‘TRANSFORMING’ Our Thinking About Second-Line Therapy for High-Risk Large B-Cell Lymphoma: Bring in the CARs

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As reported in The Lancet by Kamdar et al,1 and summarized in this issue of The ASCO Post, the international phase III TRANSFORM trial was completed in 184 patients with primary refractory or early (≤ 12 months) relapsed large B-cell lymphoma (LBCL). Patients were randomly assigned to receive second-line lisocabtagene maraleucel in two sequential infusions of CD8+ and CD4+ chimeric antigen receptor (CAR) T cells at a total target dose of 100 × 106 CAR T cells (n = 92) or standard-of-care treatment (n = 92). The standard of care consisted of investigator’s choice of salvage immunochemotherapy with R-DHAP (rituximab, dexamethasone, cytarabine, and cisplatin); R-ICE (rituximab, ifosfamide, etoposide, and carboplatin); or R-GDP (rituximab, dexamethasone, gemcitabine, and cisplatin). The standard-of-care responders then received high-dose chemotherapy and autologous hematopoietic stem cell transplantation (HSCT).

TRANSFORM Trial: Design, Efficacy, Toxicity

Randomization was stratified by response to first-line therapy (relapsed vs refractory) and secondary age-adjusted International Prognostic Index (0–1 vs 2–3). Patients in the standard-of-care group were allowed to cross over to receive lisocabtagene maraleucel as third-line treatment if complete or partial response was not achieved after three cycles of immunochemotherapy, for progressive disease at any time, or if there was a need to start a new antineoplastic therapy due to absence of complete response after 18 weeks postrandomization. The primary endpoint was event-free survival on independent review committee assessment in the intention-to-treat population.

“New basic science that provides a better understanding of the biology of LBCL will marry the science and clinical care to improve the outcome for patients with B-cell lymphomas.”
— Leo I. Gordon, MD, FACP

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Investigators found that among the patients given lisocabtagene maraleucel, 89 patients received it and 1 received a nonconforming product. In the standard-of-care group; 91 patients started standard-of-care treatment, 43 received high-dose chemotherapy, and 42 actually got as far as autologous HSCT. The overall response rate was 86% vs 48% in favor of lisocabtagene maraleucel, with a complete response in 66% vs 39% (P < .0001).

Grade ≥ 3 adverse events occurred in 92% of the lisocabtagene maraleucel group vs 87% of the standard-of-care group, with the most common with lisocabtagene maraleucel being neutropenia, anemia, thrombocytopenia, and prolonged cytopenia. In the lisocabtagene maraleucel group, grade 3 cytokine-release syndrome occurred in one patient, and grade 3 neurologic toxicity occurred in four patients, with no grade 4 or 5 events reported.

The investigators concluded that this trial established lisocabtagene maraleucel as the preferred second-line treatment for patients with LBCL who either have primary refractory disease or who relapse within 12 months of initial complete response.

T-Cell–Directed Therapy: History, Rationale, Biology

The use of T-cell–directed therapy has been the subject of much basic research and many recent clinical trials over the past several years. We know that first-line chemotherapy is curative in most patients with LBCL, but those with high-risk features and early recurrence or primary refractory disease usually experience disease progression and have limited options for cure. Until now, the standard approach for these patients has been high-dose chemotherapy followed by autologous HSCT, and this approach can be curative in 30% to 40% of patients with recurrent disease. However, the data from SCHOLAR-12 suggest that for patients with early recurrence or primary refractory disease, median overall survival is 6.3 months. Only 20% of patients with these high-risk features are alive at 2 years.

Therefore, to improve outcomes for this group of patients, investigators have relied on basic science observations that led to novel approaches to the treatment of B-cell lymphomas. Observations from the allogeneic transplantation setting suggested that long remissions and cures in B-cell lymphomas are possible and that this is likely a result of a graft-vs-lymphoma immune response, mediated by the T cell of the donor. Unfortunately, this therapy is limited by complications of graft-vs-host disease, especially in older patients. However, the T-cell biology around allogeneic HSCT is still relevant; based on the work of Zelig Eshhar in Israel in 1989,3 Carl June,4 Phil Greenberg,5 and others in the United States, the first chimeric T-cell receptor genes were created. The technology has been modified in stepwise fashion, and the first CAR T-cell therapy was approved by the U.S. Food and Drug Administration (FDA) in 2017 for the treatment of B-cell leukemias and lymphomas.6 Subsequent trials established CAR T-cell therapy as a preferred third-line treatment in diffuse LBCL.7-9

What About Second-Line Treatment?

Because patients with recurrence within 12 months of remission or who never achieve first remission have a very poor outcome,2 investigators began to address the issue of second-line treatment. They compared the standard-of-care autologous HSCT with CAR T-cell therapy, and two other trials were reported just before TRANSFORM was published. In ZUMA-7,10 an event-free survival benefit was observed with second-line CAR T-cell therapy with axicabtagene ciloleucel; event-free survial was 8.3 vs 2 months, and the complete response rate was higher with axicabtagene ciloleucel vs autologous HSCT (65% vs 32%). However, in the BELINDA trial of tisagenlecleucel,11 the two groups had similar response rates and an event-free survival of 3 months.

Differences in trial design may account for some of the variability between BELINDA and the other two trials. Of note, in ZUMA-7, bridging with chemotherapy was not allowed, and patients with impending organ-compromising disease were ineligible. In BELINDA, bridging chemotherapy was allowed, and impending organ-compromising disease was not an exclusion criterion. The differing results between these trials suggest that the presence of bulky or rapidly progressing disease may be a barrier to successful outcomes of CAR T-cell therapy and may have biased the ZUMA-7 trial to more favorable patients. The longer manufacturing time for tisagenlecleucel than for axicabtagene ciloleucel should also be noted, as it may have resulted in fewer patients receiving their CAR T-cell infusion in BELINDA.

In TRANSFORM, the data were similar to those published in ZUMA-7, even though bridging therapy was allowed in the TRANSFORM trial. Thus, selection bias is less of an issue in TRANSFORM. Despite the short follow-up (6.2 months) on this trial, the data in TRANSFORM as well as in ZUMA-7 showing an improved event-free survival as well as a higher complete response rate strongly suggest it should be the new standard in patients at high risk, defined as recurrence within 12 months or with primary refractory disease.

It is also important to remember that the standard of care up until the time these studies were completed was not just high-dose chemotherapy followed by HSCT, but rather an interim second-line treatment (often R-ICE, R-DHAP, or R-GDP), then high-dose therapy and HSCT. Patients are required to demonstrate sensitivity to chemotherapy before proceeding to transplantation. We know from the CORAL study12 that only a fraction of patients achieved enough of a response to proceed to transplantation. In ZUMA-7, only about 30% of patients had enough of a response to get to transplantation, whereas in TRANSFORM, that number was 50%. More recent data suggest that CAR T-cell therapy offers hope for patients who might not be high risk, as defined in ZUMA-7 or TRANSFORM, but who have relapsed disease and cannot proceed to high-dose chemotherapy and autologous hematopoietic cell rescue because of age, compromised renal or cardiac function, or other comorbidities.

In the PILOT study,13 Sehgal and colleagues reported on 74 patients who were not candidates for transplantation because of significant comorbidities but had relapsed LBCL and were treated with CAR T-cell therapy. There were 61 patients treated with lisocabtagene maraleucel and with a median follow-up of 12 months; 80% responded, 54% had a complete response, and median event-free survival was 10 months in this very high-risk, older population. This led to the recent FDA approval of lisocabtagene maraleucel for this group of patients.

What’s Next?

There are many questions that remain unanswered in the treatment of recurrent or refractory LBCL. There are novel CAR T-cell constructs, including dual-targeted CARs,14,15 novel CD22-targeted CARs,16 and third-generation CARs17 that may alter the tumor microenvironment to enhance CAR T-cell therapy efficacy and modulate toxicity.18,19 Allogeneic off-the-shelf CARs20 may provide a new dimension by shortening manufacturing times, which bedeviled the BELINDA study. In addition, there are now studies published21 or planned that look at CAR T-cell therapy in the first-line setting in very high-risk groups. As this field evolves, new basic science that provides a better understanding of the biology of LBCL will marry the science and clinical care to improve the outcome for patients with B-cell lymphomas. 

Dr. Gordon is the Abby and John Friend Professor of Cancer Research and Medical Director of the John and Lillian Mathews Cellular Therapy Laboratory at the Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago.

DISCLOSURE: Dr. Gordon has served as a consultant or advisor to Bayer, Gilead Sciences, Ono Pharmaceuticals, and Juno Therapeutics and holds intellectual property in Zylem Biosciences.


1. 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.

2. Crump M, Neelapu SS, Farooq U, et al: Outcomes in refractory diffuse large B-cell lymphoma: Results from the international SCHOLAR-1 study. Blood 130:1800-1808, 2017.

3. Gross G, Waks T, Eshhar Z: Expression of immunoglobulin-T-cell receptor chimeric molecules as functional receptors with antibody-type specificity. Proc Natl Acad Sci U S A 86:10024-10028, 1989.

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5. Stromnes IM, Schmitt TM, Chapuis AG, et al: Re-adapting T cells for cancer therapy: From mouse models to clinical trials. Immunol Rev 257:145-164, 2014.

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

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10. 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.

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14. Shah NN, Johnson BD, Schneider D, et al: Bispecific anti-CD20, anti-CD19 CAR T cells for relapsed B cell malignancies: A phase 1 dose escalation and expansion trial. Nat Med 26:1569-1575, 2020.

15. Spiegel JY, Patel S, Muffly L, et al: CAR T cells with dual targeting of CD19 and CD22 in adult patients with recurrent or refractory B cell malignancies: A phase 1 trial. Nat Med 27:1419-1431, 2021.

16. Baird JH, Frank MJ, Craig J, et al: CD22-directed CAR T-cell therapy induces complete remissions in CD19-directed CAR-refractory large B-cell lymphoma. Blood 137:2321-2325, 2021.

17. Enblad G, Karlsson H, Gammelgård G, et al: A phase I/IIa trial using CD19-targeted third-generation CAR T cells for lymphoma and leukemia. Clin Cancer Res 24:6185-6194, 2018.

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20. Depil S, Duchateau P, Grupp SA, et al: ‘Off-the-shelf’ allogeneic CAR T cells: Development and challenges. Nat Rev Drug Discov 19:185-199, 2020.

21. Neelapu SS, Dickinson M, Munoz J, et al: Axicabtagene ciloleucel as first-line therapy in high-risk large B-cell lymphoma: The phase 2 ZUMA-12 trial. Nat Med 28:735-742, 2022.