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ASCT or novel therapies in early relapsing follicular lymphoma?
NEW YORK – For patients with newly diagnosed follicular lymphoma and other indolent non-Hodgkin lymphoma, the combination of bendamustine (Treanda) and rituximab is associated with significantly better progression-free survival (PFS) and longer time-to-next treatment than is rituximab plus CHOP chemotherapy, results of the BRIGHT study indicate.
But That was the question taken on in a debate at an international congress on hematologic malignancies by Carla Casulo, MD of the James P. Wilmot Cancer Institute at the University of Rochester (N.Y.), and Brian K. Link, MD, of the University of Iowa Hospitals & Clinics in Iowa City.
Dr. Casulo: ASCT
“Follicular lymphoma with a short remission duration has been established as a poor prognostic marker for survival, and the optimal therapy for these patients is really not known,” Dr. Casulo said.
“Of course, [novel] therapies can be considered, I think, for the appropriate patient, and hopefully in the context of a clinical study,” she added.
To lay out her argument for ASCT, Dr. Casulo pointed to four studies suggesting that about 20% of patients with follicular lymphoma will experience disease progression within 24 months of chemoimmunotherapy. Similar patterns of progression at 24 months were seen with R-CHOP in the SWOG S0016 trial, with both bendamustine-rituximab and R-CHOP in the StiL Study, with lenalidomide (Revlimid) and rituximab in a phase 3 clinical trial, and with one of three rituximab-based immunochemotherapy regimens in the PRIMA trial.
The results from these trials suggest that “there is an inherent biology to this population that relapses early, regardless of what induction strategy is used. However, what’s not known, until now, is whether early relapse implies poor survival in this disease,” she said.
To examine this question Dr. Casulo and her colleagues performed an analysis of time to progression among patients with newly-diagnosed follicular lymphoma treated with R-CHOP who were enrolled in the National LymphoCare Study (NLCS). “What we found was that there were very poor outcomes associated with early-relapsing follicular lymphoma,” she said.
Overall survival (OS) at 8 years was 50% for patients with disease progression within 24 months of therapy, compared with 90% for patients who did not have early progression, a finding that was validated in a cohort of patients from the University of Iowa and the Mayo Clinic in which 8-year OS for early progressors was 34%, compared with 90% for other patients. The results held up when the researchers controlled for Follicular Lymphoma International Prognostic Index scores and in patients treated with rituximab and the cyclophosphamide, vincristine, and prednisone regimen rather than CHOP, Dr. Casulo noted.
“So, given these findings, how does one navigate the treatment landscape for patients with early relapsing follicular lymphoma? The reality is that there is really no standard of care or best approach,” she said.
“Ultimately, the goal of therapy, at least in my opinion, should be overcoming the chemoresistance that’s inherent to this biology, and establishing durable disease control, and there are a couple of strategies that might be able to achieve that,” she added.
There have been only two clinical trials of ASCT in patients with relapsed follicular lymphoma.
In the CUP trial, initiated prior to the introduction of rituximab, 89 patients with relapsed follicular lymphoma were treated with three cycles of CHOP, and those with a response were then randomized to either purged or unpurged ASCT, or to three additional cycles of CHOP. Four-year OS in this study was 70% for patients who underwent ASCT vs. 50% for those who received six cycles of CHOP.
In the EBMT LYM1 trial, 280 rituximab-naive patients with relapsed follicular lymphoma after a partial or complete remission were randomized to rituximab-purged or unpurged ASCT, followed by randomization to observation or rituximab maintenance. In this trial, the 10-year OS with ASCT ranged from 68% to 73%.
A Spanish registry study presented in a poster session at the 14th International Conference on Malignant Lymphoma in Lugano, Italy, showed long-term efficacy of ASCT in relapsed follicular lymphoma, with plateaus in both PFS and OS about 9 years after transplant for both rituximab-exposed and rituximab-naive patients, “suggesting that perhaps a subset of patients with relapsed follicular lymphoma can be cured with this approach,” Dr. Casulo said.
Similarly, a trial from the German Low Grade Lymphoma Studies group, presented at the 2016 American Society of Hematology annual meeting, showed 5-year OS of 77% with ASCT vs. 46% for patients who did not receive a transplant.
Dr. Casulo and her colleagues collaborated with investigators at the Center for International Blood and Marrow Transplant Research and the NLCS to see whether ASCT can improve OS compared with no transplant in patients with early-relapsed follicular lymphoma. They found that patients who received ASCT within 1 year of therapy failure had a 5-year OS of 73%, compared with 60% for those who did not receive ASCT (P = .02).
She acknowledged that toxicities associated with ASCT are a concern, pointing to a 2007 study looking at long-term follow-up of myeloablative ASCT for follicular lymphoma at the time of second or subsequent remission. The investigators found that rates of myelodysplasia were as high as 20% at 10 years, especially among patients who had undergone total body irradiation, a practice that has since fallen out of favor.
A separate study led by Matt Kalaycio, MD, of the Cleveland Clinic, showed that more lines of prior therapy (4-6 vs. 1-3) and radiation were both risk factors for subsequent myelodysplastic syndrome and acute myeloid leukemia.
“I hope we have demonstrated that autologous transplant can have durable response in these patients, with possibly a cure in a subset; but, ultimately, I think strategies that combine novel agents and autologous transplant in a clinical trial are the way to go to improve outcomes,” she said.
Dr. Link: Novel agents
“I actually happen to agree with very much of what Carla had to share, but I do have a couple of caveats,” Dr. Link said.
“The focus of this discussion is on patients with high-risk follicular lymphoma, as Carla very carefully defined in her analysis of the NLCS. These are the early progressors,” he said.
He cited data from the University of Iowa/Mayo Clinic series, validated in a cohort of patients from Lyon, France, showing that high-risk patients with early progression after immunochemotherapy had “especially poor outcomes.” In contrast, patients who were not early progressors fared quite well.
“It suggested that with agents that were available as of 2015, if you’re not an early progressor, your survival at least matches, or essentially matches with statistical power, that of the expected age- and gender-matched populations. So, novel agents are not required necessarily nor are clinical trials necessarily required for people who have good early outcomes,” Dr. Link said.
The best snapshot of current practice for high-risk patients comes from unpublished data from the NLCS showing that after a median follow-up of 8 years, 889 of 2,652 patients had received a second line of therapy, with the choice of agents or approaches generally similar between early progressors and others.
Early progressors were slightly less likely to receive rituximab monotherapy (30% vs. 36%) or an investigational agent (4.4% vs. 5.5%), whereas they were slightly more likely to receive an anthracycline (18% vs. 13%) or to undergo ASCT (3.5% vs. 1.1%).
In the treatment of patients with high-risk follicular lymphoma, a novel agent can be considered as one that was either not available or had not been used in follicular lymphoma when the previously mentioned survival data were generated, including immunomodulators such as thalidomide analogues, targeted kinase inhibitors, new anti-CD20 antibodies such as obinutuzumab (Gazyva), and immune checkpoint inhibitors.
For example, in Alliance 50803, a phase 2 trial in patients with previously untreated stage II-IV follicular lymphoma, the combination of lenalidomide (Revlimid) and rituximab was associated with a 95% overall response rate (ORR), including 72% complete response, and 5-year PFS rate of 70%, comparable to trials with rituximab plus bendamustine, CHOP, or cyclophosphamide-vincristine-prednisone, Dr. Link said.
In the phase 2 GALEN study, the combination of lenalidomide and obinutuzumab was associated with an ORR of 74% among 86 patients with relapsed/refractory follicular lymphoma, with a 1-year PFS rate of 76%.
An analysis of responses by time to relapse in GALEN showed that the ORR among 24 patients with disease progression within 24 months was 70.8%, including 33.3% complete or unconfirmed complete responses by the 1999 International Working Group criteria, and 66.7% with 54.2% complete or unconfirmed complete responses by the 2007 criteria.
Idelalisib, an inhibitor of the delta isoform of phosphatidylinositol 3-kinase (PI3K), was granted accelerated approval in 2014 for treatment of patients with follicular lymphoma after two or more prior lines of therapy, but toxicities associated with this agent caused the drug maker Gilead to dial back its development of this agent.
“But idelalisib is not the only PI3 kinase inhibitor on the block,” Dr. Link said, noting that more than a dozen similar agents are currently in development.
In clinical trials, PI3 kinase inhibitors have been associated with ORRs of about 60% in patients who experience early disease progression on other therapies, “suggesting an uncoupling between the paradigm that says that early progressors are going to have a less effective outcome than late progressors, perhaps, with targeted therapies.
The best evidence for the Bruton’s tyrosine kinase inhibitor ibrutinib (Imbruvica) comes from the DAWN study, a phase 2 trial in patients with follicular lymphoma refractory to immunochemotherapy. The drug showed some biologic activity, but only a 21% ORR.
Dr. Link noted that the S1608 trial, currently recruiting patients, may give clinicians a better idea of which novel agent is most effective. The phase 2 trial is enrolling patients with early-progressing or refractory follicular lymphoma who will be randomized to receive obinutuzumab with either the investigational PI3 kinase inhibitor TGR-1202, lenalidomide, or CHOP chemotherapy.
“High-risk follicular lymphoma is a bad hombre,” Dr. Link said. “If we want to be any smarter as a society 10 years from now, we should incorporate clinical trials with novel therapies as standard operating practice into this setting of high-risk follicular lymphoma.”
Dr. Casulo reported serving on the speakers bureau for Gilead. Dr. Link reported serving as a consultant to AbbVie, Celgene, Genentech, and Gilead.
NEW YORK – For patients with newly diagnosed follicular lymphoma and other indolent non-Hodgkin lymphoma, the combination of bendamustine (Treanda) and rituximab is associated with significantly better progression-free survival (PFS) and longer time-to-next treatment than is rituximab plus CHOP chemotherapy, results of the BRIGHT study indicate.
But That was the question taken on in a debate at an international congress on hematologic malignancies by Carla Casulo, MD of the James P. Wilmot Cancer Institute at the University of Rochester (N.Y.), and Brian K. Link, MD, of the University of Iowa Hospitals & Clinics in Iowa City.
Dr. Casulo: ASCT
“Follicular lymphoma with a short remission duration has been established as a poor prognostic marker for survival, and the optimal therapy for these patients is really not known,” Dr. Casulo said.
“Of course, [novel] therapies can be considered, I think, for the appropriate patient, and hopefully in the context of a clinical study,” she added.
To lay out her argument for ASCT, Dr. Casulo pointed to four studies suggesting that about 20% of patients with follicular lymphoma will experience disease progression within 24 months of chemoimmunotherapy. Similar patterns of progression at 24 months were seen with R-CHOP in the SWOG S0016 trial, with both bendamustine-rituximab and R-CHOP in the StiL Study, with lenalidomide (Revlimid) and rituximab in a phase 3 clinical trial, and with one of three rituximab-based immunochemotherapy regimens in the PRIMA trial.
The results from these trials suggest that “there is an inherent biology to this population that relapses early, regardless of what induction strategy is used. However, what’s not known, until now, is whether early relapse implies poor survival in this disease,” she said.
To examine this question Dr. Casulo and her colleagues performed an analysis of time to progression among patients with newly-diagnosed follicular lymphoma treated with R-CHOP who were enrolled in the National LymphoCare Study (NLCS). “What we found was that there were very poor outcomes associated with early-relapsing follicular lymphoma,” she said.
Overall survival (OS) at 8 years was 50% for patients with disease progression within 24 months of therapy, compared with 90% for patients who did not have early progression, a finding that was validated in a cohort of patients from the University of Iowa and the Mayo Clinic in which 8-year OS for early progressors was 34%, compared with 90% for other patients. The results held up when the researchers controlled for Follicular Lymphoma International Prognostic Index scores and in patients treated with rituximab and the cyclophosphamide, vincristine, and prednisone regimen rather than CHOP, Dr. Casulo noted.
“So, given these findings, how does one navigate the treatment landscape for patients with early relapsing follicular lymphoma? The reality is that there is really no standard of care or best approach,” she said.
“Ultimately, the goal of therapy, at least in my opinion, should be overcoming the chemoresistance that’s inherent to this biology, and establishing durable disease control, and there are a couple of strategies that might be able to achieve that,” she added.
There have been only two clinical trials of ASCT in patients with relapsed follicular lymphoma.
In the CUP trial, initiated prior to the introduction of rituximab, 89 patients with relapsed follicular lymphoma were treated with three cycles of CHOP, and those with a response were then randomized to either purged or unpurged ASCT, or to three additional cycles of CHOP. Four-year OS in this study was 70% for patients who underwent ASCT vs. 50% for those who received six cycles of CHOP.
In the EBMT LYM1 trial, 280 rituximab-naive patients with relapsed follicular lymphoma after a partial or complete remission were randomized to rituximab-purged or unpurged ASCT, followed by randomization to observation or rituximab maintenance. In this trial, the 10-year OS with ASCT ranged from 68% to 73%.
A Spanish registry study presented in a poster session at the 14th International Conference on Malignant Lymphoma in Lugano, Italy, showed long-term efficacy of ASCT in relapsed follicular lymphoma, with plateaus in both PFS and OS about 9 years after transplant for both rituximab-exposed and rituximab-naive patients, “suggesting that perhaps a subset of patients with relapsed follicular lymphoma can be cured with this approach,” Dr. Casulo said.
Similarly, a trial from the German Low Grade Lymphoma Studies group, presented at the 2016 American Society of Hematology annual meeting, showed 5-year OS of 77% with ASCT vs. 46% for patients who did not receive a transplant.
Dr. Casulo and her colleagues collaborated with investigators at the Center for International Blood and Marrow Transplant Research and the NLCS to see whether ASCT can improve OS compared with no transplant in patients with early-relapsed follicular lymphoma. They found that patients who received ASCT within 1 year of therapy failure had a 5-year OS of 73%, compared with 60% for those who did not receive ASCT (P = .02).
She acknowledged that toxicities associated with ASCT are a concern, pointing to a 2007 study looking at long-term follow-up of myeloablative ASCT for follicular lymphoma at the time of second or subsequent remission. The investigators found that rates of myelodysplasia were as high as 20% at 10 years, especially among patients who had undergone total body irradiation, a practice that has since fallen out of favor.
A separate study led by Matt Kalaycio, MD, of the Cleveland Clinic, showed that more lines of prior therapy (4-6 vs. 1-3) and radiation were both risk factors for subsequent myelodysplastic syndrome and acute myeloid leukemia.
“I hope we have demonstrated that autologous transplant can have durable response in these patients, with possibly a cure in a subset; but, ultimately, I think strategies that combine novel agents and autologous transplant in a clinical trial are the way to go to improve outcomes,” she said.
Dr. Link: Novel agents
“I actually happen to agree with very much of what Carla had to share, but I do have a couple of caveats,” Dr. Link said.
“The focus of this discussion is on patients with high-risk follicular lymphoma, as Carla very carefully defined in her analysis of the NLCS. These are the early progressors,” he said.
He cited data from the University of Iowa/Mayo Clinic series, validated in a cohort of patients from Lyon, France, showing that high-risk patients with early progression after immunochemotherapy had “especially poor outcomes.” In contrast, patients who were not early progressors fared quite well.
“It suggested that with agents that were available as of 2015, if you’re not an early progressor, your survival at least matches, or essentially matches with statistical power, that of the expected age- and gender-matched populations. So, novel agents are not required necessarily nor are clinical trials necessarily required for people who have good early outcomes,” Dr. Link said.
The best snapshot of current practice for high-risk patients comes from unpublished data from the NLCS showing that after a median follow-up of 8 years, 889 of 2,652 patients had received a second line of therapy, with the choice of agents or approaches generally similar between early progressors and others.
Early progressors were slightly less likely to receive rituximab monotherapy (30% vs. 36%) or an investigational agent (4.4% vs. 5.5%), whereas they were slightly more likely to receive an anthracycline (18% vs. 13%) or to undergo ASCT (3.5% vs. 1.1%).
In the treatment of patients with high-risk follicular lymphoma, a novel agent can be considered as one that was either not available or had not been used in follicular lymphoma when the previously mentioned survival data were generated, including immunomodulators such as thalidomide analogues, targeted kinase inhibitors, new anti-CD20 antibodies such as obinutuzumab (Gazyva), and immune checkpoint inhibitors.
For example, in Alliance 50803, a phase 2 trial in patients with previously untreated stage II-IV follicular lymphoma, the combination of lenalidomide (Revlimid) and rituximab was associated with a 95% overall response rate (ORR), including 72% complete response, and 5-year PFS rate of 70%, comparable to trials with rituximab plus bendamustine, CHOP, or cyclophosphamide-vincristine-prednisone, Dr. Link said.
In the phase 2 GALEN study, the combination of lenalidomide and obinutuzumab was associated with an ORR of 74% among 86 patients with relapsed/refractory follicular lymphoma, with a 1-year PFS rate of 76%.
An analysis of responses by time to relapse in GALEN showed that the ORR among 24 patients with disease progression within 24 months was 70.8%, including 33.3% complete or unconfirmed complete responses by the 1999 International Working Group criteria, and 66.7% with 54.2% complete or unconfirmed complete responses by the 2007 criteria.
Idelalisib, an inhibitor of the delta isoform of phosphatidylinositol 3-kinase (PI3K), was granted accelerated approval in 2014 for treatment of patients with follicular lymphoma after two or more prior lines of therapy, but toxicities associated with this agent caused the drug maker Gilead to dial back its development of this agent.
“But idelalisib is not the only PI3 kinase inhibitor on the block,” Dr. Link said, noting that more than a dozen similar agents are currently in development.
In clinical trials, PI3 kinase inhibitors have been associated with ORRs of about 60% in patients who experience early disease progression on other therapies, “suggesting an uncoupling between the paradigm that says that early progressors are going to have a less effective outcome than late progressors, perhaps, with targeted therapies.
The best evidence for the Bruton’s tyrosine kinase inhibitor ibrutinib (Imbruvica) comes from the DAWN study, a phase 2 trial in patients with follicular lymphoma refractory to immunochemotherapy. The drug showed some biologic activity, but only a 21% ORR.
Dr. Link noted that the S1608 trial, currently recruiting patients, may give clinicians a better idea of which novel agent is most effective. The phase 2 trial is enrolling patients with early-progressing or refractory follicular lymphoma who will be randomized to receive obinutuzumab with either the investigational PI3 kinase inhibitor TGR-1202, lenalidomide, or CHOP chemotherapy.
“High-risk follicular lymphoma is a bad hombre,” Dr. Link said. “If we want to be any smarter as a society 10 years from now, we should incorporate clinical trials with novel therapies as standard operating practice into this setting of high-risk follicular lymphoma.”
Dr. Casulo reported serving on the speakers bureau for Gilead. Dr. Link reported serving as a consultant to AbbVie, Celgene, Genentech, and Gilead.
NEW YORK – For patients with newly diagnosed follicular lymphoma and other indolent non-Hodgkin lymphoma, the combination of bendamustine (Treanda) and rituximab is associated with significantly better progression-free survival (PFS) and longer time-to-next treatment than is rituximab plus CHOP chemotherapy, results of the BRIGHT study indicate.
But That was the question taken on in a debate at an international congress on hematologic malignancies by Carla Casulo, MD of the James P. Wilmot Cancer Institute at the University of Rochester (N.Y.), and Brian K. Link, MD, of the University of Iowa Hospitals & Clinics in Iowa City.
Dr. Casulo: ASCT
“Follicular lymphoma with a short remission duration has been established as a poor prognostic marker for survival, and the optimal therapy for these patients is really not known,” Dr. Casulo said.
“Of course, [novel] therapies can be considered, I think, for the appropriate patient, and hopefully in the context of a clinical study,” she added.
To lay out her argument for ASCT, Dr. Casulo pointed to four studies suggesting that about 20% of patients with follicular lymphoma will experience disease progression within 24 months of chemoimmunotherapy. Similar patterns of progression at 24 months were seen with R-CHOP in the SWOG S0016 trial, with both bendamustine-rituximab and R-CHOP in the StiL Study, with lenalidomide (Revlimid) and rituximab in a phase 3 clinical trial, and with one of three rituximab-based immunochemotherapy regimens in the PRIMA trial.
The results from these trials suggest that “there is an inherent biology to this population that relapses early, regardless of what induction strategy is used. However, what’s not known, until now, is whether early relapse implies poor survival in this disease,” she said.
To examine this question Dr. Casulo and her colleagues performed an analysis of time to progression among patients with newly-diagnosed follicular lymphoma treated with R-CHOP who were enrolled in the National LymphoCare Study (NLCS). “What we found was that there were very poor outcomes associated with early-relapsing follicular lymphoma,” she said.
Overall survival (OS) at 8 years was 50% for patients with disease progression within 24 months of therapy, compared with 90% for patients who did not have early progression, a finding that was validated in a cohort of patients from the University of Iowa and the Mayo Clinic in which 8-year OS for early progressors was 34%, compared with 90% for other patients. The results held up when the researchers controlled for Follicular Lymphoma International Prognostic Index scores and in patients treated with rituximab and the cyclophosphamide, vincristine, and prednisone regimen rather than CHOP, Dr. Casulo noted.
“So, given these findings, how does one navigate the treatment landscape for patients with early relapsing follicular lymphoma? The reality is that there is really no standard of care or best approach,” she said.
“Ultimately, the goal of therapy, at least in my opinion, should be overcoming the chemoresistance that’s inherent to this biology, and establishing durable disease control, and there are a couple of strategies that might be able to achieve that,” she added.
There have been only two clinical trials of ASCT in patients with relapsed follicular lymphoma.
In the CUP trial, initiated prior to the introduction of rituximab, 89 patients with relapsed follicular lymphoma were treated with three cycles of CHOP, and those with a response were then randomized to either purged or unpurged ASCT, or to three additional cycles of CHOP. Four-year OS in this study was 70% for patients who underwent ASCT vs. 50% for those who received six cycles of CHOP.
In the EBMT LYM1 trial, 280 rituximab-naive patients with relapsed follicular lymphoma after a partial or complete remission were randomized to rituximab-purged or unpurged ASCT, followed by randomization to observation or rituximab maintenance. In this trial, the 10-year OS with ASCT ranged from 68% to 73%.
A Spanish registry study presented in a poster session at the 14th International Conference on Malignant Lymphoma in Lugano, Italy, showed long-term efficacy of ASCT in relapsed follicular lymphoma, with plateaus in both PFS and OS about 9 years after transplant for both rituximab-exposed and rituximab-naive patients, “suggesting that perhaps a subset of patients with relapsed follicular lymphoma can be cured with this approach,” Dr. Casulo said.
Similarly, a trial from the German Low Grade Lymphoma Studies group, presented at the 2016 American Society of Hematology annual meeting, showed 5-year OS of 77% with ASCT vs. 46% for patients who did not receive a transplant.
Dr. Casulo and her colleagues collaborated with investigators at the Center for International Blood and Marrow Transplant Research and the NLCS to see whether ASCT can improve OS compared with no transplant in patients with early-relapsed follicular lymphoma. They found that patients who received ASCT within 1 year of therapy failure had a 5-year OS of 73%, compared with 60% for those who did not receive ASCT (P = .02).
She acknowledged that toxicities associated with ASCT are a concern, pointing to a 2007 study looking at long-term follow-up of myeloablative ASCT for follicular lymphoma at the time of second or subsequent remission. The investigators found that rates of myelodysplasia were as high as 20% at 10 years, especially among patients who had undergone total body irradiation, a practice that has since fallen out of favor.
A separate study led by Matt Kalaycio, MD, of the Cleveland Clinic, showed that more lines of prior therapy (4-6 vs. 1-3) and radiation were both risk factors for subsequent myelodysplastic syndrome and acute myeloid leukemia.
“I hope we have demonstrated that autologous transplant can have durable response in these patients, with possibly a cure in a subset; but, ultimately, I think strategies that combine novel agents and autologous transplant in a clinical trial are the way to go to improve outcomes,” she said.
Dr. Link: Novel agents
“I actually happen to agree with very much of what Carla had to share, but I do have a couple of caveats,” Dr. Link said.
“The focus of this discussion is on patients with high-risk follicular lymphoma, as Carla very carefully defined in her analysis of the NLCS. These are the early progressors,” he said.
He cited data from the University of Iowa/Mayo Clinic series, validated in a cohort of patients from Lyon, France, showing that high-risk patients with early progression after immunochemotherapy had “especially poor outcomes.” In contrast, patients who were not early progressors fared quite well.
“It suggested that with agents that were available as of 2015, if you’re not an early progressor, your survival at least matches, or essentially matches with statistical power, that of the expected age- and gender-matched populations. So, novel agents are not required necessarily nor are clinical trials necessarily required for people who have good early outcomes,” Dr. Link said.
The best snapshot of current practice for high-risk patients comes from unpublished data from the NLCS showing that after a median follow-up of 8 years, 889 of 2,652 patients had received a second line of therapy, with the choice of agents or approaches generally similar between early progressors and others.
Early progressors were slightly less likely to receive rituximab monotherapy (30% vs. 36%) or an investigational agent (4.4% vs. 5.5%), whereas they were slightly more likely to receive an anthracycline (18% vs. 13%) or to undergo ASCT (3.5% vs. 1.1%).
In the treatment of patients with high-risk follicular lymphoma, a novel agent can be considered as one that was either not available or had not been used in follicular lymphoma when the previously mentioned survival data were generated, including immunomodulators such as thalidomide analogues, targeted kinase inhibitors, new anti-CD20 antibodies such as obinutuzumab (Gazyva), and immune checkpoint inhibitors.
For example, in Alliance 50803, a phase 2 trial in patients with previously untreated stage II-IV follicular lymphoma, the combination of lenalidomide (Revlimid) and rituximab was associated with a 95% overall response rate (ORR), including 72% complete response, and 5-year PFS rate of 70%, comparable to trials with rituximab plus bendamustine, CHOP, or cyclophosphamide-vincristine-prednisone, Dr. Link said.
In the phase 2 GALEN study, the combination of lenalidomide and obinutuzumab was associated with an ORR of 74% among 86 patients with relapsed/refractory follicular lymphoma, with a 1-year PFS rate of 76%.
An analysis of responses by time to relapse in GALEN showed that the ORR among 24 patients with disease progression within 24 months was 70.8%, including 33.3% complete or unconfirmed complete responses by the 1999 International Working Group criteria, and 66.7% with 54.2% complete or unconfirmed complete responses by the 2007 criteria.
Idelalisib, an inhibitor of the delta isoform of phosphatidylinositol 3-kinase (PI3K), was granted accelerated approval in 2014 for treatment of patients with follicular lymphoma after two or more prior lines of therapy, but toxicities associated with this agent caused the drug maker Gilead to dial back its development of this agent.
“But idelalisib is not the only PI3 kinase inhibitor on the block,” Dr. Link said, noting that more than a dozen similar agents are currently in development.
In clinical trials, PI3 kinase inhibitors have been associated with ORRs of about 60% in patients who experience early disease progression on other therapies, “suggesting an uncoupling between the paradigm that says that early progressors are going to have a less effective outcome than late progressors, perhaps, with targeted therapies.
The best evidence for the Bruton’s tyrosine kinase inhibitor ibrutinib (Imbruvica) comes from the DAWN study, a phase 2 trial in patients with follicular lymphoma refractory to immunochemotherapy. The drug showed some biologic activity, but only a 21% ORR.
Dr. Link noted that the S1608 trial, currently recruiting patients, may give clinicians a better idea of which novel agent is most effective. The phase 2 trial is enrolling patients with early-progressing or refractory follicular lymphoma who will be randomized to receive obinutuzumab with either the investigational PI3 kinase inhibitor TGR-1202, lenalidomide, or CHOP chemotherapy.
“High-risk follicular lymphoma is a bad hombre,” Dr. Link said. “If we want to be any smarter as a society 10 years from now, we should incorporate clinical trials with novel therapies as standard operating practice into this setting of high-risk follicular lymphoma.”
Dr. Casulo reported serving on the speakers bureau for Gilead. Dr. Link reported serving as a consultant to AbbVie, Celgene, Genentech, and Gilead.
EXPERT ANALYSIS AT LYMPHOMA & MYELOMA
Marginal zone lymphoma treatment studies to be presented at ASH
Findings from several studies on marginal zone lymphoma (MZL) will be presented during oral and poster sessions at the annual meeting of the American Society of Hematology, with a focus on evaluating combination treatment approaches.
Some of the MZL treatment–related studies include the assessment of chlorambucil plus rituximab in patients with extranodal marginal zone B-cell lymphoma of mucosa associated lymphoid tissue, the combination of bendamustine with rituximab for first-line treatment of splenic MZL, and the safety and progression-free survival associated with lenalidomide and rituximab in previously untreated patients with MZL.
Other studies consider how to approach refractory disease. One study looks at the use of ibrutinib in patients with relapsed/refractory MZL, and researchers will also present findings from a systematic literature review of the efficacy and safety of various treatments among patients with relapsed/refractory MZL.
Abstract 1506: IELSG-38: A Phase II Study of Chlorambucil in Combination with Rituximab Followed by Maintenance Therapy with Subcutaneous Rituximab in Patients with Extranodal Marginal Zone B-Cell Lymphoma of Mucosa Associated Lymphoid Tissue (MALT) .
Abstract 4062: Bendamustine in Combination with Rituximab as First-Line Treatment of Splenic Marginal Zone Lymphoma (BRISMA). Results of the IELSG-36 Phase II Study.
Abstract 3026: Ibrutinib Therapy in Patients with Relapsed/Refractory Marginal Zone Lymphoma: Analysis by Prior Rituximab Treatment and Baseline Mutations.
Abstract 4040: Safety and Activity of Lenalidomide and Rituximab in Previously Untreated Marginal Zone Lymphoma: Subgroup Analysis and Long-Term Follow-Up of an Open-Label Phase II Trial.
Abstract 2783: Systematic Literature Review of the Clinical Efficacy and Safety of Treatments in the Relapsed/Refractory Setting for Patients with Follicular Lymphoma or Marginal Zone Lymphoma.
Findings from several studies on marginal zone lymphoma (MZL) will be presented during oral and poster sessions at the annual meeting of the American Society of Hematology, with a focus on evaluating combination treatment approaches.
Some of the MZL treatment–related studies include the assessment of chlorambucil plus rituximab in patients with extranodal marginal zone B-cell lymphoma of mucosa associated lymphoid tissue, the combination of bendamustine with rituximab for first-line treatment of splenic MZL, and the safety and progression-free survival associated with lenalidomide and rituximab in previously untreated patients with MZL.
Other studies consider how to approach refractory disease. One study looks at the use of ibrutinib in patients with relapsed/refractory MZL, and researchers will also present findings from a systematic literature review of the efficacy and safety of various treatments among patients with relapsed/refractory MZL.
Abstract 1506: IELSG-38: A Phase II Study of Chlorambucil in Combination with Rituximab Followed by Maintenance Therapy with Subcutaneous Rituximab in Patients with Extranodal Marginal Zone B-Cell Lymphoma of Mucosa Associated Lymphoid Tissue (MALT) .
Abstract 4062: Bendamustine in Combination with Rituximab as First-Line Treatment of Splenic Marginal Zone Lymphoma (BRISMA). Results of the IELSG-36 Phase II Study.
Abstract 3026: Ibrutinib Therapy in Patients with Relapsed/Refractory Marginal Zone Lymphoma: Analysis by Prior Rituximab Treatment and Baseline Mutations.
Abstract 4040: Safety and Activity of Lenalidomide and Rituximab in Previously Untreated Marginal Zone Lymphoma: Subgroup Analysis and Long-Term Follow-Up of an Open-Label Phase II Trial.
Abstract 2783: Systematic Literature Review of the Clinical Efficacy and Safety of Treatments in the Relapsed/Refractory Setting for Patients with Follicular Lymphoma or Marginal Zone Lymphoma.
Findings from several studies on marginal zone lymphoma (MZL) will be presented during oral and poster sessions at the annual meeting of the American Society of Hematology, with a focus on evaluating combination treatment approaches.
Some of the MZL treatment–related studies include the assessment of chlorambucil plus rituximab in patients with extranodal marginal zone B-cell lymphoma of mucosa associated lymphoid tissue, the combination of bendamustine with rituximab for first-line treatment of splenic MZL, and the safety and progression-free survival associated with lenalidomide and rituximab in previously untreated patients with MZL.
Other studies consider how to approach refractory disease. One study looks at the use of ibrutinib in patients with relapsed/refractory MZL, and researchers will also present findings from a systematic literature review of the efficacy and safety of various treatments among patients with relapsed/refractory MZL.
Abstract 1506: IELSG-38: A Phase II Study of Chlorambucil in Combination with Rituximab Followed by Maintenance Therapy with Subcutaneous Rituximab in Patients with Extranodal Marginal Zone B-Cell Lymphoma of Mucosa Associated Lymphoid Tissue (MALT) .
Abstract 4062: Bendamustine in Combination with Rituximab as First-Line Treatment of Splenic Marginal Zone Lymphoma (BRISMA). Results of the IELSG-36 Phase II Study.
Abstract 3026: Ibrutinib Therapy in Patients with Relapsed/Refractory Marginal Zone Lymphoma: Analysis by Prior Rituximab Treatment and Baseline Mutations.
Abstract 4040: Safety and Activity of Lenalidomide and Rituximab in Previously Untreated Marginal Zone Lymphoma: Subgroup Analysis and Long-Term Follow-Up of an Open-Label Phase II Trial.
Abstract 2783: Systematic Literature Review of the Clinical Efficacy and Safety of Treatments in the Relapsed/Refractory Setting for Patients with Follicular Lymphoma or Marginal Zone Lymphoma.
FROM ASH 2017
CAR T-cells gain ground against hematologic cancers
Chimeric antigen receptor (CAR) T-cell therapies are driving ever faster forward, with impressive response rates – including a high level of complete responses – in treatment of patients with lymphomas and multiple myeloma as shown by clinical trial results to be presented at the annual meeting of the American Society of Hematology.
Investigators will be presenting data on the first two CAR T constructs to receive Food and Drug Administration approval, each directed against CD19.
ZUMA-1 for non-Hodgkin lymphoma
Long-term follow-up results with the use of axicabtagene ciloleucel (Yescarta; axi-cel) in patients with refractory aggressive non-Hodgkin lymphoma will be presented by Sattva S. Neelapu, MD, of the University of Texas MD Anderson Cancer Center in Houston, on behalf of colleagues in the ZUMA-1 trial (Abstract 578).
At the 2017 European Hematology Association Congress in Madrid, ZUMA-1 investigators reported that axi-cel, an autologous anti-CD19 CAR-T product, was associated with an 82% objective response rate (ORR), including 54% complete responses, in patients with refractory diffuse large B cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma, or transformed follicular lymphoma. The 54% complete response rate was nearly sevenfold higher than that reported for historical controls, according to coinvestigator Yi Lin, MD, PhD, of the Mayo Clinic, Rochester, Minn.
The treatment was generally safe, with 13% of patients experiencing grade 3 or greater cytokine release syndrome (CRS), and 28% having grade 3 or greater neurologic events. The events were generally reversible, and the rates of each declined over time. The use of tocilizumab or steroids to control adverse events did not have a negative effect on responses.
This CAR T-cell construct received FDA approval in October 2017.
At ASH 2017, Dr. Neelapu will present 1-year follow-up data from the trial which will include both data on responses and toxicity, “but also some very interesting information on mechanisms of resistance, whether patients’ tumor cells become CD19 negative, or checkpoint, like PD-L1, positive,” said Kenneth Anderson, MD, of the Dana-Farber Cancer Institute in Boston, who discussed noteworthy abstracts in a media briefing prior to the meeting.
JULIET for DLBCL
Data on the use of another anti-CD19 CAR construct, tisagenlecleucel (Kymriah) in adults with relapsed or refractory DLBCL will be presented by Stephen J. Schuster, MD, of the University of Pennsylvania, Philadelphia, on behalf of investigators in the JULIET trial.
At the 2017 European Hematology Association Congress, coinvestigator Gilles Salles, MD, PhD, of the University of Lyon, France, reported an interim analysis from the trial, showing that the CAR T construct was associated with a 59% ORR, consisting of 43% complete responses and 16% partial responses in patients with relapsed or refractory DLBCL. The analysis “confirms the high response rates and durable responses observed in the previous single-center trial,” Dr. Salles said.
Dr. Schuster will present the primary analysis of the global phase 2 pivotal trial at ASH 2017 (Abstract 577), looking at patients who received the product from the U.S. manufacturing site.
As of the data cutoff in March 2017, the best ORR among 81 patients with at least 3 months of follow-up, or earlier discontinuation, was 53.1% with 39.5% complete responses and 13.6% partial responses. For 46 patients evaluable at 6 months, the complete response rate was 30% and partial response rate was 7%.
The response rates were consistent across subgroups, including patients who had previously undergone autologous stem cell transplant and those with double-hit lymphoma (i.e, with mutation in MYC and BCL2 or BCL6).
The responses also appeared to be durable, with the median duration not reached. The 6-month probability of being relapse free was 73.5%. Similarly, median overall survival was not reached; the 6-month probability of overall survival was 64.5%, according to the published abstract.
Adverse events included CRS in 58% of infused patients, with 15% grade 3 and 8% grade 4 in severity. CRS was managed according to protocol with tocilizumab and/or corticosteroids. There were no deaths associated with either the CRS or neurologic toxicities.
“This is a multicenter trial: 27 centers, 10 countries, 4 continents, so it sort of demonstrates to all of us that this technology can be done in an international scope,” Dr. Anderson said.
Anti-BCMA for multiple myeloma
CAR T-cells are relative newcomers in the treatment of multiple myeloma, but James N. Kochenderfer, MD, of the National Cancer Institute, Bethesda, Md., will be presenting updated results from a multicenter study of bb2121, a CAR T-cell construct directed against B-cell maturation antigen (BCMA).
BCMA was first described in myeloma in 2004 as a mechanism for the growth and survival of malignant plasma cells. As previously reported, a different anti-BCMA T-cell product induced clinical remissions in 33 of 35 patients with relapsed/refractory multiple myeloma who were treated in an early clinical trial.
With the construct being investigated by Dr. Kochenderfer and colleagues, 21 patients (median 58 years old) with a median of 5 years since a diagnosis of multiple myeloma were infused with bb2121. One-month data on clinical response was available for 18 patients at the time of data cutoff in May 2017 (Abstract 740).
In this heavily pretreated population, the ORR was 89% overall, and was 100% for patients treated with doses of 150 x 106 CAR+ T cells or higher. At this dose range or higher no patients had disease progression at up to 54 weeks after infusion. Of the four patients evaluable for minimal residual disease (MRD), all were MRD negative.
As of the data cut-off there were no dose-limiting toxicities and no treatment-related grade 3 or higher neurotoxicities. CRS was primarily grade 1 or 2 and was reported in 15 of 21 patients. Two patients had grade 3 CRS that resolved in 24 hours, and four patients received tocilizumab (one with steroids) for CRS management.
There was one on-study death, from cardiopulmonary arrest more than 4 months after bb2121 infusion in a patient with an extensive cardiac history. The death was judged to be unrelated to CAR T-cell therapy.
Dr. Kochenderfer will present data and analysis on an additional 5 months of follow-up.
“This abstract demonstrates that again, in patients, this time with myeloma with literally no other option, you can achieve very impressive response,” Dr. Anderson said.
The ZUMA-1 study is funded by Kite Pharma. Dr. Neelapu reported research funding from BMS, Poseida, Merck, Kite Pharma, and Cellectis. He reported consultancy and membership on the board of directors or advisory committees for Merck, Kite Pharma, and Celgene.
The JULIET study is funded by Novartis. Dr. Schuster reported consultancy and research funding from Novartis Pharmaceuticals, Celgene, Genentech, Bristol-Myers Squibb, Janssen R&D, and Gilead. He reported consultancy with Seattle Genetics and Nordic Nanovector, and research funding from Merck.
The multicenter study of bb2121 is sponsored by bluebird bio and Celgene. Dr. Kochenderfer reported research funding from bluebird bio and Kite Pharma. He reported having multiple patents in the CAR field.
Abstract 578 Long-Term Follow-up ZUMA-1: A Pivotal Trial of Axicabtagene Ciloleucel (Axi-Cel; KTE-C19) in Patients with Refractory Aggressive Non-Hodgkin Lymphoma (NHL) will be presented in session 626, Monday, Dec. 11, 2017, at 7:15 a.m.
Abstract 577 Primary Analysis of Juliet: A Global, Pivotal, Phase 2 Trial of CTL019 in Adult Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma will be presented in session 626, Monday, Dec. 11, 2017 at 7:00 a.m.
Abstract 740 Durable Clinical Responses in Heavily Pretreated Patients with Relapsed/Refractory Multiple Myeloma: Updated Results from a Multicenter Study of bb2121 Anti-BCMA CAR T Cell Therapy will be presented in session 653, Monday, Dec. 11, 2017 at 3:00 p.m.
Chimeric antigen receptor (CAR) T-cell therapies are driving ever faster forward, with impressive response rates – including a high level of complete responses – in treatment of patients with lymphomas and multiple myeloma as shown by clinical trial results to be presented at the annual meeting of the American Society of Hematology.
Investigators will be presenting data on the first two CAR T constructs to receive Food and Drug Administration approval, each directed against CD19.
ZUMA-1 for non-Hodgkin lymphoma
Long-term follow-up results with the use of axicabtagene ciloleucel (Yescarta; axi-cel) in patients with refractory aggressive non-Hodgkin lymphoma will be presented by Sattva S. Neelapu, MD, of the University of Texas MD Anderson Cancer Center in Houston, on behalf of colleagues in the ZUMA-1 trial (Abstract 578).
At the 2017 European Hematology Association Congress in Madrid, ZUMA-1 investigators reported that axi-cel, an autologous anti-CD19 CAR-T product, was associated with an 82% objective response rate (ORR), including 54% complete responses, in patients with refractory diffuse large B cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma, or transformed follicular lymphoma. The 54% complete response rate was nearly sevenfold higher than that reported for historical controls, according to coinvestigator Yi Lin, MD, PhD, of the Mayo Clinic, Rochester, Minn.
The treatment was generally safe, with 13% of patients experiencing grade 3 or greater cytokine release syndrome (CRS), and 28% having grade 3 or greater neurologic events. The events were generally reversible, and the rates of each declined over time. The use of tocilizumab or steroids to control adverse events did not have a negative effect on responses.
This CAR T-cell construct received FDA approval in October 2017.
At ASH 2017, Dr. Neelapu will present 1-year follow-up data from the trial which will include both data on responses and toxicity, “but also some very interesting information on mechanisms of resistance, whether patients’ tumor cells become CD19 negative, or checkpoint, like PD-L1, positive,” said Kenneth Anderson, MD, of the Dana-Farber Cancer Institute in Boston, who discussed noteworthy abstracts in a media briefing prior to the meeting.
JULIET for DLBCL
Data on the use of another anti-CD19 CAR construct, tisagenlecleucel (Kymriah) in adults with relapsed or refractory DLBCL will be presented by Stephen J. Schuster, MD, of the University of Pennsylvania, Philadelphia, on behalf of investigators in the JULIET trial.
At the 2017 European Hematology Association Congress, coinvestigator Gilles Salles, MD, PhD, of the University of Lyon, France, reported an interim analysis from the trial, showing that the CAR T construct was associated with a 59% ORR, consisting of 43% complete responses and 16% partial responses in patients with relapsed or refractory DLBCL. The analysis “confirms the high response rates and durable responses observed in the previous single-center trial,” Dr. Salles said.
Dr. Schuster will present the primary analysis of the global phase 2 pivotal trial at ASH 2017 (Abstract 577), looking at patients who received the product from the U.S. manufacturing site.
As of the data cutoff in March 2017, the best ORR among 81 patients with at least 3 months of follow-up, or earlier discontinuation, was 53.1% with 39.5% complete responses and 13.6% partial responses. For 46 patients evaluable at 6 months, the complete response rate was 30% and partial response rate was 7%.
The response rates were consistent across subgroups, including patients who had previously undergone autologous stem cell transplant and those with double-hit lymphoma (i.e, with mutation in MYC and BCL2 or BCL6).
The responses also appeared to be durable, with the median duration not reached. The 6-month probability of being relapse free was 73.5%. Similarly, median overall survival was not reached; the 6-month probability of overall survival was 64.5%, according to the published abstract.
Adverse events included CRS in 58% of infused patients, with 15% grade 3 and 8% grade 4 in severity. CRS was managed according to protocol with tocilizumab and/or corticosteroids. There were no deaths associated with either the CRS or neurologic toxicities.
“This is a multicenter trial: 27 centers, 10 countries, 4 continents, so it sort of demonstrates to all of us that this technology can be done in an international scope,” Dr. Anderson said.
Anti-BCMA for multiple myeloma
CAR T-cells are relative newcomers in the treatment of multiple myeloma, but James N. Kochenderfer, MD, of the National Cancer Institute, Bethesda, Md., will be presenting updated results from a multicenter study of bb2121, a CAR T-cell construct directed against B-cell maturation antigen (BCMA).
BCMA was first described in myeloma in 2004 as a mechanism for the growth and survival of malignant plasma cells. As previously reported, a different anti-BCMA T-cell product induced clinical remissions in 33 of 35 patients with relapsed/refractory multiple myeloma who were treated in an early clinical trial.
With the construct being investigated by Dr. Kochenderfer and colleagues, 21 patients (median 58 years old) with a median of 5 years since a diagnosis of multiple myeloma were infused with bb2121. One-month data on clinical response was available for 18 patients at the time of data cutoff in May 2017 (Abstract 740).
In this heavily pretreated population, the ORR was 89% overall, and was 100% for patients treated with doses of 150 x 106 CAR+ T cells or higher. At this dose range or higher no patients had disease progression at up to 54 weeks after infusion. Of the four patients evaluable for minimal residual disease (MRD), all were MRD negative.
As of the data cut-off there were no dose-limiting toxicities and no treatment-related grade 3 or higher neurotoxicities. CRS was primarily grade 1 or 2 and was reported in 15 of 21 patients. Two patients had grade 3 CRS that resolved in 24 hours, and four patients received tocilizumab (one with steroids) for CRS management.
There was one on-study death, from cardiopulmonary arrest more than 4 months after bb2121 infusion in a patient with an extensive cardiac history. The death was judged to be unrelated to CAR T-cell therapy.
Dr. Kochenderfer will present data and analysis on an additional 5 months of follow-up.
“This abstract demonstrates that again, in patients, this time with myeloma with literally no other option, you can achieve very impressive response,” Dr. Anderson said.
The ZUMA-1 study is funded by Kite Pharma. Dr. Neelapu reported research funding from BMS, Poseida, Merck, Kite Pharma, and Cellectis. He reported consultancy and membership on the board of directors or advisory committees for Merck, Kite Pharma, and Celgene.
The JULIET study is funded by Novartis. Dr. Schuster reported consultancy and research funding from Novartis Pharmaceuticals, Celgene, Genentech, Bristol-Myers Squibb, Janssen R&D, and Gilead. He reported consultancy with Seattle Genetics and Nordic Nanovector, and research funding from Merck.
The multicenter study of bb2121 is sponsored by bluebird bio and Celgene. Dr. Kochenderfer reported research funding from bluebird bio and Kite Pharma. He reported having multiple patents in the CAR field.
Abstract 578 Long-Term Follow-up ZUMA-1: A Pivotal Trial of Axicabtagene Ciloleucel (Axi-Cel; KTE-C19) in Patients with Refractory Aggressive Non-Hodgkin Lymphoma (NHL) will be presented in session 626, Monday, Dec. 11, 2017, at 7:15 a.m.
Abstract 577 Primary Analysis of Juliet: A Global, Pivotal, Phase 2 Trial of CTL019 in Adult Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma will be presented in session 626, Monday, Dec. 11, 2017 at 7:00 a.m.
Abstract 740 Durable Clinical Responses in Heavily Pretreated Patients with Relapsed/Refractory Multiple Myeloma: Updated Results from a Multicenter Study of bb2121 Anti-BCMA CAR T Cell Therapy will be presented in session 653, Monday, Dec. 11, 2017 at 3:00 p.m.
Chimeric antigen receptor (CAR) T-cell therapies are driving ever faster forward, with impressive response rates – including a high level of complete responses – in treatment of patients with lymphomas and multiple myeloma as shown by clinical trial results to be presented at the annual meeting of the American Society of Hematology.
Investigators will be presenting data on the first two CAR T constructs to receive Food and Drug Administration approval, each directed against CD19.
ZUMA-1 for non-Hodgkin lymphoma
Long-term follow-up results with the use of axicabtagene ciloleucel (Yescarta; axi-cel) in patients with refractory aggressive non-Hodgkin lymphoma will be presented by Sattva S. Neelapu, MD, of the University of Texas MD Anderson Cancer Center in Houston, on behalf of colleagues in the ZUMA-1 trial (Abstract 578).
At the 2017 European Hematology Association Congress in Madrid, ZUMA-1 investigators reported that axi-cel, an autologous anti-CD19 CAR-T product, was associated with an 82% objective response rate (ORR), including 54% complete responses, in patients with refractory diffuse large B cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma, or transformed follicular lymphoma. The 54% complete response rate was nearly sevenfold higher than that reported for historical controls, according to coinvestigator Yi Lin, MD, PhD, of the Mayo Clinic, Rochester, Minn.
The treatment was generally safe, with 13% of patients experiencing grade 3 or greater cytokine release syndrome (CRS), and 28% having grade 3 or greater neurologic events. The events were generally reversible, and the rates of each declined over time. The use of tocilizumab or steroids to control adverse events did not have a negative effect on responses.
This CAR T-cell construct received FDA approval in October 2017.
At ASH 2017, Dr. Neelapu will present 1-year follow-up data from the trial which will include both data on responses and toxicity, “but also some very interesting information on mechanisms of resistance, whether patients’ tumor cells become CD19 negative, or checkpoint, like PD-L1, positive,” said Kenneth Anderson, MD, of the Dana-Farber Cancer Institute in Boston, who discussed noteworthy abstracts in a media briefing prior to the meeting.
JULIET for DLBCL
Data on the use of another anti-CD19 CAR construct, tisagenlecleucel (Kymriah) in adults with relapsed or refractory DLBCL will be presented by Stephen J. Schuster, MD, of the University of Pennsylvania, Philadelphia, on behalf of investigators in the JULIET trial.
At the 2017 European Hematology Association Congress, coinvestigator Gilles Salles, MD, PhD, of the University of Lyon, France, reported an interim analysis from the trial, showing that the CAR T construct was associated with a 59% ORR, consisting of 43% complete responses and 16% partial responses in patients with relapsed or refractory DLBCL. The analysis “confirms the high response rates and durable responses observed in the previous single-center trial,” Dr. Salles said.
Dr. Schuster will present the primary analysis of the global phase 2 pivotal trial at ASH 2017 (Abstract 577), looking at patients who received the product from the U.S. manufacturing site.
As of the data cutoff in March 2017, the best ORR among 81 patients with at least 3 months of follow-up, or earlier discontinuation, was 53.1% with 39.5% complete responses and 13.6% partial responses. For 46 patients evaluable at 6 months, the complete response rate was 30% and partial response rate was 7%.
The response rates were consistent across subgroups, including patients who had previously undergone autologous stem cell transplant and those with double-hit lymphoma (i.e, with mutation in MYC and BCL2 or BCL6).
The responses also appeared to be durable, with the median duration not reached. The 6-month probability of being relapse free was 73.5%. Similarly, median overall survival was not reached; the 6-month probability of overall survival was 64.5%, according to the published abstract.
Adverse events included CRS in 58% of infused patients, with 15% grade 3 and 8% grade 4 in severity. CRS was managed according to protocol with tocilizumab and/or corticosteroids. There were no deaths associated with either the CRS or neurologic toxicities.
“This is a multicenter trial: 27 centers, 10 countries, 4 continents, so it sort of demonstrates to all of us that this technology can be done in an international scope,” Dr. Anderson said.
Anti-BCMA for multiple myeloma
CAR T-cells are relative newcomers in the treatment of multiple myeloma, but James N. Kochenderfer, MD, of the National Cancer Institute, Bethesda, Md., will be presenting updated results from a multicenter study of bb2121, a CAR T-cell construct directed against B-cell maturation antigen (BCMA).
BCMA was first described in myeloma in 2004 as a mechanism for the growth and survival of malignant plasma cells. As previously reported, a different anti-BCMA T-cell product induced clinical remissions in 33 of 35 patients with relapsed/refractory multiple myeloma who were treated in an early clinical trial.
With the construct being investigated by Dr. Kochenderfer and colleagues, 21 patients (median 58 years old) with a median of 5 years since a diagnosis of multiple myeloma were infused with bb2121. One-month data on clinical response was available for 18 patients at the time of data cutoff in May 2017 (Abstract 740).
In this heavily pretreated population, the ORR was 89% overall, and was 100% for patients treated with doses of 150 x 106 CAR+ T cells or higher. At this dose range or higher no patients had disease progression at up to 54 weeks after infusion. Of the four patients evaluable for minimal residual disease (MRD), all were MRD negative.
As of the data cut-off there were no dose-limiting toxicities and no treatment-related grade 3 or higher neurotoxicities. CRS was primarily grade 1 or 2 and was reported in 15 of 21 patients. Two patients had grade 3 CRS that resolved in 24 hours, and four patients received tocilizumab (one with steroids) for CRS management.
There was one on-study death, from cardiopulmonary arrest more than 4 months after bb2121 infusion in a patient with an extensive cardiac history. The death was judged to be unrelated to CAR T-cell therapy.
Dr. Kochenderfer will present data and analysis on an additional 5 months of follow-up.
“This abstract demonstrates that again, in patients, this time with myeloma with literally no other option, you can achieve very impressive response,” Dr. Anderson said.
The ZUMA-1 study is funded by Kite Pharma. Dr. Neelapu reported research funding from BMS, Poseida, Merck, Kite Pharma, and Cellectis. He reported consultancy and membership on the board of directors or advisory committees for Merck, Kite Pharma, and Celgene.
The JULIET study is funded by Novartis. Dr. Schuster reported consultancy and research funding from Novartis Pharmaceuticals, Celgene, Genentech, Bristol-Myers Squibb, Janssen R&D, and Gilead. He reported consultancy with Seattle Genetics and Nordic Nanovector, and research funding from Merck.
The multicenter study of bb2121 is sponsored by bluebird bio and Celgene. Dr. Kochenderfer reported research funding from bluebird bio and Kite Pharma. He reported having multiple patents in the CAR field.
Abstract 578 Long-Term Follow-up ZUMA-1: A Pivotal Trial of Axicabtagene Ciloleucel (Axi-Cel; KTE-C19) in Patients with Refractory Aggressive Non-Hodgkin Lymphoma (NHL) will be presented in session 626, Monday, Dec. 11, 2017, at 7:15 a.m.
Abstract 577 Primary Analysis of Juliet: A Global, Pivotal, Phase 2 Trial of CTL019 in Adult Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma will be presented in session 626, Monday, Dec. 11, 2017 at 7:00 a.m.
Abstract 740 Durable Clinical Responses in Heavily Pretreated Patients with Relapsed/Refractory Multiple Myeloma: Updated Results from a Multicenter Study of bb2121 Anti-BCMA CAR T Cell Therapy will be presented in session 653, Monday, Dec. 11, 2017 at 3:00 p.m.
FROM ASH 2017
Method identifies effective treatments for leukemias, lymphomas
An ex vivo drug screening method can reveal optimal therapies for patients with hematologic malignancies, according to research published in The Lancet Haematology.
Researchers used a method called pharmacoscopy to measure single-cell responses to possible treatments in samples from patients with leukemias and lymphomas.
The team then used these results to guide treatment decisions and found that pharmacoscopy-guided treatment greatly improved response rates and progression-free survival (PFS).
“Having a robust, fast, and reliable predictive test at our disposal during the patient treatment process, especially at the time of relapse where a new intervention must be selected quickly, will change how medical doctors prioritize drugs to use for late-stage patients,” said study author Philipp Staber, MD, of Medical University of Vienna in Austria.
With pharmacoscopy, hundreds of drug options can be pre-tested ex vivo in small liquid biopsy samples collected from individual patients. The effects of each drug on the individual cells are quantified using high-throughput and high-content automated confocal microscopy.
In combination with specially developed analysis methods, machine learning, and other algorithms, pharmacoscopy allows quantification of never-before visualized phenotypes. The method was first described last April in Nature Chemical Biology.
Now, Dr Staber and his colleagues have reported, in The Lancet Haematology, an interim analysis of the first clinical trial testing pharmacoscopy-guided treatment.
There were 17 evaluable patients, all of whom had aggressive hematologic malignancies. This included diffuse large B-cell lymphoma (n=6), acute myeloid leukemia (n=3), B-cell acute lymphoblastic leukemia (n=2), precursor B-cell lymphoblastic lymphoma (n=1), peripheral T-cell lymphoma (n=1), primary mediastinal B-cell lymphoma (n=1), T-cell lymphoblastic lymphoma (n=1), follicular lymphoma (n=1), and T-cell prolymphocytic leukemia (n=1).
The researchers compared outcomes with pharmacoscopy-guided treatment to outcomes with the most recent regimen on which the patient had progressed.
The overall response rate was 88% with pharmacoscopy-guided treatment and 24% with the patients’ most recent previous treatment regimen (odds ratio=24.38; 95%, CI 3.99–125.4; P=0.0013).
None of the patients had progressive disease as their best overall response when they received pharmacoscopy-guided treatment. However, 7 patients had progressive disease in response to their most recent prior regimen.
At the time of analysis, 8 patients (47%) still had ongoing responses after pharmacoscopy-guided treatment.
In addition, pharmacoscopy-guided treatment significantly improved PFS. The median PFS was 22.6 weeks with pharmacoscopy-guided treatment and 5.7 weeks with the most recent prior regimen (hazard ratio=3.14; 95%, CI 1.37–7.22; P=0.0075).
“Evidence that the pharmacoscopy approach is helpful for clinical evaluation of therapy is wonderful,” said study author Giulio Superti-Furga, PhD, of CeMM Research Center for Molecular Medicine in Vienna, Austria.
“Single-cell functional analysis of primary material gives unprecedented resolution and precision that we are sure to further develop in the future to address yet more diseases.” 
An ex vivo drug screening method can reveal optimal therapies for patients with hematologic malignancies, according to research published in The Lancet Haematology.
Researchers used a method called pharmacoscopy to measure single-cell responses to possible treatments in samples from patients with leukemias and lymphomas.
The team then used these results to guide treatment decisions and found that pharmacoscopy-guided treatment greatly improved response rates and progression-free survival (PFS).
“Having a robust, fast, and reliable predictive test at our disposal during the patient treatment process, especially at the time of relapse where a new intervention must be selected quickly, will change how medical doctors prioritize drugs to use for late-stage patients,” said study author Philipp Staber, MD, of Medical University of Vienna in Austria.
With pharmacoscopy, hundreds of drug options can be pre-tested ex vivo in small liquid biopsy samples collected from individual patients. The effects of each drug on the individual cells are quantified using high-throughput and high-content automated confocal microscopy.
In combination with specially developed analysis methods, machine learning, and other algorithms, pharmacoscopy allows quantification of never-before visualized phenotypes. The method was first described last April in Nature Chemical Biology.
Now, Dr Staber and his colleagues have reported, in The Lancet Haematology, an interim analysis of the first clinical trial testing pharmacoscopy-guided treatment.
There were 17 evaluable patients, all of whom had aggressive hematologic malignancies. This included diffuse large B-cell lymphoma (n=6), acute myeloid leukemia (n=3), B-cell acute lymphoblastic leukemia (n=2), precursor B-cell lymphoblastic lymphoma (n=1), peripheral T-cell lymphoma (n=1), primary mediastinal B-cell lymphoma (n=1), T-cell lymphoblastic lymphoma (n=1), follicular lymphoma (n=1), and T-cell prolymphocytic leukemia (n=1).
The researchers compared outcomes with pharmacoscopy-guided treatment to outcomes with the most recent regimen on which the patient had progressed.
The overall response rate was 88% with pharmacoscopy-guided treatment and 24% with the patients’ most recent previous treatment regimen (odds ratio=24.38; 95%, CI 3.99–125.4; P=0.0013).
None of the patients had progressive disease as their best overall response when they received pharmacoscopy-guided treatment. However, 7 patients had progressive disease in response to their most recent prior regimen.
At the time of analysis, 8 patients (47%) still had ongoing responses after pharmacoscopy-guided treatment.
In addition, pharmacoscopy-guided treatment significantly improved PFS. The median PFS was 22.6 weeks with pharmacoscopy-guided treatment and 5.7 weeks with the most recent prior regimen (hazard ratio=3.14; 95%, CI 1.37–7.22; P=0.0075).
“Evidence that the pharmacoscopy approach is helpful for clinical evaluation of therapy is wonderful,” said study author Giulio Superti-Furga, PhD, of CeMM Research Center for Molecular Medicine in Vienna, Austria.
“Single-cell functional analysis of primary material gives unprecedented resolution and precision that we are sure to further develop in the future to address yet more diseases.”
An ex vivo drug screening method can reveal optimal therapies for patients with hematologic malignancies, according to research published in The Lancet Haematology.
Researchers used a method called pharmacoscopy to measure single-cell responses to possible treatments in samples from patients with leukemias and lymphomas.
The team then used these results to guide treatment decisions and found that pharmacoscopy-guided treatment greatly improved response rates and progression-free survival (PFS).
“Having a robust, fast, and reliable predictive test at our disposal during the patient treatment process, especially at the time of relapse where a new intervention must be selected quickly, will change how medical doctors prioritize drugs to use for late-stage patients,” said study author Philipp Staber, MD, of Medical University of Vienna in Austria.
With pharmacoscopy, hundreds of drug options can be pre-tested ex vivo in small liquid biopsy samples collected from individual patients. The effects of each drug on the individual cells are quantified using high-throughput and high-content automated confocal microscopy.
In combination with specially developed analysis methods, machine learning, and other algorithms, pharmacoscopy allows quantification of never-before visualized phenotypes. The method was first described last April in Nature Chemical Biology.
Now, Dr Staber and his colleagues have reported, in The Lancet Haematology, an interim analysis of the first clinical trial testing pharmacoscopy-guided treatment.
There were 17 evaluable patients, all of whom had aggressive hematologic malignancies. This included diffuse large B-cell lymphoma (n=6), acute myeloid leukemia (n=3), B-cell acute lymphoblastic leukemia (n=2), precursor B-cell lymphoblastic lymphoma (n=1), peripheral T-cell lymphoma (n=1), primary mediastinal B-cell lymphoma (n=1), T-cell lymphoblastic lymphoma (n=1), follicular lymphoma (n=1), and T-cell prolymphocytic leukemia (n=1).
The researchers compared outcomes with pharmacoscopy-guided treatment to outcomes with the most recent regimen on which the patient had progressed.
The overall response rate was 88% with pharmacoscopy-guided treatment and 24% with the patients’ most recent previous treatment regimen (odds ratio=24.38; 95%, CI 3.99–125.4; P=0.0013).
None of the patients had progressive disease as their best overall response when they received pharmacoscopy-guided treatment. However, 7 patients had progressive disease in response to their most recent prior regimen.
At the time of analysis, 8 patients (47%) still had ongoing responses after pharmacoscopy-guided treatment.
In addition, pharmacoscopy-guided treatment significantly improved PFS. The median PFS was 22.6 weeks with pharmacoscopy-guided treatment and 5.7 weeks with the most recent prior regimen (hazard ratio=3.14; 95%, CI 1.37–7.22; P=0.0075).
“Evidence that the pharmacoscopy approach is helpful for clinical evaluation of therapy is wonderful,” said study author Giulio Superti-Furga, PhD, of CeMM Research Center for Molecular Medicine in Vienna, Austria.
“Single-cell functional analysis of primary material gives unprecedented resolution and precision that we are sure to further develop in the future to address yet more diseases.”
FDA approves obinutuzumab for follicular lymphoma
The Food and Drug Administration has approved obinutuzumab in combination with chemotherapy, followed by obinutuzumab alone in those who responded, for people with previously untreated advanced follicular lymphoma (stage II bulky, III or IV).
The most common adverse events associated with obinutuzumab were infusion reactions, low white blood cell count, upper respiratory tract infection, cough, constipation, and diarrhea. The most common significant adverse events are low white blood cell count, low white blood cell count with fever, and low platelet count.
Obinutuzumab is marketed as Gazyva by Genentech.
“Today’s Gazyva approval is an important advance for the thousands of people diagnosed each year with follicular lymphoma who hope to delay disease progression for as long as possible,” said Sarah Horning, MD, chief medical officer and head of global product development at Genentech, in the company press release.
The Food and Drug Administration has approved obinutuzumab in combination with chemotherapy, followed by obinutuzumab alone in those who responded, for people with previously untreated advanced follicular lymphoma (stage II bulky, III or IV).
The most common adverse events associated with obinutuzumab were infusion reactions, low white blood cell count, upper respiratory tract infection, cough, constipation, and diarrhea. The most common significant adverse events are low white blood cell count, low white blood cell count with fever, and low platelet count.
Obinutuzumab is marketed as Gazyva by Genentech.
“Today’s Gazyva approval is an important advance for the thousands of people diagnosed each year with follicular lymphoma who hope to delay disease progression for as long as possible,” said Sarah Horning, MD, chief medical officer and head of global product development at Genentech, in the company press release.
The Food and Drug Administration has approved obinutuzumab in combination with chemotherapy, followed by obinutuzumab alone in those who responded, for people with previously untreated advanced follicular lymphoma (stage II bulky, III or IV).
The most common adverse events associated with obinutuzumab were infusion reactions, low white blood cell count, upper respiratory tract infection, cough, constipation, and diarrhea. The most common significant adverse events are low white blood cell count, low white blood cell count with fever, and low platelet count.
Obinutuzumab is marketed as Gazyva by Genentech.
“Today’s Gazyva approval is an important advance for the thousands of people diagnosed each year with follicular lymphoma who hope to delay disease progression for as long as possible,” said Sarah Horning, MD, chief medical officer and head of global product development at Genentech, in the company press release.
Debate: Is MRD ready for prime time in multiple myeloma?
NEW YORK – Evidence of minimal residual disease (MRD) has been shown to be an important prognostic factor in several different hematologic malignancies, including acute and chronic myeloid leukemias, but its clinical utility in day-to-day practice in multiple myeloma is still uncertain.
At the annual Lymphoma & Myeloma International Congress on Hematologic Malignancies, C. Ola Landgren, MD, PhD, chief of the myeloma service at Memorial Sloan Kettering Cancer Center in New York, and Paul G. Richardson, MD, clinical program leader and director of clinical research at the Jerome Lipper Myeloma Center at the Dana-Farber Cancer Institute in Boston, debated the question: “Is MRD ready for prime time?”
Yes: Dr. Landgren
“As we all know, with older drugs for myeloma, only a small proportion of patients reached a complete response, so there was really no reason to talk about MRD. But this belongs to the past: using the modern combination therapies, about 100% of our patients have a response, an overall response, and up to 80% of patients are reaching a complete response. So it’s really necessary, a logical step to go forward, to look at MRD,” Dr. Landgren said.
He cited evidence from two meta-analyses showing that MRD negativity is a strong predictor of clinical outcomes, including long-term survival.
“Our results show that MRD negativity is a strong predictor of clinical outcomes, supportive of MRD becoming a regulatory end point for drug approval in newly diagnosed multiple myeloma,” they wrote.
In a second meta-analysis, Nikhil Munshi, MD, from the Dana-Farber Cancer Institute, and his colleagues, reviewed PFS data from 14 studies with a total of 1,273 patients, and OS data from 12 studies with a total of 1,100 patients.
This second meta-analysis found that MRD negativity was associated with significantly better PFS (HR, 0.41; P less than .001), including among patients in studies looking specifically at complete response (CR) (HR, 0.44; P less than .001).
Munshi et al. also saw a significant benefit for MRD negativity among all patients in trials with OS as the endpoint (HR, 0.57; P less than .001) and in those focusing on patients with a CR (HR, 0.47; P less than .001).
They concluded that MRD-negative status after treatment for new newly diagnosed multiple myeloma is associated with long-term survival, and like Landgren et al. contended that their findings “provide quantitative evidence to support the integration of MRD assessment as an end point in clinical trials of multiple myeloma.”
Dr. Landgren noted that 2016 International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma, coauthored by both Dr. Landgren and Dr. Richardson, now incorporate MRD.
In addition, in the IFM/DFCI 2009 trial comparing induction therapy for patients with newly diagnosed multiple myeloma with or without autologous stem cell transplant after three cycles of lenalidomide, bortezomib, and dexamethasone, patients in each trial arm who were MRD negative had significantly better PFS than patients who were MRD positive after consolidation, regardless of assigned treatment, Dr. Landgren noted.
In the relapsed/refractory multiple myeloma setting, MRD negativity was associated with better PFS for patients in the POLLUX trial, whether subjects were assigned to receive daratumumab plus lenalidomide and dexamethasone, or len-dex alone.
“This raises an important question: Is MRD more important than treatment modality?” Dr. Landgren said.
“The debate is: Is MRD ready for prime time? And as I have shown you with all the data, the answer is ‘Yes’,” he concluded.
No: Dr. Richardson
“My position on this is that MRD testing is absolutely ready for prime time in the research and regulatory arena. The question for me as a clinician in my clinic is: ‘Do I apply it to everyday practice?’ And I would simply suggest to you at this point we’re not ready for that, and we’re not ready for that for a variety of complex reasons,” Dr. Richardson said in his rebuttal.
He cited a definition of MRD offered by Simone Ferrero, MD, and his colleagues from the University of Turin (Italy) in 2011 in Hematological Oncology: “Any approach aimed at detecting and possibly quantifying residual tumor cells beyond the sensitivity level of routine imaging and laboratory techniques.”
“We recognize in hematologic malignancies in particular, and increasingly in myeloma, that achievement of complete clinical remission and assessing this needs a variety of different scenarios,” he said.
These scenarios may include establishing the full eradication of the neoplastic clone, determining the long-term persistence of quiescent or nonclonogenic or immunologically regulated tumor cells, or persistence of clonogenic cells capable of giving rise to a full clinical relapse within a number of years.
Myeloma specialists recognize that MRD is a real phenomenon, made more challenging by the “extraordinary” heterogeneity of myeloma, he said.
Determination of MRD using sensitive molecular techniques may allow analysis of treatments that induce a greater depth of response than others, and may also identify patients who are experiencing early relapse and will need further treatment, Dr. Richardson acknowledged.
“The question is, should it dictate what you and I do every afternoon in the clinic with a particular patient, for example, outside of a clinical trial?”
He noted that MRD is still a secondary endpoint in trials for acute lymphoblastic leukemia, acute myeloid leukemia, acute promyelocytic leukemia, and chronic lymphocytic leukemia, although it has been accepted by the FDA as a primary endpoint to assess molecular responses to second-generation tyrosine kinase inhibitors.
MRD is also still a secondary endpoint in trials for therapies against follicular and mantle cell lymphomas as well.
“So my hypothesis, or suggestion to you this morning, is that whilst MRD clearly is a vital area of research – and I especially applaud Ola for being on the forefront of this, and I fully support all the points he made – I would just simply suggest to you that it’s less advanced than in leukemia and lymphoma, and we are currently at the point where MRD assessments are clearly secondary endpoints and an important research tool,” he said,
MRD remains a research tool in multiple myeloma because, despite the wealth of new therapies and combinations approved in just the past few years, “we’re not able to eradicate it completely, and cure remains in myeloma, frankly, evasive,” he added.
Immunotherapy, for example, is not the “mutationally agnostic” approach that clinicians had hoped for, with recent evidence suggesting that it cannot overcome every genetic variation that may give rise to multiple myeloma.
For MRD to become a useful clinical tool rather than a research/regulatory tool, standardization of testing methods will be needed. Flow cytometry until recently has been the mainstay for detecting MRD, but molecular strategies are currently being investigated, and rapid next-generation sequencing has the potential to become a gold standard, with its ability to identify and quantify all clonotypes in a sample.
“What’s critical is, therapeutic adjustment for what? What is the difference? For example, [if] one arm of a trial has 20% MRD positivity vs. 40% in another, what does that really mean for overall survival? These are enormous challenges that we still face,” Dr. Richardson said.
“I do think the lack of standardization broadly across the country is a challenge, and so with that in mind, I would simply suggest that it is not yet a standard of care in clinical practice, but may be,” he concluded.
Dr. Landgren disclosed serving as a consultant to AbbVie, Amgen, Bristol-Myers Squibb, Celgene and Janssen. Dr. Richardson disclosed consulting for Celgene and Takeda.
NEW YORK – Evidence of minimal residual disease (MRD) has been shown to be an important prognostic factor in several different hematologic malignancies, including acute and chronic myeloid leukemias, but its clinical utility in day-to-day practice in multiple myeloma is still uncertain.
At the annual Lymphoma & Myeloma International Congress on Hematologic Malignancies, C. Ola Landgren, MD, PhD, chief of the myeloma service at Memorial Sloan Kettering Cancer Center in New York, and Paul G. Richardson, MD, clinical program leader and director of clinical research at the Jerome Lipper Myeloma Center at the Dana-Farber Cancer Institute in Boston, debated the question: “Is MRD ready for prime time?”
Yes: Dr. Landgren
“As we all know, with older drugs for myeloma, only a small proportion of patients reached a complete response, so there was really no reason to talk about MRD. But this belongs to the past: using the modern combination therapies, about 100% of our patients have a response, an overall response, and up to 80% of patients are reaching a complete response. So it’s really necessary, a logical step to go forward, to look at MRD,” Dr. Landgren said.
He cited evidence from two meta-analyses showing that MRD negativity is a strong predictor of clinical outcomes, including long-term survival.
“Our results show that MRD negativity is a strong predictor of clinical outcomes, supportive of MRD becoming a regulatory end point for drug approval in newly diagnosed multiple myeloma,” they wrote.
In a second meta-analysis, Nikhil Munshi, MD, from the Dana-Farber Cancer Institute, and his colleagues, reviewed PFS data from 14 studies with a total of 1,273 patients, and OS data from 12 studies with a total of 1,100 patients.
This second meta-analysis found that MRD negativity was associated with significantly better PFS (HR, 0.41; P less than .001), including among patients in studies looking specifically at complete response (CR) (HR, 0.44; P less than .001).
Munshi et al. also saw a significant benefit for MRD negativity among all patients in trials with OS as the endpoint (HR, 0.57; P less than .001) and in those focusing on patients with a CR (HR, 0.47; P less than .001).
They concluded that MRD-negative status after treatment for new newly diagnosed multiple myeloma is associated with long-term survival, and like Landgren et al. contended that their findings “provide quantitative evidence to support the integration of MRD assessment as an end point in clinical trials of multiple myeloma.”
Dr. Landgren noted that 2016 International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma, coauthored by both Dr. Landgren and Dr. Richardson, now incorporate MRD.
In addition, in the IFM/DFCI 2009 trial comparing induction therapy for patients with newly diagnosed multiple myeloma with or without autologous stem cell transplant after three cycles of lenalidomide, bortezomib, and dexamethasone, patients in each trial arm who were MRD negative had significantly better PFS than patients who were MRD positive after consolidation, regardless of assigned treatment, Dr. Landgren noted.
In the relapsed/refractory multiple myeloma setting, MRD negativity was associated with better PFS for patients in the POLLUX trial, whether subjects were assigned to receive daratumumab plus lenalidomide and dexamethasone, or len-dex alone.
“This raises an important question: Is MRD more important than treatment modality?” Dr. Landgren said.
“The debate is: Is MRD ready for prime time? And as I have shown you with all the data, the answer is ‘Yes’,” he concluded.
No: Dr. Richardson
“My position on this is that MRD testing is absolutely ready for prime time in the research and regulatory arena. The question for me as a clinician in my clinic is: ‘Do I apply it to everyday practice?’ And I would simply suggest to you at this point we’re not ready for that, and we’re not ready for that for a variety of complex reasons,” Dr. Richardson said in his rebuttal.
He cited a definition of MRD offered by Simone Ferrero, MD, and his colleagues from the University of Turin (Italy) in 2011 in Hematological Oncology: “Any approach aimed at detecting and possibly quantifying residual tumor cells beyond the sensitivity level of routine imaging and laboratory techniques.”
“We recognize in hematologic malignancies in particular, and increasingly in myeloma, that achievement of complete clinical remission and assessing this needs a variety of different scenarios,” he said.
These scenarios may include establishing the full eradication of the neoplastic clone, determining the long-term persistence of quiescent or nonclonogenic or immunologically regulated tumor cells, or persistence of clonogenic cells capable of giving rise to a full clinical relapse within a number of years.
Myeloma specialists recognize that MRD is a real phenomenon, made more challenging by the “extraordinary” heterogeneity of myeloma, he said.
Determination of MRD using sensitive molecular techniques may allow analysis of treatments that induce a greater depth of response than others, and may also identify patients who are experiencing early relapse and will need further treatment, Dr. Richardson acknowledged.
“The question is, should it dictate what you and I do every afternoon in the clinic with a particular patient, for example, outside of a clinical trial?”
He noted that MRD is still a secondary endpoint in trials for acute lymphoblastic leukemia, acute myeloid leukemia, acute promyelocytic leukemia, and chronic lymphocytic leukemia, although it has been accepted by the FDA as a primary endpoint to assess molecular responses to second-generation tyrosine kinase inhibitors.
MRD is also still a secondary endpoint in trials for therapies against follicular and mantle cell lymphomas as well.
“So my hypothesis, or suggestion to you this morning, is that whilst MRD clearly is a vital area of research – and I especially applaud Ola for being on the forefront of this, and I fully support all the points he made – I would just simply suggest to you that it’s less advanced than in leukemia and lymphoma, and we are currently at the point where MRD assessments are clearly secondary endpoints and an important research tool,” he said,
MRD remains a research tool in multiple myeloma because, despite the wealth of new therapies and combinations approved in just the past few years, “we’re not able to eradicate it completely, and cure remains in myeloma, frankly, evasive,” he added.
Immunotherapy, for example, is not the “mutationally agnostic” approach that clinicians had hoped for, with recent evidence suggesting that it cannot overcome every genetic variation that may give rise to multiple myeloma.
For MRD to become a useful clinical tool rather than a research/regulatory tool, standardization of testing methods will be needed. Flow cytometry until recently has been the mainstay for detecting MRD, but molecular strategies are currently being investigated, and rapid next-generation sequencing has the potential to become a gold standard, with its ability to identify and quantify all clonotypes in a sample.
“What’s critical is, therapeutic adjustment for what? What is the difference? For example, [if] one arm of a trial has 20% MRD positivity vs. 40% in another, what does that really mean for overall survival? These are enormous challenges that we still face,” Dr. Richardson said.
“I do think the lack of standardization broadly across the country is a challenge, and so with that in mind, I would simply suggest that it is not yet a standard of care in clinical practice, but may be,” he concluded.
Dr. Landgren disclosed serving as a consultant to AbbVie, Amgen, Bristol-Myers Squibb, Celgene and Janssen. Dr. Richardson disclosed consulting for Celgene and Takeda.
NEW YORK – Evidence of minimal residual disease (MRD) has been shown to be an important prognostic factor in several different hematologic malignancies, including acute and chronic myeloid leukemias, but its clinical utility in day-to-day practice in multiple myeloma is still uncertain.
At the annual Lymphoma & Myeloma International Congress on Hematologic Malignancies, C. Ola Landgren, MD, PhD, chief of the myeloma service at Memorial Sloan Kettering Cancer Center in New York, and Paul G. Richardson, MD, clinical program leader and director of clinical research at the Jerome Lipper Myeloma Center at the Dana-Farber Cancer Institute in Boston, debated the question: “Is MRD ready for prime time?”
Yes: Dr. Landgren
“As we all know, with older drugs for myeloma, only a small proportion of patients reached a complete response, so there was really no reason to talk about MRD. But this belongs to the past: using the modern combination therapies, about 100% of our patients have a response, an overall response, and up to 80% of patients are reaching a complete response. So it’s really necessary, a logical step to go forward, to look at MRD,” Dr. Landgren said.
He cited evidence from two meta-analyses showing that MRD negativity is a strong predictor of clinical outcomes, including long-term survival.
“Our results show that MRD negativity is a strong predictor of clinical outcomes, supportive of MRD becoming a regulatory end point for drug approval in newly diagnosed multiple myeloma,” they wrote.
In a second meta-analysis, Nikhil Munshi, MD, from the Dana-Farber Cancer Institute, and his colleagues, reviewed PFS data from 14 studies with a total of 1,273 patients, and OS data from 12 studies with a total of 1,100 patients.
This second meta-analysis found that MRD negativity was associated with significantly better PFS (HR, 0.41; P less than .001), including among patients in studies looking specifically at complete response (CR) (HR, 0.44; P less than .001).
Munshi et al. also saw a significant benefit for MRD negativity among all patients in trials with OS as the endpoint (HR, 0.57; P less than .001) and in those focusing on patients with a CR (HR, 0.47; P less than .001).
They concluded that MRD-negative status after treatment for new newly diagnosed multiple myeloma is associated with long-term survival, and like Landgren et al. contended that their findings “provide quantitative evidence to support the integration of MRD assessment as an end point in clinical trials of multiple myeloma.”
Dr. Landgren noted that 2016 International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma, coauthored by both Dr. Landgren and Dr. Richardson, now incorporate MRD.
In addition, in the IFM/DFCI 2009 trial comparing induction therapy for patients with newly diagnosed multiple myeloma with or without autologous stem cell transplant after three cycles of lenalidomide, bortezomib, and dexamethasone, patients in each trial arm who were MRD negative had significantly better PFS than patients who were MRD positive after consolidation, regardless of assigned treatment, Dr. Landgren noted.
In the relapsed/refractory multiple myeloma setting, MRD negativity was associated with better PFS for patients in the POLLUX trial, whether subjects were assigned to receive daratumumab plus lenalidomide and dexamethasone, or len-dex alone.
“This raises an important question: Is MRD more important than treatment modality?” Dr. Landgren said.
“The debate is: Is MRD ready for prime time? And as I have shown you with all the data, the answer is ‘Yes’,” he concluded.
No: Dr. Richardson
“My position on this is that MRD testing is absolutely ready for prime time in the research and regulatory arena. The question for me as a clinician in my clinic is: ‘Do I apply it to everyday practice?’ And I would simply suggest to you at this point we’re not ready for that, and we’re not ready for that for a variety of complex reasons,” Dr. Richardson said in his rebuttal.
He cited a definition of MRD offered by Simone Ferrero, MD, and his colleagues from the University of Turin (Italy) in 2011 in Hematological Oncology: “Any approach aimed at detecting and possibly quantifying residual tumor cells beyond the sensitivity level of routine imaging and laboratory techniques.”
“We recognize in hematologic malignancies in particular, and increasingly in myeloma, that achievement of complete clinical remission and assessing this needs a variety of different scenarios,” he said.
These scenarios may include establishing the full eradication of the neoplastic clone, determining the long-term persistence of quiescent or nonclonogenic or immunologically regulated tumor cells, or persistence of clonogenic cells capable of giving rise to a full clinical relapse within a number of years.
Myeloma specialists recognize that MRD is a real phenomenon, made more challenging by the “extraordinary” heterogeneity of myeloma, he said.
Determination of MRD using sensitive molecular techniques may allow analysis of treatments that induce a greater depth of response than others, and may also identify patients who are experiencing early relapse and will need further treatment, Dr. Richardson acknowledged.
“The question is, should it dictate what you and I do every afternoon in the clinic with a particular patient, for example, outside of a clinical trial?”
He noted that MRD is still a secondary endpoint in trials for acute lymphoblastic leukemia, acute myeloid leukemia, acute promyelocytic leukemia, and chronic lymphocytic leukemia, although it has been accepted by the FDA as a primary endpoint to assess molecular responses to second-generation tyrosine kinase inhibitors.
MRD is also still a secondary endpoint in trials for therapies against follicular and mantle cell lymphomas as well.
“So my hypothesis, or suggestion to you this morning, is that whilst MRD clearly is a vital area of research – and I especially applaud Ola for being on the forefront of this, and I fully support all the points he made – I would just simply suggest to you that it’s less advanced than in leukemia and lymphoma, and we are currently at the point where MRD assessments are clearly secondary endpoints and an important research tool,” he said,
MRD remains a research tool in multiple myeloma because, despite the wealth of new therapies and combinations approved in just the past few years, “we’re not able to eradicate it completely, and cure remains in myeloma, frankly, evasive,” he added.
Immunotherapy, for example, is not the “mutationally agnostic” approach that clinicians had hoped for, with recent evidence suggesting that it cannot overcome every genetic variation that may give rise to multiple myeloma.
For MRD to become a useful clinical tool rather than a research/regulatory tool, standardization of testing methods will be needed. Flow cytometry until recently has been the mainstay for detecting MRD, but molecular strategies are currently being investigated, and rapid next-generation sequencing has the potential to become a gold standard, with its ability to identify and quantify all clonotypes in a sample.
“What’s critical is, therapeutic adjustment for what? What is the difference? For example, [if] one arm of a trial has 20% MRD positivity vs. 40% in another, what does that really mean for overall survival? These are enormous challenges that we still face,” Dr. Richardson said.
“I do think the lack of standardization broadly across the country is a challenge, and so with that in mind, I would simply suggest that it is not yet a standard of care in clinical practice, but may be,” he concluded.
Dr. Landgren disclosed serving as a consultant to AbbVie, Amgen, Bristol-Myers Squibb, Celgene and Janssen. Dr. Richardson disclosed consulting for Celgene and Takeda.
AT LYMPHOMA & MYELOMA 2017
Is MRD ready for prime time in multiple myeloma?
NEW YORK, NY—Speakers faced off over the issue of minimal residual disease (MRD) testing in multiple myeloma (MM) at Lymphoma & Myeloma 2017.
Ola Landgren, MD, PhD, of Weill Cornell Medicine in New York, New York, said, “it’s really a necessary and logical step forward to look at MRD.”
On the other hand, Paul Richardson, MD, of Dana-Farber Cancer Institute in Boston, Massachusetts, took the clinicians’ perspective and suggested that, at this point, “we’re not yet ready to apply it to everyday practice.”
“[P]atients who have a complete response (CR) and are MRD negative have longer progression-free survival (PFS),” Dr Landgren pointed out, “and there are indications that their overall survival (OS) is better than in those patients who are just CR and MRD positive.”
“My position on this is that MRD testing is absolutely ready for prime time in the research and regulatory arena,” Dr Richardson contended. “The question for me, as a clinician, in my clinic, is ‘Do I apply it to everyday practice?’ And I would simply suggest to you, at this point, we’re not ready for that.”
Yes—MRD is ready for prime time
Dr Landgren based his argument on 2 meta-analyses published in 2016 and 2017 that outline the importance of MRD status in newly diagnosed MM patients.
The first analysis (Landgren et al 2016) showed that MRD negativity was associated with better PFS (hazard ratio [HR]=0.35] and OS (HR=0.48) than MRD positivity.
“So using more simple language,” Dr Landgren said, “this means that MRD negativity reduces the risk of progression by 65%, and it also reduces the risk of dying by 52%.”
The second analysis (Munshi et al 2017) also associated MRD-negative status with superior survival outcomes for both PFS (HR=0.41) and OS (HR=0.57).
As further confirmation of the importance of MRD status, the International Myeloma Working Group last year published response definitions that include MRD negativity at a sensitivity of 1 in 105 cells or higher as the deepest level of treatment response in MM.
Dr Landgren drew on additional studies to support routine MRD testing in patient care.
The IFM Study Group found that, in newly diagnosed patients treated with lenalidomide, bortezomib, and dexamethasone followed by 1 year of lenalidomide maintenance, patients who received a subsequent transplant achieved superior outcomes compared to non-transplanted patients, in terms of CR (58% vs 46%) and 3-year PFS (61% vs 48%).
However, in patients who were MRD negative in both arms, the PFS rates were very similar, Dr Landgren said. And in terms of 3-year OS, there was no difference, at 88% in both arms.
The experience with daratumumab in relapsed/refractory patients exhibited a similar pattern.
The phase 3 POLLUX trial first showed that adding daratumumab to lenalidomide and dexamethasone was superior to lenalidomide and dexamethasone only, with a PFS at 18 months of 78% and 52%, respectively. This amounted to a 63% reduction in the risk of disease progression.
Investigators then took one more step forward, Dr Landgren said, and looked at MRD.
At a sensitivity of 10-5, almost 25% of patients on the 3-drug regimen were MRD negative, “which is kind of amazing,” Dr Landgren said. “This is a very big step forward.”
“If you break down the results by MRD status, which is not the primary endpoint of the study, you see very similar patterns for PFS for MRD negative patients in each of the 2 arms,” he continued.
This raises the question of whether attaining MRD negativity is more important than the treatment modality.
MRD negativity has implications for speeding drug approvals, developing more sensitive assays, and future treatment management, Dr Landgren said.
No—MRD is not ready for prime time
Dr Richardson acknowledged that MRD assessment is important. However, he pointed out a number of caveats regarding how MRD assessment would be applied in clinical practice to support his position.
“I’d simply suggest to you that, in day-to-day practice, the definition [of MRD] is somewhat fluid,” he said. “And it varies, obviously, between diseases and technology used.”
For most malignancies, Dr Richardson said, 109 to 1010 malignant cells are undetectable with conventional methods. These may or may not lead to a full clinical relapse within months or even years.
Using a sensitive technique to determine the presence of MRD could permit analysis of treatments that induce a greater depth of response or identify patients at risk of early relapse who need further treatment.
Dr Richardson enumerated hematologic malignancies that utilize MRD as secondary endpoints—acute lymphoblastic leukemia, acute myeloid leukemia, acute promyelocytic leukemia, chronic lymphocytic leukemia, follicular lymphoma, and mantle cell lymphoma.
In chronic myeloid leukemia, MRD is used as a primary endpoint that dictates practice.
“And I would applaud the field in that area because, obviously, molecular response accepted as an endpoint by FDA for second-generation TKIs has been a bedrock of that approval process, and it now applies in clinical practice,” Dr Richardson said.
“Obviously, that’s where we’d like to be, but I’d suggest to you, just again, with a certain amount of moderation and a certain amount of caution, that we may not be quite there yet.”
Dr Richardson suggested that MRD assessment in MM is less advanced than in leukemia and lymphoma.
“[W]e are currently at the point where MRD assessments are clearly secondary endpoints, an important research tool,” he said.
Some “remarkable combination therapies,” he added, have abrogated some of the “extraordinary genetic complexity” in MM.
“The critical point here, though, is that, while we’re more successful in terms of these triplets and quadruplets and now with the introduction of monoclonal antibodies and similar approaches, we’re able to throw a bigger net around the disease,” Dr Richardson said.
“We’re not able to eradicate it completely, and cure remains, in myeloma, frankly, evasive. And I think that’s a critical point.”
Dr Richardson reviewed various strategies for molecular response monitoring, from flow cytometry to polymerase chain reaction and next-generation sequencing, noting that there is variance in applicability and sensitivity.
For example, the limits of detection among 91 labs ranged from 0.10% to 0.001%.
Dr Richardson returned to the “very robust” meta-analysis by Munshi and colleagues discussed by Dr Landgren.
While the authors’ analysis demonstrated that MRD is predictive of both longer PFS and OS, they concluded that the evidence supported MRD as an endpoint and research tool in clinical trials.
“So I would humbly suggest perhaps it’s not ready for clinical prime time yet,” Dr Richardson said.
He also referred to the IFM Study Group trial described by Dr Landgren, calling it a “critical forward effort.”
“[W]hat’s so interesting is that there was no difference in overall survival,” Dr Richardson said. “Now, that’s a very important point as we soberly look at these data and judge what they mean for each patient.”
And so Dr Richardson stood by his assessment that MRD is not yet a standard of care but may be one day.
NEW YORK, NY—Speakers faced off over the issue of minimal residual disease (MRD) testing in multiple myeloma (MM) at Lymphoma & Myeloma 2017.
Ola Landgren, MD, PhD, of Weill Cornell Medicine in New York, New York, said, “it’s really a necessary and logical step forward to look at MRD.”
On the other hand, Paul Richardson, MD, of Dana-Farber Cancer Institute in Boston, Massachusetts, took the clinicians’ perspective and suggested that, at this point, “we’re not yet ready to apply it to everyday practice.”
“[P]atients who have a complete response (CR) and are MRD negative have longer progression-free survival (PFS),” Dr Landgren pointed out, “and there are indications that their overall survival (OS) is better than in those patients who are just CR and MRD positive.”
“My position on this is that MRD testing is absolutely ready for prime time in the research and regulatory arena,” Dr Richardson contended. “The question for me, as a clinician, in my clinic, is ‘Do I apply it to everyday practice?’ And I would simply suggest to you, at this point, we’re not ready for that.”
Yes—MRD is ready for prime time
Dr Landgren based his argument on 2 meta-analyses published in 2016 and 2017 that outline the importance of MRD status in newly diagnosed MM patients.
The first analysis (Landgren et al 2016) showed that MRD negativity was associated with better PFS (hazard ratio [HR]=0.35] and OS (HR=0.48) than MRD positivity.
“So using more simple language,” Dr Landgren said, “this means that MRD negativity reduces the risk of progression by 65%, and it also reduces the risk of dying by 52%.”
The second analysis (Munshi et al 2017) also associated MRD-negative status with superior survival outcomes for both PFS (HR=0.41) and OS (HR=0.57).
As further confirmation of the importance of MRD status, the International Myeloma Working Group last year published response definitions that include MRD negativity at a sensitivity of 1 in 105 cells or higher as the deepest level of treatment response in MM.
Dr Landgren drew on additional studies to support routine MRD testing in patient care.
The IFM Study Group found that, in newly diagnosed patients treated with lenalidomide, bortezomib, and dexamethasone followed by 1 year of lenalidomide maintenance, patients who received a subsequent transplant achieved superior outcomes compared to non-transplanted patients, in terms of CR (58% vs 46%) and 3-year PFS (61% vs 48%).
However, in patients who were MRD negative in both arms, the PFS rates were very similar, Dr Landgren said. And in terms of 3-year OS, there was no difference, at 88% in both arms.
The experience with daratumumab in relapsed/refractory patients exhibited a similar pattern.
The phase 3 POLLUX trial first showed that adding daratumumab to lenalidomide and dexamethasone was superior to lenalidomide and dexamethasone only, with a PFS at 18 months of 78% and 52%, respectively. This amounted to a 63% reduction in the risk of disease progression.
Investigators then took one more step forward, Dr Landgren said, and looked at MRD.
At a sensitivity of 10-5, almost 25% of patients on the 3-drug regimen were MRD negative, “which is kind of amazing,” Dr Landgren said. “This is a very big step forward.”
“If you break down the results by MRD status, which is not the primary endpoint of the study, you see very similar patterns for PFS for MRD negative patients in each of the 2 arms,” he continued.
This raises the question of whether attaining MRD negativity is more important than the treatment modality.
MRD negativity has implications for speeding drug approvals, developing more sensitive assays, and future treatment management, Dr Landgren said.
No—MRD is not ready for prime time
Dr Richardson acknowledged that MRD assessment is important. However, he pointed out a number of caveats regarding how MRD assessment would be applied in clinical practice to support his position.
“I’d simply suggest to you that, in day-to-day practice, the definition [of MRD] is somewhat fluid,” he said. “And it varies, obviously, between diseases and technology used.”
For most malignancies, Dr Richardson said, 109 to 1010 malignant cells are undetectable with conventional methods. These may or may not lead to a full clinical relapse within months or even years.
Using a sensitive technique to determine the presence of MRD could permit analysis of treatments that induce a greater depth of response or identify patients at risk of early relapse who need further treatment.
Dr Richardson enumerated hematologic malignancies that utilize MRD as secondary endpoints—acute lymphoblastic leukemia, acute myeloid leukemia, acute promyelocytic leukemia, chronic lymphocytic leukemia, follicular lymphoma, and mantle cell lymphoma.
In chronic myeloid leukemia, MRD is used as a primary endpoint that dictates practice.
“And I would applaud the field in that area because, obviously, molecular response accepted as an endpoint by FDA for second-generation TKIs has been a bedrock of that approval process, and it now applies in clinical practice,” Dr Richardson said.
“Obviously, that’s where we’d like to be, but I’d suggest to you, just again, with a certain amount of moderation and a certain amount of caution, that we may not be quite there yet.”
Dr Richardson suggested that MRD assessment in MM is less advanced than in leukemia and lymphoma.
“[W]e are currently at the point where MRD assessments are clearly secondary endpoints, an important research tool,” he said.
Some “remarkable combination therapies,” he added, have abrogated some of the “extraordinary genetic complexity” in MM.
“The critical point here, though, is that, while we’re more successful in terms of these triplets and quadruplets and now with the introduction of monoclonal antibodies and similar approaches, we’re able to throw a bigger net around the disease,” Dr Richardson said.
“We’re not able to eradicate it completely, and cure remains, in myeloma, frankly, evasive. And I think that’s a critical point.”
Dr Richardson reviewed various strategies for molecular response monitoring, from flow cytometry to polymerase chain reaction and next-generation sequencing, noting that there is variance in applicability and sensitivity.
For example, the limits of detection among 91 labs ranged from 0.10% to 0.001%.
Dr Richardson returned to the “very robust” meta-analysis by Munshi and colleagues discussed by Dr Landgren.
While the authors’ analysis demonstrated that MRD is predictive of both longer PFS and OS, they concluded that the evidence supported MRD as an endpoint and research tool in clinical trials.
“So I would humbly suggest perhaps it’s not ready for clinical prime time yet,” Dr Richardson said.
He also referred to the IFM Study Group trial described by Dr Landgren, calling it a “critical forward effort.”
“[W]hat’s so interesting is that there was no difference in overall survival,” Dr Richardson said. “Now, that’s a very important point as we soberly look at these data and judge what they mean for each patient.”
And so Dr Richardson stood by his assessment that MRD is not yet a standard of care but may be one day.
NEW YORK, NY—Speakers faced off over the issue of minimal residual disease (MRD) testing in multiple myeloma (MM) at Lymphoma & Myeloma 2017.
Ola Landgren, MD, PhD, of Weill Cornell Medicine in New York, New York, said, “it’s really a necessary and logical step forward to look at MRD.”
On the other hand, Paul Richardson, MD, of Dana-Farber Cancer Institute in Boston, Massachusetts, took the clinicians’ perspective and suggested that, at this point, “we’re not yet ready to apply it to everyday practice.”
“[P]atients who have a complete response (CR) and are MRD negative have longer progression-free survival (PFS),” Dr Landgren pointed out, “and there are indications that their overall survival (OS) is better than in those patients who are just CR and MRD positive.”
“My position on this is that MRD testing is absolutely ready for prime time in the research and regulatory arena,” Dr Richardson contended. “The question for me, as a clinician, in my clinic, is ‘Do I apply it to everyday practice?’ And I would simply suggest to you, at this point, we’re not ready for that.”
Yes—MRD is ready for prime time
Dr Landgren based his argument on 2 meta-analyses published in 2016 and 2017 that outline the importance of MRD status in newly diagnosed MM patients.
The first analysis (Landgren et al 2016) showed that MRD negativity was associated with better PFS (hazard ratio [HR]=0.35] and OS (HR=0.48) than MRD positivity.
“So using more simple language,” Dr Landgren said, “this means that MRD negativity reduces the risk of progression by 65%, and it also reduces the risk of dying by 52%.”
The second analysis (Munshi et al 2017) also associated MRD-negative status with superior survival outcomes for both PFS (HR=0.41) and OS (HR=0.57).
As further confirmation of the importance of MRD status, the International Myeloma Working Group last year published response definitions that include MRD negativity at a sensitivity of 1 in 105 cells or higher as the deepest level of treatment response in MM.
Dr Landgren drew on additional studies to support routine MRD testing in patient care.
The IFM Study Group found that, in newly diagnosed patients treated with lenalidomide, bortezomib, and dexamethasone followed by 1 year of lenalidomide maintenance, patients who received a subsequent transplant achieved superior outcomes compared to non-transplanted patients, in terms of CR (58% vs 46%) and 3-year PFS (61% vs 48%).
However, in patients who were MRD negative in both arms, the PFS rates were very similar, Dr Landgren said. And in terms of 3-year OS, there was no difference, at 88% in both arms.
The experience with daratumumab in relapsed/refractory patients exhibited a similar pattern.
The phase 3 POLLUX trial first showed that adding daratumumab to lenalidomide and dexamethasone was superior to lenalidomide and dexamethasone only, with a PFS at 18 months of 78% and 52%, respectively. This amounted to a 63% reduction in the risk of disease progression.
Investigators then took one more step forward, Dr Landgren said, and looked at MRD.
At a sensitivity of 10-5, almost 25% of patients on the 3-drug regimen were MRD negative, “which is kind of amazing,” Dr Landgren said. “This is a very big step forward.”
“If you break down the results by MRD status, which is not the primary endpoint of the study, you see very similar patterns for PFS for MRD negative patients in each of the 2 arms,” he continued.
This raises the question of whether attaining MRD negativity is more important than the treatment modality.
MRD negativity has implications for speeding drug approvals, developing more sensitive assays, and future treatment management, Dr Landgren said.
No—MRD is not ready for prime time
Dr Richardson acknowledged that MRD assessment is important. However, he pointed out a number of caveats regarding how MRD assessment would be applied in clinical practice to support his position.
“I’d simply suggest to you that, in day-to-day practice, the definition [of MRD] is somewhat fluid,” he said. “And it varies, obviously, between diseases and technology used.”
For most malignancies, Dr Richardson said, 109 to 1010 malignant cells are undetectable with conventional methods. These may or may not lead to a full clinical relapse within months or even years.
Using a sensitive technique to determine the presence of MRD could permit analysis of treatments that induce a greater depth of response or identify patients at risk of early relapse who need further treatment.
Dr Richardson enumerated hematologic malignancies that utilize MRD as secondary endpoints—acute lymphoblastic leukemia, acute myeloid leukemia, acute promyelocytic leukemia, chronic lymphocytic leukemia, follicular lymphoma, and mantle cell lymphoma.
In chronic myeloid leukemia, MRD is used as a primary endpoint that dictates practice.
“And I would applaud the field in that area because, obviously, molecular response accepted as an endpoint by FDA for second-generation TKIs has been a bedrock of that approval process, and it now applies in clinical practice,” Dr Richardson said.
“Obviously, that’s where we’d like to be, but I’d suggest to you, just again, with a certain amount of moderation and a certain amount of caution, that we may not be quite there yet.”
Dr Richardson suggested that MRD assessment in MM is less advanced than in leukemia and lymphoma.
“[W]e are currently at the point where MRD assessments are clearly secondary endpoints, an important research tool,” he said.
Some “remarkable combination therapies,” he added, have abrogated some of the “extraordinary genetic complexity” in MM.
“The critical point here, though, is that, while we’re more successful in terms of these triplets and quadruplets and now with the introduction of monoclonal antibodies and similar approaches, we’re able to throw a bigger net around the disease,” Dr Richardson said.
“We’re not able to eradicate it completely, and cure remains, in myeloma, frankly, evasive. And I think that’s a critical point.”
Dr Richardson reviewed various strategies for molecular response monitoring, from flow cytometry to polymerase chain reaction and next-generation sequencing, noting that there is variance in applicability and sensitivity.
For example, the limits of detection among 91 labs ranged from 0.10% to 0.001%.
Dr Richardson returned to the “very robust” meta-analysis by Munshi and colleagues discussed by Dr Landgren.
While the authors’ analysis demonstrated that MRD is predictive of both longer PFS and OS, they concluded that the evidence supported MRD as an endpoint and research tool in clinical trials.
“So I would humbly suggest perhaps it’s not ready for clinical prime time yet,” Dr Richardson said.
He also referred to the IFM Study Group trial described by Dr Landgren, calling it a “critical forward effort.”
“[W]hat’s so interesting is that there was no difference in overall survival,” Dr Richardson said. “Now, that’s a very important point as we soberly look at these data and judge what they mean for each patient.”
And so Dr Richardson stood by his assessment that MRD is not yet a standard of care but may be one day.
EMA recommends orphan designation for G100 to treat FL
The European Medicines Agency’s (EMA’s) Committee for Orphan Medicinal Products has recommended orphan designation for G100 for the treatment of follicular lymphoma (FL).
G100 contains the synthetic small molecule toll-like receptor-4 agonist glucopyranosyl lipid A.
G100 works by activating innate and adaptive immunity in the tumor microenvironment to generate an immune response against the tumor’s pre-existing antigens.
Clinical and preclinical data have demonstrated G100’s ability to activate tumor-infiltrating lymphocytes, macrophages, and dendritic cells, and promote antigen-presentation and the recruitment of T cells to the tumor.
The induction of local and systemic immune responses has been shown in preclinical studies to result in local and abscopal tumor control.
Immune Design, the company developing G100, is currently evaluating G100 plus local radiation, with or without pembrolizumab, in a phase 1/2 trial of FL patients.
Results from this trial were presented at the 2017 ASCO Annual Meeting (abstract 7537). Nine patients who received G100 (3 patients each at the 5, 10, or 20 μg dose) with radiation (but not pembrolizumab) were evaluable for safety and efficacy.
The overall response rate was 44%, and all of these were partial responses (n=4). Thirty-three percent of patients had stable disease (n=3).
Among the responders, tumor regression ranged from 58% to 89%, which included up to 56% shrinkage of abscopal sites. Tumor biopsies showed increased inflammatory responses and T-cell infiltrates in abscopal tumors.
An additional 13 patients treated at the 10 μg dose were evaluable for safety. There were no dose-limiting toxicities, serious adverse events (AEs), or grade 3/4 AEs observed.
Common AEs included injection site disorders, abdominal pain/discomfort, nausea, pruritus, and decrease in lymphocytes.
Immune Design said that, if this trial produces a sufficiently robust clinical benefit for patients, the company may pursue FL as the first indication for regulatory approval of G100.
About orphan designation
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 EMA during the product development phase and direct access to the centralized authorization procedure.
The EMA’s Committee for Orphan Medicinal Products adopts an opinion on the granting of orphan drug designation, and that opinion is submitted to the European Commission for a final decision. The commission typically makes a decision within 30 days of the submission.
The European Medicines Agency’s (EMA’s) Committee for Orphan Medicinal Products has recommended orphan designation for G100 for the treatment of follicular lymphoma (FL).
G100 contains the synthetic small molecule toll-like receptor-4 agonist glucopyranosyl lipid A.
G100 works by activating innate and adaptive immunity in the tumor microenvironment to generate an immune response against the tumor’s pre-existing antigens.
Clinical and preclinical data have demonstrated G100’s ability to activate tumor-infiltrating lymphocytes, macrophages, and dendritic cells, and promote antigen-presentation and the recruitment of T cells to the tumor.
The induction of local and systemic immune responses has been shown in preclinical studies to result in local and abscopal tumor control.
Immune Design, the company developing G100, is currently evaluating G100 plus local radiation, with or without pembrolizumab, in a phase 1/2 trial of FL patients.
Results from this trial were presented at the 2017 ASCO Annual Meeting (abstract 7537). Nine patients who received G100 (3 patients each at the 5, 10, or 20 μg dose) with radiation (but not pembrolizumab) were evaluable for safety and efficacy.
The overall response rate was 44%, and all of these were partial responses (n=4). Thirty-three percent of patients had stable disease (n=3).
Among the responders, tumor regression ranged from 58% to 89%, which included up to 56% shrinkage of abscopal sites. Tumor biopsies showed increased inflammatory responses and T-cell infiltrates in abscopal tumors.
An additional 13 patients treated at the 10 μg dose were evaluable for safety. There were no dose-limiting toxicities, serious adverse events (AEs), or grade 3/4 AEs observed.
Common AEs included injection site disorders, abdominal pain/discomfort, nausea, pruritus, and decrease in lymphocytes.
Immune Design said that, if this trial produces a sufficiently robust clinical benefit for patients, the company may pursue FL as the first indication for regulatory approval of G100.
About orphan designation
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 EMA during the product development phase and direct access to the centralized authorization procedure.
The EMA’s Committee for Orphan Medicinal Products adopts an opinion on the granting of orphan drug designation, and that opinion is submitted to the European Commission for a final decision. The commission typically makes a decision within 30 days of the submission.
The European Medicines Agency’s (EMA’s) Committee for Orphan Medicinal Products has recommended orphan designation for G100 for the treatment of follicular lymphoma (FL).
G100 contains the synthetic small molecule toll-like receptor-4 agonist glucopyranosyl lipid A.
G100 works by activating innate and adaptive immunity in the tumor microenvironment to generate an immune response against the tumor’s pre-existing antigens.
Clinical and preclinical data have demonstrated G100’s ability to activate tumor-infiltrating lymphocytes, macrophages, and dendritic cells, and promote antigen-presentation and the recruitment of T cells to the tumor.
The induction of local and systemic immune responses has been shown in preclinical studies to result in local and abscopal tumor control.
Immune Design, the company developing G100, is currently evaluating G100 plus local radiation, with or without pembrolizumab, in a phase 1/2 trial of FL patients.
Results from this trial were presented at the 2017 ASCO Annual Meeting (abstract 7537). Nine patients who received G100 (3 patients each at the 5, 10, or 20 μg dose) with radiation (but not pembrolizumab) were evaluable for safety and efficacy.
The overall response rate was 44%, and all of these were partial responses (n=4). Thirty-three percent of patients had stable disease (n=3).
Among the responders, tumor regression ranged from 58% to 89%, which included up to 56% shrinkage of abscopal sites. Tumor biopsies showed increased inflammatory responses and T-cell infiltrates in abscopal tumors.
An additional 13 patients treated at the 10 μg dose were evaluable for safety. There were no dose-limiting toxicities, serious adverse events (AEs), or grade 3/4 AEs observed.
Common AEs included injection site disorders, abdominal pain/discomfort, nausea, pruritus, and decrease in lymphocytes.
Immune Design said that, if this trial produces a sufficiently robust clinical benefit for patients, the company may pursue FL as the first indication for regulatory approval of G100.
About orphan designation
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 EMA during the product development phase and direct access to the centralized authorization procedure.
The EMA’s Committee for Orphan Medicinal Products adopts an opinion on the granting of orphan drug designation, and that opinion is submitted to the European Commission for a final decision. The commission typically makes a decision within 30 days of the submission.
Obinutuzumab edges out rituximab for PFS in follicular lymphoma
In a head-to-head trial of anti-CD20 monoclonal antibodies in first-line therapy for follicular lymphoma, obinutuzumab-based chemotherapy was associated with slightly but significantly better progression-free survival than rituximab-based therapy, but at the cost of higher toxicities, including severe adverse events.
Among 1,202 patients with follicular lymphoma followed for a median of 34.5 months, the estimated 3-year rate of progression-free survival (PFS) for patients randomized to obinutuzumab-based chemotherapy and maintenance was 80%, compared with 73.3% for patients randomized to rituximab chemotherapy and maintenance. Response rates and overall survival were similar between the treatment groups, Robert Marcus, MB, BS, of King’s College Hospital, London, and his coinvestigators reported in the GALLIUM trial.
They acknowledged, however, that there were substantial differences between the treatment groups in the cumulative doses of obinutuzumab (Gazyva) and rituximab (Rituxan and others), which could have affected the relative efficacy of each regimen.
In addition, while patients were randomly assigned to one monoclonal antibody or the other, the choice of chemotherapy regimens, while standardized, was left to the discretion of investigators at each treatment site, another factor that might have influenced outcomes.
The investigators reported the results of a preplanned interim efficacy analysis. They compared obinutuzumab or rituximab plus chemotherapy in patients with indolent non-Hodgkin lymphoma, but the trial was powered to detect a PFS difference only in patients with follicular lymphoma. Patients who had a clinical response to induction therapy went on to maintenance therapy with the same monoclonal antibody.
In all, 1,202 patients with follicular lymphoma were enrolled and randomized, 601 in each arm, to receive induction with either intravenous obinutuzumab 1,000 mg on days 1, 8, and 15 of cycle 1 and on day 1 of subsequent cycles, or rituximab 375 mg/m2 on day 1 of each cycle for six or eight cycles, depending on the accompanying chemotherapy regimen. The regimens used were either CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), CVP (cyclophosphamide, vincristine, and prednisone), or bendamustine.
Patients with partial or complete responses were then maintained on the same monoclonal antibody they had received during induction, either obinutuzumab 1,000 mg or rituximab 375 mg/m2 every 2 months for 2 years, or until disease progression. Patients were not allowed to be crossed over to the other maintenance therapy.
Patients with stable disease after induction continued to be followed, but did not receive maintenance therapy.
The interim analysis was performed after 245 of 370 anticipated events (disease progression, relapse, or death) had occurred. At that time, the independent data and safety monitoring committee recommended full analysis of the trial data, and the sponsor agreed.
After a median follow-up of 34.5 months, an intention-to-treat analysis showed that the investigator-assessed, estimated 3-year rate of PFS was 80.0% in the obinutuzumab arm, compared with 73.3%; in the rituximab arm. This translated into a hazard ratio (HR) for progression, relapse, or death of 0.66 (P = .001). An independent review committee calculated a HR favoring obinutuzumab of 0.71 (P = .01).
Estimated 3-year overall survival rates were not significantly different at 94% and 92.1%, respectively.
Overall response rates were similar between the groups, at 88.5% with obinutuzumab group and 86.9% with rituximab, a difference that was not significant.
Obinutuzumab was associated with a higher rate of prespecified events of special interest, including infections, cardiac events, second neoplasms, infusion-related events, neutropenia, and thrombocytopenia.
Adverse events deemed to be related to the antibodies occurred in 59.3% of patients on obinutuzumab, and 48.9% of patients on rituximab.
There were more frequent grade 3 or 4 adverse events and deaths with obinutuzumab, occurring in 74.6% of patients vs. 67.8% on rituximab. Fatal adverse events occurred in 4% and 3.4% of patients, respectively.
A total of 81 patients died during the trial, including 35 in the obinutuzumab group and 46 in the rituximab group.
F. Hoffmann–La Roche supported the trial. Dr. Marcus disclosed consulting fees and lecture fees from Takeda Pharmaceuticals and travel support, consulting fees, and lecture fees from Roche. The majority of coauthors disclosed similar relationships.
Should obinutuzumab replace rituximab as the standard antibody in the treatment of patients receiving chemoimmunotherapy regimens for follicular lymphoma? Results from this trial would suggest that there might be no advantage for an obinutuzumab-containing chemoimmunotherapy regimen if maintenance treatment was not planned. Even with maintenance therapy, there is no evidence from this trial of an overall survival benefit with obinutuzumab. These findings, combined with the higher rate of toxic effects and, presumably, the higher cost of obinutuzumab, raise important questions regarding the advantage of its use. This issue is complicated further because it is possible that giving rituximab at a dose of 1,000 mg might reduce or eliminate any difference in progression-free survival – that is, if the difference is primarily a dose effect.
When the data on minimal residual disease are made available, the case in favor of obinutuzumab may appear to be more compelling if indeed a higher proportion of patients who received obinutuzumab have minimal residual disease status at some point in treatment and remain in remission longer than those who received rituximab. At the moment, the competition between these agents looks too close to call.
These comments are excerpted from an editorial (N Engl J Med. 2017 Oct 5;377;14:1389-90) by James O. Armitage, MD, University of Nebraska, Omaha, and Dan L. Longo, MD, Dana-Farber Cancer Institute, Boston. Dr. Armitage reported personal fees from Conatus, Samus Therapeutics, and Tesaro. Dr. Longo reported no relevant disclosures. He is deputy editor of The New England Journal of Medicine.
Should obinutuzumab replace rituximab as the standard antibody in the treatment of patients receiving chemoimmunotherapy regimens for follicular lymphoma? Results from this trial would suggest that there might be no advantage for an obinutuzumab-containing chemoimmunotherapy regimen if maintenance treatment was not planned. Even with maintenance therapy, there is no evidence from this trial of an overall survival benefit with obinutuzumab. These findings, combined with the higher rate of toxic effects and, presumably, the higher cost of obinutuzumab, raise important questions regarding the advantage of its use. This issue is complicated further because it is possible that giving rituximab at a dose of 1,000 mg might reduce or eliminate any difference in progression-free survival – that is, if the difference is primarily a dose effect.
When the data on minimal residual disease are made available, the case in favor of obinutuzumab may appear to be more compelling if indeed a higher proportion of patients who received obinutuzumab have minimal residual disease status at some point in treatment and remain in remission longer than those who received rituximab. At the moment, the competition between these agents looks too close to call.
These comments are excerpted from an editorial (N Engl J Med. 2017 Oct 5;377;14:1389-90) by James O. Armitage, MD, University of Nebraska, Omaha, and Dan L. Longo, MD, Dana-Farber Cancer Institute, Boston. Dr. Armitage reported personal fees from Conatus, Samus Therapeutics, and Tesaro. Dr. Longo reported no relevant disclosures. He is deputy editor of The New England Journal of Medicine.
Should obinutuzumab replace rituximab as the standard antibody in the treatment of patients receiving chemoimmunotherapy regimens for follicular lymphoma? Results from this trial would suggest that there might be no advantage for an obinutuzumab-containing chemoimmunotherapy regimen if maintenance treatment was not planned. Even with maintenance therapy, there is no evidence from this trial of an overall survival benefit with obinutuzumab. These findings, combined with the higher rate of toxic effects and, presumably, the higher cost of obinutuzumab, raise important questions regarding the advantage of its use. This issue is complicated further because it is possible that giving rituximab at a dose of 1,000 mg might reduce or eliminate any difference in progression-free survival – that is, if the difference is primarily a dose effect.
When the data on minimal residual disease are made available, the case in favor of obinutuzumab may appear to be more compelling if indeed a higher proportion of patients who received obinutuzumab have minimal residual disease status at some point in treatment and remain in remission longer than those who received rituximab. At the moment, the competition between these agents looks too close to call.
These comments are excerpted from an editorial (N Engl J Med. 2017 Oct 5;377;14:1389-90) by James O. Armitage, MD, University of Nebraska, Omaha, and Dan L. Longo, MD, Dana-Farber Cancer Institute, Boston. Dr. Armitage reported personal fees from Conatus, Samus Therapeutics, and Tesaro. Dr. Longo reported no relevant disclosures. He is deputy editor of The New England Journal of Medicine.
In a head-to-head trial of anti-CD20 monoclonal antibodies in first-line therapy for follicular lymphoma, obinutuzumab-based chemotherapy was associated with slightly but significantly better progression-free survival than rituximab-based therapy, but at the cost of higher toxicities, including severe adverse events.
Among 1,202 patients with follicular lymphoma followed for a median of 34.5 months, the estimated 3-year rate of progression-free survival (PFS) for patients randomized to obinutuzumab-based chemotherapy and maintenance was 80%, compared with 73.3% for patients randomized to rituximab chemotherapy and maintenance. Response rates and overall survival were similar between the treatment groups, Robert Marcus, MB, BS, of King’s College Hospital, London, and his coinvestigators reported in the GALLIUM trial.
They acknowledged, however, that there were substantial differences between the treatment groups in the cumulative doses of obinutuzumab (Gazyva) and rituximab (Rituxan and others), which could have affected the relative efficacy of each regimen.
In addition, while patients were randomly assigned to one monoclonal antibody or the other, the choice of chemotherapy regimens, while standardized, was left to the discretion of investigators at each treatment site, another factor that might have influenced outcomes.
The investigators reported the results of a preplanned interim efficacy analysis. They compared obinutuzumab or rituximab plus chemotherapy in patients with indolent non-Hodgkin lymphoma, but the trial was powered to detect a PFS difference only in patients with follicular lymphoma. Patients who had a clinical response to induction therapy went on to maintenance therapy with the same monoclonal antibody.
In all, 1,202 patients with follicular lymphoma were enrolled and randomized, 601 in each arm, to receive induction with either intravenous obinutuzumab 1,000 mg on days 1, 8, and 15 of cycle 1 and on day 1 of subsequent cycles, or rituximab 375 mg/m2 on day 1 of each cycle for six or eight cycles, depending on the accompanying chemotherapy regimen. The regimens used were either CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), CVP (cyclophosphamide, vincristine, and prednisone), or bendamustine.
Patients with partial or complete responses were then maintained on the same monoclonal antibody they had received during induction, either obinutuzumab 1,000 mg or rituximab 375 mg/m2 every 2 months for 2 years, or until disease progression. Patients were not allowed to be crossed over to the other maintenance therapy.
Patients with stable disease after induction continued to be followed, but did not receive maintenance therapy.
The interim analysis was performed after 245 of 370 anticipated events (disease progression, relapse, or death) had occurred. At that time, the independent data and safety monitoring committee recommended full analysis of the trial data, and the sponsor agreed.
After a median follow-up of 34.5 months, an intention-to-treat analysis showed that the investigator-assessed, estimated 3-year rate of PFS was 80.0% in the obinutuzumab arm, compared with 73.3%; in the rituximab arm. This translated into a hazard ratio (HR) for progression, relapse, or death of 0.66 (P = .001). An independent review committee calculated a HR favoring obinutuzumab of 0.71 (P = .01).
Estimated 3-year overall survival rates were not significantly different at 94% and 92.1%, respectively.
Overall response rates were similar between the groups, at 88.5% with obinutuzumab group and 86.9% with rituximab, a difference that was not significant.
Obinutuzumab was associated with a higher rate of prespecified events of special interest, including infections, cardiac events, second neoplasms, infusion-related events, neutropenia, and thrombocytopenia.
Adverse events deemed to be related to the antibodies occurred in 59.3% of patients on obinutuzumab, and 48.9% of patients on rituximab.
There were more frequent grade 3 or 4 adverse events and deaths with obinutuzumab, occurring in 74.6% of patients vs. 67.8% on rituximab. Fatal adverse events occurred in 4% and 3.4% of patients, respectively.
A total of 81 patients died during the trial, including 35 in the obinutuzumab group and 46 in the rituximab group.
F. Hoffmann–La Roche supported the trial. Dr. Marcus disclosed consulting fees and lecture fees from Takeda Pharmaceuticals and travel support, consulting fees, and lecture fees from Roche. The majority of coauthors disclosed similar relationships.
In a head-to-head trial of anti-CD20 monoclonal antibodies in first-line therapy for follicular lymphoma, obinutuzumab-based chemotherapy was associated with slightly but significantly better progression-free survival than rituximab-based therapy, but at the cost of higher toxicities, including severe adverse events.
Among 1,202 patients with follicular lymphoma followed for a median of 34.5 months, the estimated 3-year rate of progression-free survival (PFS) for patients randomized to obinutuzumab-based chemotherapy and maintenance was 80%, compared with 73.3% for patients randomized to rituximab chemotherapy and maintenance. Response rates and overall survival were similar between the treatment groups, Robert Marcus, MB, BS, of King’s College Hospital, London, and his coinvestigators reported in the GALLIUM trial.
They acknowledged, however, that there were substantial differences between the treatment groups in the cumulative doses of obinutuzumab (Gazyva) and rituximab (Rituxan and others), which could have affected the relative efficacy of each regimen.
In addition, while patients were randomly assigned to one monoclonal antibody or the other, the choice of chemotherapy regimens, while standardized, was left to the discretion of investigators at each treatment site, another factor that might have influenced outcomes.
The investigators reported the results of a preplanned interim efficacy analysis. They compared obinutuzumab or rituximab plus chemotherapy in patients with indolent non-Hodgkin lymphoma, but the trial was powered to detect a PFS difference only in patients with follicular lymphoma. Patients who had a clinical response to induction therapy went on to maintenance therapy with the same monoclonal antibody.
In all, 1,202 patients with follicular lymphoma were enrolled and randomized, 601 in each arm, to receive induction with either intravenous obinutuzumab 1,000 mg on days 1, 8, and 15 of cycle 1 and on day 1 of subsequent cycles, or rituximab 375 mg/m2 on day 1 of each cycle for six or eight cycles, depending on the accompanying chemotherapy regimen. The regimens used were either CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), CVP (cyclophosphamide, vincristine, and prednisone), or bendamustine.
Patients with partial or complete responses were then maintained on the same monoclonal antibody they had received during induction, either obinutuzumab 1,000 mg or rituximab 375 mg/m2 every 2 months for 2 years, or until disease progression. Patients were not allowed to be crossed over to the other maintenance therapy.
Patients with stable disease after induction continued to be followed, but did not receive maintenance therapy.
The interim analysis was performed after 245 of 370 anticipated events (disease progression, relapse, or death) had occurred. At that time, the independent data and safety monitoring committee recommended full analysis of the trial data, and the sponsor agreed.
After a median follow-up of 34.5 months, an intention-to-treat analysis showed that the investigator-assessed, estimated 3-year rate of PFS was 80.0% in the obinutuzumab arm, compared with 73.3%; in the rituximab arm. This translated into a hazard ratio (HR) for progression, relapse, or death of 0.66 (P = .001). An independent review committee calculated a HR favoring obinutuzumab of 0.71 (P = .01).
Estimated 3-year overall survival rates were not significantly different at 94% and 92.1%, respectively.
Overall response rates were similar between the groups, at 88.5% with obinutuzumab group and 86.9% with rituximab, a difference that was not significant.
Obinutuzumab was associated with a higher rate of prespecified events of special interest, including infections, cardiac events, second neoplasms, infusion-related events, neutropenia, and thrombocytopenia.
Adverse events deemed to be related to the antibodies occurred in 59.3% of patients on obinutuzumab, and 48.9% of patients on rituximab.
There were more frequent grade 3 or 4 adverse events and deaths with obinutuzumab, occurring in 74.6% of patients vs. 67.8% on rituximab. Fatal adverse events occurred in 4% and 3.4% of patients, respectively.
A total of 81 patients died during the trial, including 35 in the obinutuzumab group and 46 in the rituximab group.
F. Hoffmann–La Roche supported the trial. Dr. Marcus disclosed consulting fees and lecture fees from Takeda Pharmaceuticals and travel support, consulting fees, and lecture fees from Roche. The majority of coauthors disclosed similar relationships.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Key clinical point: Obinutuzumab-based chemotherapy and maintenance was associated with better progression-free survival, but not overall survival, compared with rituximab-based chemotherapy and maintenance.
Major finding: Three-year progression-free survival was 80% with obinutuzumab, vs. 73.3% with rituximab.
Data source: Interim analysis of a randomized phase 3, open-label trial of 1,202 patients with follicular lymphoma.
Disclosures: F. Hoffmann–La Roche supported the trial. Dr. Marcus disclosed consulting fees and lecture fees from Takeda Pharmaceuticals and travel support, consulting fees, and lecture fees from Roche. The majority of coauthors disclosed similar relationships.
VCR regimen showed efficacy in mantle cell and indolent lymphomas
The combination of bortezomib, cladribine, and rituximab (VCR) was an effective treatment regimen for patients with CD20-positive mantle cell lymphoma (MCL) and indolent non-Hodgkin’s lymphoma (iNHL), based on results of a recent phase 2, open-label study.
The overall response rate was 92% in the single-center, 24-patient study. The 2-year progression-free survival (PFS) was 82% and 54%, respectively, for MCL and iNHL patients; PFS was 80% for treatment-naive patients and 57% for those with refractory/recalcitrant disease, according to Soham D. Puvvada, MD, of the University of Arizona Cancer Center in Tucson, and her associates.
Two-year overall survival was 91% for MCL and 69% for iNHL patients. Median time to progression was 34.5 months, and median PFS had not been reached at 2 years, according to the researchers.
While the study (NCT00980395) was small and limited by its single-center design, the VCR combination “has encouraging activity in both MCL and iNHL and could be compared to standard therapies in future studies,” the researchers wrote. “For MCL in particular, we believe a noninferiority comparison to standard therapies would be justified by our results.”
Adverse events were most commonly hematologic, and three patients experienced febrile neutropenia, data show.
“Although hematological toxicity can be an issue, the regimen provides an alternative option in transplant ineligible relapsed/refractory MCL and iNHL,” wrote Dr. Puvvada and her colleagues. The study was published in Clinical Lymphoma, Myeloma & Leukemia (doi: 10.1016/j.clml.2017.09.001).
The researchers studied the combination of bortezomib, the proteasome inhibitor initially approved for relapsed/refractory MCL, cladribine, which has shown activity and promising response rates in patients with indolent lymphomas, and rituximab in patients with CD20-positive mantle cell or indolent lymphoma.
Patients with follicular lymphomas were eligible to be included in the study if they had received at least one previous line of therapy. All other participants could be treatment naive or have relapsed after previous treatment.
Of the 24 patients enrolled, 11 had MCL, 5 had follicular lymphoma, 4 had marginal zone lymphoma, 3 had lymphoplasmacytic lymphoma, and 1 had small lymphocytic lymphoma.
The VCR regimen, given every 28 days for no more than six cycles, included rituximab at 375 mg/m2 given intravenously on day 1 of each cycle, cladribine 4 mg/m2 given intravenously over 2 hours on days 1 through 5, and bortezomib 1.3 mg/m2 given intravenously on days 1 and 4. Patients received a median of five cycles of therapy.
Adverse events of grade 3 or greater occurred in 14 patients (58%); 8 patients had leukopenia, 6 had thrombocytopenia, 5 had fatigue, and 5 had neutropenia, which included febrile neutropenia in 3 patients.
With a median follow-up of 38.5 months, overall response rate for VCR was 96%. Complete responses occurred in 8 of 23 evaluable patients (35%) and partial responses in 14 more patients (61%).
The combination of bortezomib, cladribine, and rituximab (VCR) was an effective treatment regimen for patients with CD20-positive mantle cell lymphoma (MCL) and indolent non-Hodgkin’s lymphoma (iNHL), based on results of a recent phase 2, open-label study.
The overall response rate was 92% in the single-center, 24-patient study. The 2-year progression-free survival (PFS) was 82% and 54%, respectively, for MCL and iNHL patients; PFS was 80% for treatment-naive patients and 57% for those with refractory/recalcitrant disease, according to Soham D. Puvvada, MD, of the University of Arizona Cancer Center in Tucson, and her associates.
Two-year overall survival was 91% for MCL and 69% for iNHL patients. Median time to progression was 34.5 months, and median PFS had not been reached at 2 years, according to the researchers.
While the study (NCT00980395) was small and limited by its single-center design, the VCR combination “has encouraging activity in both MCL and iNHL and could be compared to standard therapies in future studies,” the researchers wrote. “For MCL in particular, we believe a noninferiority comparison to standard therapies would be justified by our results.”
Adverse events were most commonly hematologic, and three patients experienced febrile neutropenia, data show.
“Although hematological toxicity can be an issue, the regimen provides an alternative option in transplant ineligible relapsed/refractory MCL and iNHL,” wrote Dr. Puvvada and her colleagues. The study was published in Clinical Lymphoma, Myeloma & Leukemia (doi: 10.1016/j.clml.2017.09.001).
The researchers studied the combination of bortezomib, the proteasome inhibitor initially approved for relapsed/refractory MCL, cladribine, which has shown activity and promising response rates in patients with indolent lymphomas, and rituximab in patients with CD20-positive mantle cell or indolent lymphoma.
Patients with follicular lymphomas were eligible to be included in the study if they had received at least one previous line of therapy. All other participants could be treatment naive or have relapsed after previous treatment.
Of the 24 patients enrolled, 11 had MCL, 5 had follicular lymphoma, 4 had marginal zone lymphoma, 3 had lymphoplasmacytic lymphoma, and 1 had small lymphocytic lymphoma.
The VCR regimen, given every 28 days for no more than six cycles, included rituximab at 375 mg/m2 given intravenously on day 1 of each cycle, cladribine 4 mg/m2 given intravenously over 2 hours on days 1 through 5, and bortezomib 1.3 mg/m2 given intravenously on days 1 and 4. Patients received a median of five cycles of therapy.
Adverse events of grade 3 or greater occurred in 14 patients (58%); 8 patients had leukopenia, 6 had thrombocytopenia, 5 had fatigue, and 5 had neutropenia, which included febrile neutropenia in 3 patients.
With a median follow-up of 38.5 months, overall response rate for VCR was 96%. Complete responses occurred in 8 of 23 evaluable patients (35%) and partial responses in 14 more patients (61%).
The combination of bortezomib, cladribine, and rituximab (VCR) was an effective treatment regimen for patients with CD20-positive mantle cell lymphoma (MCL) and indolent non-Hodgkin’s lymphoma (iNHL), based on results of a recent phase 2, open-label study.
The overall response rate was 92% in the single-center, 24-patient study. The 2-year progression-free survival (PFS) was 82% and 54%, respectively, for MCL and iNHL patients; PFS was 80% for treatment-naive patients and 57% for those with refractory/recalcitrant disease, according to Soham D. Puvvada, MD, of the University of Arizona Cancer Center in Tucson, and her associates.
Two-year overall survival was 91% for MCL and 69% for iNHL patients. Median time to progression was 34.5 months, and median PFS had not been reached at 2 years, according to the researchers.
While the study (NCT00980395) was small and limited by its single-center design, the VCR combination “has encouraging activity in both MCL and iNHL and could be compared to standard therapies in future studies,” the researchers wrote. “For MCL in particular, we believe a noninferiority comparison to standard therapies would be justified by our results.”
Adverse events were most commonly hematologic, and three patients experienced febrile neutropenia, data show.
“Although hematological toxicity can be an issue, the regimen provides an alternative option in transplant ineligible relapsed/refractory MCL and iNHL,” wrote Dr. Puvvada and her colleagues. The study was published in Clinical Lymphoma, Myeloma & Leukemia (doi: 10.1016/j.clml.2017.09.001).
The researchers studied the combination of bortezomib, the proteasome inhibitor initially approved for relapsed/refractory MCL, cladribine, which has shown activity and promising response rates in patients with indolent lymphomas, and rituximab in patients with CD20-positive mantle cell or indolent lymphoma.
Patients with follicular lymphomas were eligible to be included in the study if they had received at least one previous line of therapy. All other participants could be treatment naive or have relapsed after previous treatment.
Of the 24 patients enrolled, 11 had MCL, 5 had follicular lymphoma, 4 had marginal zone lymphoma, 3 had lymphoplasmacytic lymphoma, and 1 had small lymphocytic lymphoma.
The VCR regimen, given every 28 days for no more than six cycles, included rituximab at 375 mg/m2 given intravenously on day 1 of each cycle, cladribine 4 mg/m2 given intravenously over 2 hours on days 1 through 5, and bortezomib 1.3 mg/m2 given intravenously on days 1 and 4. Patients received a median of five cycles of therapy.
Adverse events of grade 3 or greater occurred in 14 patients (58%); 8 patients had leukopenia, 6 had thrombocytopenia, 5 had fatigue, and 5 had neutropenia, which included febrile neutropenia in 3 patients.
With a median follow-up of 38.5 months, overall response rate for VCR was 96%. Complete responses occurred in 8 of 23 evaluable patients (35%) and partial responses in 14 more patients (61%).
FROM LYMPHOMA, MYELOMA & LEUKEMIA
Key clinical point:
Major finding: The overall response rate was 92%, with a 2-year PFS of 82% and 54% for patients with mantle cell lymphoma (MCL) and indolent non-Hodgkin’s lymphoma (iNHL), respectively. Adverse events were most commonly hematologic, and three patients experienced febrile neutropenia.
Data source: A phase 2, open-label study including 24 patients with mantle cell or indolent lymphomas.
Disclosures: No disclosures were reported in the accepted manuscript.