Second-Line BCL Treatment Landscape Shifts From ASCT to CAR T-Cell Therapy

Manali Kamdar, MD

Hematologic malignancies have been impacted heavily by the introduction of chimeric antigen receptor (CAR) T-cell therapy, which has demonstrated long remission in major clinical trials and received approvals by the FDA. CAR T-cell therapy provides a new option for patients with relapsed/refractory B-cell lymphoma (BCL).

“The current treatment landscape for patients with relapsed/refractory [BCL] looks extremely promising, thanks to the positive results from clinical trials and thus the subsequent FDA approvals of these therapeutics,” Manali Kamdar, MD, associate professor of medicine-hematology and clinical director of lymphoma services at the University of Colorado Medicine in Aurora, said in an interview with the SOHO Daily News beforethe 10th Annual Meeting of the Society of Hematologic Oncology (SOHO 2022).

Optimal Sequence

Kamdar’s presentation on September 30, 2022, at 1:40 pm during the conference concerns the question of when to use CAR T-cell therapy vs autologous stem cell transplant (ASCT) in patients with relapsed/refractory aggressive BCL. She says the 3 phase 3 studies of CAR T-cell products that were presented at the 2021 American Society of Hematology Annual Meeting and Exposition (ASH 2021) have made a major difference in answering this question for high-risk patients.

Patients with diffuse large BCL who relapse within 12 months of frontline chemoimmunotherapy with R-CHOP (rituximab [Rituxan], cyclophosphamide, doxorubicin, vincristine [Oncovin], prednisone) are considered primary refractory, and these patients have very poor outcomes. In the past, they would receive salvage chemotherapy followed by an ASCT. Kamdar says only a quarter of these high-risk patients would achieve long-term remission following ASCT.

This led to an urgent need for CAR T-cell therapy in the second line for these patients. CAR T cells had shown efficacy for R/R BCL, leading to the approval of these therapies in patients with at least 2 prior lines of treatment, the first being axicabtagene ciloleucel (axi-cel; Yescarta) in 2017.^1,2

The results of 3 pivotal phase 3 trials of CAR T-cell products were first presented at ASH 2021, comparing them with salvage chemotherapy and ASCT in patients with aggressive non-Hodgkin BCL who relapsed within 12 months of frontline chemoimmunotherapy. The ZUMA-7 trial (NCT03391466) that evaluated axi-cel and the TRANSFORM trial (NCT03575351) that evaluated lisocabtagene maraleucel (liso-cel; Breyanzi) showed significantly higher event-free survival (EFS) rates in patients who received CAR T-cell therapy vs ASCT, but the BELINDA trial (NCT03570892) that evaluated tisagenlecleucel (tisa-cel; Kymriah) failed to show improved EFS over standard-of-care second-line therapy^.3-5 Kamdar plans to discuss the possible reasons for the different outcomes of these trials in greater detail in her presentation.

With axi-cel and liso-cel receiving FDA approvals as second-line therapy, CAR T-cell therapy stands to replace ASCT in this stage of sequencing.^6,7 “Within this high-risk R/R large BCL subset, I will have to say I no longer recommend an ASCT based on these 2 positive studies, and that we take patients to CAR T-cell therapy,” Kamdar said.

Trial Outcomes

Kamdar’s presentation will focus on the outcomes demonstrated by these trials, including the statistically significant EFS, progression-free survival, and complete response rate of CAR T-cell therapy. Additionally, she will discuss the manageable levels of toxicity seen in the 2 positive trials, with no grade 4 or 5 cytokine release syndrome or neurotoxicity being reported. Longer follow-up is needed to observe overall survival outcomes and other long-term impacts of these therapies.

Despite these results, CAR T-cell therapy is not an option for those who are chemotherapy-sensitive who relapsed more than 12 months after frontline therapy. “Currently, ASCT remains the standard of care,” Kamdar said. “But it’d be nice to see [whether] there is something else that can actually be better.”

Additionally, the role of CAR T-cell therapy is being investigated in patients who are transplant-ineligible in the phase 2 TRANSCEND-PILOT 017006 study (NCT03483103) that evaluates liso-cel. Durable responses to liso-cel were reported in the primary analysis presented at the 2022 American Society of Clinical Oncology Annual Meeting.⁸

For patients with high-risk R/R BCL, Kamdar says it’s crucial to start referring patients for CAR T-cell therapy as soon as they are determined to be primary refractory. “CAR T-cell therapy is certainly a process that takes time, because manufacturing of the cells requires a minimum of 17 to 34 days based on the construct you choose,” she said. Additionally, insurance approvals and logistical concerns can cause further delays to starting therapy. CAR T-cell production time and accessibility may be improved by new approaches that are being investigated, including allogeneic CAR T cells that do not require patients to undergo leukapheresis.

One rising area of need is therapies for patients who fail CAR T-cell therapy, who may have limited treatment options if they are CD19 negative. Kamdar anticipates that novel therapies, including bispecific antibodies, bispecific T-cell engagers, and natural killer T cells, could fill this unmet need in patients with R/R BCL. “[Approximately] 20% of patients [in recent trials of bispecific agents] may have actually received prior CAR T-[cell therapy], and they are showing a response in patients who have failed prior CAR T-cell therapy,” she said.

She suggests novel time-limited bispecific therapies will not only benefit those who relapsed or who cannot receive CAR T-cell therapy, but they are also valuable for physicians who want to treat patients while waiting to start CAR T-cell therapy.

Kamdar is looking forward to discussing the shift from ASCT to CAR T-cell therapy in second-line therapy in greater detail at SOHO 2022. “I’m very excited to see all my colleagues after so long,” Kamdar said. “I’m thrilled to be able to connect in person with everyone. It’s been too long.”

_REFERENCES:

_{1. Schuster SJ, Svoboda J, Chong EA, et al. Chimeric antigen receptor T cells in refractory B-cell lymphomas. N Engl J Med. 2017;377(26):2545-2554. doi:10.1056/NEJMoa1708566}

_{2. FDA approves CAR-T cell therapy to treat adults with certain types of large B-cell lymphoma. News release. FDA; October 18, 2017. Updated March 21, 2018. Accessed August 25, 2022. https://bit.ly/3ANA0k5}

_{3. 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(7):640-654. doi:10.1056/NEJMoa2116133}

_{4. 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(10343):2294-2308. Published correction appears in Lancet. 2022;400(10347):160.}

_{5. Bishop MR, Dickinson M, Purtill D, et al. Second-line tisagenlecleucel or standard care in aggressive B-cell lymphoma. N Engl J Med. 2022;386(7):629-639. doi:10.1056/NEJMoa2116596}

_{6. FDA approves axicabtagene ciloleucel for second-line treatment of large B-cell lymphoma. FDA. April 1, 2022. Accessed August 25, 2022. https://bit.ly/3ANmZab}

_{7. FDA approves lisocabtagene maraleucel for second-line treatment of large B-cell lymphoma. FDA. June 24, 2022. Accessed August 25, 2022. https://bit.ly/3Q52NVT}

_{8. Seghal A, Hoda D, Riedell PA, et al. Lisocabtagene maraleucel (liso-cel) as second-line (2L) therapy for R/R large B-cell lymphoma (LBCL) in patients (pt) not intended for hematopoietic stem cell transplantation (HSCT): primary analysis from the phase 2 PILOT study. J Clin Oncol. 2022;40(suppl 16):7062. doi:10.1200/JCO.2022.40.16_suppl.7062}