Blinatumomab Nonresponse Is Associated with Poor CD19-CAR Outcome in B-ALL

Although CD19-directed chimeric antigen receptor T cells (CD19-CAR) and blinatumomab, a CD3-CD19 bispecific T-cell engager antibody, are both effective in inducing remission of B-cell acute lymphoblastic leukemia (B-ALL), how blinatumomab affects subsequent CD19-CAR outcomes is unknown. A critical concern is that the sequential targeting of CD19 by both treatments could increase the risk of antigen escape. To address this, Myers and colleagues conducted a retrospective multicenter study of 420 children and young adults who received CD19-CAR for relapsed or refractory B-ALL. Relapse-free survival (RFS) and event-free survival (EFS) were evaluated 6 months after CD19-CAR treatment, inclusive of patients who had and had not previously received blinatumomab. Complete remission (CR) rates, RFS, EFS, and overall survival (OS) were comparable in blinatumomab-naïve and blinatumomab-exposed patients who responded to blinatumomab, suggesting that blinatumomab does not directly preclude CD19-CAR response. However, RFS, EFS, and OS were reduced as was the CR rate in blinatumomab-exposed nonresponders or those who did not achieve CR, supporting that these blinatumomab-exposed nonresponding patients likely were a high-risk population inherently resistant to CD19-CAR. In addition, partial or complete loss of CD19 was more common in blinatumomab-exposed than blinatumomab-naïve patients, but for patients who had normal CD19 expression pre-CAR, antigen escape was comparable for both blinatumomab-naïve and exposed patients. Furthermore, high disease burden amplified poor outcomes of blinatumomab-exposed nonresponders. Overall, this indicates that, while blinatumomab may lead to CD19 downregulation, there is likely an inherent risk factor other than CD19 escape responsible for the poor outcomes of blinatumomab-exposed, post–CD19-CAR patients. In summary, this study highlights blinatumomab-exposed nonresponse and high disease burden as risk factors for resistance to CD19-CAR and suggests further investigation into mechanisms of blinatumomab nonresponse and its impact on CD19-CAR response as well as serial CD19 expression monitoring pre- and post-blinatumomab to increase the understanding of its impact on future single or sequential antigen-targeted therapy.

Myers RM, Taraseviciute A, Steinberg SM, Lamble AJ, Sheppard J, Yates B, et al. Blinatumomab nonresponse and high-disease burden are associated with inferior outcomes after CD19-CAR for B-ALL. J Clin Oncol 2021 Nov 12 [Epub ahead of print].

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