Changing the Algorithm for Relapsed or Refractory Large B-Cell Lymphomas

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Despite a significant potential for cure, relapsed and refractory large B-cell lymphomas (LBCL) comprise the most common cause of lymphoma-related mortality. Sequential relapses reflect the limits of repeated exposure to chemotherapy, even when delivered at high doses.

More than 30 years ago, randomized trials such as the PARMA trial1 hailed the superiority of “more is better,” whereby high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (HSCT) showed superior outcomes compared with standard salvage regimens in relapsed, aggressive B-cell lymphomas. The PARMA trial established an algorithm for relapsed disease, with subsequent studies focused on optimizing salvage regimens, preparative regimens, and testing posttransplantation consolidation approaches.

Sonali M. Smith, MD, FASCO

Sonali M. Smith, MD, FASCO

However, the drawbacks of relying primarily on intensive chemotherapy became increasingly clear, with the CORAL trial and others showing that relapsed disease and refractory disease in the modern era offer a diminished benefit compared with earlier times.2,3 These limitations are particularly evident if relapse occurs early after initial chemoimmunotherapy. For many years, relapse and primary refractory disease after autologous HSCT remained the major unmet needs in lymphomas, with no effective options.

The Arrival of Immunotherapies

In 2017, axicabtagene ciloleucel became the first engineered autologous T-cell therapy for B-cell lymphomas to be approved by the U.S. Food and Drug Administration in the third-line setting, followed soon by tisagenlecleucel and then lisocabtagene maraleucel.4 The differences between each of these constructs have been discussed in detail elsewhere, but they include important distinctions in manufacturing time, the composition of the T-cell costimulatory domain, and the timing and severity of adverse effects such as cytokine-release syndrome and neurotoxicity syndromes. In aggregate, anti-CD19–directed chimeric antigen receptor (CAR) T-cell therapy leads to durable remissions in approximately 30% to 40% of patients with relapsed and refractory LBCL in the third- line setting, even in patients with clearly chemorefractory disease. The ability to exploit the immune system to develop a “living drug” that persists is an exciting advance, and innumerable ongoing investigations are further refining CAR T-cell therapies.

The success of cellular therapy in the third-line setting for LBCL naturally prompted investigations into earlier lines of treatment. Specifically, can CAR T cells replace the old paradigm of salvage chemotherapy followed by autologous HSCT for second-line treatment in LBCL?

As summarized in this issue of The ASCO Post, Locke et al tested this question in the multinational phase III ZUMA-7 trial comparing axicabtagene ciloleucel against standard-of-care salvage chemotherapy followed by autologous HSCT.5 The results showed superior outcomes for patients assigned to axicabtagene ciloleucel, with significant improvements in overall (83% vs 50%) and complete (65% vs 32%) response rates, median event-free survival (8.3 months vs 2 months), and median progression-free survival (14.7 months vs 3.7 months). Despite more than half of patients on the standard-of-care arm proceeding to axicabtagene ciloleucel as third-line therapy, median overall survival was not reached with axicabtagene ciloleucel, whereas it was 35.1 months with the standard of care (P = .054). On a sobering note, only one-third of patients on the standard-of-care arm had a sufficient response to proceed to autologous HSCT, with a 24-month event-free survival of just 16%.

Key Takeaways From ZUMA-7

There are several key takeaways from this study. The first notable point is that nearly all patients (94%) on the axicabtagene ciloleucel arm were successfully able to receive the intended treatment, with roughly one-third needing bridging steroids but no cytotoxic therapy. Considering how quickly LBCL can progress at relapse, this is an encouraging and impressive reflection of feasibility.

A second point is that outcomes were equally good for patients with primary refractory disease and those with early relapse. There were also excellent outcomes for high-grade B-cell lymphomas with or without rearrangements of MYC or BCL2 (ie, “double hit” lymphoma). The median follow-up time of more than 24 months is also noteworthy, as most relapses occur early, and there is a real possibility that patients are cured. The axicabtagene ciloleucel arm did have several unique toxicities, including significant cytokine-release syndrome, neurotoxicity syndromes, and prolonged cytopenias in nearly 30% of patients.

So, should all patients now receive CAR T-cell therapy as second-line treatment? It is important to acknowledge that two other recent trials evaluated CAR T-cell therapy in this space. The BELINDA trial randomly assigned patients with refractory and early relapsing LBCL to receive either tisagenlecleucel or the standard of care; the BELINDA investigators did not find a difference in outcome.6 The TRANSFORM trial similarly randomly assigned patients between lisocabtagene maraleucel and the standard of care; although there was superiority for lisocabtagene maraleucel, the follow-up is just 6 months.7 The reasons for differences likely reflect patient selection, challenges with manufacturing times, and varying toxicity profiles.

Words of Caution

There are some caveats to consider when CAR T-cell therapy is moved to the second-line setting. For example, “real-world” patients with multiple comorbidities, older age, financial hurdles, and logistic barriers need more study. Cost and access remain major barriers. And, despite being a major advance, the 24-month event-free survival is 41%, meaning that more than half of patients did not have the desired outcome from treatment. Despite these issues, it is clear the algorithm has indeed changed for many patients with aggressive B-cell lymphomas, and a new framework is finally here. 

Dr. Smith is the Elwood V. Jensen Professor in Medicine, Interim Chief of Hematology/Oncology, and Director of the Lymphoma Program at the University of Chicago Medical Center.

DISCLOSURE: Dr. Smith has served as a consultant or advisor to AbbVie/Genentech, AstraZeneca, Bayer, Bristol Myers Squibb, Celgene, Gilead Sciences, Kite Pharma, Pharmacyclics, Portola Pharmaceuticals, Seattle Genetics, and TG Therapeutics and has received research funding from Acerta Pharma/AstraZeneca, Celgene, and Pharmacyclics/Janssen.


1. Philip T, Guglielmi C, Hagenbeek A, et al: Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin’s lymphoma. N Engl J Med 333:1540-1545, 1995.

2. Gisselbrecht C, Glass B, Mounier N, et al: Salvage regimens with autologous transplantation for relapsed large B-cell lymphoma in the rituximab era. J Clin Oncol 28:4184-4190, 2010.

3. Hamadani M, Hari PN, Zhang Y, et al: Early failure of frontline rituximab-containing chemo-immunotherapy in diffuse large B cell lymphoma does not predict futility of autologous hematopoietic cell transplantation. Biol Blood Marrow Transplant 20:1729-1736, 2014.

4. Roschewski M, Longo DL, Wilson WH: CAR T-cell therapy for large B-cell lymphoma: Who, when, and how? N Engl J Med 386:692-696, 2022.

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

6. Bishop MR, Dickinson M, Purtill D, et al: Second-line tisagenlecleucel or standard care in aggressive B-cell lymphoma. N Engl J Med 386:629-639, 2022.

7. 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 399:2294-2308, 2022.


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