Commentary: New treatment strategies for diffuse large B-cell lymphoma, March 2023

One therapy that has transformed the management of this disease is anti-CD19 chimeric antigen receptor (CAR) T-cell therapy. Currently there are three FDA-approved options for patients with relapsed/refractory large B-cell lymphoma (LBCL) who have received at least two prior lines of therapy.^[1-3] More recently, axicabtagene ciloleucel (axi-cel) and lisocabtagene maraleucel (liso-cel) have also been approved for second-line therapy on the basis of results of the ZUMA-7 and TRANSFORM studies, respectively.^[4,5]The primary analysis of the TRANSFORM study, which included patients with primary refractory or early relapse of large B-cell lymphoma, is now available. In this study, 184 patients were randomly assigned to receive liso-cel or three cycles of the standard of care (high-dose chemotherapy and autologous stem cell transplantation). After a 17.5-month median follow-up, the liso-cel vs standard-of-care group had significantly improved median event-free survival (hazard ratio [HR] 0.356; 95% CI 0.243-0.522), median progression-free survival (HR 0.400; P < .0001), and complete response rate (74% vs 43%; P < .0001), along with low rates of grade 3 cytokine release syndrome (1%) and neurologic events (4%). This confirms the role of liso-cel in the second-line setting for high-risk patients.

Another promising treatment approach across lymphoma subtypes, including DLBCL, are CD20/CD3 bispecific monoclonal antibodies. The results of the phase 2 trial of glofitamab for patients with relapsed/refractory DLBCL were published recently. This study included 155 patients with relapsed/refractory DLBCL after at least two prior lines of therapy. Approximately one third of patients had received prior CAR T-cell therapy. Patients were treated for a fixed duration of 12 cycles. At a median follow-up of 12.6 months, 39% (95% CI 32%-48%) and 52% (95% CI 43%-60%) of patients achieved complete and objective responses, respectively. Seventy-eight percent of patients with a complete response continued to be in remission at 12 months. Grade 3 or higher cytokine release syndrome was rare and occurred in less than 5% of patients.

Bispecific antibodies have many advantages, including off-the-shelf access and favorable toxicity profiles. Longer follow-up, however, will be required to determine the durability of response beyond 1 year. As bispecific antibodies become available, many questions will emerge, including how best to sequence with CAR T-cell therapy and whether to combine them with other regimens. Additional studies of bispecific antibodies in combination with chemoimmunotherapy and other treatment approaches are underway.

Additional References

1.         Neelapu SS, Locke FL, Bartlett NL, et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med. 2017;377:2531-2544. Doi:10.1056/NEJMoa1707447

2.         Schuster SJ, Bishop MR, Tam CS, et al. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med. 2019;380:45-56. Doi:10.1056/NEJMoa1804980

3.         Abramson JS, Palomba ML, Gordon LI, et al. Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): A multicentre seamless design study. Lancet. 2020;396:839-852. Doi:10.1016/S0140-6736(20)31366-0

4.         Locke FL, Miklos DB, Jacobson CA, et al. Axicabtagene ciloleucel as second-line therapy for large B-cell lymphoma. N Engl J Med. 2022;386:640-654. Doi:10.1056/NEJMoa2116133

5.         Kamdar M, Solomon SR, Arnason J, et al. Lisocabtagene maraleucel versus standard of care with salvage chemotherapy followed by autologous stem cell transplantation as second-line treatment in patients with relapsed or refractory large B-cell lymphoma (TRANSFORM): Results from an interim analysis of an open-label, randomised, phase 3 trial. Lancet. 2022;399:2294-2308. Doi:10.1016/S0140-6736(22)00662-6

One therapy that has transformed the management of this disease is anti-CD19 chimeric antigen receptor (CAR) T-cell therapy. Currently there are three FDA-approved options for patients with relapsed/refractory large B-cell lymphoma (LBCL) who have received at least two prior lines of therapy.^[1-3] More recently, axicabtagene ciloleucel (axi-cel) and lisocabtagene maraleucel (liso-cel) have also been approved for second-line therapy on the basis of results of the ZUMA-7 and TRANSFORM studies, respectively.^[4,5]The primary analysis of the TRANSFORM study, which included patients with primary refractory or early relapse of large B-cell lymphoma, is now available. In this study, 184 patients were randomly assigned to receive liso-cel or three cycles of the standard of care (high-dose chemotherapy and autologous stem cell transplantation). After a 17.5-month median follow-up, the liso-cel vs standard-of-care group had significantly improved median event-free survival (hazard ratio [HR] 0.356; 95% CI 0.243-0.522), median progression-free survival (HR 0.400; P < .0001), and complete response rate (74% vs 43%; P < .0001), along with low rates of grade 3 cytokine release syndrome (1%) and neurologic events (4%). This confirms the role of liso-cel in the second-line setting for high-risk patients.

Another promising treatment approach across lymphoma subtypes, including DLBCL, are CD20/CD3 bispecific monoclonal antibodies. The results of the phase 2 trial of glofitamab for patients with relapsed/refractory DLBCL were published recently. This study included 155 patients with relapsed/refractory DLBCL after at least two prior lines of therapy. Approximately one third of patients had received prior CAR T-cell therapy. Patients were treated for a fixed duration of 12 cycles. At a median follow-up of 12.6 months, 39% (95% CI 32%-48%) and 52% (95% CI 43%-60%) of patients achieved complete and objective responses, respectively. Seventy-eight percent of patients with a complete response continued to be in remission at 12 months. Grade 3 or higher cytokine release syndrome was rare and occurred in less than 5% of patients.

Bispecific antibodies have many advantages, including off-the-shelf access and favorable toxicity profiles. Longer follow-up, however, will be required to determine the durability of response beyond 1 year. As bispecific antibodies become available, many questions will emerge, including how best to sequence with CAR T-cell therapy and whether to combine them with other regimens. Additional studies of bispecific antibodies in combination with chemoimmunotherapy and other treatment approaches are underway.

Additional References

1.         Neelapu SS, Locke FL, Bartlett NL, et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med. 2017;377:2531-2544. Doi:10.1056/NEJMoa1707447

2.         Schuster SJ, Bishop MR, Tam CS, et al. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med. 2019;380:45-56. Doi:10.1056/NEJMoa1804980

3.         Abramson JS, Palomba ML, Gordon LI, et al. Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): A multicentre seamless design study. Lancet. 2020;396:839-852. Doi:10.1016/S0140-6736(20)31366-0

4.         Locke FL, Miklos DB, Jacobson CA, et al. Axicabtagene ciloleucel as second-line therapy for large B-cell lymphoma. N Engl J Med. 2022;386:640-654. Doi:10.1056/NEJMoa2116133

5.         Kamdar M, Solomon SR, Arnason J, et al. Lisocabtagene maraleucel versus standard of care with salvage chemotherapy followed by autologous stem cell transplantation as second-line treatment in patients with relapsed or refractory large B-cell lymphoma (TRANSFORM): Results from an interim analysis of an open-label, randomised, phase 3 trial. Lancet. 2022;399:2294-2308. Doi:10.1016/S0140-6736(22)00662-6

One therapy that has transformed the management of this disease is anti-CD19 chimeric antigen receptor (CAR) T-cell therapy. Currently there are three FDA-approved options for patients with relapsed/refractory large B-cell lymphoma (LBCL) who have received at least two prior lines of therapy.^[1-3] More recently, axicabtagene ciloleucel (axi-cel) and lisocabtagene maraleucel (liso-cel) have also been approved for second-line therapy on the basis of results of the ZUMA-7 and TRANSFORM studies, respectively.^[4,5]The primary analysis of the TRANSFORM study, which included patients with primary refractory or early relapse of large B-cell lymphoma, is now available. In this study, 184 patients were randomly assigned to receive liso-cel or three cycles of the standard of care (high-dose chemotherapy and autologous stem cell transplantation). After a 17.5-month median follow-up, the liso-cel vs standard-of-care group had significantly improved median event-free survival (hazard ratio [HR] 0.356; 95% CI 0.243-0.522), median progression-free survival (HR 0.400; P < .0001), and complete response rate (74% vs 43%; P < .0001), along with low rates of grade 3 cytokine release syndrome (1%) and neurologic events (4%). This confirms the role of liso-cel in the second-line setting for high-risk patients.

Another promising treatment approach across lymphoma subtypes, including DLBCL, are CD20/CD3 bispecific monoclonal antibodies. The results of the phase 2 trial of glofitamab for patients with relapsed/refractory DLBCL were published recently. This study included 155 patients with relapsed/refractory DLBCL after at least two prior lines of therapy. Approximately one third of patients had received prior CAR T-cell therapy. Patients were treated for a fixed duration of 12 cycles. At a median follow-up of 12.6 months, 39% (95% CI 32%-48%) and 52% (95% CI 43%-60%) of patients achieved complete and objective responses, respectively. Seventy-eight percent of patients with a complete response continued to be in remission at 12 months. Grade 3 or higher cytokine release syndrome was rare and occurred in less than 5% of patients.

Bispecific antibodies have many advantages, including off-the-shelf access and favorable toxicity profiles. Longer follow-up, however, will be required to determine the durability of response beyond 1 year. As bispecific antibodies become available, many questions will emerge, including how best to sequence with CAR T-cell therapy and whether to combine them with other regimens. Additional studies of bispecific antibodies in combination with chemoimmunotherapy and other treatment approaches are underway.

Additional References

1.         Neelapu SS, Locke FL, Bartlett NL, et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med. 2017;377:2531-2544. Doi:10.1056/NEJMoa1707447

2.         Schuster SJ, Bishop MR, Tam CS, et al. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med. 2019;380:45-56. Doi:10.1056/NEJMoa1804980

3.         Abramson JS, Palomba ML, Gordon LI, et al. Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): A multicentre seamless design study. Lancet. 2020;396:839-852. Doi:10.1016/S0140-6736(20)31366-0

4.         Locke FL, Miklos DB, Jacobson CA, et al. Axicabtagene ciloleucel as second-line therapy for large B-cell lymphoma. N Engl J Med. 2022;386:640-654. Doi:10.1056/NEJMoa2116133

5.         Kamdar M, Solomon SR, Arnason J, et al. Lisocabtagene maraleucel versus standard of care with salvage chemotherapy followed by autologous stem cell transplantation as second-line treatment in patients with relapsed or refractory large B-cell lymphoma (TRANSFORM): Results from an interim analysis of an open-label, randomised, phase 3 trial. Lancet. 2022;399:2294-2308. Doi:10.1016/S0140-6736(22)00662-6