Chimeric antigen receptor (CAR) T-cell therapy has changed the treatment paradigm for B-cell malignancies. Developing strategies to identify patients at risk of inferior outcomes with CAR T-cell therapy continues to be a major focus of international research efforts, given that robust response rates are coupled with unique toxicities and access challenges with this type of treatment.1-3 It is well established that T-cell fitness is an integral component of CAR T-cell expansion and robust anti-tumor response.4,5 Researchers are now seeking to understand the clinical impact of prior cytotoxic chemotherapies, including alkylating agents, on T-cell fitness and CAR T-cell outcomes.
Bendamustine is often used to treat lymphoma, due to the perception of improved tolerability and efficacy, with varying frequency across lymphoma subtypes. Concerns have been raised about the potential prolonged negative impact on lymphocytes with bendamustine exposure, and its impact on subsequent T-cell–directed therapy.
Recently, Gloria Iacoboni, MD, PhD, and colleagues investigated the impact of bendamustine exposure prior to apheresis in patients with relapsed/refractory large B-cell lymphoma (LBCL) who were undergoing autologous anti-CD19 CAR T-cell therapy.6 In this retrospective, multicenter analysis, from seven European sites, the investigators evaluated safety, efficacy, and CAR T-cell kinetics in patients receiving third-line or later axicabtagene ciloleucel or tisagenlecleucel. The study comprised 439 patients, 80 of whom were bendamustine-exposed and 359 of whom were bendamustine-naïve. Baseline characteristics between the two groups were significantly different. Although the International Prognostic Index scores and lactate dehydrogenase values were comparable, the bendamustine-exposed group was older, had worse performance status, had received more lines of prior therapy, and had a greater frequency of transformed indolent histology. Baseline laboratory data prior to apheresis revealed patients exposed to bendamustine had a lower median absolute lymphocyte count, platelet levels, and CD3+ and CD3+CD4+ cell counts. Given these differences, it is important to note that the authors additionally performed inverse probability of treatment weighting (IPTW) and 1:1 propensity score matching (PSM).
Bendamustine-exposed patients had lower objective response rates compared with bendamustine-naïve patients (53% vs. 72%; p<0.01), as well as lower complete response rates (39% vs. 52%; p<0.04). With a median follow-up of 20.6 months, researchers also observed inferior median progression-free survival (3.1 vs. 6.2 months; p=0.04) and overall survival (10.3 vs. 23.5 months; p=0.01) among bendamustine-exposed patients. For both efficacy and survival analyses, IPTW adjustment continued to reveal inferior efficacy and survival outcomes in bendamustine-exposed patients; however, the statistical significance threshold was not reached. Each patient group experienced a similar rate of cytokine release syndrome and immune effector cell–associated neurotoxicity syndrome, although bendamustine-exposed patients had greater rates of hematologic toxicity and severe infections.
CAR T-cell expansion and the timing of bendamustine exposure were also analyzed. Notably, researchers observed lower rates of median peak expansion and area under the curve (AUC0-28) in patients exposed to bendamustine compared to bendamustine-naïve patients; however, these findings did not reach statistical significance. Regarding the timing of bendamustine exposure, patients receiving bendamustine less than nine months before apheresis had reduced efficacy and survival outcomes. These findings were significant in both the IPTW and PSM analyses. Thus, the authors pointed toward nine months as an optimal washout period following bendamustine for patients planned for apheresis.
In Brief
Prior bendamustine exposure may have a potentially negative impact on outcomes in patients receiving autologous anti–CD19-directed CAR T-cell therapy for LBCL. Exposure to bendamustine, especially within nine months of apheresis, was associated with reduced CAR T-cell efficacy and shorter survival. Although retrospective, this study certainly brings into question whether bendamustine should be used in earlier lines of therapy for LBCL. The findings also may prompt practices to decide against the use of bendamustine for patients with LBCL who potentially could be considered for CAR T-cell therapy. This research raises additional questions, such as whether similar findings would be observed in other lymphoma subtypes or with other T-cell–engaging therapies, such as bispecific antibodies.
Competing Interests
Dr. Chohan indicated no relevant conflicts of interest. Dr. Nastoupil has received research funding and honorarium from Bristol Myers Squibb, Kite/Gilead, and Novartis.
