Follicular Lymphoma

 

2016 ASH Annual Meeting
© 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.

 

2016 ASH Annual Meeting
© 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.

 

2016 ASH Annual Meeting
© 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.

 

 

Micrograph showing DLBCL

 

The chimeric antigen receptor (CAR) T-cell therapy JCAR017 has received breakthrough therapy designation from the US Food and Drug Administration (FDA) and access to the European Medicines Agency’s (EMA) Priority Medicines (PRIME) program.

JCAR017 has gained access to the PRIME program as a treatment for relapsed/refractory diffuse large B-cell lymphoma (DLBCL).

The breakthrough designation is for JCAR017 in the treatment of patients with relapsed/refractory, aggressive, large B-cell non-Hodgkin lymphoma, including DLBCL not otherwise specified (de novo or transformed from indolent lymphoma), primary mediastinal B-cell lymphoma, and grade 3B follicular lymphoma.

JCAR017 uses a defined CD4:CD8 cell composition and 4-1BB as the costimulatory domain. The product is being developed by Juno Therapeutics, Inc. and Celgene Corporation.

The breakthrough therapy designation and PRIME eligibility for JCAR017 were granted by the FDA and EMA, respectively, on the basis of early clinical results with JCAR017 in relapsed/refractory DLBCL.

Results from a phase 1 trial of JCAR017 in relapsed/refractory DLBCL and mantle cell lymphoma were recently presented at the 2016 ASH Annual Meeting (abstract 4192).

About the PRIME program

The goal of the EMA’s PRIME program is to accelerate the development of therapies that target unmet medical needs.

The program provides enhanced EMA support and increased interaction to developers, in order to optimize development plans and speed regulatory evaluations to potentially bring these therapies to patients more quickly.

To be accepted for PRIME, a therapy must demonstrate the potential to benefit patients with unmet medical need through early clinical or nonclinical data.

About breakthrough designation

The FDA’s breakthrough therapy designation is intended to expedite the development and review of new treatments for serious or life-threatening conditions.

Breakthrough designation entitles the company developing a therapy to more intensive FDA guidance on an efficient and accelerated development program, as well as eligibility for other actions to expedite FDA review, such as a rolling submission and priority review.

To earn breakthrough designation, a treatment must show encouraging early clinical results demonstrating substantial improvement over available therapies with regard to a clinically significant endpoint, or it must fulfill an unmet need.

 

 

Micrograph showing DLBCL

 

The chimeric antigen receptor (CAR) T-cell therapy JCAR017 has received breakthrough therapy designation from the US Food and Drug Administration (FDA) and access to the European Medicines Agency’s (EMA) Priority Medicines (PRIME) program.

JCAR017 has gained access to the PRIME program as a treatment for relapsed/refractory diffuse large B-cell lymphoma (DLBCL).

The breakthrough designation is for JCAR017 in the treatment of patients with relapsed/refractory, aggressive, large B-cell non-Hodgkin lymphoma, including DLBCL not otherwise specified (de novo or transformed from indolent lymphoma), primary mediastinal B-cell lymphoma, and grade 3B follicular lymphoma.

JCAR017 uses a defined CD4:CD8 cell composition and 4-1BB as the costimulatory domain. The product is being developed by Juno Therapeutics, Inc. and Celgene Corporation.

The breakthrough therapy designation and PRIME eligibility for JCAR017 were granted by the FDA and EMA, respectively, on the basis of early clinical results with JCAR017 in relapsed/refractory DLBCL.

Results from a phase 1 trial of JCAR017 in relapsed/refractory DLBCL and mantle cell lymphoma were recently presented at the 2016 ASH Annual Meeting (abstract 4192).

About the PRIME program

The goal of the EMA’s PRIME program is to accelerate the development of therapies that target unmet medical needs.

The program provides enhanced EMA support and increased interaction to developers, in order to optimize development plans and speed regulatory evaluations to potentially bring these therapies to patients more quickly.

To be accepted for PRIME, a therapy must demonstrate the potential to benefit patients with unmet medical need through early clinical or nonclinical data.

About breakthrough designation

The FDA’s breakthrough therapy designation is intended to expedite the development and review of new treatments for serious or life-threatening conditions.

Breakthrough designation entitles the company developing a therapy to more intensive FDA guidance on an efficient and accelerated development program, as well as eligibility for other actions to expedite FDA review, such as a rolling submission and priority review.

To earn breakthrough designation, a treatment must show encouraging early clinical results demonstrating substantial improvement over available therapies with regard to a clinically significant endpoint, or it must fulfill an unmet need.

 

 

Micrograph showing DLBCL

 

The chimeric antigen receptor (CAR) T-cell therapy JCAR017 has received breakthrough therapy designation from the US Food and Drug Administration (FDA) and access to the European Medicines Agency’s (EMA) Priority Medicines (PRIME) program.

JCAR017 has gained access to the PRIME program as a treatment for relapsed/refractory diffuse large B-cell lymphoma (DLBCL).

The breakthrough designation is for JCAR017 in the treatment of patients with relapsed/refractory, aggressive, large B-cell non-Hodgkin lymphoma, including DLBCL not otherwise specified (de novo or transformed from indolent lymphoma), primary mediastinal B-cell lymphoma, and grade 3B follicular lymphoma.

JCAR017 uses a defined CD4:CD8 cell composition and 4-1BB as the costimulatory domain. The product is being developed by Juno Therapeutics, Inc. and Celgene Corporation.

The breakthrough therapy designation and PRIME eligibility for JCAR017 were granted by the FDA and EMA, respectively, on the basis of early clinical results with JCAR017 in relapsed/refractory DLBCL.

Results from a phase 1 trial of JCAR017 in relapsed/refractory DLBCL and mantle cell lymphoma were recently presented at the 2016 ASH Annual Meeting (abstract 4192).

About the PRIME program

The goal of the EMA’s PRIME program is to accelerate the development of therapies that target unmet medical needs.

The program provides enhanced EMA support and increased interaction to developers, in order to optimize development plans and speed regulatory evaluations to potentially bring these therapies to patients more quickly.

To be accepted for PRIME, a therapy must demonstrate the potential to benefit patients with unmet medical need through early clinical or nonclinical data.

About breakthrough designation

The FDA’s breakthrough therapy designation is intended to expedite the development and review of new treatments for serious or life-threatening conditions.

Breakthrough designation entitles the company developing a therapy to more intensive FDA guidance on an efficient and accelerated development program, as well as eligibility for other actions to expedite FDA review, such as a rolling submission and priority review.

To earn breakthrough designation, a treatment must show encouraging early clinical results demonstrating substantial improvement over available therapies with regard to a clinically significant endpoint, or it must fulfill an unmet need.

 

 

Attendees at the

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.

 

 

Attendees at the

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.

 

 

Attendees at the

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.

 

 

Micrograph showing FL

 

Patients with transformed follicular lymphoma (FL) and FL patients with early progression have “widely divergent patterns of clonal

dynamics,” according to researchers.

The team investigated the molecular events underlying transformation and early progression in FL and found that disparate evolutionary trajectories and mutational profiles drive these 2 distinct clinical endpoints.

Sohrab Shah, PhD, of the University of British Columbia in Vancouver, Canada, and his colleagues reported these findings in PLOS Medicine.

The researchers used whole-genome sequencing to analyze tumor specimens and matched normal specimens from 41 FL patients.

The team then classified the patients according to the following clinical endpoints:

• Patients who presented with transformation (n=15)
• Patients who experienced tumor progression within 2.5 years of starting treatment, without evidence of transformation (n=6)
• Patients who had neither transformation nor progression up to 5 years post-diagnosis (n=20).

The researchers also used targeted capture sequencing of known FL-associated genes in a larger cohort of 277 FL patients (395 samples) to investigate discrete genetic events that drive transformation and early progression.

Results showed that tumors that progress early evolve in different ways from those that transform.

The team found that, for tumors that transform, the cells or clones that constitute the majority of the aggressive tumor were extremely rare at diagnosis, if they were present at all.

In contrast, for early progressive FL, the clonal architecture remained similar from the time of diagnosis to relapse, indicating that the diagnostic tumor may already contain the properties that confer resistance to treatment.

Analysis of the larger cohort revealed genes and biological processes that were associated with transformation and progression.

The researchers identified 12 genes that were more commonly mutated at the time of transformation than the time of diagnosis—TP53, B2M, EZH2, MYC, CCND3, EBF1, PIM1, GNA13, ITPKB, CHD8, S1PR2, and P2RY8.

The team said their findings suggest that defective DNA damage response, increased proliferation, escape from immune surveillance, and loss of confinement within the germinal center are key features that drive histological transformation from indolent to aggressive lymphoma.

The researchers also identified 10 genes that were more commonly mutated in patients with early progression than in patients with late/no progression—B2M, BTG1, FAS, IKZF3, KMT2C, MKI67, MYD88, SOCS1, TP53, and XBP1.

The team noted that most patients with early progression (80%) had mutations in at least 1 of these 10 genes, but none of the genes were mutated at a frequency greater than 27%. This suggests that early progression is related to relatively infrequent genetic alterations.

The researchers said these findings provide a basis for future research on prognostic assay development and potential strategies for monitoring and treatment of patients with FL.

 

 

Micrograph showing FL

 

Patients with transformed follicular lymphoma (FL) and FL patients with early progression have “widely divergent patterns of clonal

dynamics,” according to researchers.

The team investigated the molecular events underlying transformation and early progression in FL and found that disparate evolutionary trajectories and mutational profiles drive these 2 distinct clinical endpoints.

Sohrab Shah, PhD, of the University of British Columbia in Vancouver, Canada, and his colleagues reported these findings in PLOS Medicine.

The researchers used whole-genome sequencing to analyze tumor specimens and matched normal specimens from 41 FL patients.

The team then classified the patients according to the following clinical endpoints:

• Patients who presented with transformation (n=15)
• Patients who experienced tumor progression within 2.5 years of starting treatment, without evidence of transformation (n=6)
• Patients who had neither transformation nor progression up to 5 years post-diagnosis (n=20).

The researchers also used targeted capture sequencing of known FL-associated genes in a larger cohort of 277 FL patients (395 samples) to investigate discrete genetic events that drive transformation and early progression.

Results showed that tumors that progress early evolve in different ways from those that transform.

The team found that, for tumors that transform, the cells or clones that constitute the majority of the aggressive tumor were extremely rare at diagnosis, if they were present at all.

In contrast, for early progressive FL, the clonal architecture remained similar from the time of diagnosis to relapse, indicating that the diagnostic tumor may already contain the properties that confer resistance to treatment.

Analysis of the larger cohort revealed genes and biological processes that were associated with transformation and progression.

The researchers identified 12 genes that were more commonly mutated at the time of transformation than the time of diagnosis—TP53, B2M, EZH2, MYC, CCND3, EBF1, PIM1, GNA13, ITPKB, CHD8, S1PR2, and P2RY8.

The team said their findings suggest that defective DNA damage response, increased proliferation, escape from immune surveillance, and loss of confinement within the germinal center are key features that drive histological transformation from indolent to aggressive lymphoma.

The researchers also identified 10 genes that were more commonly mutated in patients with early progression than in patients with late/no progression—B2M, BTG1, FAS, IKZF3, KMT2C, MKI67, MYD88, SOCS1, TP53, and XBP1.

The team noted that most patients with early progression (80%) had mutations in at least 1 of these 10 genes, but none of the genes were mutated at a frequency greater than 27%. This suggests that early progression is related to relatively infrequent genetic alterations.

The researchers said these findings provide a basis for future research on prognostic assay development and potential strategies for monitoring and treatment of patients with FL.

 

 

Micrograph showing FL

 

Patients with transformed follicular lymphoma (FL) and FL patients with early progression have “widely divergent patterns of clonal

dynamics,” according to researchers.

The team investigated the molecular events underlying transformation and early progression in FL and found that disparate evolutionary trajectories and mutational profiles drive these 2 distinct clinical endpoints.

Sohrab Shah, PhD, of the University of British Columbia in Vancouver, Canada, and his colleagues reported these findings in PLOS Medicine.

The researchers used whole-genome sequencing to analyze tumor specimens and matched normal specimens from 41 FL patients.

The team then classified the patients according to the following clinical endpoints:

• Patients who presented with transformation (n=15)
• Patients who experienced tumor progression within 2.5 years of starting treatment, without evidence of transformation (n=6)
• Patients who had neither transformation nor progression up to 5 years post-diagnosis (n=20).

The researchers also used targeted capture sequencing of known FL-associated genes in a larger cohort of 277 FL patients (395 samples) to investigate discrete genetic events that drive transformation and early progression.

Results showed that tumors that progress early evolve in different ways from those that transform.

The team found that, for tumors that transform, the cells or clones that constitute the majority of the aggressive tumor were extremely rare at diagnosis, if they were present at all.

In contrast, for early progressive FL, the clonal architecture remained similar from the time of diagnosis to relapse, indicating that the diagnostic tumor may already contain the properties that confer resistance to treatment.

Analysis of the larger cohort revealed genes and biological processes that were associated with transformation and progression.

The researchers identified 12 genes that were more commonly mutated at the time of transformation than the time of diagnosis—TP53, B2M, EZH2, MYC, CCND3, EBF1, PIM1, GNA13, ITPKB, CHD8, S1PR2, and P2RY8.

The team said their findings suggest that defective DNA damage response, increased proliferation, escape from immune surveillance, and loss of confinement within the germinal center are key features that drive histological transformation from indolent to aggressive lymphoma.

The researchers also identified 10 genes that were more commonly mutated in patients with early progression than in patients with late/no progression—B2M, BTG1, FAS, IKZF3, KMT2C, MKI67, MYD88, SOCS1, TP53, and XBP1.

The team noted that most patients with early progression (80%) had mutations in at least 1 of these 10 genes, but none of the genes were mutated at a frequency greater than 27%. This suggests that early progression is related to relatively infrequent genetic alterations.

The researchers said these findings provide a basis for future research on prognostic assay development and potential strategies for monitoring and treatment of patients with FL.

SAN DIEGO – For patients with indolent non-Hodgkin lymphoma, adding the anti-CD20 antibody rituximab to a standard-combination chemotherapy regimen resulted in significant improvements in survival, compared with chemotherapy alone. Obinutuzumab (Gazyva), a second-generation anti-CD20 antibody touted as the heir apparent to rituximab, is being explored in various combinations for the treatment of indolent lymphomas, including follicular lymphoma and marginal zone lymphoma.

In this video interview from the annual meeting of the American Society of Hematology, Robert Marcus, FRCP, of King’s College Hospital, London, discussed results of the phase III GALLIUM study, in which patients with untreated follicular lymphoma were randomly assigned to one of three chemotherapy regimens with either obinutuzumab or rituximab. The primary endpoint of investigator-assessed 3-year progression-free survival (PFS) at a median follow-up of 34.5 months was 80% for patients with follicular lymphoma treated with obinutuzumab and one of three standard chemotherapy regimens, compared with 73.3% for patients treated with rituximab and chemotherapy. This difference translated into a hazard ratio (HR) favoring obinutuzumab of 0.68 (P = .0012).

Respective 3-year overall survival rates at 3 years were similar, however, at 94% and 92.1% (HR, 0.75; P = .21).

The GALLIUM trial is sponsored by F. Hoffmann-La Roche. Dr. Marcus disclosed consulting with and receiving honoraria from the company, and relationships with other companies.

SAN DIEGO – For patients with indolent non-Hodgkin lymphoma, adding the anti-CD20 antibody rituximab to a standard-combination chemotherapy regimen resulted in significant improvements in survival, compared with chemotherapy alone. Obinutuzumab (Gazyva), a second-generation anti-CD20 antibody touted as the heir apparent to rituximab, is being explored in various combinations for the treatment of indolent lymphomas, including follicular lymphoma and marginal zone lymphoma.

In this video interview from the annual meeting of the American Society of Hematology, Robert Marcus, FRCP, of King’s College Hospital, London, discussed results of the phase III GALLIUM study, in which patients with untreated follicular lymphoma were randomly assigned to one of three chemotherapy regimens with either obinutuzumab or rituximab. The primary endpoint of investigator-assessed 3-year progression-free survival (PFS) at a median follow-up of 34.5 months was 80% for patients with follicular lymphoma treated with obinutuzumab and one of three standard chemotherapy regimens, compared with 73.3% for patients treated with rituximab and chemotherapy. This difference translated into a hazard ratio (HR) favoring obinutuzumab of 0.68 (P = .0012).

Respective 3-year overall survival rates at 3 years were similar, however, at 94% and 92.1% (HR, 0.75; P = .21).

The GALLIUM trial is sponsored by F. Hoffmann-La Roche. Dr. Marcus disclosed consulting with and receiving honoraria from the company, and relationships with other companies.

SAN DIEGO – For patients with indolent non-Hodgkin lymphoma, adding the anti-CD20 antibody rituximab to a standard-combination chemotherapy regimen resulted in significant improvements in survival, compared with chemotherapy alone. Obinutuzumab (Gazyva), a second-generation anti-CD20 antibody touted as the heir apparent to rituximab, is being explored in various combinations for the treatment of indolent lymphomas, including follicular lymphoma and marginal zone lymphoma.

In this video interview from the annual meeting of the American Society of Hematology, Robert Marcus, FRCP, of King’s College Hospital, London, discussed results of the phase III GALLIUM study, in which patients with untreated follicular lymphoma were randomly assigned to one of three chemotherapy regimens with either obinutuzumab or rituximab. The primary endpoint of investigator-assessed 3-year progression-free survival (PFS) at a median follow-up of 34.5 months was 80% for patients with follicular lymphoma treated with obinutuzumab and one of three standard chemotherapy regimens, compared with 73.3% for patients treated with rituximab and chemotherapy. This difference translated into a hazard ratio (HR) favoring obinutuzumab of 0.68 (P = .0012).

Respective 3-year overall survival rates at 3 years were similar, however, at 94% and 92.1% (HR, 0.75; P = .21).

The GALLIUM trial is sponsored by F. Hoffmann-La Roche. Dr. Marcus disclosed consulting with and receiving honoraria from the company, and relationships with other companies.

SAN DIEGO – Obinutuzumab, a second-generation anti-CD20 antibody touted as the heir apparent to rituximab, offered a progression-free survival (PFS) edge over rituximab when combined with standard chemotherapy in patients with previously untreated advanced follicular lymphoma.

attended the presentation of the GALLIUM data at a plenary session during the American Society of Hematology annual meeting indicated that despite the data, they weren’t ready to make a switch to the newer, costlier antibody.

“I feel that it is not convincing for practice-changing,” said Kanti R. Rai, MD, professor of medicine and molecular medicine at Hofstra University, Hempstead, N.Y.

“Unless we have evidence of a survival advantage in indolent disease, progression-free survivorship is not an adequate reason to jump to another antibody,” he said in an interview.

In GALLIUM, the primary endpoint of investigator-assessed 3-year PFS at a median follow-up of 34.5 months was 80% for patients with follicular lymphoma treated with obinutuzumab and one of three standard chemotherapy regimens, compared with 73.3% for patients treated with rituximab and chemotherapy. This difference translated into a hazard ratio of 0.68 favoring obinutuzumab (P = .0012).

Respective 3-year overall survival rates were similar, however, at 94% and 92.1% (HR, 0.75; P = .21).

Indolent lymphoma trial

The GALLIUM trial is a phase III study comparing obinutuzumab with rituximab when paired with one of three standard chemotherapy regimens for indolent non-Hodgkin lymphomas, including follicular lymphoma and splenic, nodal, or extranodal marginal zone lymphoma. Dr. Marcus presented data on patients with follicular lymphoma only.

The antibodies were delivered in combination with either CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone; 33.1% of patients), CVP (cyclophosphamide, vincristine, prednisone; 9.8%) or bendamustine alone (B; 57.1%) as the chemotherapy backbone. The choice of regimen was at the discretion of the treating center.

A total of 1,202 patients with follicular lymphoma were enrolled and randomized to treatment and were included in an intention-to-treat analysis.

The treatment arms were well balanced with regard to distribution of patients characteristics, with approximately 21% in each arm having Follicular Lymphoma International Prognostic Index low-risk disease; 37% having intermediate-risk disease; and 34% having high-risk disease.

Roughly half of patients in each arm had bone marrow involvement, and two-thirds had extranodal involvement.

Obinutuzumab was dosed 1,000 mg IV on days 1, 8, and 15 of cycle one, and either on day 1 of cycles two through eight every 3 weeks, or every 4 weeks during cycles two through six.

Overall response rates at the end of induction were 86.9% with rituximab and 88.5% with obinutuzumab, with complete responses of 23.8% and 19.5%, respectively.

As noted before, investigator-assessed PFS favored obinutuzumab, as did PFS assessed by independent reviewer, at 81.9% vs. 77.9% for rituximab (HR, 0.71; P = .0138).

The newer antibody also had a slight edge in time to new treatment, with 87.1% of patients on obinutuzumab not starting on new therapy, compared with 81.2% of patients on rituximab.

More bendamustine deaths

Nearly all patients in each arm had an adverse event, with grade 3 or greater events occurring in 74.6% of patients on obinutuzumab vs. 67.8% on rituximab. Rates of neutropenia, leukopenia, febrile neutropenia, infusion reactions, and thrombocytopenia were all slightly higher with obinutuzumab. Grade 3 or greater infections occurred in 20% with obinutuzumab, compared with 15.6% with rituximab.

“What we did note, however, was a high level of mortality in patients receiving either obinutuzumab-based therapy or rituximab-based therapy, which were no different between the two arms and were somewhat higher than one might expect from patients receiving induction treatment in follicular lymphoma. Hence, we did a more detailed analysis of safety by treatment regimen,” Dr. Marcus said.

There were more deaths among patients treated with bendamustine (5.6% for patients in the B-obinutuzumab cohort, and 4.4% of patients in the B-rituximab cohort) vs. 1.6% and 2.0%, respectively, for patients on CHOP, and 1.6 and 1.8% for patients on CVP.

Dose effect?

John P. Leonard, MD, from Cornell University, New York , who introduced Dr. Marcus, commented that PFS may not be the ideal endpoint for patients with follicular lymphoma.

He pointed out that in trials comparing rituximab with obinutuzumab for other diseases, results have been mixed, with obinutuzumab showing superiority in chronic lymphocytic leukemia, but in data presented elsewhere at ASH 2016, obinutuzumab was not superior to rituximab for treatment of diffuse large B-cell lymphoma.

“One question is whether obinutuzumab, which is generally administered at a higher mg dose to patients, is in fact a better antibody or if it is in fact a dose effect,” he said.

In response to a similar question following his presentation, Dr. Marcus replied that, despite sharing a target, the two antibodies are different, with different mechanisms of action. He also noted that there is no evidence to suggest that rituximab potency would be greater in follicular lymphoma if it were given at higher doses.

The GALLIUM trial is sponsored by Hoffmann-La Roche, Dr, Marcus disclosed consulting with and receiving honoraria from the company, and relationships with other companies.

SAN DIEGO – Obinutuzumab, a second-generation anti-CD20 antibody touted as the heir apparent to rituximab, offered a progression-free survival (PFS) edge over rituximab when combined with standard chemotherapy in patients with previously untreated advanced follicular lymphoma.

attended the presentation of the GALLIUM data at a plenary session during the American Society of Hematology annual meeting indicated that despite the data, they weren’t ready to make a switch to the newer, costlier antibody.

“I feel that it is not convincing for practice-changing,” said Kanti R. Rai, MD, professor of medicine and molecular medicine at Hofstra University, Hempstead, N.Y.

“Unless we have evidence of a survival advantage in indolent disease, progression-free survivorship is not an adequate reason to jump to another antibody,” he said in an interview.

In GALLIUM, the primary endpoint of investigator-assessed 3-year PFS at a median follow-up of 34.5 months was 80% for patients with follicular lymphoma treated with obinutuzumab and one of three standard chemotherapy regimens, compared with 73.3% for patients treated with rituximab and chemotherapy. This difference translated into a hazard ratio of 0.68 favoring obinutuzumab (P = .0012).

Respective 3-year overall survival rates were similar, however, at 94% and 92.1% (HR, 0.75; P = .21).

Indolent lymphoma trial

The GALLIUM trial is a phase III study comparing obinutuzumab with rituximab when paired with one of three standard chemotherapy regimens for indolent non-Hodgkin lymphomas, including follicular lymphoma and splenic, nodal, or extranodal marginal zone lymphoma. Dr. Marcus presented data on patients with follicular lymphoma only.

The antibodies were delivered in combination with either CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone; 33.1% of patients), CVP (cyclophosphamide, vincristine, prednisone; 9.8%) or bendamustine alone (B; 57.1%) as the chemotherapy backbone. The choice of regimen was at the discretion of the treating center.

A total of 1,202 patients with follicular lymphoma were enrolled and randomized to treatment and were included in an intention-to-treat analysis.

The treatment arms were well balanced with regard to distribution of patients characteristics, with approximately 21% in each arm having Follicular Lymphoma International Prognostic Index low-risk disease; 37% having intermediate-risk disease; and 34% having high-risk disease.

Roughly half of patients in each arm had bone marrow involvement, and two-thirds had extranodal involvement.

Obinutuzumab was dosed 1,000 mg IV on days 1, 8, and 15 of cycle one, and either on day 1 of cycles two through eight every 3 weeks, or every 4 weeks during cycles two through six.

Overall response rates at the end of induction were 86.9% with rituximab and 88.5% with obinutuzumab, with complete responses of 23.8% and 19.5%, respectively.

As noted before, investigator-assessed PFS favored obinutuzumab, as did PFS assessed by independent reviewer, at 81.9% vs. 77.9% for rituximab (HR, 0.71; P = .0138).

The newer antibody also had a slight edge in time to new treatment, with 87.1% of patients on obinutuzumab not starting on new therapy, compared with 81.2% of patients on rituximab.

More bendamustine deaths

Nearly all patients in each arm had an adverse event, with grade 3 or greater events occurring in 74.6% of patients on obinutuzumab vs. 67.8% on rituximab. Rates of neutropenia, leukopenia, febrile neutropenia, infusion reactions, and thrombocytopenia were all slightly higher with obinutuzumab. Grade 3 or greater infections occurred in 20% with obinutuzumab, compared with 15.6% with rituximab.

“What we did note, however, was a high level of mortality in patients receiving either obinutuzumab-based therapy or rituximab-based therapy, which were no different between the two arms and were somewhat higher than one might expect from patients receiving induction treatment in follicular lymphoma. Hence, we did a more detailed analysis of safety by treatment regimen,” Dr. Marcus said.

There were more deaths among patients treated with bendamustine (5.6% for patients in the B-obinutuzumab cohort, and 4.4% of patients in the B-rituximab cohort) vs. 1.6% and 2.0%, respectively, for patients on CHOP, and 1.6 and 1.8% for patients on CVP.

Dose effect?

John P. Leonard, MD, from Cornell University, New York , who introduced Dr. Marcus, commented that PFS may not be the ideal endpoint for patients with follicular lymphoma.

He pointed out that in trials comparing rituximab with obinutuzumab for other diseases, results have been mixed, with obinutuzumab showing superiority in chronic lymphocytic leukemia, but in data presented elsewhere at ASH 2016, obinutuzumab was not superior to rituximab for treatment of diffuse large B-cell lymphoma.

“One question is whether obinutuzumab, which is generally administered at a higher mg dose to patients, is in fact a better antibody or if it is in fact a dose effect,” he said.

In response to a similar question following his presentation, Dr. Marcus replied that, despite sharing a target, the two antibodies are different, with different mechanisms of action. He also noted that there is no evidence to suggest that rituximab potency would be greater in follicular lymphoma if it were given at higher doses.

The GALLIUM trial is sponsored by Hoffmann-La Roche, Dr, Marcus disclosed consulting with and receiving honoraria from the company, and relationships with other companies.

SAN DIEGO – Obinutuzumab, a second-generation anti-CD20 antibody touted as the heir apparent to rituximab, offered a progression-free survival (PFS) edge over rituximab when combined with standard chemotherapy in patients with previously untreated advanced follicular lymphoma.

attended the presentation of the GALLIUM data at a plenary session during the American Society of Hematology annual meeting indicated that despite the data, they weren’t ready to make a switch to the newer, costlier antibody.

“I feel that it is not convincing for practice-changing,” said Kanti R. Rai, MD, professor of medicine and molecular medicine at Hofstra University, Hempstead, N.Y.

“Unless we have evidence of a survival advantage in indolent disease, progression-free survivorship is not an adequate reason to jump to another antibody,” he said in an interview.

In GALLIUM, the primary endpoint of investigator-assessed 3-year PFS at a median follow-up of 34.5 months was 80% for patients with follicular lymphoma treated with obinutuzumab and one of three standard chemotherapy regimens, compared with 73.3% for patients treated with rituximab and chemotherapy. This difference translated into a hazard ratio of 0.68 favoring obinutuzumab (P = .0012).

Respective 3-year overall survival rates were similar, however, at 94% and 92.1% (HR, 0.75; P = .21).

Indolent lymphoma trial

The GALLIUM trial is a phase III study comparing obinutuzumab with rituximab when paired with one of three standard chemotherapy regimens for indolent non-Hodgkin lymphomas, including follicular lymphoma and splenic, nodal, or extranodal marginal zone lymphoma. Dr. Marcus presented data on patients with follicular lymphoma only.

The antibodies were delivered in combination with either CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone; 33.1% of patients), CVP (cyclophosphamide, vincristine, prednisone; 9.8%) or bendamustine alone (B; 57.1%) as the chemotherapy backbone. The choice of regimen was at the discretion of the treating center.

A total of 1,202 patients with follicular lymphoma were enrolled and randomized to treatment and were included in an intention-to-treat analysis.

The treatment arms were well balanced with regard to distribution of patients characteristics, with approximately 21% in each arm having Follicular Lymphoma International Prognostic Index low-risk disease; 37% having intermediate-risk disease; and 34% having high-risk disease.

Roughly half of patients in each arm had bone marrow involvement, and two-thirds had extranodal involvement.

Obinutuzumab was dosed 1,000 mg IV on days 1, 8, and 15 of cycle one, and either on day 1 of cycles two through eight every 3 weeks, or every 4 weeks during cycles two through six.

Overall response rates at the end of induction were 86.9% with rituximab and 88.5% with obinutuzumab, with complete responses of 23.8% and 19.5%, respectively.

As noted before, investigator-assessed PFS favored obinutuzumab, as did PFS assessed by independent reviewer, at 81.9% vs. 77.9% for rituximab (HR, 0.71; P = .0138).

The newer antibody also had a slight edge in time to new treatment, with 87.1% of patients on obinutuzumab not starting on new therapy, compared with 81.2% of patients on rituximab.

More bendamustine deaths

Nearly all patients in each arm had an adverse event, with grade 3 or greater events occurring in 74.6% of patients on obinutuzumab vs. 67.8% on rituximab. Rates of neutropenia, leukopenia, febrile neutropenia, infusion reactions, and thrombocytopenia were all slightly higher with obinutuzumab. Grade 3 or greater infections occurred in 20% with obinutuzumab, compared with 15.6% with rituximab.

“What we did note, however, was a high level of mortality in patients receiving either obinutuzumab-based therapy or rituximab-based therapy, which were no different between the two arms and were somewhat higher than one might expect from patients receiving induction treatment in follicular lymphoma. Hence, we did a more detailed analysis of safety by treatment regimen,” Dr. Marcus said.

There were more deaths among patients treated with bendamustine (5.6% for patients in the B-obinutuzumab cohort, and 4.4% of patients in the B-rituximab cohort) vs. 1.6% and 2.0%, respectively, for patients on CHOP, and 1.6 and 1.8% for patients on CVP.

Dose effect?

John P. Leonard, MD, from Cornell University, New York , who introduced Dr. Marcus, commented that PFS may not be the ideal endpoint for patients with follicular lymphoma.

He pointed out that in trials comparing rituximab with obinutuzumab for other diseases, results have been mixed, with obinutuzumab showing superiority in chronic lymphocytic leukemia, but in data presented elsewhere at ASH 2016, obinutuzumab was not superior to rituximab for treatment of diffuse large B-cell lymphoma.

“One question is whether obinutuzumab, which is generally administered at a higher mg dose to patients, is in fact a better antibody or if it is in fact a dose effect,” he said.

In response to a similar question following his presentation, Dr. Marcus replied that, despite sharing a target, the two antibodies are different, with different mechanisms of action. He also noted that there is no evidence to suggest that rituximab potency would be greater in follicular lymphoma if it were given at higher doses.

The GALLIUM trial is sponsored by Hoffmann-La Roche, Dr, Marcus disclosed consulting with and receiving honoraria from the company, and relationships with other companies.

 

 

Micrograph showing DLBCL

 

The US Food and Drug Administration (FDA) has granted fast track designation for tazemetostat as a treatment for patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) with EZH2 activating mutations.

Tazemetostat inhibits EZH2, a histone methyltransferase that appears to play a role in the growth and proliferation of a number of cancers, including DLBCL.

Tazemetostat is being developed by Epizyme, Inc.

The FDA’s fast track program is designed to facilitate the development and expedite the review of products intended to treat or prevent serious or life-threatening conditions and address unmet medical need.

Through the FDA’s fast track program, a product may be eligible for priority review. In addition, the company developing the product may be allowed to submit sections of the biologic license application or new drug application on a rolling basis as data become available.

Fast track designation also provides the company with opportunities for more frequent meetings and written communications with the FDA.

Tazemetostat trials

Tazemetostat is under investigation as monotherapy and in combination with other agents as a treatment for multiple cancers.

Results from a phase 1 study suggested tazemetostat monotherapy can produce durable responses in patients with advanced non-Hodgkin lymphomas, including DLBCL. The study was presented at the 2015 ASH Annual Meeting.

Now, Epizyme is conducting a phase 2 study of tazemetostat monotherapy in adults with relapsed or refractory DLBCL or follicular lymphoma.

Tazemetostat is also being evaluated in 2 combination studies in patients with DLBCL.

In a phase 1b/2 trial, researchers are investigating tazemetostat in combination with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) as a front-line treatment for patients with DLBCL.

In a phase 1b study, researchers are evaluating tazemetostat in combination with atezolizumab, an anti-PD-L1 immunotherapy, in patients with relapsed and refractory DLBCL.

 

 

Micrograph showing DLBCL

 

The US Food and Drug Administration (FDA) has granted fast track designation for tazemetostat as a treatment for patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) with EZH2 activating mutations.

Tazemetostat inhibits EZH2, a histone methyltransferase that appears to play a role in the growth and proliferation of a number of cancers, including DLBCL.

Tazemetostat is being developed by Epizyme, Inc.

The FDA’s fast track program is designed to facilitate the development and expedite the review of products intended to treat or prevent serious or life-threatening conditions and address unmet medical need.

Through the FDA’s fast track program, a product may be eligible for priority review. In addition, the company developing the product may be allowed to submit sections of the biologic license application or new drug application on a rolling basis as data become available.

Fast track designation also provides the company with opportunities for more frequent meetings and written communications with the FDA.

Tazemetostat trials

Tazemetostat is under investigation as monotherapy and in combination with other agents as a treatment for multiple cancers.

Results from a phase 1 study suggested tazemetostat monotherapy can produce durable responses in patients with advanced non-Hodgkin lymphomas, including DLBCL. The study was presented at the 2015 ASH Annual Meeting.

Now, Epizyme is conducting a phase 2 study of tazemetostat monotherapy in adults with relapsed or refractory DLBCL or follicular lymphoma.

Tazemetostat is also being evaluated in 2 combination studies in patients with DLBCL.

In a phase 1b/2 trial, researchers are investigating tazemetostat in combination with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) as a front-line treatment for patients with DLBCL.

In a phase 1b study, researchers are evaluating tazemetostat in combination with atezolizumab, an anti-PD-L1 immunotherapy, in patients with relapsed and refractory DLBCL.

 

 

Micrograph showing DLBCL

 

The US Food and Drug Administration (FDA) has granted fast track designation for tazemetostat as a treatment for patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) with EZH2 activating mutations.

Tazemetostat inhibits EZH2, a histone methyltransferase that appears to play a role in the growth and proliferation of a number of cancers, including DLBCL.

Tazemetostat is being developed by Epizyme, Inc.

The FDA’s fast track program is designed to facilitate the development and expedite the review of products intended to treat or prevent serious or life-threatening conditions and address unmet medical need.

Through the FDA’s fast track program, a product may be eligible for priority review. In addition, the company developing the product may be allowed to submit sections of the biologic license application or new drug application on a rolling basis as data become available.

Fast track designation also provides the company with opportunities for more frequent meetings and written communications with the FDA.

Tazemetostat trials

Tazemetostat is under investigation as monotherapy and in combination with other agents as a treatment for multiple cancers.

Results from a phase 1 study suggested tazemetostat monotherapy can produce durable responses in patients with advanced non-Hodgkin lymphomas, including DLBCL. The study was presented at the 2015 ASH Annual Meeting.

Now, Epizyme is conducting a phase 2 study of tazemetostat monotherapy in adults with relapsed or refractory DLBCL or follicular lymphoma.

Tazemetostat is also being evaluated in 2 combination studies in patients with DLBCL.

In a phase 1b/2 trial, researchers are investigating tazemetostat in combination with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) as a front-line treatment for patients with DLBCL.

In a phase 1b study, researchers are evaluating tazemetostat in combination with atezolizumab, an anti-PD-L1 immunotherapy, in patients with relapsed and refractory DLBCL.

 

 

Blood sample collection

Photo by Juan D. Alfonso

 

A blood test can reveal genetic features linked to outcomes in patients with diffuse large B-cell lymphoma (DLBCL), according to research published in Science Translational Medicine.

Investigators used targeted sequencing to analyze circulating tumor DNA (ctDNA) in blood samples from DLBCL patients.

This allowed the team to identify the cell of origin, detect minimal residual disease (MRD), and predict progression-free survival (PFS) in these patients.

Florian Scherer, MD, of Stanford University in California, and his colleagues conducted this research.

They used cancer personalized profiling by deep sequencing (CAPP-Seq) to analyze tumor biopsies and cell-free DNA samples from 92 patients with DLBCL and 24 healthy controls.

The investigators found that CAPP-Seq could effectively detect somatic mutations in DLBCL plasma samples as well as tumor biopsies. They said their results suggest ctDNA is a “robust surrogate for direct assessment of primary tumor genotypes” in most DLBCL patients.

In addition, ctDNA profiling with CAPP-Seq revealed mutations associated with resistance to the BTK inhibitor ibrutinib.

The investigators also said their results suggest ctDNA profiling can be used to classify DLBCL subtypes. The overall concordance in cell of origin predictions between tumor tissue and plasma genotyping was 88%.

Another key finding of this study is that the amount of ctDNA at DLBCL diagnosis was predictive of PFS. The investigators said higher ctDNA levels at diagnosis were “continuously and independently” correlated with inferior PFS.

Dr Scherer and his colleagues also discovered that ctDNA profiling could detect MRD with greater accuracy than immunoglobulin sequencing and radiographic imaging. And patients with ctDNA in their plasma had significantly worse PFS than patients with undetectable ctDNA.

Finally, the investigators found evidence to suggest that ctDNA profiling could provide early detection of disease transformation. They identified “distinct patterns of clonal evolution” by which they could distinguish indolent follicular lymphomas from follicular lymphomas that transformed into DLBCL.

 

 

Blood sample collection

Photo by Juan D. Alfonso

 

A blood test can reveal genetic features linked to outcomes in patients with diffuse large B-cell lymphoma (DLBCL), according to research published in Science Translational Medicine.

Investigators used targeted sequencing to analyze circulating tumor DNA (ctDNA) in blood samples from DLBCL patients.

This allowed the team to identify the cell of origin, detect minimal residual disease (MRD), and predict progression-free survival (PFS) in these patients.

Florian Scherer, MD, of Stanford University in California, and his colleagues conducted this research.

They used cancer personalized profiling by deep sequencing (CAPP-Seq) to analyze tumor biopsies and cell-free DNA samples from 92 patients with DLBCL and 24 healthy controls.

The investigators found that CAPP-Seq could effectively detect somatic mutations in DLBCL plasma samples as well as tumor biopsies. They said their results suggest ctDNA is a “robust surrogate for direct assessment of primary tumor genotypes” in most DLBCL patients.

In addition, ctDNA profiling with CAPP-Seq revealed mutations associated with resistance to the BTK inhibitor ibrutinib.

The investigators also said their results suggest ctDNA profiling can be used to classify DLBCL subtypes. The overall concordance in cell of origin predictions between tumor tissue and plasma genotyping was 88%.

Another key finding of this study is that the amount of ctDNA at DLBCL diagnosis was predictive of PFS. The investigators said higher ctDNA levels at diagnosis were “continuously and independently” correlated with inferior PFS.

Dr Scherer and his colleagues also discovered that ctDNA profiling could detect MRD with greater accuracy than immunoglobulin sequencing and radiographic imaging. And patients with ctDNA in their plasma had significantly worse PFS than patients with undetectable ctDNA.

Finally, the investigators found evidence to suggest that ctDNA profiling could provide early detection of disease transformation. They identified “distinct patterns of clonal evolution” by which they could distinguish indolent follicular lymphomas from follicular lymphomas that transformed into DLBCL.

 

 

Blood sample collection

Photo by Juan D. Alfonso

 

A blood test can reveal genetic features linked to outcomes in patients with diffuse large B-cell lymphoma (DLBCL), according to research published in Science Translational Medicine.

Investigators used targeted sequencing to analyze circulating tumor DNA (ctDNA) in blood samples from DLBCL patients.

This allowed the team to identify the cell of origin, detect minimal residual disease (MRD), and predict progression-free survival (PFS) in these patients.

Florian Scherer, MD, of Stanford University in California, and his colleagues conducted this research.

They used cancer personalized profiling by deep sequencing (CAPP-Seq) to analyze tumor biopsies and cell-free DNA samples from 92 patients with DLBCL and 24 healthy controls.

The investigators found that CAPP-Seq could effectively detect somatic mutations in DLBCL plasma samples as well as tumor biopsies. They said their results suggest ctDNA is a “robust surrogate for direct assessment of primary tumor genotypes” in most DLBCL patients.

In addition, ctDNA profiling with CAPP-Seq revealed mutations associated with resistance to the BTK inhibitor ibrutinib.

The investigators also said their results suggest ctDNA profiling can be used to classify DLBCL subtypes. The overall concordance in cell of origin predictions between tumor tissue and plasma genotyping was 88%.

Another key finding of this study is that the amount of ctDNA at DLBCL diagnosis was predictive of PFS. The investigators said higher ctDNA levels at diagnosis were “continuously and independently” correlated with inferior PFS.

Dr Scherer and his colleagues also discovered that ctDNA profiling could detect MRD with greater accuracy than immunoglobulin sequencing and radiographic imaging. And patients with ctDNA in their plasma had significantly worse PFS than patients with undetectable ctDNA.

Finally, the investigators found evidence to suggest that ctDNA profiling could provide early detection of disease transformation. They identified “distinct patterns of clonal evolution” by which they could distinguish indolent follicular lymphomas from follicular lymphomas that transformed into DLBCL.

 

 

Genome testing

Photo courtesy of the

National Institute

of General Medical Science

 

NEW YORK—Research has shown that family history is a strong risk factor for developing chronic lymphocytic leukemia (CLL).

First-degree relatives have an 8.5-fold risk of getting CLL and an increased risk of other lymphoproliferative disorders, according to a study published in 2009.

However, despite the strong evidence of a genetic contribution, one expert believes it’s premature to bring genetic testing into the clinic for screening in CLL.

“At this time, we do not recommend genetic screening,” said Susan Slager, PhD, of the Mayo Clinic in Rochester, Minnesota.

“There’s no known relationship between the inherited variants and treatment response,” she explained, and the relatively low incidence of CLL argues against active screening in affected families at present.

Dr Slager discussed genetic and non-genetic factors associated with CLL and the clinical implications of these factors at Lymphoma & Myeloma 2016.

Demographic risk factors

Dr Slager noted that age, gender, and race are risk factors for CLL.

Individuals aged 65 to 74 have the highest incidence of CLL, at 28%, while the risk is almost non-existent for those under age 20, she said.

There is a higher incidence of CLL in males than in females, and the reason for this gender disparity is unknown.

There is a higher incidence of CLL in Caucasians than Asians, for both males and females.

“Again, it’s unknown why there’s this variability in incidence in CLL,” Dr Slager said. “Obviously, age, sex, and race—these are things you can’t modify. You’re stuck with them.”

However, several studies have been undertaken to look at some of the potentially modifiable factors associated with CLL.

Beyond demographic factors

The International Lymphoma Epidemiology Consortium, known as InterLymph, was initiated in 2001 to evaluate the association of risk factors in CLL. Study centers are located primarily in North America and Europe, with one in Australia.

In one of the larger InterLymph studies, investigators evaluated risk factors—lifestyle exposure, reproductive history, medical history, occupational exposures, farming exposure, and family history—in 2440 CLL patients and 15,186 controls.

The investigators found that sun exposure and atopy—allergies, asthma, eczema, and hay fever—have a protective effect in CLL, while serological hepatitis C virus (HCV) infections, farming exposure, and family history carry an increased risk of CLL.

This confirmed an earlier study conducted in New South Wales, Australia, that had uncovered an inverse association between sun exposure and non-Hodgkin lymphoma (NHL) risk, which fell significantly with increasing recreational sun exposure.

Medical history

Another earlier study from New South Wales revealed a 20% reduction in the risk of NHL for any specific allergy.

However, the investigators of the large, more recent study observed little to no evidence of reduced risk for asthma and eczema.

The underlying biology for atopy or allergies is a hyper-immune system, Dr Slager explained.

“So if you have a hyper-immune system, then we hypothesize that you have protection against CLL,” she said.

Another medical exposure investigators analyzed that impacts CLL risk is HCV. People infected with HCV have an increased risk of CLL, perhaps due to chronic antigen stimulation or possibly disruption of the T-cell function.

Height is also associated with CLL. CLL risk increases with greater height. The concept is that taller individuals have increased exposure to growth hormones that possibly result in cell proliferation.

Another hypothesis supporting the height association is that people of shorter stature experience more infections, which could result in a stronger immune system. And a stronger immune system perhaps protects against NHL.

Occupational exposures

Investigators consistently observed a 20% increased risk of CLL for people living or working on a farm.

Animal farmers, as opposed to crop farmers, experienced some protection. However, the sample size was too small to be conclusive, with only 29 people across all studies being animal farmers.

Among other occupations evaluated, hairdressers also had an increased risk of CLL, although this too was based on a small sample size.

Family history

One of the strongest risk factors for CLL is family history.

Using population-based registry data from Sweden, investigators found that people with a first-degree relative with CLL have an 8.5-fold risk of CLL.

They also have an elevated risk of other lymphoproliferative disorders, including NHL (1.9-fold risk), Waldenström’s macroglobulinemia (4.0-fold risk), hairy cell leukemia (3.3-fold risk), and follicular lymphoma (1.6-fold risk).

GWAS in CLL

Investigators conducted genome-wide association studies (GWAS) to determine what is driving the familial risk.

Dr Slager described these studies as an agnostic approach that looks across the entire genome to determine which regions are associated with a trait of interest.

Typically, many markers are genotyped—somewhere between half a million to 5 million markers—and each is looked at individually with respect to CLL, she said.

Unrelated cases and controls are included in the studies.

The first GWAS study identifying susceptibility loci for CLL was published in 2008. Subsequently, more studies were published with increasing sample sizes—more cases, more controls, and more genetic variants identified.

In the largest meta-analysis for CLL to date (Slager and Houlston et al, not yet published), investigators analyzed 4400 CLL cases and 13,000 controls.

They identified 9 more inherited variances with CLL, for a total of 43 identified to date.

The genes involved follow an apoptosis pathway, the telomere length pathway, and the B-cell lymphocyte development pathway.

“We have to remember, though, that these are non-causal,” Dr Slager cautioned. “We are just identifying the region in the genome that’s associated with CLL . . . . So now we have to dig deeper in these relationships to understand what’s going on.”

Using the identified CLL single-nucleotide polymorphisms, the investigators computed a polygenic risk score. CLL cases in the highest quintile had 2.7-fold increased risk of CLL.

However, the most common GWAS variants explain only 17% of the genetic heritability of CLL, which suggests that more loci are yet to be identified, Dr Slager clarified.

She went on to say that CLL incidence varies by ethnicity. Caucasians have a very high rate of CLL, while Asians have a very low rate. And African Americans have an incidence rate between those of Caucasians and Asians.

Investigators have hypothesized that the differences in incidence are based on the distinct genetic variants that are associated with the ethnicities.

For example, 4 of the variants with more than 20% frequency in Caucasians are quite rare in Chinese individuals and are also quite uncommon in African Americans, with frequencies less than 10%.

Dr Slager suggested that conducting these kinds of studies in Asians and African Americans will take a large sample size and most likely require an international consortium to bring enough CLL cases together.

Impact on clinical practice

Because of the strong genetic risk, patients with CLL naturally want to know about their offspring and their siblings, Dr Slager has found.

Patients who have monoclonal B-cell lymphocytosis (MBL), which is a precursor to CLL, pose the biggest quandary.

MBL is detected in about 5% of people over age 40. However, it’s detected in about 15% to 18% of people with a first-degree relative with CLL.

“These are individuals who have lymphocytosis,” Dr Slager said. “They come to your clinic and have an elevated blood cell count, flow cytometry. [So] you screen them for MBL, and these individuals who have more than 500 cells per microliter, they are the ones who progress to CLL, at 1% per year.”

Individuals who don’t have the elevated blood counts do have the clonal cells, Dr Slager noted.

“They just don’t have the expansion,” she said. “The progression of these individuals to CLL is still yet to be determined.”

For these reasons, Dr Slager believes “it’s still premature to bring genetic testing into clinical practice.”

Future directions include bringing together the non-environmental issues and the inherited issues to create a model that will accurately predict the risk of CLL.

 

 

Genome testing

Photo courtesy of the

National Institute

of General Medical Science

 

NEW YORK—Research has shown that family history is a strong risk factor for developing chronic lymphocytic leukemia (CLL).

First-degree relatives have an 8.5-fold risk of getting CLL and an increased risk of other lymphoproliferative disorders, according to a study published in 2009.

However, despite the strong evidence of a genetic contribution, one expert believes it’s premature to bring genetic testing into the clinic for screening in CLL.

“At this time, we do not recommend genetic screening,” said Susan Slager, PhD, of the Mayo Clinic in Rochester, Minnesota.

“There’s no known relationship between the inherited variants and treatment response,” she explained, and the relatively low incidence of CLL argues against active screening in affected families at present.

Dr Slager discussed genetic and non-genetic factors associated with CLL and the clinical implications of these factors at Lymphoma & Myeloma 2016.

Demographic risk factors

Dr Slager noted that age, gender, and race are risk factors for CLL.

Individuals aged 65 to 74 have the highest incidence of CLL, at 28%, while the risk is almost non-existent for those under age 20, she said.

There is a higher incidence of CLL in males than in females, and the reason for this gender disparity is unknown.

There is a higher incidence of CLL in Caucasians than Asians, for both males and females.

“Again, it’s unknown why there’s this variability in incidence in CLL,” Dr Slager said. “Obviously, age, sex, and race—these are things you can’t modify. You’re stuck with them.”

However, several studies have been undertaken to look at some of the potentially modifiable factors associated with CLL.

Beyond demographic factors

The International Lymphoma Epidemiology Consortium, known as InterLymph, was initiated in 2001 to evaluate the association of risk factors in CLL. Study centers are located primarily in North America and Europe, with one in Australia.

In one of the larger InterLymph studies, investigators evaluated risk factors—lifestyle exposure, reproductive history, medical history, occupational exposures, farming exposure, and family history—in 2440 CLL patients and 15,186 controls.

The investigators found that sun exposure and atopy—allergies, asthma, eczema, and hay fever—have a protective effect in CLL, while serological hepatitis C virus (HCV) infections, farming exposure, and family history carry an increased risk of CLL.

This confirmed an earlier study conducted in New South Wales, Australia, that had uncovered an inverse association between sun exposure and non-Hodgkin lymphoma (NHL) risk, which fell significantly with increasing recreational sun exposure.

Medical history

Another earlier study from New South Wales revealed a 20% reduction in the risk of NHL for any specific allergy.

However, the investigators of the large, more recent study observed little to no evidence of reduced risk for asthma and eczema.

The underlying biology for atopy or allergies is a hyper-immune system, Dr Slager explained.

“So if you have a hyper-immune system, then we hypothesize that you have protection against CLL,” she said.

Another medical exposure investigators analyzed that impacts CLL risk is HCV. People infected with HCV have an increased risk of CLL, perhaps due to chronic antigen stimulation or possibly disruption of the T-cell function.

Height is also associated with CLL. CLL risk increases with greater height. The concept is that taller individuals have increased exposure to growth hormones that possibly result in cell proliferation.

Another hypothesis supporting the height association is that people of shorter stature experience more infections, which could result in a stronger immune system. And a stronger immune system perhaps protects against NHL.

Occupational exposures

Investigators consistently observed a 20% increased risk of CLL for people living or working on a farm.

Animal farmers, as opposed to crop farmers, experienced some protection. However, the sample size was too small to be conclusive, with only 29 people across all studies being animal farmers.

Among other occupations evaluated, hairdressers also had an increased risk of CLL, although this too was based on a small sample size.

Family history

One of the strongest risk factors for CLL is family history.

Using population-based registry data from Sweden, investigators found that people with a first-degree relative with CLL have an 8.5-fold risk of CLL.

They also have an elevated risk of other lymphoproliferative disorders, including NHL (1.9-fold risk), Waldenström’s macroglobulinemia (4.0-fold risk), hairy cell leukemia (3.3-fold risk), and follicular lymphoma (1.6-fold risk).

GWAS in CLL

Investigators conducted genome-wide association studies (GWAS) to determine what is driving the familial risk.

Dr Slager described these studies as an agnostic approach that looks across the entire genome to determine which regions are associated with a trait of interest.

Typically, many markers are genotyped—somewhere between half a million to 5 million markers—and each is looked at individually with respect to CLL, she said.

Unrelated cases and controls are included in the studies.

The first GWAS study identifying susceptibility loci for CLL was published in 2008. Subsequently, more studies were published with increasing sample sizes—more cases, more controls, and more genetic variants identified.

In the largest meta-analysis for CLL to date (Slager and Houlston et al, not yet published), investigators analyzed 4400 CLL cases and 13,000 controls.

They identified 9 more inherited variances with CLL, for a total of 43 identified to date.

The genes involved follow an apoptosis pathway, the telomere length pathway, and the B-cell lymphocyte development pathway.

“We have to remember, though, that these are non-causal,” Dr Slager cautioned. “We are just identifying the region in the genome that’s associated with CLL . . . . So now we have to dig deeper in these relationships to understand what’s going on.”

Using the identified CLL single-nucleotide polymorphisms, the investigators computed a polygenic risk score. CLL cases in the highest quintile had 2.7-fold increased risk of CLL.

However, the most common GWAS variants explain only 17% of the genetic heritability of CLL, which suggests that more loci are yet to be identified, Dr Slager clarified.

She went on to say that CLL incidence varies by ethnicity. Caucasians have a very high rate of CLL, while Asians have a very low rate. And African Americans have an incidence rate between those of Caucasians and Asians.

Investigators have hypothesized that the differences in incidence are based on the distinct genetic variants that are associated with the ethnicities.

For example, 4 of the variants with more than 20% frequency in Caucasians are quite rare in Chinese individuals and are also quite uncommon in African Americans, with frequencies less than 10%.

Dr Slager suggested that conducting these kinds of studies in Asians and African Americans will take a large sample size and most likely require an international consortium to bring enough CLL cases together.

Impact on clinical practice

Because of the strong genetic risk, patients with CLL naturally want to know about their offspring and their siblings, Dr Slager has found.

Patients who have monoclonal B-cell lymphocytosis (MBL), which is a precursor to CLL, pose the biggest quandary.

MBL is detected in about 5% of people over age 40. However, it’s detected in about 15% to 18% of people with a first-degree relative with CLL.

“These are individuals who have lymphocytosis,” Dr Slager said. “They come to your clinic and have an elevated blood cell count, flow cytometry. [So] you screen them for MBL, and these individuals who have more than 500 cells per microliter, they are the ones who progress to CLL, at 1% per year.”

Individuals who don’t have the elevated blood counts do have the clonal cells, Dr Slager noted.

“They just don’t have the expansion,” she said. “The progression of these individuals to CLL is still yet to be determined.”

For these reasons, Dr Slager believes “it’s still premature to bring genetic testing into clinical practice.”

Future directions include bringing together the non-environmental issues and the inherited issues to create a model that will accurately predict the risk of CLL.

 

 

Genome testing

Photo courtesy of the

National Institute

of General Medical Science

 

NEW YORK—Research has shown that family history is a strong risk factor for developing chronic lymphocytic leukemia (CLL).

First-degree relatives have an 8.5-fold risk of getting CLL and an increased risk of other lymphoproliferative disorders, according to a study published in 2009.

However, despite the strong evidence of a genetic contribution, one expert believes it’s premature to bring genetic testing into the clinic for screening in CLL.

“At this time, we do not recommend genetic screening,” said Susan Slager, PhD, of the Mayo Clinic in Rochester, Minnesota.

“There’s no known relationship between the inherited variants and treatment response,” she explained, and the relatively low incidence of CLL argues against active screening in affected families at present.

Dr Slager discussed genetic and non-genetic factors associated with CLL and the clinical implications of these factors at Lymphoma & Myeloma 2016.

Demographic risk factors

Dr Slager noted that age, gender, and race are risk factors for CLL.

Individuals aged 65 to 74 have the highest incidence of CLL, at 28%, while the risk is almost non-existent for those under age 20, she said.

There is a higher incidence of CLL in males than in females, and the reason for this gender disparity is unknown.

There is a higher incidence of CLL in Caucasians than Asians, for both males and females.

“Again, it’s unknown why there’s this variability in incidence in CLL,” Dr Slager said. “Obviously, age, sex, and race—these are things you can’t modify. You’re stuck with them.”

However, several studies have been undertaken to look at some of the potentially modifiable factors associated with CLL.

Beyond demographic factors

The International Lymphoma Epidemiology Consortium, known as InterLymph, was initiated in 2001 to evaluate the association of risk factors in CLL. Study centers are located primarily in North America and Europe, with one in Australia.

In one of the larger InterLymph studies, investigators evaluated risk factors—lifestyle exposure, reproductive history, medical history, occupational exposures, farming exposure, and family history—in 2440 CLL patients and 15,186 controls.

The investigators found that sun exposure and atopy—allergies, asthma, eczema, and hay fever—have a protective effect in CLL, while serological hepatitis C virus (HCV) infections, farming exposure, and family history carry an increased risk of CLL.

This confirmed an earlier study conducted in New South Wales, Australia, that had uncovered an inverse association between sun exposure and non-Hodgkin lymphoma (NHL) risk, which fell significantly with increasing recreational sun exposure.

Medical history

Another earlier study from New South Wales revealed a 20% reduction in the risk of NHL for any specific allergy.

However, the investigators of the large, more recent study observed little to no evidence of reduced risk for asthma and eczema.

The underlying biology for atopy or allergies is a hyper-immune system, Dr Slager explained.

“So if you have a hyper-immune system, then we hypothesize that you have protection against CLL,” she said.

Another medical exposure investigators analyzed that impacts CLL risk is HCV. People infected with HCV have an increased risk of CLL, perhaps due to chronic antigen stimulation or possibly disruption of the T-cell function.

Height is also associated with CLL. CLL risk increases with greater height. The concept is that taller individuals have increased exposure to growth hormones that possibly result in cell proliferation.

Another hypothesis supporting the height association is that people of shorter stature experience more infections, which could result in a stronger immune system. And a stronger immune system perhaps protects against NHL.

Occupational exposures

Investigators consistently observed a 20% increased risk of CLL for people living or working on a farm.

Animal farmers, as opposed to crop farmers, experienced some protection. However, the sample size was too small to be conclusive, with only 29 people across all studies being animal farmers.

Among other occupations evaluated, hairdressers also had an increased risk of CLL, although this too was based on a small sample size.

Family history

One of the strongest risk factors for CLL is family history.

Using population-based registry data from Sweden, investigators found that people with a first-degree relative with CLL have an 8.5-fold risk of CLL.

They also have an elevated risk of other lymphoproliferative disorders, including NHL (1.9-fold risk), Waldenström’s macroglobulinemia (4.0-fold risk), hairy cell leukemia (3.3-fold risk), and follicular lymphoma (1.6-fold risk).

GWAS in CLL

Investigators conducted genome-wide association studies (GWAS) to determine what is driving the familial risk.

Dr Slager described these studies as an agnostic approach that looks across the entire genome to determine which regions are associated with a trait of interest.

Typically, many markers are genotyped—somewhere between half a million to 5 million markers—and each is looked at individually with respect to CLL, she said.

Unrelated cases and controls are included in the studies.

The first GWAS study identifying susceptibility loci for CLL was published in 2008. Subsequently, more studies were published with increasing sample sizes—more cases, more controls, and more genetic variants identified.

In the largest meta-analysis for CLL to date (Slager and Houlston et al, not yet published), investigators analyzed 4400 CLL cases and 13,000 controls.

They identified 9 more inherited variances with CLL, for a total of 43 identified to date.

The genes involved follow an apoptosis pathway, the telomere length pathway, and the B-cell lymphocyte development pathway.

“We have to remember, though, that these are non-causal,” Dr Slager cautioned. “We are just identifying the region in the genome that’s associated with CLL . . . . So now we have to dig deeper in these relationships to understand what’s going on.”

Using the identified CLL single-nucleotide polymorphisms, the investigators computed a polygenic risk score. CLL cases in the highest quintile had 2.7-fold increased risk of CLL.

However, the most common GWAS variants explain only 17% of the genetic heritability of CLL, which suggests that more loci are yet to be identified, Dr Slager clarified.

She went on to say that CLL incidence varies by ethnicity. Caucasians have a very high rate of CLL, while Asians have a very low rate. And African Americans have an incidence rate between those of Caucasians and Asians.

Investigators have hypothesized that the differences in incidence are based on the distinct genetic variants that are associated with the ethnicities.

For example, 4 of the variants with more than 20% frequency in Caucasians are quite rare in Chinese individuals and are also quite uncommon in African Americans, with frequencies less than 10%.

Dr Slager suggested that conducting these kinds of studies in Asians and African Americans will take a large sample size and most likely require an international consortium to bring enough CLL cases together.

Impact on clinical practice

Because of the strong genetic risk, patients with CLL naturally want to know about their offspring and their siblings, Dr Slager has found.

Patients who have monoclonal B-cell lymphocytosis (MBL), which is a precursor to CLL, pose the biggest quandary.

MBL is detected in about 5% of people over age 40. However, it’s detected in about 15% to 18% of people with a first-degree relative with CLL.

“These are individuals who have lymphocytosis,” Dr Slager said. “They come to your clinic and have an elevated blood cell count, flow cytometry. [So] you screen them for MBL, and these individuals who have more than 500 cells per microliter, they are the ones who progress to CLL, at 1% per year.”

Individuals who don’t have the elevated blood counts do have the clonal cells, Dr Slager noted.

“They just don’t have the expansion,” she said. “The progression of these individuals to CLL is still yet to be determined.”

For these reasons, Dr Slager believes “it’s still premature to bring genetic testing into clinical practice.”

Future directions include bringing together the non-environmental issues and the inherited issues to create a model that will accurately predict the risk of CLL.

 

 

Micrograph showing CMV

 

The European Medicines Agency’s Committee for Orphan Medicinal Products (COMP) is recommending orphan designation for a cytomegalovirus-specific cytotoxic T-lymphocyte product (CMV-CTLs) intended to treat CMV infection in patients with impaired cell-mediated immunity.

The CMV-CTLs are designed to find and kill cells expressing CMV.

To create CMV-CTLs, T cells are collected from the blood of third-party donors and then exposed to CMV antigens.

The resulting activated T cells are then expanded, characterized, and stored for future use in a partially HLA-matched patient.

The CMV-CTLs are being developed by Atara Biotherapeutics, Inc.

The cells are currently under investigation in a pair of phase 2 trials (NCT01646645 and NCT02136797).

Results of a phase 1 trial (published in Biology of Blood and Marrow Transplantation in 2015) suggested CMV-CTLs are safe and can clear CMV infection in patients who have undergone allogeneic hematopoietic stem cell transplant.

The trial included 17 transplant recipients with CMV viremia or clinical infection that persisted despite prolonged treatment with antiviral drugs. Fourteen of the patients had received T-cell-depleted transplants without graft-versus-host disease (GVHD) prophylaxis.

Sixteen of the patients received CMV-CTLs created using cells derived from their transplant donor, and 1 patient received cells from a third-party donor.

Fifteen patients achieved clearance of CMV viremia, including 3 of the 5 patients with overt disease and the patient who received cells from a third-party donor.

In addition, the researchers said CMV-CTLs were well-tolerated. None of the patients experienced fever, alterations in vital signs, or other toxicities during the first 48 hours of observation.

None of the patients developed manifestations of de novo acute GVHD, and GHVD did not worsen in either of the 2 patients who had GVHD prior to infusion.

About orphan designation

The COMP adopts an opinion on the granting of orphan drug designation, and that opinion is submitted to the European Commission for a final decision.

Orphan designation provides regulatory and financial incentives for companies to develop and market therapies that treat life-threatening or chronically debilitating conditions affecting no more than 5 in 10,000 people in the European Union, and where no satisfactory treatment is available.

Orphan designation provides a 10-year period of marketing exclusivity if the drug receives regulatory approval.

The designation also provides incentives for companies seeking protocol assistance from the European Medicines Agency during the product development phase and direct access to the centralized authorization procedure.

 

 

Micrograph showing CMV

 

The European Medicines Agency’s Committee for Orphan Medicinal Products (COMP) is recommending orphan designation for a cytomegalovirus-specific cytotoxic T-lymphocyte product (CMV-CTLs) intended to treat CMV infection in patients with impaired cell-mediated immunity.

The CMV-CTLs are designed to find and kill cells expressing CMV.

To create CMV-CTLs, T cells are collected from the blood of third-party donors and then exposed to CMV antigens.

The resulting activated T cells are then expanded, characterized, and stored for future use in a partially HLA-matched patient.

The CMV-CTLs are being developed by Atara Biotherapeutics, Inc.

The cells are currently under investigation in a pair of phase 2 trials (NCT01646645 and NCT02136797).

Results of a phase 1 trial (published in Biology of Blood and Marrow Transplantation in 2015) suggested CMV-CTLs are safe and can clear CMV infection in patients who have undergone allogeneic hematopoietic stem cell transplant.

The trial included 17 transplant recipients with CMV viremia or clinical infection that persisted despite prolonged treatment with antiviral drugs. Fourteen of the patients had received T-cell-depleted transplants without graft-versus-host disease (GVHD) prophylaxis.

Sixteen of the patients received CMV-CTLs created using cells derived from their transplant donor, and 1 patient received cells from a third-party donor.

Fifteen patients achieved clearance of CMV viremia, including 3 of the 5 patients with overt disease and the patient who received cells from a third-party donor.

In addition, the researchers said CMV-CTLs were well-tolerated. None of the patients experienced fever, alterations in vital signs, or other toxicities during the first 48 hours of observation.

None of the patients developed manifestations of de novo acute GVHD, and GHVD did not worsen in either of the 2 patients who had GVHD prior to infusion.

About orphan designation

The COMP adopts an opinion on the granting of orphan drug designation, and that opinion is submitted to the European Commission for a final decision.

Orphan designation provides regulatory and financial incentives for companies to develop and market therapies that treat life-threatening or chronically debilitating conditions affecting no more than 5 in 10,000 people in the European Union, and where no satisfactory treatment is available.

Orphan designation provides a 10-year period of marketing exclusivity if the drug receives regulatory approval.

The designation also provides incentives for companies seeking protocol assistance from the European Medicines Agency during the product development phase and direct access to the centralized authorization procedure.

 

 

Micrograph showing CMV

 

The European Medicines Agency’s Committee for Orphan Medicinal Products (COMP) is recommending orphan designation for a cytomegalovirus-specific cytotoxic T-lymphocyte product (CMV-CTLs) intended to treat CMV infection in patients with impaired cell-mediated immunity.

The CMV-CTLs are designed to find and kill cells expressing CMV.

To create CMV-CTLs, T cells are collected from the blood of third-party donors and then exposed to CMV antigens.

The resulting activated T cells are then expanded, characterized, and stored for future use in a partially HLA-matched patient.

The CMV-CTLs are being developed by Atara Biotherapeutics, Inc.

The cells are currently under investigation in a pair of phase 2 trials (NCT01646645 and NCT02136797).

Results of a phase 1 trial (published in Biology of Blood and Marrow Transplantation in 2015) suggested CMV-CTLs are safe and can clear CMV infection in patients who have undergone allogeneic hematopoietic stem cell transplant.

The trial included 17 transplant recipients with CMV viremia or clinical infection that persisted despite prolonged treatment with antiviral drugs. Fourteen of the patients had received T-cell-depleted transplants without graft-versus-host disease (GVHD) prophylaxis.

Sixteen of the patients received CMV-CTLs created using cells derived from their transplant donor, and 1 patient received cells from a third-party donor.

Fifteen patients achieved clearance of CMV viremia, including 3 of the 5 patients with overt disease and the patient who received cells from a third-party donor.

In addition, the researchers said CMV-CTLs were well-tolerated. None of the patients experienced fever, alterations in vital signs, or other toxicities during the first 48 hours of observation.

None of the patients developed manifestations of de novo acute GVHD, and GHVD did not worsen in either of the 2 patients who had GVHD prior to infusion.

About orphan designation

The COMP adopts an opinion on the granting of orphan drug designation, and that opinion is submitted to the European Commission for a final decision.

Orphan designation provides regulatory and financial incentives for companies to develop and market therapies that treat life-threatening or chronically debilitating conditions affecting no more than 5 in 10,000 people in the European Union, and where no satisfactory treatment is available.

Orphan designation provides a 10-year period of marketing exclusivity if the drug receives regulatory approval.

The designation also provides incentives for companies seeking protocol assistance from the European Medicines Agency during the product development phase and direct access to the centralized authorization procedure.