Aggressive Lymphomas

ATLANTA – In the ZUMA-1 trial, 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; axi-cel) had durable responses, with some patients having complete responses lasting more than 1 year after a single infusion.

Updated combined phase 1 and 2 results in 108 patients with diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, or transformed follicular lymphoma showed an objective response rate of 82% of patients – including 58% showing complete responses – after a median follow-up of 15.4 months.

In a video interview at the annual meeting of the American Society of Hematology, Sattva S. Neelapu, MD, from the University of Texas MD Anderson Cancer Center in Houston discusses the use of CAR T cells directed against the CD19 antigen in patients with relapsed/refractory B-cell lymphomas and describes efforts to improve responses while managing adverse events common to CAR T-cell therapies, notably cytokine release syndrome.

ZUMA-1 is supported by Kite Pharma, which developed axicabtagene ciloleucel, and the Leukemia & Lymphoma Society’s Therapy Acceleration Program. Dr. Neelapu reported receiving advisory board fees from the company.

ATLANTA – In the ZUMA-1 trial, 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; axi-cel) had durable responses, with some patients having complete responses lasting more than 1 year after a single infusion.

Updated combined phase 1 and 2 results in 108 patients with diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, or transformed follicular lymphoma showed an objective response rate of 82% of patients – including 58% showing complete responses – after a median follow-up of 15.4 months.

In a video interview at the annual meeting of the American Society of Hematology, Sattva S. Neelapu, MD, from the University of Texas MD Anderson Cancer Center in Houston discusses the use of CAR T cells directed against the CD19 antigen in patients with relapsed/refractory B-cell lymphomas and describes efforts to improve responses while managing adverse events common to CAR T-cell therapies, notably cytokine release syndrome.

ZUMA-1 is supported by Kite Pharma, which developed axicabtagene ciloleucel, and the Leukemia & Lymphoma Society’s Therapy Acceleration Program. Dr. Neelapu reported receiving advisory board fees from the company.

ATLANTA – In the ZUMA-1 trial, 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; axi-cel) had durable responses, with some patients having complete responses lasting more than 1 year after a single infusion.

Updated combined phase 1 and 2 results in 108 patients with diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, or transformed follicular lymphoma showed an objective response rate of 82% of patients – including 58% showing complete responses – after a median follow-up of 15.4 months.

In a video interview at the annual meeting of the American Society of Hematology, Sattva S. Neelapu, MD, from the University of Texas MD Anderson Cancer Center in Houston discusses the use of CAR T cells directed against the CD19 antigen in patients with relapsed/refractory B-cell lymphomas and describes efforts to improve responses while managing adverse events common to CAR T-cell therapies, notably cytokine release syndrome.

ZUMA-1 is supported by Kite Pharma, which developed axicabtagene ciloleucel, and the Leukemia & Lymphoma Society’s Therapy Acceleration Program. Dr. Neelapu reported receiving advisory board fees from the company.

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.

Photo by Linda Bartlett

Combination treatment with 2 monoclonal antibodies (mAbs) has demonstrated preclinical efficacy against B-cell lymphomas, according to researchers.

The investigators tested different combinations of mAbs to see how they interact with each other and what effect this has on how the immune system fights cancer.

One combination—an anti-CD27 mAb and anti-CD20 mAb—greatly increased survival in mouse models of B-cell lymphoma.

The researchers reported these results in Cancer Cell.

“By combining 2 specific antibodies—anti-CD27 and anti-CD20—we’ve increased the ability of the immune system to destroy cancer cells,” said study author Sean Lim, MBChB, PhD, of the University of Southampton in the UK.

“It’s very exciting to see that this drug combination has an impact on survival of mice with lymphoma, as improvements in treatment are urgently needed. The next stage will be to see if what we’ve discovered can be replicated in patients.”

For this study, Dr Lim and her colleagues tested combinations of tumor-targeting mAbs and immunomodulatory mAbs. The group found that an anti-CD27 mAb enhanced anti-CD20 therapy in various preclinical models.

The investigators first tested anti-CD20 and anti-CD27 (both alone and in combination) in the murine B-cell lymphoma model BCL1.

All control BCL1 mice had died by 30 days from baseline, all mice that received anti-CD20 alone died by day 40, and 30% of mice that received anti-CD27 alone were still alive past 100 days.

In contrast, 100% of mice that received anti-CD20 and anti-CD27 in combination were still alive and lymphoma-free past the 100-day mark.

The researchers also tested the mAbs in the A31 B-cell lymphoma model and the Eµ-TCL1 B-chronic lymphocytic leukemia model.

Results were similar to those observed with the BCL1 model. The combination of anti-CD20 and anti-CD27 significantly improved survival in A31 and Eµ-TCL1 mice, with all mice that received this combination surviving past 100 days.

As far as mechanisms of action, the investigators noted that anti-CD20 binds to B cells and mediates antibody-dependent cellular phagocytosis of the mAb-opsonized cells.

The researchers said the addition of anti-CD27 stimulates CD8+ T cells and natural killer cells, which induces the release of CCL3, CCL4, and CCL5, and this potentially attracts myeloid cells.

In addition, anti-CD27 (via the stimulation of CD8+ T and natural killer cells) induces the release of interferon gamma, which activates macrophages to express more Fc gamma receptor IV and promotes their inflammatory capacity. This increases the number of macrophages available for antibody-dependent cellular phagocytosis as well as the cells’ phagocytic ability.

Based on these findings, researchers are now conducting a phase 2 trial to test the anti-CD20 mAb rituximab and the anti-CD27 mAb varililumab in patients with relapsed and/or refractory B-cell non-Hodgkin lymphoma. 

Photo by Linda Bartlett

Combination treatment with 2 monoclonal antibodies (mAbs) has demonstrated preclinical efficacy against B-cell lymphomas, according to researchers.

The investigators tested different combinations of mAbs to see how they interact with each other and what effect this has on how the immune system fights cancer.

One combination—an anti-CD27 mAb and anti-CD20 mAb—greatly increased survival in mouse models of B-cell lymphoma.

The researchers reported these results in Cancer Cell.

“By combining 2 specific antibodies—anti-CD27 and anti-CD20—we’ve increased the ability of the immune system to destroy cancer cells,” said study author Sean Lim, MBChB, PhD, of the University of Southampton in the UK.

“It’s very exciting to see that this drug combination has an impact on survival of mice with lymphoma, as improvements in treatment are urgently needed. The next stage will be to see if what we’ve discovered can be replicated in patients.”

For this study, Dr Lim and her colleagues tested combinations of tumor-targeting mAbs and immunomodulatory mAbs. The group found that an anti-CD27 mAb enhanced anti-CD20 therapy in various preclinical models.

The investigators first tested anti-CD20 and anti-CD27 (both alone and in combination) in the murine B-cell lymphoma model BCL1.

All control BCL1 mice had died by 30 days from baseline, all mice that received anti-CD20 alone died by day 40, and 30% of mice that received anti-CD27 alone were still alive past 100 days.

In contrast, 100% of mice that received anti-CD20 and anti-CD27 in combination were still alive and lymphoma-free past the 100-day mark.

The researchers also tested the mAbs in the A31 B-cell lymphoma model and the Eµ-TCL1 B-chronic lymphocytic leukemia model.

Results were similar to those observed with the BCL1 model. The combination of anti-CD20 and anti-CD27 significantly improved survival in A31 and Eµ-TCL1 mice, with all mice that received this combination surviving past 100 days.

As far as mechanisms of action, the investigators noted that anti-CD20 binds to B cells and mediates antibody-dependent cellular phagocytosis of the mAb-opsonized cells.

The researchers said the addition of anti-CD27 stimulates CD8+ T cells and natural killer cells, which induces the release of CCL3, CCL4, and CCL5, and this potentially attracts myeloid cells.

In addition, anti-CD27 (via the stimulation of CD8+ T and natural killer cells) induces the release of interferon gamma, which activates macrophages to express more Fc gamma receptor IV and promotes their inflammatory capacity. This increases the number of macrophages available for antibody-dependent cellular phagocytosis as well as the cells’ phagocytic ability.

Based on these findings, researchers are now conducting a phase 2 trial to test the anti-CD20 mAb rituximab and the anti-CD27 mAb varililumab in patients with relapsed and/or refractory B-cell non-Hodgkin lymphoma. 

Photo by Linda Bartlett

Combination treatment with 2 monoclonal antibodies (mAbs) has demonstrated preclinical efficacy against B-cell lymphomas, according to researchers.

The investigators tested different combinations of mAbs to see how they interact with each other and what effect this has on how the immune system fights cancer.

One combination—an anti-CD27 mAb and anti-CD20 mAb—greatly increased survival in mouse models of B-cell lymphoma.

The researchers reported these results in Cancer Cell.

“By combining 2 specific antibodies—anti-CD27 and anti-CD20—we’ve increased the ability of the immune system to destroy cancer cells,” said study author Sean Lim, MBChB, PhD, of the University of Southampton in the UK.

“It’s very exciting to see that this drug combination has an impact on survival of mice with lymphoma, as improvements in treatment are urgently needed. The next stage will be to see if what we’ve discovered can be replicated in patients.”

For this study, Dr Lim and her colleagues tested combinations of tumor-targeting mAbs and immunomodulatory mAbs. The group found that an anti-CD27 mAb enhanced anti-CD20 therapy in various preclinical models.

The investigators first tested anti-CD20 and anti-CD27 (both alone and in combination) in the murine B-cell lymphoma model BCL1.

All control BCL1 mice had died by 30 days from baseline, all mice that received anti-CD20 alone died by day 40, and 30% of mice that received anti-CD27 alone were still alive past 100 days.

In contrast, 100% of mice that received anti-CD20 and anti-CD27 in combination were still alive and lymphoma-free past the 100-day mark.

The researchers also tested the mAbs in the A31 B-cell lymphoma model and the Eµ-TCL1 B-chronic lymphocytic leukemia model.

Results were similar to those observed with the BCL1 model. The combination of anti-CD20 and anti-CD27 significantly improved survival in A31 and Eµ-TCL1 mice, with all mice that received this combination surviving past 100 days.

As far as mechanisms of action, the investigators noted that anti-CD20 binds to B cells and mediates antibody-dependent cellular phagocytosis of the mAb-opsonized cells.

The researchers said the addition of anti-CD27 stimulates CD8+ T cells and natural killer cells, which induces the release of CCL3, CCL4, and CCL5, and this potentially attracts myeloid cells.

In addition, anti-CD27 (via the stimulation of CD8+ T and natural killer cells) induces the release of interferon gamma, which activates macrophages to express more Fc gamma receptor IV and promotes their inflammatory capacity. This increases the number of macrophages available for antibody-dependent cellular phagocytosis as well as the cells’ phagocytic ability.

Based on these findings, researchers are now conducting a phase 2 trial to test the anti-CD20 mAb rituximab and the anti-CD27 mAb varililumab in patients with relapsed and/or refractory B-cell non-Hodgkin 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 when a patient with follicular lymphoma experiences early disease progression on bendamustine, what should the next treatment be? Autologous stem cell transplantation (ASCT)? Novel therapies? 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.

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.

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 when a patient with follicular lymphoma experiences early disease progression on bendamustine, what should the next treatment be? Autologous stem cell transplantation (ASCT)? Novel therapies? 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.

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.

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 when a patient with follicular lymphoma experiences early disease progression on bendamustine, what should the next treatment be? Autologous stem cell transplantation (ASCT)? Novel therapies? 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.

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.

Micrograph showing DLBCL

Preclinical research suggests the dual PI3K/mTOR inhibitor PQR309 has activity against several types of lymphoma and works well in combination with other agents.

PQR309 exhibited anti-lymphoma activity as a single agent and in combination with venetoclax, panobinostat, ibrutinib, lenalidomide, ARV-825, marizomib, and rituximab.

PQR309 demonstrated greater activity against B-cell lymphoma than T-cell lymphoma, and the inhibitor was able to overcome both primary and acquired resistance to idelalisib.

Francesco Bertoni, MD, of the Institute of Oncology Research in Bellinzona, Switzerland, and his colleagues conducted this research and reported the results in Clinical Cancer Research.

The work was funded by PIQUR Therapeutics AG, the company developing PQR309, and some study authors are PIQUR employees.

The researchers tested PQR309 in 49 human lymphoma cell lines—7 activated B-cell-like (ABC) diffuse large B-cell lymphoma (DLBCL), 18 germinal center B-cell (GCB) DLBCL, 10 mantle cell lymphoma (MCL), 3 splenic marginal zone lymphoma (SMZL), 2 chronic lymphocytic leukemia (CLL), 4 Hodgkin lymphoma, and 5 anaplastic large-cell lymphoma (ALCL).

In most cell lines, PQR309 halted proliferation, mainly due to cell-cycle arrest with a block in G1. However, PQR309 induced apoptosis in 2 cell lines tested—SU-DHL-4 and TMD8.

The researchers noted that PQR309 was significantly more active in the B-cell lymphoma cell lines (DLBCL, MCL, CLL, and SMZL) than in the T-cell lymphoma cell line ALCL (P=0.028).

PQR309 exhibited similar activity in ABC and GCB DLBCL cell lines, de novo DLBCL, and DLBCL derived from transformed follicular lymphoma. TP53, MYC, and BCL2 status also had no significant effect on PQR309 activity.

The researchers compared cell lines that were very sensitive to PQR309 to those with low sensitivity to the drug and identified differences.

The team said that transcripts preferentially expressed in PQR309-sensitive cell lines were significantly enriched of genes involved in BCR pathway/signaling and BLIMP1 targets. Transcripts associated with less sensitive cell lines were enriched of members of proteasome pathway, response to unfolded proteins, MYC targets, XBP1 targets, genes downregulated by mTOR inhibitors, and genes involved in oxidative phosphorylation.

PQR309 demonstrated synergistic effects when combined with the BTK inhibitor ibrutinib, the immunomodulatory drug lenalidomide, the anti-CD20 monoclonal antibody rituximab, and the proteasome inhibitor marizomib.

PQR309 demonstrated synergistic or additive effects when combined with the BCL2 inhibitor venetoclax, the HDAC inhibitor panobinostat, and the PROTAC BET inhibitor ARV-825.

In addition, PQR309 was active in lymphoma cell lines with primary and secondary resistance to the PI3K inhibitor idelalisib.

The researchers believe the results of this study, together with ongoing clinical studies of PQR309, can lead to better treatments for lymphoma patients and better understanding of the mechanisms of anti-lymphoma agents.

Micrograph showing DLBCL

Preclinical research suggests the dual PI3K/mTOR inhibitor PQR309 has activity against several types of lymphoma and works well in combination with other agents.

PQR309 exhibited anti-lymphoma activity as a single agent and in combination with venetoclax, panobinostat, ibrutinib, lenalidomide, ARV-825, marizomib, and rituximab.

PQR309 demonstrated greater activity against B-cell lymphoma than T-cell lymphoma, and the inhibitor was able to overcome both primary and acquired resistance to idelalisib.

Francesco Bertoni, MD, of the Institute of Oncology Research in Bellinzona, Switzerland, and his colleagues conducted this research and reported the results in Clinical Cancer Research.

The work was funded by PIQUR Therapeutics AG, the company developing PQR309, and some study authors are PIQUR employees.

The researchers tested PQR309 in 49 human lymphoma cell lines—7 activated B-cell-like (ABC) diffuse large B-cell lymphoma (DLBCL), 18 germinal center B-cell (GCB) DLBCL, 10 mantle cell lymphoma (MCL), 3 splenic marginal zone lymphoma (SMZL), 2 chronic lymphocytic leukemia (CLL), 4 Hodgkin lymphoma, and 5 anaplastic large-cell lymphoma (ALCL).

In most cell lines, PQR309 halted proliferation, mainly due to cell-cycle arrest with a block in G1. However, PQR309 induced apoptosis in 2 cell lines tested—SU-DHL-4 and TMD8.

The researchers noted that PQR309 was significantly more active in the B-cell lymphoma cell lines (DLBCL, MCL, CLL, and SMZL) than in the T-cell lymphoma cell line ALCL (P=0.028).

PQR309 exhibited similar activity in ABC and GCB DLBCL cell lines, de novo DLBCL, and DLBCL derived from transformed follicular lymphoma. TP53, MYC, and BCL2 status also had no significant effect on PQR309 activity.

The researchers compared cell lines that were very sensitive to PQR309 to those with low sensitivity to the drug and identified differences.

The team said that transcripts preferentially expressed in PQR309-sensitive cell lines were significantly enriched of genes involved in BCR pathway/signaling and BLIMP1 targets. Transcripts associated with less sensitive cell lines were enriched of members of proteasome pathway, response to unfolded proteins, MYC targets, XBP1 targets, genes downregulated by mTOR inhibitors, and genes involved in oxidative phosphorylation.

PQR309 demonstrated synergistic effects when combined with the BTK inhibitor ibrutinib, the immunomodulatory drug lenalidomide, the anti-CD20 monoclonal antibody rituximab, and the proteasome inhibitor marizomib.

PQR309 demonstrated synergistic or additive effects when combined with the BCL2 inhibitor venetoclax, the HDAC inhibitor panobinostat, and the PROTAC BET inhibitor ARV-825.

In addition, PQR309 was active in lymphoma cell lines with primary and secondary resistance to the PI3K inhibitor idelalisib.

The researchers believe the results of this study, together with ongoing clinical studies of PQR309, can lead to better treatments for lymphoma patients and better understanding of the mechanisms of anti-lymphoma agents.

Micrograph showing DLBCL

Preclinical research suggests the dual PI3K/mTOR inhibitor PQR309 has activity against several types of lymphoma and works well in combination with other agents.

PQR309 exhibited anti-lymphoma activity as a single agent and in combination with venetoclax, panobinostat, ibrutinib, lenalidomide, ARV-825, marizomib, and rituximab.

PQR309 demonstrated greater activity against B-cell lymphoma than T-cell lymphoma, and the inhibitor was able to overcome both primary and acquired resistance to idelalisib.

Francesco Bertoni, MD, of the Institute of Oncology Research in Bellinzona, Switzerland, and his colleagues conducted this research and reported the results in Clinical Cancer Research.

The work was funded by PIQUR Therapeutics AG, the company developing PQR309, and some study authors are PIQUR employees.

The researchers tested PQR309 in 49 human lymphoma cell lines—7 activated B-cell-like (ABC) diffuse large B-cell lymphoma (DLBCL), 18 germinal center B-cell (GCB) DLBCL, 10 mantle cell lymphoma (MCL), 3 splenic marginal zone lymphoma (SMZL), 2 chronic lymphocytic leukemia (CLL), 4 Hodgkin lymphoma, and 5 anaplastic large-cell lymphoma (ALCL).

In most cell lines, PQR309 halted proliferation, mainly due to cell-cycle arrest with a block in G1. However, PQR309 induced apoptosis in 2 cell lines tested—SU-DHL-4 and TMD8.

The researchers noted that PQR309 was significantly more active in the B-cell lymphoma cell lines (DLBCL, MCL, CLL, and SMZL) than in the T-cell lymphoma cell line ALCL (P=0.028).

PQR309 exhibited similar activity in ABC and GCB DLBCL cell lines, de novo DLBCL, and DLBCL derived from transformed follicular lymphoma. TP53, MYC, and BCL2 status also had no significant effect on PQR309 activity.

The researchers compared cell lines that were very sensitive to PQR309 to those with low sensitivity to the drug and identified differences.

The team said that transcripts preferentially expressed in PQR309-sensitive cell lines were significantly enriched of genes involved in BCR pathway/signaling and BLIMP1 targets. Transcripts associated with less sensitive cell lines were enriched of members of proteasome pathway, response to unfolded proteins, MYC targets, XBP1 targets, genes downregulated by mTOR inhibitors, and genes involved in oxidative phosphorylation.

PQR309 demonstrated synergistic effects when combined with the BTK inhibitor ibrutinib, the immunomodulatory drug lenalidomide, the anti-CD20 monoclonal antibody rituximab, and the proteasome inhibitor marizomib.

PQR309 demonstrated synergistic or additive effects when combined with the BCL2 inhibitor venetoclax, the HDAC inhibitor panobinostat, and the PROTAC BET inhibitor ARV-825.

In addition, PQR309 was active in lymphoma cell lines with primary and secondary resistance to the PI3K inhibitor idelalisib.

The researchers believe the results of this study, together with ongoing clinical studies of PQR309, can lead to better treatments for lymphoma patients and better understanding of the mechanisms of anti-lymphoma agents.

Photo from NIH

A study of childhood cancer survivors (CCSs) suggests these individuals have an increased risk of developing hypertension as adults.

The CCSs studied had more than double the rate of hypertension observed in the matched general population.

Sex, age, race, and weight were all significantly associated with hypertension among CCSs, but most treatment types were not.

The exception was nephrectomy, which was associated with an increased risk of hypertension.

Todd M. Gibson, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues conducted this research and reported the results in Cancer Epidemiology, Biomarkers & Prevention.

“High blood pressure is an important modifiable risk factor that increases the risk of heart problems in everyone,” Dr Gibson said. “Research has shown that high blood pressure can have an even greater negative impact on survivors of childhood cancer who were treated with cardiotoxic therapies such as anthracyclines or chest radiation.”

To assess the prevalence of hypertension among CCSs, Dr Gibson and his colleagues examined 3016 adults who were 10-year survivors of childhood cancers. The subjects were enrolled in the St. Jude Lifetime Cohort Study, which provides ongoing medical assessments of CCSs to advance knowledge of their long-term health outcomes.

The subjects’ mean age at the initial study assessment was 32, and 52% were male. Most (83%) were non-Hispanic white, 14% were non-Hispanic black, 2% were Hispanic, and 1% were “other.”

Thirty-seven percent of subjects had leukemia, 12% had Hodgkin lymphoma, and 7% had non-Hodgkin lymphoma.

Eighty-six percent of subjects had received chemotherapy, and 59% received radiation.

Results

Subjects were considered to have hypertension if their systolic blood pressure was 140 or greater, their diastolic blood pressure was 90 or greater, or if they had been previously diagnosed with hypertension and were taking antihypertensive medication.

The prevalence of hypertension was 2.6 times higher among CCSs than expected, based on age-, sex-, race- and body mass index-specific rates in the general population.

In addition, the incidence of hypertension increased for CCSs over time. Thirteen percent of CCSs had hypertension at age 30, 37% had it at age 40, and more than 70% had it at age 50.

Dr Gibson said rates of hypertension in CCSs matched rates in the general population of people about a decade older.

The researchers identified several factors that were significantly associated with hypertension among CCSs, including:

• Male sex (odd ratio [OR], 1.38; 95% CI, 1.14–1.67)
• Non-Hispanic black race (OR, 1.66; 95% CI, 1.28–2.16)
• Older age at assessment (OR per 1 year of age, 1.10; 95% CI, 1.08–1.11)
• Being overweight (OR, 1.58; 95% CI, 1.21–2.07)
• Obesity (OR, 3.02; 95% CI, 2.34–3.88).

Exposure to any type of radiation or chemotherapy was not significantly associated with hypertension, but nephrectomy was (OR, 1.68; 95% CI, 1.11–2.53).

Dr Gibson said the lack of an association between hypertension and radiation/chemotherapy was surprising. It suggests the connection between childhood cancer survival and adult hypertension is multifactorial and worthy of future research.

In the meantime, he said, clinicians should be mindful that CCSs are more likely than the general public to develop hypertension.

“The good news is that, unlike prior cancer therapy, high blood pressure is a modifiable risk factor,” Dr Gibson noted. “Research is needed to identify effective interventions to prevent hypertension in survivors, but our results emphasize the importance of blood pressure surveillance and management.”

Dr Gibson said a limitation of this study is that it was based on blood pressure measurements taken at a single study visit. A clinical diagnosis of hypertension typically requires measurements taken at multiple intervals.

In addition, the St. Jude Lifetime Cohort is a group of CCSs who undergo frequent clinical follow-up, so its participants may have benefited from being monitored and may therefore be in better health than CCSs who have less comprehensive follow-up.

Photo from NIH

A study of childhood cancer survivors (CCSs) suggests these individuals have an increased risk of developing hypertension as adults.

The CCSs studied had more than double the rate of hypertension observed in the matched general population.

Sex, age, race, and weight were all significantly associated with hypertension among CCSs, but most treatment types were not.

The exception was nephrectomy, which was associated with an increased risk of hypertension.

Todd M. Gibson, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues conducted this research and reported the results in Cancer Epidemiology, Biomarkers & Prevention.

“High blood pressure is an important modifiable risk factor that increases the risk of heart problems in everyone,” Dr Gibson said. “Research has shown that high blood pressure can have an even greater negative impact on survivors of childhood cancer who were treated with cardiotoxic therapies such as anthracyclines or chest radiation.”

To assess the prevalence of hypertension among CCSs, Dr Gibson and his colleagues examined 3016 adults who were 10-year survivors of childhood cancers. The subjects were enrolled in the St. Jude Lifetime Cohort Study, which provides ongoing medical assessments of CCSs to advance knowledge of their long-term health outcomes.

The subjects’ mean age at the initial study assessment was 32, and 52% were male. Most (83%) were non-Hispanic white, 14% were non-Hispanic black, 2% were Hispanic, and 1% were “other.”

Thirty-seven percent of subjects had leukemia, 12% had Hodgkin lymphoma, and 7% had non-Hodgkin lymphoma.

Eighty-six percent of subjects had received chemotherapy, and 59% received radiation.

Results

Subjects were considered to have hypertension if their systolic blood pressure was 140 or greater, their diastolic blood pressure was 90 or greater, or if they had been previously diagnosed with hypertension and were taking antihypertensive medication.

The prevalence of hypertension was 2.6 times higher among CCSs than expected, based on age-, sex-, race- and body mass index-specific rates in the general population.

In addition, the incidence of hypertension increased for CCSs over time. Thirteen percent of CCSs had hypertension at age 30, 37% had it at age 40, and more than 70% had it at age 50.

Dr Gibson said rates of hypertension in CCSs matched rates in the general population of people about a decade older.

The researchers identified several factors that were significantly associated with hypertension among CCSs, including:

• Male sex (odd ratio [OR], 1.38; 95% CI, 1.14–1.67)
• Non-Hispanic black race (OR, 1.66; 95% CI, 1.28–2.16)
• Older age at assessment (OR per 1 year of age, 1.10; 95% CI, 1.08–1.11)
• Being overweight (OR, 1.58; 95% CI, 1.21–2.07)
• Obesity (OR, 3.02; 95% CI, 2.34–3.88).

Exposure to any type of radiation or chemotherapy was not significantly associated with hypertension, but nephrectomy was (OR, 1.68; 95% CI, 1.11–2.53).

Dr Gibson said the lack of an association between hypertension and radiation/chemotherapy was surprising. It suggests the connection between childhood cancer survival and adult hypertension is multifactorial and worthy of future research.

In the meantime, he said, clinicians should be mindful that CCSs are more likely than the general public to develop hypertension.

“The good news is that, unlike prior cancer therapy, high blood pressure is a modifiable risk factor,” Dr Gibson noted. “Research is needed to identify effective interventions to prevent hypertension in survivors, but our results emphasize the importance of blood pressure surveillance and management.”

Dr Gibson said a limitation of this study is that it was based on blood pressure measurements taken at a single study visit. A clinical diagnosis of hypertension typically requires measurements taken at multiple intervals.

In addition, the St. Jude Lifetime Cohort is a group of CCSs who undergo frequent clinical follow-up, so its participants may have benefited from being monitored and may therefore be in better health than CCSs who have less comprehensive follow-up.

Photo from NIH

A study of childhood cancer survivors (CCSs) suggests these individuals have an increased risk of developing hypertension as adults.

The CCSs studied had more than double the rate of hypertension observed in the matched general population.

Sex, age, race, and weight were all significantly associated with hypertension among CCSs, but most treatment types were not.

The exception was nephrectomy, which was associated with an increased risk of hypertension.

Todd M. Gibson, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues conducted this research and reported the results in Cancer Epidemiology, Biomarkers & Prevention.

“High blood pressure is an important modifiable risk factor that increases the risk of heart problems in everyone,” Dr Gibson said. “Research has shown that high blood pressure can have an even greater negative impact on survivors of childhood cancer who were treated with cardiotoxic therapies such as anthracyclines or chest radiation.”

To assess the prevalence of hypertension among CCSs, Dr Gibson and his colleagues examined 3016 adults who were 10-year survivors of childhood cancers. The subjects were enrolled in the St. Jude Lifetime Cohort Study, which provides ongoing medical assessments of CCSs to advance knowledge of their long-term health outcomes.

The subjects’ mean age at the initial study assessment was 32, and 52% were male. Most (83%) were non-Hispanic white, 14% were non-Hispanic black, 2% were Hispanic, and 1% were “other.”

Thirty-seven percent of subjects had leukemia, 12% had Hodgkin lymphoma, and 7% had non-Hodgkin lymphoma.

Eighty-six percent of subjects had received chemotherapy, and 59% received radiation.

Results

Subjects were considered to have hypertension if their systolic blood pressure was 140 or greater, their diastolic blood pressure was 90 or greater, or if they had been previously diagnosed with hypertension and were taking antihypertensive medication.

The prevalence of hypertension was 2.6 times higher among CCSs than expected, based on age-, sex-, race- and body mass index-specific rates in the general population.

In addition, the incidence of hypertension increased for CCSs over time. Thirteen percent of CCSs had hypertension at age 30, 37% had it at age 40, and more than 70% had it at age 50.

Dr Gibson said rates of hypertension in CCSs matched rates in the general population of people about a decade older.

The researchers identified several factors that were significantly associated with hypertension among CCSs, including:

• Male sex (odd ratio [OR], 1.38; 95% CI, 1.14–1.67)
• Non-Hispanic black race (OR, 1.66; 95% CI, 1.28–2.16)
• Older age at assessment (OR per 1 year of age, 1.10; 95% CI, 1.08–1.11)
• Being overweight (OR, 1.58; 95% CI, 1.21–2.07)
• Obesity (OR, 3.02; 95% CI, 2.34–3.88).

Exposure to any type of radiation or chemotherapy was not significantly associated with hypertension, but nephrectomy was (OR, 1.68; 95% CI, 1.11–2.53).

Dr Gibson said the lack of an association between hypertension and radiation/chemotherapy was surprising. It suggests the connection between childhood cancer survival and adult hypertension is multifactorial and worthy of future research.

In the meantime, he said, clinicians should be mindful that CCSs are more likely than the general public to develop hypertension.

“The good news is that, unlike prior cancer therapy, high blood pressure is a modifiable risk factor,” Dr Gibson noted. “Research is needed to identify effective interventions to prevent hypertension in survivors, but our results emphasize the importance of blood pressure surveillance and management.”

Dr Gibson said a limitation of this study is that it was based on blood pressure measurements taken at a single study visit. A clinical diagnosis of hypertension typically requires measurements taken at multiple intervals.

In addition, the St. Jude Lifetime Cohort is a group of CCSs who undergo frequent clinical follow-up, so its participants may have benefited from being monitored and may therefore be in better health than CCSs who have less comprehensive follow-up.

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.

Wolfgang Däuble

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.”

Wolfgang Däuble

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.”

Wolfgang Däuble

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.”