infusions and 4 breakthrough bleeds. After SPK-9001, he had a FIX activity level of 33% of normal at 52 weeks, no bleeding episodes, and required no rescue factor.
He had no vector-related adverse events, required no immunosuppression, and was safely off prophylaxis.
“Clinically, what this has meant for this man is he is now off his prophylaxis, he has no longer had breakthrough bleeding events, and he has not required factor for any reason,” Dr George said.
Capsid immune responses
Seven patients had less than 1:1 Spark100 neutralizing antibody at baseline and did not require steroids.
Their mean steady-state FIX activity was 31.9 + 7.4% at a follow-up of 12 to 52 weeks. Their liver function tests remained less than 1.5 times the upper limit of normal.
Two patients had capsid immune responses requiring steroid treatment.
One patient, a 45-year-old male, had a FIX:C of 1.9%, experienced 49 bleeding events prior to receiving SPK-9001, and was treated on-demand.
After SPK-9001, he had no vector-related adverse events, received a course of prednisone, and, at 20 weeks follow-up, had experienced no bleeding events and did not require factor use.
The second patient who had a capsid immune response was 36 years of age and on FIX prophylaxis. He had a history of HCV and no history of HIV.
After SPK-9001, he experienced no bleeding and required no factor use. He had grade 1 transaminase toxicity, which returned to within normal limits.
He is taking 40 mg prednisone daily and has stable FIX:C activity at 49 days after vector infusion.
Overall transgene-derived FIX activity
At a follow-up of 7 to 52 weeks, for a cumulative 238 weeks for all patients, their mean steady-state FIX activity was 28.3 + 10.0% of normal.
They had no vector or procedure-related unexpected adverse events, although 1 patient had transient grade 1 transaminase toxicity.
No patient developed FIX alloinhibitory antibodies.
One patient had FIX:C activity of 68% of normal at 7 weeks, and the first patient infused had 33% FIX:C activity at 52 weeks.
The transgene-derived FIX activity resulted in a significant reduction in bleeding events (P<0.05) and factor use (P<0.05). All patients stopped their prophylaxis.
The researchers recommend a larger cohort and continued observation to confirm these results.
Dr George noted that SPK-9001 has received breakthrough therapy designation from the US Food and Drug Administration.
*Information presented at the meeting differs from the abstract.
SAN DIEGO—Researchers say they have optimized the SPK-9001 adeno-associated viral (AAV) vector
so that a “simple infusion” has significantly reduced bleeding events and the need for regular factor IX (FIX) infusions in 9 hemophilia B patients.
Eight of the patients were able to stop receiving FIX infusions and achieved an annualized bleeding rate (ABR) of 0. One patient had an ABR of 2 and required on-demand FIX therapy.
Lindsey George, MD, of the University of Pennsylvania in Philadelphia, presented these data, updating the interim results from the phase 1/2 trial of SPK-9001, during the plenary session of the 2016 ASH Annual Meeting (abstract 3*).
The trial is sponsored by Spark Therapeutics in collaboration with Pfizer.
Dr George explained that the bulk of hemophilia gene transfer efforts have coalesced around the use of in vitro, liver-directed, recombinant AAV vectors.
Earlier data showed sustained FIX activity at approximately 5% with AAV-serotype 8 (AAV8) vectors at 2 x 1012 vg/kg. However, levels of FIX:C at 12% are necessary to avoid bleeding into the joints, and higher doses elicit a capsid immune response.
Therefore, the team hypothesized that a highly efficient vector capsid and expression cassette, administered at low doses, would increase FIX expression to therapeutic levels and minimize the risk of a capsid immune response.
They developed an AAV capsid (Spark100) with a liver promoter and an expression cassette consisting of a codon-optimized, single-strand transgene encoding FIX-Padua.
In a prior AAV liver-directed gene transfer clinical trial, no patient developed inhibitors.
So the team conducted a phase 1/2 trial in males age 18 and older who had FIX:C levels of 2% or less.
The patients had to have less than 1:5 neutralizing antibodies to Spark100, more than 50 factor exposure days, no prior history of FIX inhibitors, no active hepatitis B or C virus, and liver fibrosis of stage 2 or less. They had to have a negative HIV viral load with CD4 levels of 200/mm3 or more.
At baseline, patients had to be on prophylaxis or be receiving on-demand therapy and have 4 or more bleeding events the year prior to infusion or a history of hemophilic arthropathy.
Results
The researchers enrolled 9 participants, ages 18 to 52. Six patients were on prophylaxis, and 3 had on-demand therapy at baseline.
They received a 1-hour, outpatient, intravenous infusion of SPK-9001 at 5 x 1011 vg/kg and were followed up for 52 weeks, with a long-term follow-up of 14 years.
Five patients had a history of HCV, and 1 had a history of HIV and was maintained on antiretroviral therapy.
One patient had neutralizing antibody titers to Spark100 capsid at a 1:1 ratio.
Prior to receiving SPK-9001, the patients required an annual number of infusions ranging from 0 to 159. Three patients had ABRs of 0, but the remaining patients had ABRs of 1, 2, 4, 10, 12, and 49.
After receiving SPK-9001, 8 of the patients were able to stop receiving FIX infusions and
achieved an ABR of 0. One patient had an ABR of 2 and required on-demand FIX therapy.
Dr George described one patient, a 23-year-old male who had severe hemophilia B and was maintained on weekly rFIX-Fc prophylaxis. He had no history of HCV or HIV.
Prior to receiving SPK-9001, he had 98 infusions and 4 breakthrough bleeds. After SPK-9001, he had a FIX activity level of 33% of normal at 52 weeks, no bleeding episodes, and required no rescue factor.
He had no vector-related adverse events, required no immunosuppression, and was safely off prophylaxis.
“Clinically, what this has meant for this man is he is now off his prophylaxis, he has no longer had breakthrough bleeding events, and he has not required factor for any reason,” Dr George said.
Capsid immune responses
Seven patients had less than 1:1 Spark100 neutralizing antibody at baseline and did not require steroids.
Their mean steady-state FIX activity was 31.9 + 7.4% at a follow-up of 12 to 52 weeks. Their liver function tests remained less than 1.5 times the upper limit of normal.
Two patients had capsid immune responses requiring steroid treatment.
One patient, a 45-year-old male, had a FIX:C of 1.9%, experienced 49 bleeding events prior to receiving SPK-9001, and was treated on-demand.
After SPK-9001, he had no vector-related adverse events, received a course of prednisone, and, at 20 weeks follow-up, had experienced no bleeding events and did not require factor use.
The second patient who had a capsid immune response was 36 years of age and on FIX prophylaxis. He had a history of HCV and no history of HIV.
After SPK-9001, he experienced no bleeding and required no factor use. He had grade 1 transaminase toxicity, which returned to within normal limits.
He is taking 40 mg prednisone daily and has stable FIX:C activity at 49 days after vector infusion.
Overall transgene-derived FIX activity
At a follow-up of 7 to 52 weeks, for a cumulative 238 weeks for all patients, their mean steady-state FIX activity was 28.3 + 10.0% of normal.
They had no vector or procedure-related unexpected adverse events, although 1 patient had transient grade 1 transaminase toxicity.
No patient developed FIX alloinhibitory antibodies.
One patient had FIX:C activity of 68% of normal at 7 weeks, and the first patient infused had 33% FIX:C activity at 52 weeks.
The transgene-derived FIX activity resulted in a significant reduction in bleeding events (P<0.05) and factor use (P<0.05). All patients stopped their prophylaxis.
The researchers recommend a larger cohort and continued observation to confirm these results.
Dr George noted that SPK-9001 has received breakthrough therapy designation from the US Food and Drug Administration.
*Information presented at the meeting differs from the abstract.