Navigating the narrow bridge to CAR T-cell therapy

Abstract

When the pivotal phase 2 ZUMA-1 trial was first published in the New England Journal of Medicine in 2017, chimeric antigen receptor (CAR) T-cell therapy was widely regarded as a major breakthrough for patients with refractory diffuse large B-cell lymphoma. These patients, who historically would have had dismal outcomes, had an objective response rate of 82% and an 18-month overall survival of 52%. 1 The results of ZUMA-1 were subsequently bolstered by the JULIET study, in which patients had an equally impressive 12-month relapse-free survival of 65%. 2 Of course, the patients on the ZUMA-1 and JULIET trials were carefully selected, as is the case in most clinical trials, and likely consisted of a less-sick cohort. In particular, the ZUMA-1 trial notably did not allow for any bridging therapy. In reality, patients who are candidates for CAR T-cell therapy often have progressive symptomatic disease that requires some form of treatment to support them during the period between leukapheresis and CAR T-cell infusion.

Use of cardiac radiation therapy as bridging therapy to CAR‐T for relapsed pediatric B‐cell acute lymphoblastic leukemia

“…Finally, in a phase 2 DLBCL study, BRT patients had higher overall response rate, less severe CRS, and less neurotoxicity compared to chemotherapy‐bridged patients 19 . These results and others suggest that priming with RT may be more effective than chemotherapy 20,21 . Our case differed from those reported in the above series in that our patient was in a clinically precarious situation, and the RT dose given (12 Gy) was selected to produce a local response as a bridge to CAR‐T, but also with the goal of avoiding significant late cardiac toxicity that may have occurred with a more definitive RT dose of 24‐30 Gy.…”

“…19 These results and others suggest that priming with RT may be more effective than chemotherapy. 20,21 Our case differed from those reported in the above series in that our patient was in a clinically precarious situation, and the RT dose given (12 Gy) was selected to produce a local response as a bridge to CAR-T, but also with the goal of avoiding significant late cardiac toxicity that may have occurred with a more definitive RT dose of 24-30 Gy. An earlier report showed that there may be a disease control advantage to irradiating all sites of disease prior to CAR-T as compared to only a subset of sites, though it remains unclear whether the potential toxicity of doing so could outweigh this benefit.…”

“…Our case differed from those reported in the above series in that our patient was in a clinically precarious situation, and the RT dose given (12 Gy) was selected to produce a local response as a bridge to CAR‐T, but also with the goal of avoiding significant late cardiac toxicity that may have occurred with a more definitive RT dose of 24‐30 Gy. An earlier report showed that there may be a disease control advantage to irradiating all sites of disease prior to CAR‐T as compared to only a subset of sites, though it remains unclear whether the potential toxicity of doing so could outweigh this benefit 20,21 . Our patient had widespread extramedullary disease also involving the kidneys, perineum, gluteal, and paraspinal tissues, and thus it would not have been feasible to treat all sites of disease; we therefore only treated those areas that were causing a significant local issue to improve symptoms and reduce the risk of adverse events after CAR‐T infusion, relying on CAR‐T to provide ultimate control of leukemia in unirradiated sites.…”

“…An earlier report showed that there may be a disease control advantage to irradiating all sites of disease prior to CAR-T as compared to only a subset of sites, though it remains unclear whether the potential toxicity of doing so could outweigh this benefit. 20,21 Our patient had widespread extramedullary disease also involving the kidneys, perineum, gluteal, and paraspinal tissues, and thus it would not have been feasible to treat all sites of disease; we therefore only treated those areas that were causing a significant local issue to improve symptoms and reduce the risk of adverse events after CAR-T infusion, relying on CAR-T to provide ultimate control of leukemia in unirradiated sites. Of note, our patient also received salvage RT to the posterior fossa after relapse and tolerated it well with an ongoing complete response, similar to a previous report of durable remissions in R/R lymphoma patients treated with RT after CAR-T. 22 With increasing use of targeted therapies in B-ALL, extramedullary relapses are becoming more common.…”

Preliminary Report of Academic CAR-T (ISIKOK-19) Cell Clinical Trial in Turkey: Characterization of Product and Outcomes of Clinical Application

“…There is a wide spectrum of bridging therapy options in the literature. 31 Radiotherapy as a bridging treatment in CAR T-cell therapy is being researched 32 and one such patient with DLBL had a partial response and no adverse events due to radiotherapy were observed in the two patients in this study.…”