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Unresolved questions in the second-line use of CAR-T cells for diffuse large B cell lymphoma

Nature Medicine volume 28, pages 2458–2459 (2022)Cite this article

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Following the positive results of the ZUMA-7 and TRANSFORM trials1,2, and the US Food and Drug Administration (FDA) approvals of axicabtagene ciloleucel and lisocabtagene maraleucel as second-line therapies for diffuse large B cell lymphoma (DLBCL), CD19-directed chimeric antigen receptor (CAR) T cell therapy is likely to become the standard of care for patients with primary-refractory or early-relapsed DLBCL in which initial remission lasted <12 months. Both axicabtagene ciloleucel and, based on interim results, lisocabtagene maraleucel showed improved event-free survival compared with salvage chemoimmunotherapy followed by autologous stem-cell transplant (ASCT). As yet, no overall survival benefit has emerged, although it may over time. These trials herald a paradigm shift for patients with high-risk relapsed or refractory DLBCL, who are in need of improved therapies. However, they raise important unanswered questions about the role of bridging therapy; the optimal treatment of patients with chemotherapy-sensitive disease; and the substantial costs of CAR-T therapy.

Given the aggressive nature of DLBCL and the logistical challenges of CAR-T therapy, many patients receive bridging chemotherapy, the role of which is both complex and controversial. CAR-T may be delayed for many reasons, including the need for CAR-T center referral, payor approval, pre-CAR-T workup, T cell collection and manufacturing, and constraints on manufacturing capacity. In real-world studies of axicabtagene ciloleucel, bridging therapy was common, received by 45%–53% of US patients3 and 78% of German patients4. Similar rates of bridging therapy (63%) were observed in the TRANSFORM trial2, whereas bridging was not permitted in ZUMA-71. The trial investigators achieved a rapid product turnaround of a median of 29 days from randomization to CAR-T infusion in ZUMA-7 and 34 days in TRANSFORM. ZUMA-7 showed the feasibility of second-line CAR-T therapy without bridging therapy, and demonstrated that CAR-T was solely responsible for the benefit seen. But disallowing bridging therapy in ZUMA-7 may have introduced selection bias, limiting enrolment of patients who were felt to be unable to tolerate the anticipated delay until CAR-T therapy could be administered.

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Author notes

  1. These authors contributed equally: Edward R. Scheffer Cliff, Reid W. Merryman.

Authors and Affiliations

  1. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

    Edward R. Scheffer Cliff, Reid W. Merryman, Philippe Armand & Caron A. Jacobson

  2. Program on Regulation, Therapeutics and Law, Brigham and Women’s Hospital, Boston, MA, USA

    Edward R. Scheffer Cliff

  3. Harvard Medical School, Boston, MA, USA

    Edward R. Scheffer Cliff, Reid W. Merryman, Philippe Armand & Caron A. Jacobson

Authors
  1. Edward R. Scheffer Cliff
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  2. Reid W. Merryman
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  3. Philippe Armand
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  4. Caron A. Jacobson
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Correspondence to Edward R. Scheffer Cliff.

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Competing interests

R.W.M has served as a consultant for Genmab/AbbVie, Adaptive Biotechnologies, Bristol-Myers Squibb, Intellia and Epizyme and received research funding (institutional) from Merck, Bristol-Myers Squibb, Genentech/Roche and Genmab. P.A. has served as a consultant for Merck, Bristol-Myers Squibb, Pfizer, Affimed, Adaptive, Infinity, ADC Therapeutics, Celgene and MorphoSys; received research funding (institutional) from Merck, Bristol-Myers Squibb, Affimed, Adaptive, Roche, Tensha, Otsuka, Sigma-Tau, Genentech and IGM; and received honoraria from Bristol-Myers Squibb and Merck. C.A.J. has served as a consultant for Kite, Novartis, Pfizer, Humanigen, Precision Bioscience, Bayer and Celgene and has received research funding from Pfizer and Kite.

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Cliff, E.R.S., Merryman, R.W., Armand, P. et al. Unresolved questions in the second-line use of CAR-T cells for diffuse large B cell lymphoma. Nat Med 28, 2458–2459 (2022). https://doi.org/10.1038/s41591-022-02067-9

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