Non-Hodgkin Lymphoma Hub

ATLANTA – Responses 3 months after chimeric antigen receptor (CAR) T-cell therapy look durable in adults with transplant-ineligible relapsed/refractory diffuse large B-cell lymphoma (DLBCL), according to updated results from the single-arm, global, phase 2 JULIET trial.

Fully 95% of patients who had a complete response to CTL019 (tisagenlecleucel; Kymriah) at 3 months maintained that complete response at 6 months, Stephen J. Schuster, MD, said at the annual meeting of the American Society of Hematology.

Courtesy American Society of Hematology

SOURCE: Schuster S et al. ASH 2017 Abstract 577.

ATLANTA – Responses 3 months after chimeric antigen receptor (CAR) T-cell therapy look durable in adults with transplant-ineligible relapsed/refractory diffuse large B-cell lymphoma (DLBCL), according to updated results from the single-arm, global, phase 2 JULIET trial.

Fully 95% of patients who had a complete response to CTL019 (tisagenlecleucel; Kymriah) at 3 months maintained that complete response at 6 months, Stephen J. Schuster, MD, said at the annual meeting of the American Society of Hematology.

Courtesy American Society of Hematology

SOURCE: Schuster S et al. ASH 2017 Abstract 577.

ATLANTA – Responses 3 months after chimeric antigen receptor (CAR) T-cell therapy look durable in adults with transplant-ineligible relapsed/refractory diffuse large B-cell lymphoma (DLBCL), according to updated results from the single-arm, global, phase 2 JULIET trial.

Fully 95% of patients who had a complete response to CTL019 (tisagenlecleucel; Kymriah) at 3 months maintained that complete response at 6 months, Stephen J. Schuster, MD, said at the annual meeting of the American Society of Hematology.

Courtesy American Society of Hematology

SOURCE: Schuster S et al. ASH 2017 Abstract 577.

ATLANTA – Intravenous treatment with mogamulizumab, an investigational antibody targeting CC chemokine receptor 4, more than doubled progression-free survival (PFS), compared with oral vorinostat in a phase 3 trial of 372 patients with heavily pretreated cutaneous T-cell lymphoma (CTCL).

Courtesy ASH

After a median of three treatment cycles, median PFS with mogamulizumab was 7.7 months vs. 3.1 months with vorinostat (hazard ratio, 0.53; 95% confidence interval, 0.41-0.69; P less than .0001), Youn H. Kim, MD, reported at the annual meeting of the American Society of Hematology.

Mogamulizumab also topped vorinostat in terms of overall response to treatment (28% vs 5%; P less than 001) and on several quality of life scales, said Dr. Kim, the Joanne and Peter Haas, Jr. Professor for Cutaneous Lymphoma Research at Stanford (Calif.) University. Adverse effects, such as infusion reactions, were expected and manageable, she added.

Mogamulizumab is approved in Japan for treating CTCL and received an FDA breakthrough therapy designation in August 2017.

Based on audits so far, the agency might green-light mogamulizumab for previously treated CTCL by early 2018 – its first approval in the United States, Dr. Kim said in an interview.

Cutaneous T-cell lymphoma responds poorly to treatments that work in other, more common types of non-Hodgkin lymphoma. Moreover, extensive disease can destroy quality of life.

“There’s a major psychosocial impact because if you’re infected, you smell bad,” Dr. Kim said during a press briefing. “Itch is very severe – patients often cannot sleep because of it.”

Mogamulizumab is a humanized monoclonal antibody that targets CC chemokine receptor 4 (CCR4), which facilitates trafficking of lymphocytes to skin and other organs. It is defucosylated, augmenting its toxicity against malignant T cells. In a prior phase 1/2 study in the United States, mogamulizumab showed a tolerable safety profile and a 37% overall response rate – “a good response, considering that other CTCL drugs are usually in the 30% range,” Dr. Kim said.

For the phase 3 study (MAVORIC), 372 patients with previously treated stage IB to stage IVB CTCL (mycosis fungoides or Sézary syndrome) without large-cell transformation received mogamulizumab (1.0 mg/kg IV weekly for 28 days; days 1 and 15 of subsequent 28-day cycles) or vorinostat (400 mg per oral daily). Treatment continued until disease progression or intolerable toxicity. Researchers evaluated PFS based on a global composite response score that covers the skin, blood, lymph nodes, and viscera, in accordance with international consensus guidelines (J Clin Oncol. 2011 Jun 20;29(18):2598-607; doi: 10.1200/JCO.2010.32.0630).

Treatment groups resembled each other at baseline. Most had received three systemic therapies for CTCL, and some had received as many as 18. Median duration of response was 14 months in the mogamulizumab arm and 9 months in the vorinostat arm. Patients tended to respond to mogamulizumab 2 months sooner than to vorinostat (3.3 vs. 5.1 months), Dr. Kim said.

Mogamulizumab also significantly improved quality of life on the Skindex-29 Symptoms (P less than .05), Skindex-29 Function (P less than 05), and FACT-G Functional Well-Being (P less than .05) quality of life scales, which is part of what earned it a breakthrough therapy designation, Dr. Kim said.

MAVORIC is the largest randomized study to compare systemic therapies in CTCL and the first to use PFS as the primary endpoint, Dr. Kim noted. Patients’ level of CCR4 expression was not a criterion for enrollment because CCR4 is consistently and highly expressed in this disease, she noted. Thus, using mogamulizumab to treat CTCL in the United States would not require CCR4 testing.

Joseph M. Connors, MD, who specializes in lymphoid cancers at the BC Cancer Agency, a division of the British Columbia Provincial Health Services Authority, and who was not involved in the study, agreed that these data represent real headway in treating CTCL.

“I can state unequivocally that we just haven’t had effective therapy for CTCL,” he said at the press briefing. “We’ve had treatments that might help patients feel somewhat better, but we’ve had no consensus on a treatment that is right for this disease. These data provide an opportunity to have that consensus. They could create a platform for making further progress.”

Kyowa Kirin Pharmaceutical Development provided funding. Dr. Kim disclosed research and advisory relationships with Kyowa Kirin and ties to Millennium Pharmaceuticals, Seattle Genetics, Soligenix, and other companies.

SOURCE: Kim YH et al. ASH 2017 Abstract 817.

ATLANTA – Intravenous treatment with mogamulizumab, an investigational antibody targeting CC chemokine receptor 4, more than doubled progression-free survival (PFS), compared with oral vorinostat in a phase 3 trial of 372 patients with heavily pretreated cutaneous T-cell lymphoma (CTCL).

Courtesy ASH

After a median of three treatment cycles, median PFS with mogamulizumab was 7.7 months vs. 3.1 months with vorinostat (hazard ratio, 0.53; 95% confidence interval, 0.41-0.69; P less than .0001), Youn H. Kim, MD, reported at the annual meeting of the American Society of Hematology.

Mogamulizumab also topped vorinostat in terms of overall response to treatment (28% vs 5%; P less than 001) and on several quality of life scales, said Dr. Kim, the Joanne and Peter Haas, Jr. Professor for Cutaneous Lymphoma Research at Stanford (Calif.) University. Adverse effects, such as infusion reactions, were expected and manageable, she added.

Mogamulizumab is approved in Japan for treating CTCL and received an FDA breakthrough therapy designation in August 2017.

Based on audits so far, the agency might green-light mogamulizumab for previously treated CTCL by early 2018 – its first approval in the United States, Dr. Kim said in an interview.

Cutaneous T-cell lymphoma responds poorly to treatments that work in other, more common types of non-Hodgkin lymphoma. Moreover, extensive disease can destroy quality of life.

“There’s a major psychosocial impact because if you’re infected, you smell bad,” Dr. Kim said during a press briefing. “Itch is very severe – patients often cannot sleep because of it.”

Mogamulizumab is a humanized monoclonal antibody that targets CC chemokine receptor 4 (CCR4), which facilitates trafficking of lymphocytes to skin and other organs. It is defucosylated, augmenting its toxicity against malignant T cells. In a prior phase 1/2 study in the United States, mogamulizumab showed a tolerable safety profile and a 37% overall response rate – “a good response, considering that other CTCL drugs are usually in the 30% range,” Dr. Kim said.

For the phase 3 study (MAVORIC), 372 patients with previously treated stage IB to stage IVB CTCL (mycosis fungoides or Sézary syndrome) without large-cell transformation received mogamulizumab (1.0 mg/kg IV weekly for 28 days; days 1 and 15 of subsequent 28-day cycles) or vorinostat (400 mg per oral daily). Treatment continued until disease progression or intolerable toxicity. Researchers evaluated PFS based on a global composite response score that covers the skin, blood, lymph nodes, and viscera, in accordance with international consensus guidelines (J Clin Oncol. 2011 Jun 20;29(18):2598-607; doi: 10.1200/JCO.2010.32.0630).

Treatment groups resembled each other at baseline. Most had received three systemic therapies for CTCL, and some had received as many as 18. Median duration of response was 14 months in the mogamulizumab arm and 9 months in the vorinostat arm. Patients tended to respond to mogamulizumab 2 months sooner than to vorinostat (3.3 vs. 5.1 months), Dr. Kim said.

Mogamulizumab also significantly improved quality of life on the Skindex-29 Symptoms (P less than .05), Skindex-29 Function (P less than 05), and FACT-G Functional Well-Being (P less than .05) quality of life scales, which is part of what earned it a breakthrough therapy designation, Dr. Kim said.

MAVORIC is the largest randomized study to compare systemic therapies in CTCL and the first to use PFS as the primary endpoint, Dr. Kim noted. Patients’ level of CCR4 expression was not a criterion for enrollment because CCR4 is consistently and highly expressed in this disease, she noted. Thus, using mogamulizumab to treat CTCL in the United States would not require CCR4 testing.

Joseph M. Connors, MD, who specializes in lymphoid cancers at the BC Cancer Agency, a division of the British Columbia Provincial Health Services Authority, and who was not involved in the study, agreed that these data represent real headway in treating CTCL.

“I can state unequivocally that we just haven’t had effective therapy for CTCL,” he said at the press briefing. “We’ve had treatments that might help patients feel somewhat better, but we’ve had no consensus on a treatment that is right for this disease. These data provide an opportunity to have that consensus. They could create a platform for making further progress.”

Kyowa Kirin Pharmaceutical Development provided funding. Dr. Kim disclosed research and advisory relationships with Kyowa Kirin and ties to Millennium Pharmaceuticals, Seattle Genetics, Soligenix, and other companies.

SOURCE: Kim YH et al. ASH 2017 Abstract 817.

ATLANTA – Intravenous treatment with mogamulizumab, an investigational antibody targeting CC chemokine receptor 4, more than doubled progression-free survival (PFS), compared with oral vorinostat in a phase 3 trial of 372 patients with heavily pretreated cutaneous T-cell lymphoma (CTCL).

Courtesy ASH

After a median of three treatment cycles, median PFS with mogamulizumab was 7.7 months vs. 3.1 months with vorinostat (hazard ratio, 0.53; 95% confidence interval, 0.41-0.69; P less than .0001), Youn H. Kim, MD, reported at the annual meeting of the American Society of Hematology.

Mogamulizumab also topped vorinostat in terms of overall response to treatment (28% vs 5%; P less than 001) and on several quality of life scales, said Dr. Kim, the Joanne and Peter Haas, Jr. Professor for Cutaneous Lymphoma Research at Stanford (Calif.) University. Adverse effects, such as infusion reactions, were expected and manageable, she added.

Mogamulizumab is approved in Japan for treating CTCL and received an FDA breakthrough therapy designation in August 2017.

Based on audits so far, the agency might green-light mogamulizumab for previously treated CTCL by early 2018 – its first approval in the United States, Dr. Kim said in an interview.

Cutaneous T-cell lymphoma responds poorly to treatments that work in other, more common types of non-Hodgkin lymphoma. Moreover, extensive disease can destroy quality of life.

“There’s a major psychosocial impact because if you’re infected, you smell bad,” Dr. Kim said during a press briefing. “Itch is very severe – patients often cannot sleep because of it.”

Mogamulizumab is a humanized monoclonal antibody that targets CC chemokine receptor 4 (CCR4), which facilitates trafficking of lymphocytes to skin and other organs. It is defucosylated, augmenting its toxicity against malignant T cells. In a prior phase 1/2 study in the United States, mogamulizumab showed a tolerable safety profile and a 37% overall response rate – “a good response, considering that other CTCL drugs are usually in the 30% range,” Dr. Kim said.

For the phase 3 study (MAVORIC), 372 patients with previously treated stage IB to stage IVB CTCL (mycosis fungoides or Sézary syndrome) without large-cell transformation received mogamulizumab (1.0 mg/kg IV weekly for 28 days; days 1 and 15 of subsequent 28-day cycles) or vorinostat (400 mg per oral daily). Treatment continued until disease progression or intolerable toxicity. Researchers evaluated PFS based on a global composite response score that covers the skin, blood, lymph nodes, and viscera, in accordance with international consensus guidelines (J Clin Oncol. 2011 Jun 20;29(18):2598-607; doi: 10.1200/JCO.2010.32.0630).

Treatment groups resembled each other at baseline. Most had received three systemic therapies for CTCL, and some had received as many as 18. Median duration of response was 14 months in the mogamulizumab arm and 9 months in the vorinostat arm. Patients tended to respond to mogamulizumab 2 months sooner than to vorinostat (3.3 vs. 5.1 months), Dr. Kim said.

Mogamulizumab also significantly improved quality of life on the Skindex-29 Symptoms (P less than .05), Skindex-29 Function (P less than 05), and FACT-G Functional Well-Being (P less than .05) quality of life scales, which is part of what earned it a breakthrough therapy designation, Dr. Kim said.

MAVORIC is the largest randomized study to compare systemic therapies in CTCL and the first to use PFS as the primary endpoint, Dr. Kim noted. Patients’ level of CCR4 expression was not a criterion for enrollment because CCR4 is consistently and highly expressed in this disease, she noted. Thus, using mogamulizumab to treat CTCL in the United States would not require CCR4 testing.

Joseph M. Connors, MD, who specializes in lymphoid cancers at the BC Cancer Agency, a division of the British Columbia Provincial Health Services Authority, and who was not involved in the study, agreed that these data represent real headway in treating CTCL.

“I can state unequivocally that we just haven’t had effective therapy for CTCL,” he said at the press briefing. “We’ve had treatments that might help patients feel somewhat better, but we’ve had no consensus on a treatment that is right for this disease. These data provide an opportunity to have that consensus. They could create a platform for making further progress.”

Kyowa Kirin Pharmaceutical Development provided funding. Dr. Kim disclosed research and advisory relationships with Kyowa Kirin and ties to Millennium Pharmaceuticals, Seattle Genetics, Soligenix, and other companies.

SOURCE: Kim YH et al. ASH 2017 Abstract 817.

ATLANTA – More than one-third of patients with refractory large B-cell lymphomas treated with the chimeric antigen receptor (CAR) T-cell product axicabtagene ciloleucel (Yescarta), often called axi-cel, had durable responses, with some patients having complete responses lasting more than 1 year after a single infusion, according to investigators in the ZUMA-1 trial.

Neil Osterweil/Frontline Medical News

Updated combined phase 1 and phase 2 results in 108 patients with diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), or transformed follicular lymphoma (TFL) showed an objective response rate (ORR) of 82%, including 58% complete responses, after a median follow-up of 15.4 months, reported Sattva S. Neelapu, MD, from the University of Texas MD Anderson Cancer Center in Houston.

“Axi-cel is highly effective in patients with large B-cell lymphoma who otherwise have no curative treatment options,” he said in a briefing at the annual meeting of the American Society of Hematology, prior to his presentation of the data in an oral session.

The trial results were also published simultaneously in the New England Journal of Medicine.As previously reported, in the multicenter phase 2 ZUMA-1 trial, 111 patients with treatment refractory DLBCL, PMBCL, or TFL were enrolled and treated with axi-cel at a target dose of 2 x 10⁶ cells/kg, following a conditioning regimen with low-dose cyclophosphamide and fludarabine.

The median patient age was 58 years. Patients had stage III or IV disease, 48% had International Prognostic Index scores of 3-4, 76% had disease that was refractory to third-line therapies or beyond, and 21% had disease that relapsed within 12 months of an autologous bone marrow transplant

Axi-cel was successfully manufactured with sufficient cells for transfusion in all but one of the 111 patients, and 101 patients eventually received infusions in phase 2 (modified intention-to-treat population). The average turnaround time from apheresis to the clinical site was 17 days.

Dr. Neelapu also presented data on seven patients enrolled in phase 1; the data were combined with the phase 2 results for an updated analysis of those patients who had at least 1 year of follow-up.

The phase 2 trial met its primary endpoint at the time of the primary analysis, with an 82% ORR, consisting of 54% complete responses and 28% partial responses at a median follow-up of 8.7 months.

In the updated analysis, the ORR and respective remission rates were 82%, 58%, and 34%, at a median of 15.4 months follow-up.

The median duration of response in the updated analysis was 11.1 months. The median duration of complete responses had not been reached at the time of data cutoff in August 2017. The median duration of partial responses was 1.9 months.

At the 15.4-month mark, 42% of patients remained free of disease progression, and 56% were alive, with the median overall survival not yet reached.

The treatment had generally acceptable toxicities, with only 13% of patients in phase 2 experiencing grade 3 or greater cytokine release syndrome (CRS), although one patient with CRS died from hemophagocytic lymphohistiocytosis, and one with CRS died from cardiac arrest. Grade 3 or greater neurologic events occurred in 28% of patients, and included encephalopathy, confusional state, aphasia, and somnolence.

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.

Since the primary analysis with at least 6 months of follow-up, there have been no new axi-cel–related cases of CRS, neurologic events, or deaths.

Dr. Neelapu also presented safety data on serious adverse events occurring more than 6 months after therapy in 10 patients who developed symptoms after the data cutoff.

Grade 3 events in these patients included lung infection, recurrent upper respiratory viral infection, and rotavirus infection, pneumonias, atrial fibrillation with rapid ventricular response, lung infection, febrile neutropenia, and influenza B infection. One patient had grade 4 sepsis.

In an editorial accompanying the study in the New England Journal of Medicine, Eric Tran, PhD, and Walter J. Urba, MD, PhD, from the Earle A. Chiles Research Institute and the Providence Portland (Ore.) Medical Center, and Dan L. Longo, MD, deputy editor of the journal, praised ZUMA-1 as “a landmark study because it involved 22 institutions and showed that a personalized gene-engineered T-cell product could be rapidly generated at a centralized cell-manufacturing facility and safely administered to patients at transplantation-capable medical centers.”

They noted, however, that about half of all patients with relapsed or refractory large B-cell lymphomas will not have durable responses to CAR T-cell therapy directed against CD19, and that new strategies will be needed to improve responses (N Engl J Med. 2017 Dec 10; doi: 10.1056/NEJMe1714680).

In the question and answer session at the end of the briefing, Dr. Neelapu said the preliminary observations of mechanisms of relapse or disease progression in some patients may be related to the loss of the CD19 antigen, which occurs in about one-third of patients who experience relapse, and to high expression of the programmed death ligand-1, which can potentially inhibit CAR-T cell function. A clinical trial is currently underway to evaluate potential strategies for improving response rates to CAR-T therapies, he said.

ZUMA-1 is supported by Kite Pharma and the Leukemia and Lymphoma Society Therapy Acceleration Program. Dr. Neelapu reported receiving advisory board fees from the company. Myriad coauthors also reported financial relationship with multiple companies.

SOURCE: Neelapu S et al. ASH 2017 Abstract 578.

ATLANTA – More than one-third of patients with refractory large B-cell lymphomas treated with the chimeric antigen receptor (CAR) T-cell product axicabtagene ciloleucel (Yescarta), often called axi-cel, had durable responses, with some patients having complete responses lasting more than 1 year after a single infusion, according to investigators in the ZUMA-1 trial.

Neil Osterweil/Frontline Medical News

Updated combined phase 1 and phase 2 results in 108 patients with diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), or transformed follicular lymphoma (TFL) showed an objective response rate (ORR) of 82%, including 58% complete responses, after a median follow-up of 15.4 months, reported Sattva S. Neelapu, MD, from the University of Texas MD Anderson Cancer Center in Houston.

“Axi-cel is highly effective in patients with large B-cell lymphoma who otherwise have no curative treatment options,” he said in a briefing at the annual meeting of the American Society of Hematology, prior to his presentation of the data in an oral session.

The trial results were also published simultaneously in the New England Journal of Medicine.As previously reported, in the multicenter phase 2 ZUMA-1 trial, 111 patients with treatment refractory DLBCL, PMBCL, or TFL were enrolled and treated with axi-cel at a target dose of 2 x 10⁶ cells/kg, following a conditioning regimen with low-dose cyclophosphamide and fludarabine.

The median patient age was 58 years. Patients had stage III or IV disease, 48% had International Prognostic Index scores of 3-4, 76% had disease that was refractory to third-line therapies or beyond, and 21% had disease that relapsed within 12 months of an autologous bone marrow transplant

Axi-cel was successfully manufactured with sufficient cells for transfusion in all but one of the 111 patients, and 101 patients eventually received infusions in phase 2 (modified intention-to-treat population). The average turnaround time from apheresis to the clinical site was 17 days.

Dr. Neelapu also presented data on seven patients enrolled in phase 1; the data were combined with the phase 2 results for an updated analysis of those patients who had at least 1 year of follow-up.

The phase 2 trial met its primary endpoint at the time of the primary analysis, with an 82% ORR, consisting of 54% complete responses and 28% partial responses at a median follow-up of 8.7 months.

In the updated analysis, the ORR and respective remission rates were 82%, 58%, and 34%, at a median of 15.4 months follow-up.

The median duration of response in the updated analysis was 11.1 months. The median duration of complete responses had not been reached at the time of data cutoff in August 2017. The median duration of partial responses was 1.9 months.

At the 15.4-month mark, 42% of patients remained free of disease progression, and 56% were alive, with the median overall survival not yet reached.

The treatment had generally acceptable toxicities, with only 13% of patients in phase 2 experiencing grade 3 or greater cytokine release syndrome (CRS), although one patient with CRS died from hemophagocytic lymphohistiocytosis, and one with CRS died from cardiac arrest. Grade 3 or greater neurologic events occurred in 28% of patients, and included encephalopathy, confusional state, aphasia, and somnolence.

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.

Since the primary analysis with at least 6 months of follow-up, there have been no new axi-cel–related cases of CRS, neurologic events, or deaths.

Dr. Neelapu also presented safety data on serious adverse events occurring more than 6 months after therapy in 10 patients who developed symptoms after the data cutoff.

Grade 3 events in these patients included lung infection, recurrent upper respiratory viral infection, and rotavirus infection, pneumonias, atrial fibrillation with rapid ventricular response, lung infection, febrile neutropenia, and influenza B infection. One patient had grade 4 sepsis.

In an editorial accompanying the study in the New England Journal of Medicine, Eric Tran, PhD, and Walter J. Urba, MD, PhD, from the Earle A. Chiles Research Institute and the Providence Portland (Ore.) Medical Center, and Dan L. Longo, MD, deputy editor of the journal, praised ZUMA-1 as “a landmark study because it involved 22 institutions and showed that a personalized gene-engineered T-cell product could be rapidly generated at a centralized cell-manufacturing facility and safely administered to patients at transplantation-capable medical centers.”

They noted, however, that about half of all patients with relapsed or refractory large B-cell lymphomas will not have durable responses to CAR T-cell therapy directed against CD19, and that new strategies will be needed to improve responses (N Engl J Med. 2017 Dec 10; doi: 10.1056/NEJMe1714680).

In the question and answer session at the end of the briefing, Dr. Neelapu said the preliminary observations of mechanisms of relapse or disease progression in some patients may be related to the loss of the CD19 antigen, which occurs in about one-third of patients who experience relapse, and to high expression of the programmed death ligand-1, which can potentially inhibit CAR-T cell function. A clinical trial is currently underway to evaluate potential strategies for improving response rates to CAR-T therapies, he said.

ZUMA-1 is supported by Kite Pharma and the Leukemia and Lymphoma Society Therapy Acceleration Program. Dr. Neelapu reported receiving advisory board fees from the company. Myriad coauthors also reported financial relationship with multiple companies.

SOURCE: Neelapu S et al. ASH 2017 Abstract 578.

ATLANTA – More than one-third of patients with refractory large B-cell lymphomas treated with the chimeric antigen receptor (CAR) T-cell product axicabtagene ciloleucel (Yescarta), often called axi-cel, had durable responses, with some patients having complete responses lasting more than 1 year after a single infusion, according to investigators in the ZUMA-1 trial.

Neil Osterweil/Frontline Medical News

Updated combined phase 1 and phase 2 results in 108 patients with diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), or transformed follicular lymphoma (TFL) showed an objective response rate (ORR) of 82%, including 58% complete responses, after a median follow-up of 15.4 months, reported Sattva S. Neelapu, MD, from the University of Texas MD Anderson Cancer Center in Houston.

“Axi-cel is highly effective in patients with large B-cell lymphoma who otherwise have no curative treatment options,” he said in a briefing at the annual meeting of the American Society of Hematology, prior to his presentation of the data in an oral session.

The trial results were also published simultaneously in the New England Journal of Medicine.As previously reported, in the multicenter phase 2 ZUMA-1 trial, 111 patients with treatment refractory DLBCL, PMBCL, or TFL were enrolled and treated with axi-cel at a target dose of 2 x 10⁶ cells/kg, following a conditioning regimen with low-dose cyclophosphamide and fludarabine.

The median patient age was 58 years. Patients had stage III or IV disease, 48% had International Prognostic Index scores of 3-4, 76% had disease that was refractory to third-line therapies or beyond, and 21% had disease that relapsed within 12 months of an autologous bone marrow transplant

Axi-cel was successfully manufactured with sufficient cells for transfusion in all but one of the 111 patients, and 101 patients eventually received infusions in phase 2 (modified intention-to-treat population). The average turnaround time from apheresis to the clinical site was 17 days.

Dr. Neelapu also presented data on seven patients enrolled in phase 1; the data were combined with the phase 2 results for an updated analysis of those patients who had at least 1 year of follow-up.

The phase 2 trial met its primary endpoint at the time of the primary analysis, with an 82% ORR, consisting of 54% complete responses and 28% partial responses at a median follow-up of 8.7 months.

In the updated analysis, the ORR and respective remission rates were 82%, 58%, and 34%, at a median of 15.4 months follow-up.

The median duration of response in the updated analysis was 11.1 months. The median duration of complete responses had not been reached at the time of data cutoff in August 2017. The median duration of partial responses was 1.9 months.

At the 15.4-month mark, 42% of patients remained free of disease progression, and 56% were alive, with the median overall survival not yet reached.

The treatment had generally acceptable toxicities, with only 13% of patients in phase 2 experiencing grade 3 or greater cytokine release syndrome (CRS), although one patient with CRS died from hemophagocytic lymphohistiocytosis, and one with CRS died from cardiac arrest. Grade 3 or greater neurologic events occurred in 28% of patients, and included encephalopathy, confusional state, aphasia, and somnolence.

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.

Since the primary analysis with at least 6 months of follow-up, there have been no new axi-cel–related cases of CRS, neurologic events, or deaths.

Dr. Neelapu also presented safety data on serious adverse events occurring more than 6 months after therapy in 10 patients who developed symptoms after the data cutoff.

Grade 3 events in these patients included lung infection, recurrent upper respiratory viral infection, and rotavirus infection, pneumonias, atrial fibrillation with rapid ventricular response, lung infection, febrile neutropenia, and influenza B infection. One patient had grade 4 sepsis.

In an editorial accompanying the study in the New England Journal of Medicine, Eric Tran, PhD, and Walter J. Urba, MD, PhD, from the Earle A. Chiles Research Institute and the Providence Portland (Ore.) Medical Center, and Dan L. Longo, MD, deputy editor of the journal, praised ZUMA-1 as “a landmark study because it involved 22 institutions and showed that a personalized gene-engineered T-cell product could be rapidly generated at a centralized cell-manufacturing facility and safely administered to patients at transplantation-capable medical centers.”

They noted, however, that about half of all patients with relapsed or refractory large B-cell lymphomas will not have durable responses to CAR T-cell therapy directed against CD19, and that new strategies will be needed to improve responses (N Engl J Med. 2017 Dec 10; doi: 10.1056/NEJMe1714680).

In the question and answer session at the end of the briefing, Dr. Neelapu said the preliminary observations of mechanisms of relapse or disease progression in some patients may be related to the loss of the CD19 antigen, which occurs in about one-third of patients who experience relapse, and to high expression of the programmed death ligand-1, which can potentially inhibit CAR-T cell function. A clinical trial is currently underway to evaluate potential strategies for improving response rates to CAR-T therapies, he said.

ZUMA-1 is supported by Kite Pharma and the Leukemia and Lymphoma Society Therapy Acceleration Program. Dr. Neelapu reported receiving advisory board fees from the company. Myriad coauthors also reported financial relationship with multiple companies.

SOURCE: Neelapu S et al. ASH 2017 Abstract 578.

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.

[email protected]

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.

[email protected]

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.

[email protected]

Four to six cycles of bendamustine/rituximab is the primary regimen of choice for symptomatic, treatment-naive patients with Waldenström macroglobulinemia, especially when rapid control is needed for bulky disease, according to treatment guidelines from a multidisciplinary expert panel.

The Mayo Clinic Cancer Center Myeloma, Amyloidosis, and Dysproteinemia and Lymphoma Disease-Oriented Groups, composed of experts who have collectively treated hundreds of patients with Waldenström macroglobulinemia, updated their recommendations for management of the condition in JAMA Oncology. It’s the first update from the group since 2010. The new treatment approaches are based on clinical and observational studies published or presented through December 2015 and consensus recommendations.

The Mayo group said dexamethasone-rituximab-cyclophosphamide can be an alternative treatment for patients with symptomatic Waldenström macroglobulinemia with a low disease burden. But because of an absence of data, the group said rituximab maintenance therapy is not recommended for routine use outside of clinical trials.

Rituximab monotherapy is contraindicated if patients have symptomatic hyperviscosity; without preemptive plasmapheresis, this treatment should be avoided in those with very high serum IgM. They recommended a prompt start of therapeutic plasma exchange for hyperviscosity syndrome, before starting cytoreductive treatment. But rituximab is indicated when patients have symptomatic mild to moderate anemia, symptomatic cryoglobulinemia (in combination with steroids), or hemolytic anemia that does not respond to corticosteroids.

In cases of first or second relapse, autologous stem cell transplantation should be considered in patients with chemosensitive disease who are eligible for transplant, especially when the first remission duration was less than 2 years. Patients with refractory Waldenström macroglobulinemia should not be offered autologous stem cell transplantation.

Read the full set of recommendations in JAMA Oncology (2017 Sep 1;3[9]:1257-65).

[email protected]

On Twitter @maryellenny

Four to six cycles of bendamustine/rituximab is the primary regimen of choice for symptomatic, treatment-naive patients with Waldenström macroglobulinemia, especially when rapid control is needed for bulky disease, according to treatment guidelines from a multidisciplinary expert panel.

The Mayo Clinic Cancer Center Myeloma, Amyloidosis, and Dysproteinemia and Lymphoma Disease-Oriented Groups, composed of experts who have collectively treated hundreds of patients with Waldenström macroglobulinemia, updated their recommendations for management of the condition in JAMA Oncology. It’s the first update from the group since 2010. The new treatment approaches are based on clinical and observational studies published or presented through December 2015 and consensus recommendations.

The Mayo group said dexamethasone-rituximab-cyclophosphamide can be an alternative treatment for patients with symptomatic Waldenström macroglobulinemia with a low disease burden. But because of an absence of data, the group said rituximab maintenance therapy is not recommended for routine use outside of clinical trials.

Rituximab monotherapy is contraindicated if patients have symptomatic hyperviscosity; without preemptive plasmapheresis, this treatment should be avoided in those with very high serum IgM. They recommended a prompt start of therapeutic plasma exchange for hyperviscosity syndrome, before starting cytoreductive treatment. But rituximab is indicated when patients have symptomatic mild to moderate anemia, symptomatic cryoglobulinemia (in combination with steroids), or hemolytic anemia that does not respond to corticosteroids.

In cases of first or second relapse, autologous stem cell transplantation should be considered in patients with chemosensitive disease who are eligible for transplant, especially when the first remission duration was less than 2 years. Patients with refractory Waldenström macroglobulinemia should not be offered autologous stem cell transplantation.

Read the full set of recommendations in JAMA Oncology (2017 Sep 1;3[9]:1257-65).

[email protected]

On Twitter @maryellenny

Four to six cycles of bendamustine/rituximab is the primary regimen of choice for symptomatic, treatment-naive patients with Waldenström macroglobulinemia, especially when rapid control is needed for bulky disease, according to treatment guidelines from a multidisciplinary expert panel.

The Mayo Clinic Cancer Center Myeloma, Amyloidosis, and Dysproteinemia and Lymphoma Disease-Oriented Groups, composed of experts who have collectively treated hundreds of patients with Waldenström macroglobulinemia, updated their recommendations for management of the condition in JAMA Oncology. It’s the first update from the group since 2010. The new treatment approaches are based on clinical and observational studies published or presented through December 2015 and consensus recommendations.

The Mayo group said dexamethasone-rituximab-cyclophosphamide can be an alternative treatment for patients with symptomatic Waldenström macroglobulinemia with a low disease burden. But because of an absence of data, the group said rituximab maintenance therapy is not recommended for routine use outside of clinical trials.

Rituximab monotherapy is contraindicated if patients have symptomatic hyperviscosity; without preemptive plasmapheresis, this treatment should be avoided in those with very high serum IgM. They recommended a prompt start of therapeutic plasma exchange for hyperviscosity syndrome, before starting cytoreductive treatment. But rituximab is indicated when patients have symptomatic mild to moderate anemia, symptomatic cryoglobulinemia (in combination with steroids), or hemolytic anemia that does not respond to corticosteroids.

In cases of first or second relapse, autologous stem cell transplantation should be considered in patients with chemosensitive disease who are eligible for transplant, especially when the first remission duration was less than 2 years. Patients with refractory Waldenström macroglobulinemia should not be offered autologous stem cell transplantation.

Read the full set of recommendations in JAMA Oncology (2017 Sep 1;3[9]:1257-65).

[email protected]

On Twitter @maryellenny

Chimeric antigen receptor (CAR) T-cell therapy has generated a great deal of excitement in recent months with the approval of Novartis’ Kymriah (tisagenlecleucel) for pediatric acute lymphoblastic leukemia and Kite Pharma’s Yescarta (axicabtagene ciloleucel) for relapsed/refractory large B-cell lymphoma in adults, and experts in the field foresee a wave of approvals for additional indications in the coming months.

“CAR T is coming unbelievably fast,” Richard Maziarz, MD, professor of medicine at Oregon Health and Science University, Portland, said in an interview.

In fact, a search of clinicaltrials.gov revealed 120 open CAR T-cell–based therapy trials for cancer and other conditions such as autoimmune diseases, he said.
 

Price tag pressure

During a plenary session on genetically modified cell therapies at the annual meeting of the Society for Immunotherapy of Cancer, experts and investigators provided a glimpse of what’s in store, including new targets and smarter targeting and combinations that incorporate CAR T-cell therapy to treat solid tumors.

Cost-saving proposals

Efforts to address the cost concerns, including proposals for novel payment strategies, are already emerging. One example involves an offer by Novartis to charge for Kymriah only if treated patients go into remission within 1 month. Details of the plan haven’t been released.

Another approach is being considered in Europe and involves a graduated payment system for an investigational regulatory T cell therapy for autoimmune disease, Dr. Maziarz said. For example, if the drug costs $1 million, the government might pay $200,000 the first year and then $100,000 per year if the patient is cured. “If the patient relapses, they can stop their payment, as cure was not achieved,” he explained.

In many discussions about value, the definition is based on quality-adjusted life years (QALY) gained, he said. A recent statement from the American College of Cardiology and the American Heart Association on cost/value methodology, for example, used $50,000 per QALY gained as the cut-off for a good investment. Costs of $50,000 to less than $150,000 per QALY were considered to be of intermediate value, and costs of $150,000 or greater per QALY gained were considered to be of low value.

“A number of payers are using these guidelines to determine what drugs they will put on their portfolio and make available to enrollees,” Dr. Maziarz said.

In anticipation of cost-related issues with CAR T-cell therapy, the Institute for Clinical and Economic Review (ICER) and its California Technology Assessment Forum (CTAP) put out a request for information and input regarding their intent to collaboratively initiate an assessment of CAR T-cell effectiveness and value, he said.

In the meantime, Dr. Maziarz said that most private insurers he’s been in contact with are planning coverage of CAR T-cell therapy but are working out the details of how to do it.

“It’s typically going to involve very, very strict guidelines for the patients who go on therapy – it’s not going to be a liberal use of the product. It will involve strict adherence to the label,” he said.

The real challenge, however, will be in the Medicare and Medicaid programs, because of the current nature of the reimbursement structures and lack of clear procedural codes to define the effort and cost of care associated with the application of these novel cell therapies.

Walid F. Gellad, MD, and Aaron S. Kesselheim, MD, anticipated some of these challenges in light of accelerated approval processes for expensive drugs and proposed in a May 2017 paper that government payers reimburse only the cost of manufacturing and some predetermined mark-up for such drugs until confirmatory trials demonstrate clinical benefit (N Engl J Med. 2017;376[21]:2001-04).

“Both Yescarta and Kymriah are approved with very, very, very limited data – 100 patients, 80 patients. They absolutely look promising. I was part of those studies, so I’m a believer, but the classic approach to determining success in the medical community is a randomized controlled trial,” Dr. Maziarz said.

The proposal by Dr. Gellad and Dr. Kesselheim acknowledged this, and said perhaps full payment isn’t warranted while the drugs remain in development and until they are proven to be a good investment.

Their proposal also calls for an economic impact analysis after 1-2 years on the market for all accelerated-approval pathway drugs that cost over a predetermined amount, timely and optimally designed confirmatory trials following accelerated approval to limit the period of uncertainty about the true clinical effect of the drug, and additional price concessions to public insurance programs for such drugs until the confirmatory trials are completed. Under this proposal, the unpaid portion of drug costs would be held in escrow until the drug’s efficacy is confirmed.

“I think what’s going to happen is that, as prices and costs go up for any therapy, that backlash will occur. These types of proposals to create solutions will come not from individual companies, but from the government,” Dr. Maziarz said. “I’m 100% excited about the work. I’m extremely excited to be part of the explorations. … I just still think we have to at least try to be aware and cognizant of the issues that we’ll be facing.”

Dr. Maziarz has received consulting fees from Novartis, Juno Therapeutics, and Kite Pharma. Dr. Heslop has received consulting fees from Novartis, has conducted research for Cell Medica and holds intellectual property rights/patent from Cell Medica, and has ownership interest in ViraCyte and Marker Therapeutics. Dr. June received royalties from Novartis, has conducted research for Novartis, and has ownership interest in Tmunity Therapeutics.

[email protected]

Chimeric antigen receptor (CAR) T-cell therapy has generated a great deal of excitement in recent months with the approval of Novartis’ Kymriah (tisagenlecleucel) for pediatric acute lymphoblastic leukemia and Kite Pharma’s Yescarta (axicabtagene ciloleucel) for relapsed/refractory large B-cell lymphoma in adults, and experts in the field foresee a wave of approvals for additional indications in the coming months.

“CAR T is coming unbelievably fast,” Richard Maziarz, MD, professor of medicine at Oregon Health and Science University, Portland, said in an interview.

In fact, a search of clinicaltrials.gov revealed 120 open CAR T-cell–based therapy trials for cancer and other conditions such as autoimmune diseases, he said.
 

Price tag pressure

During a plenary session on genetically modified cell therapies at the annual meeting of the Society for Immunotherapy of Cancer, experts and investigators provided a glimpse of what’s in store, including new targets and smarter targeting and combinations that incorporate CAR T-cell therapy to treat solid tumors.

Cost-saving proposals

Efforts to address the cost concerns, including proposals for novel payment strategies, are already emerging. One example involves an offer by Novartis to charge for Kymriah only if treated patients go into remission within 1 month. Details of the plan haven’t been released.

Another approach is being considered in Europe and involves a graduated payment system for an investigational regulatory T cell therapy for autoimmune disease, Dr. Maziarz said. For example, if the drug costs $1 million, the government might pay $200,000 the first year and then $100,000 per year if the patient is cured. “If the patient relapses, they can stop their payment, as cure was not achieved,” he explained.

In many discussions about value, the definition is based on quality-adjusted life years (QALY) gained, he said. A recent statement from the American College of Cardiology and the American Heart Association on cost/value methodology, for example, used $50,000 per QALY gained as the cut-off for a good investment. Costs of $50,000 to less than $150,000 per QALY were considered to be of intermediate value, and costs of $150,000 or greater per QALY gained were considered to be of low value.

“A number of payers are using these guidelines to determine what drugs they will put on their portfolio and make available to enrollees,” Dr. Maziarz said.

In anticipation of cost-related issues with CAR T-cell therapy, the Institute for Clinical and Economic Review (ICER) and its California Technology Assessment Forum (CTAP) put out a request for information and input regarding their intent to collaboratively initiate an assessment of CAR T-cell effectiveness and value, he said.

In the meantime, Dr. Maziarz said that most private insurers he’s been in contact with are planning coverage of CAR T-cell therapy but are working out the details of how to do it.

“It’s typically going to involve very, very strict guidelines for the patients who go on therapy – it’s not going to be a liberal use of the product. It will involve strict adherence to the label,” he said.

The real challenge, however, will be in the Medicare and Medicaid programs, because of the current nature of the reimbursement structures and lack of clear procedural codes to define the effort and cost of care associated with the application of these novel cell therapies.

Walid F. Gellad, MD, and Aaron S. Kesselheim, MD, anticipated some of these challenges in light of accelerated approval processes for expensive drugs and proposed in a May 2017 paper that government payers reimburse only the cost of manufacturing and some predetermined mark-up for such drugs until confirmatory trials demonstrate clinical benefit (N Engl J Med. 2017;376[21]:2001-04).

“Both Yescarta and Kymriah are approved with very, very, very limited data – 100 patients, 80 patients. They absolutely look promising. I was part of those studies, so I’m a believer, but the classic approach to determining success in the medical community is a randomized controlled trial,” Dr. Maziarz said.

The proposal by Dr. Gellad and Dr. Kesselheim acknowledged this, and said perhaps full payment isn’t warranted while the drugs remain in development and until they are proven to be a good investment.

Their proposal also calls for an economic impact analysis after 1-2 years on the market for all accelerated-approval pathway drugs that cost over a predetermined amount, timely and optimally designed confirmatory trials following accelerated approval to limit the period of uncertainty about the true clinical effect of the drug, and additional price concessions to public insurance programs for such drugs until the confirmatory trials are completed. Under this proposal, the unpaid portion of drug costs would be held in escrow until the drug’s efficacy is confirmed.

“I think what’s going to happen is that, as prices and costs go up for any therapy, that backlash will occur. These types of proposals to create solutions will come not from individual companies, but from the government,” Dr. Maziarz said. “I’m 100% excited about the work. I’m extremely excited to be part of the explorations. … I just still think we have to at least try to be aware and cognizant of the issues that we’ll be facing.”

Dr. Maziarz has received consulting fees from Novartis, Juno Therapeutics, and Kite Pharma. Dr. Heslop has received consulting fees from Novartis, has conducted research for Cell Medica and holds intellectual property rights/patent from Cell Medica, and has ownership interest in ViraCyte and Marker Therapeutics. Dr. June received royalties from Novartis, has conducted research for Novartis, and has ownership interest in Tmunity Therapeutics.

[email protected]

Chimeric antigen receptor (CAR) T-cell therapy has generated a great deal of excitement in recent months with the approval of Novartis’ Kymriah (tisagenlecleucel) for pediatric acute lymphoblastic leukemia and Kite Pharma’s Yescarta (axicabtagene ciloleucel) for relapsed/refractory large B-cell lymphoma in adults, and experts in the field foresee a wave of approvals for additional indications in the coming months.

“CAR T is coming unbelievably fast,” Richard Maziarz, MD, professor of medicine at Oregon Health and Science University, Portland, said in an interview.

In fact, a search of clinicaltrials.gov revealed 120 open CAR T-cell–based therapy trials for cancer and other conditions such as autoimmune diseases, he said.
 

Price tag pressure

During a plenary session on genetically modified cell therapies at the annual meeting of the Society for Immunotherapy of Cancer, experts and investigators provided a glimpse of what’s in store, including new targets and smarter targeting and combinations that incorporate CAR T-cell therapy to treat solid tumors.

Cost-saving proposals

Efforts to address the cost concerns, including proposals for novel payment strategies, are already emerging. One example involves an offer by Novartis to charge for Kymriah only if treated patients go into remission within 1 month. Details of the plan haven’t been released.

Another approach is being considered in Europe and involves a graduated payment system for an investigational regulatory T cell therapy for autoimmune disease, Dr. Maziarz said. For example, if the drug costs $1 million, the government might pay $200,000 the first year and then $100,000 per year if the patient is cured. “If the patient relapses, they can stop their payment, as cure was not achieved,” he explained.

In many discussions about value, the definition is based on quality-adjusted life years (QALY) gained, he said. A recent statement from the American College of Cardiology and the American Heart Association on cost/value methodology, for example, used $50,000 per QALY gained as the cut-off for a good investment. Costs of $50,000 to less than $150,000 per QALY were considered to be of intermediate value, and costs of $150,000 or greater per QALY gained were considered to be of low value.

“A number of payers are using these guidelines to determine what drugs they will put on their portfolio and make available to enrollees,” Dr. Maziarz said.

In anticipation of cost-related issues with CAR T-cell therapy, the Institute for Clinical and Economic Review (ICER) and its California Technology Assessment Forum (CTAP) put out a request for information and input regarding their intent to collaboratively initiate an assessment of CAR T-cell effectiveness and value, he said.

In the meantime, Dr. Maziarz said that most private insurers he’s been in contact with are planning coverage of CAR T-cell therapy but are working out the details of how to do it.

“It’s typically going to involve very, very strict guidelines for the patients who go on therapy – it’s not going to be a liberal use of the product. It will involve strict adherence to the label,” he said.

The real challenge, however, will be in the Medicare and Medicaid programs, because of the current nature of the reimbursement structures and lack of clear procedural codes to define the effort and cost of care associated with the application of these novel cell therapies.

Walid F. Gellad, MD, and Aaron S. Kesselheim, MD, anticipated some of these challenges in light of accelerated approval processes for expensive drugs and proposed in a May 2017 paper that government payers reimburse only the cost of manufacturing and some predetermined mark-up for such drugs until confirmatory trials demonstrate clinical benefit (N Engl J Med. 2017;376[21]:2001-04).

“Both Yescarta and Kymriah are approved with very, very, very limited data – 100 patients, 80 patients. They absolutely look promising. I was part of those studies, so I’m a believer, but the classic approach to determining success in the medical community is a randomized controlled trial,” Dr. Maziarz said.

The proposal by Dr. Gellad and Dr. Kesselheim acknowledged this, and said perhaps full payment isn’t warranted while the drugs remain in development and until they are proven to be a good investment.

Their proposal also calls for an economic impact analysis after 1-2 years on the market for all accelerated-approval pathway drugs that cost over a predetermined amount, timely and optimally designed confirmatory trials following accelerated approval to limit the period of uncertainty about the true clinical effect of the drug, and additional price concessions to public insurance programs for such drugs until the confirmatory trials are completed. Under this proposal, the unpaid portion of drug costs would be held in escrow until the drug’s efficacy is confirmed.

“I think what’s going to happen is that, as prices and costs go up for any therapy, that backlash will occur. These types of proposals to create solutions will come not from individual companies, but from the government,” Dr. Maziarz said. “I’m 100% excited about the work. I’m extremely excited to be part of the explorations. … I just still think we have to at least try to be aware and cognizant of the issues that we’ll be facing.”

Dr. Maziarz has received consulting fees from Novartis, Juno Therapeutics, and Kite Pharma. Dr. Heslop has received consulting fees from Novartis, has conducted research for Cell Medica and holds intellectual property rights/patent from Cell Medica, and has ownership interest in ViraCyte and Marker Therapeutics. Dr. June received royalties from Novartis, has conducted research for Novartis, and has ownership interest in Tmunity Therapeutics.

[email protected]

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).

[email protected]

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).

[email protected]

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).

[email protected]

Rituximab maintenance was a key factor influencing survival in patients with mantle cell lymphoma (MCL) who had undergone autologous stem cell transplant (ASCT), according to results from a retrospective, single-center study of 191 patients.

The study, which outlines the experience across a variety of different treatment patterns at City of Hope National Medical Center, Duarte, Calif., between January 1997 and November 2013, suggests a “large benefit” of adding rituximab, wrote Matthew G. Mei, MD, of the center’s department of hematology and hematopoietic cell transplantation, and his colleagues. Further, maintenance rituximab was associated with improved survival outcomes in patients with positron emission tomography (PET)-negative status at first complete remission.

The benefit of rituximab “stands out, and adds to the increasing body of evidence supporting this practice for all MCL patients after ASCT, regardless of age and frontline induction regimens,” wrote Dr. Mei and his colleagues (Biol Blood Marrow Transplant 2017 November. doi: 10.1016/j.bbmt.2017.07.006). This was the case even with improvements in early diagnosis and supportive care, and the incorporation of novel agents such as bortezomib, lenalidomide, and ibrutinib, they wrote, noting significantly better outcomes for patients who underwent ASCT after 2007.

Wikimedia Commons/TexasPathologistMSW/CC-ASA 4.0 International

Rituximab maintenance was a key factor influencing survival in patients with mantle cell lymphoma (MCL) who had undergone autologous stem cell transplant (ASCT), according to results from a retrospective, single-center study of 191 patients.

The study, which outlines the experience across a variety of different treatment patterns at City of Hope National Medical Center, Duarte, Calif., between January 1997 and November 2013, suggests a “large benefit” of adding rituximab, wrote Matthew G. Mei, MD, of the center’s department of hematology and hematopoietic cell transplantation, and his colleagues. Further, maintenance rituximab was associated with improved survival outcomes in patients with positron emission tomography (PET)-negative status at first complete remission.

The benefit of rituximab “stands out, and adds to the increasing body of evidence supporting this practice for all MCL patients after ASCT, regardless of age and frontline induction regimens,” wrote Dr. Mei and his colleagues (Biol Blood Marrow Transplant 2017 November. doi: 10.1016/j.bbmt.2017.07.006). This was the case even with improvements in early diagnosis and supportive care, and the incorporation of novel agents such as bortezomib, lenalidomide, and ibrutinib, they wrote, noting significantly better outcomes for patients who underwent ASCT after 2007.

Wikimedia Commons/TexasPathologistMSW/CC-ASA 4.0 International

Rituximab maintenance was a key factor influencing survival in patients with mantle cell lymphoma (MCL) who had undergone autologous stem cell transplant (ASCT), according to results from a retrospective, single-center study of 191 patients.

The study, which outlines the experience across a variety of different treatment patterns at City of Hope National Medical Center, Duarte, Calif., between January 1997 and November 2013, suggests a “large benefit” of adding rituximab, wrote Matthew G. Mei, MD, of the center’s department of hematology and hematopoietic cell transplantation, and his colleagues. Further, maintenance rituximab was associated with improved survival outcomes in patients with positron emission tomography (PET)-negative status at first complete remission.

The benefit of rituximab “stands out, and adds to the increasing body of evidence supporting this practice for all MCL patients after ASCT, regardless of age and frontline induction regimens,” wrote Dr. Mei and his colleagues (Biol Blood Marrow Transplant 2017 November. doi: 10.1016/j.bbmt.2017.07.006). This was the case even with improvements in early diagnosis and supportive care, and the incorporation of novel agents such as bortezomib, lenalidomide, and ibrutinib, they wrote, noting significantly better outcomes for patients who underwent ASCT after 2007.

Wikimedia Commons/TexasPathologistMSW/CC-ASA 4.0 International

NATIONAL HARBOR, MD. – The immune checkpoint inhibitor nivolumab has promising activity in mismatch repair–deficient noncolorectal cancers, according to preliminary findings from the first sub-arm of the National Cancer Institute’s landmark Molecular Analysis for Therapy Choice (NCI-MATCH) trial.

NCI-MATCH is a 1,173-site precision medicine trial launched in 2015 to study targeted therapies for patients with relapsed/refractory solid tumors, lymphomas, and myelomas. In the first substudy (arm Z1D), the investigators identified 4,900 subjects with samples that could be tested for “actionable molecular abnormalities,” and from among those, they identified 77 with loss of mismatch repair proteins MLH1 or MSH2. Ultimately 47 patients were treated with nivolumab in the substudy.

Sharon Worcester/Frontline Medical News

[email protected]

NATIONAL HARBOR, MD. – The immune checkpoint inhibitor nivolumab has promising activity in mismatch repair–deficient noncolorectal cancers, according to preliminary findings from the first sub-arm of the National Cancer Institute’s landmark Molecular Analysis for Therapy Choice (NCI-MATCH) trial.

NCI-MATCH is a 1,173-site precision medicine trial launched in 2015 to study targeted therapies for patients with relapsed/refractory solid tumors, lymphomas, and myelomas. In the first substudy (arm Z1D), the investigators identified 4,900 subjects with samples that could be tested for “actionable molecular abnormalities,” and from among those, they identified 77 with loss of mismatch repair proteins MLH1 or MSH2. Ultimately 47 patients were treated with nivolumab in the substudy.

Sharon Worcester/Frontline Medical News

[email protected]

NATIONAL HARBOR, MD. – The immune checkpoint inhibitor nivolumab has promising activity in mismatch repair–deficient noncolorectal cancers, according to preliminary findings from the first sub-arm of the National Cancer Institute’s landmark Molecular Analysis for Therapy Choice (NCI-MATCH) trial.

NCI-MATCH is a 1,173-site precision medicine trial launched in 2015 to study targeted therapies for patients with relapsed/refractory solid tumors, lymphomas, and myelomas. In the first substudy (arm Z1D), the investigators identified 4,900 subjects with samples that could be tested for “actionable molecular abnormalities,” and from among those, they identified 77 with loss of mismatch repair proteins MLH1 or MSH2. Ultimately 47 patients were treated with nivolumab in the substudy.

Sharon Worcester/Frontline Medical News

[email protected]

Event-free survival at 24 months (EFS24) is predictive of survival in patients with peripheral T-cell lymphomas (PTCLs), according to new findings published in the Journal of Clinical Oncology.

Patients who were event free 2 years after diagnosis had a more favorable outcome, compared with those who relapsed within that time period. Some patients who remained event free for 24 months were potentially cured; conversely, events within 2 years were associated with an early death in almost all of those patients.

“Thus, EFS24 is a dichotomous end point that allows individualized risk prediction in patients with PTCL and can help inform patient counseling, biomarker discovery, clinical trial design, and precision medicine approaches,” wrote Matthew J. Maurer, MS, of the Mayo Clinic, Rochester, MN, and his coauthors (J Clin Oncol. 2017 Oct 26. doi: 10.1200/JCO.2017.73.8195).

PTCL is an uncommon and heterogeneous group of non-Hodgkin lymphomas that carry a very poor prognosis; most systemic cases are treated with anthracycline-based combination chemotherapy. Previous studies have reported that achieving EFS24 is predictive of excellent long-term outcomes, independent of baseline prognostic factors.

In this study Mr. Maurer and his coauthors assessed the association between EFS24 and overall survival in 775 patients with newly systemic PTCL who were diagnosed during 2000-2012 and received treatment with curative intent.

Among the entire cohort, 36% of patients achieved EFS24 while 64% did not, and the median overall survival following progression within that 2-year time period was 4.9 months (95% confidence interval, 3.8-5.9 months). The 5-year overall survival in the group that relapsed was 11%, with a standardized mortality ratio of 46.4 (95% CI, 41.8-51.3).

Conversely, among patients with EFS24, the median overall survival was not reached, and the 5-year overall survival was 78% (95% CI, 73%-84%). In this group, the 5-year risk of subsequent lymphoma relapse was 23%, and survival following a late relapse was generally poor (median of 10.3 months; 95% CI, 5.7-19.1 months). The best outcomes after achieving EFS24 were observed among patients aged 60 years or younger: These patients had a 5-year overall survival of 91%.

“The use of a dichotomous end point that allows individualized risk prediction is particularly important in rare diseases such as PTCL, where limited numbers of patients may make formal surrogate end point analysis difficult,” wrote the authors.

The study was supported by grants from the National Cancer Institute, the Terry Fox Research Institute, and the BC Cancer Foundation. Dr. Maurer reported research funding from Kite Pharma and Celgene, and several of the coauthors reported relationships with industry.

Event-free survival at 24 months (EFS24) is predictive of survival in patients with peripheral T-cell lymphomas (PTCLs), according to new findings published in the Journal of Clinical Oncology.

Patients who were event free 2 years after diagnosis had a more favorable outcome, compared with those who relapsed within that time period. Some patients who remained event free for 24 months were potentially cured; conversely, events within 2 years were associated with an early death in almost all of those patients.

“Thus, EFS24 is a dichotomous end point that allows individualized risk prediction in patients with PTCL and can help inform patient counseling, biomarker discovery, clinical trial design, and precision medicine approaches,” wrote Matthew J. Maurer, MS, of the Mayo Clinic, Rochester, MN, and his coauthors (J Clin Oncol. 2017 Oct 26. doi: 10.1200/JCO.2017.73.8195).

PTCL is an uncommon and heterogeneous group of non-Hodgkin lymphomas that carry a very poor prognosis; most systemic cases are treated with anthracycline-based combination chemotherapy. Previous studies have reported that achieving EFS24 is predictive of excellent long-term outcomes, independent of baseline prognostic factors.

In this study Mr. Maurer and his coauthors assessed the association between EFS24 and overall survival in 775 patients with newly systemic PTCL who were diagnosed during 2000-2012 and received treatment with curative intent.

Among the entire cohort, 36% of patients achieved EFS24 while 64% did not, and the median overall survival following progression within that 2-year time period was 4.9 months (95% confidence interval, 3.8-5.9 months). The 5-year overall survival in the group that relapsed was 11%, with a standardized mortality ratio of 46.4 (95% CI, 41.8-51.3).

Conversely, among patients with EFS24, the median overall survival was not reached, and the 5-year overall survival was 78% (95% CI, 73%-84%). In this group, the 5-year risk of subsequent lymphoma relapse was 23%, and survival following a late relapse was generally poor (median of 10.3 months; 95% CI, 5.7-19.1 months). The best outcomes after achieving EFS24 were observed among patients aged 60 years or younger: These patients had a 5-year overall survival of 91%.

“The use of a dichotomous end point that allows individualized risk prediction is particularly important in rare diseases such as PTCL, where limited numbers of patients may make formal surrogate end point analysis difficult,” wrote the authors.

The study was supported by grants from the National Cancer Institute, the Terry Fox Research Institute, and the BC Cancer Foundation. Dr. Maurer reported research funding from Kite Pharma and Celgene, and several of the coauthors reported relationships with industry.

Event-free survival at 24 months (EFS24) is predictive of survival in patients with peripheral T-cell lymphomas (PTCLs), according to new findings published in the Journal of Clinical Oncology.

Patients who were event free 2 years after diagnosis had a more favorable outcome, compared with those who relapsed within that time period. Some patients who remained event free for 24 months were potentially cured; conversely, events within 2 years were associated with an early death in almost all of those patients.

“Thus, EFS24 is a dichotomous end point that allows individualized risk prediction in patients with PTCL and can help inform patient counseling, biomarker discovery, clinical trial design, and precision medicine approaches,” wrote Matthew J. Maurer, MS, of the Mayo Clinic, Rochester, MN, and his coauthors (J Clin Oncol. 2017 Oct 26. doi: 10.1200/JCO.2017.73.8195).

PTCL is an uncommon and heterogeneous group of non-Hodgkin lymphomas that carry a very poor prognosis; most systemic cases are treated with anthracycline-based combination chemotherapy. Previous studies have reported that achieving EFS24 is predictive of excellent long-term outcomes, independent of baseline prognostic factors.

In this study Mr. Maurer and his coauthors assessed the association between EFS24 and overall survival in 775 patients with newly systemic PTCL who were diagnosed during 2000-2012 and received treatment with curative intent.

Among the entire cohort, 36% of patients achieved EFS24 while 64% did not, and the median overall survival following progression within that 2-year time period was 4.9 months (95% confidence interval, 3.8-5.9 months). The 5-year overall survival in the group that relapsed was 11%, with a standardized mortality ratio of 46.4 (95% CI, 41.8-51.3).

Conversely, among patients with EFS24, the median overall survival was not reached, and the 5-year overall survival was 78% (95% CI, 73%-84%). In this group, the 5-year risk of subsequent lymphoma relapse was 23%, and survival following a late relapse was generally poor (median of 10.3 months; 95% CI, 5.7-19.1 months). The best outcomes after achieving EFS24 were observed among patients aged 60 years or younger: These patients had a 5-year overall survival of 91%.

“The use of a dichotomous end point that allows individualized risk prediction is particularly important in rare diseases such as PTCL, where limited numbers of patients may make formal surrogate end point analysis difficult,” wrote the authors.

The study was supported by grants from the National Cancer Institute, the Terry Fox Research Institute, and the BC Cancer Foundation. Dr. Maurer reported research funding from Kite Pharma and Celgene, and several of the coauthors reported relationships with industry.