Impact of Prior Response to Blinatumomab on Outcomes of Brexucabtagene Autoleucel (Brexu-cel) in Adult Patients with Relapsed or Refractory (r/r) B-Cell Acute Lymphoblastic Leukemia (B-ALL): Results from the Real-World Outcomes Collaborative of CAR-T in Adult ALL (ROCCA)
Authors: Gupta Vishal K , Roloff Gregory W , Muffly Lori S. , Aldoss Ibrahim , Kopmar Noam E. , Lin Chenyu , Dekker Simone E. , Jeyakumar Nikeshan , O'Connor Timothy E , Zhang Amy , Miller Katharine , Dykes Kaitlyn C , Ahmed Mohamed , Bradshaw Danielle , Mercadal Santiago , Schwartz Marc , Tracy Sean , Dholaria Bhagirathbhai , Kubiak Michal , Mukherjee Akash , Majhail Navneet , Battiwalla Minoo , Mountjoy Luke , Malik Shabaz , Mathews John , Shaughnessy Paul , Logan Aaron C. , Ladha Abdullah , Yaghmour George , Advani Anjali S. , Stefan Maryann , Guzowski Caitlin , Hoeg Rasmus T. , Hilal Talal , Moore Jozal , O'Dwyer Kristen M. , Tsai Stephanie B. , Sasine Joshua , Lee Catherine J. , Kota Vamsi K. , Koura Divya , Veeraputhiran Muthu , Blunk Betsy , Leonard Jessica T. , Stock Wendy , Galal Ahmed , Pullarkat Vinod , Cassaday Ryan D , Shah Bijal D. , Faramand Rawan , Oliai Caspian H. 
Published: December 2023

Introduction: Brexucabtagene autoleucel (brexu-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for adults with relapsed or refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL). Blinatumomab is a CD19-directed bispecific T-cell engager that is also approved for r/r B-ALL, and often used as early salvage therapy. Data in the pediatric/AYA population suggest that patients who did not respond to blinatumomab may have inferior outcomes to CD19-directed CAR-T products compared to those who have achieved a response to blinatumomab or were blinatumomab-naïve (Myers et al. J Clin Oncol 2022). In this study, we evaluate the response to blinatumomab and subsequent response to brexu-cel in adults with r/r B-ALL.

Methods: Retrospective data were collected from 25 centers across the U.S. as part of the real-world outcomes collaborative study of CAR-T in B-ALL (ROCCA). Consecutive patients treated with brexu-cel from 2021 to 2023 were categorized by blinatumomab exposure status. Those exposed were separated into “blinatumomab responders” (B-R), defined as patients achieving a CR/CRi in response to any number of cycles of blinatumomab, and “non-responders” (B-NR). Each cohort was compared for outcomes of interest. The primary outcome was CR/CRi rate at day 28 following brexu-cel administration. Secondary outcomes were duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Survival outcomes were calculated from day of brexu-cel infusion and were not censored for allogeneic hematopoietic cell transplantation or maintenance therapy. All living patients were censored at data cutoff on June 30, 2023. Survival comparisons were made by log rank test.

Results: Among 152 patients who received brexu-cel, the median follow-up time was 8.4 months. Eighty-eight (57%) of 152 r/r B-ALL brexu-cel recipients had received blinatumomab prior to apheresis. The median number of pre-apheresis blinatumomab cycles was 2 (range 1-12). The baseline characteristics of B-R, B-NR, and blinatumomab-naïve (B-NV) patients were similar, including pre-apheresis disease burden and receipt of maintenance therapy following brexu-cel infusion (Table 1). Seventy percent (N= 62) of the blinatumomab-exposed patients were B-R, while 30% (N=26) were B-NR. Rates of CR/CRi at day 28 following brexu-cel infusion were similar between B-R, B-NR, and B-NV patients (79% vs 84% vs 78%, respectively). Most of these remissions were negative for measurable residual disease (MRD), with similar MRD negativity rates in the three groups (table 2). 1-year DOR and PFS were significantly higher in the B-NV group compared to B-R or B-NR (77% vs 49% vs 50%, p&lt;.0001; 60% vs 37% vs 30%, p&lt;.0001). B-NV and B-R had better 1-year survival compared to B-NR (71% vs 65% vs 32%, p&lt;.0001). There were more CD19-negative relapses following brexu-cel in B-NR (29%) and B-R (18%) compared to B-NV patients (8%), although this was not statistically significant.

Conclusions: Brexu-cel induced deep responses in a majority of adults with r/r B-ALL, irrespective of prior exposure or response to blinatumomab. Similar to data published by the pediatric CAR-T cell groups, our data draw speculation that adult patients who did not respond to blinatumomab experience shorter overall survival following brexu-cel compared to those who responded to or did not receive blinatumomab. This should be confirmed in a larger, prospective clinical trial. Because this analysis could not account for patients who achieved durable remission after blinatumomab, these differences may not reflect superiority of sequencing brexu-cel before blinatumomab. The higher number of CD19-negative relapses in the blinatumomab-exposed cohort add to the interest in pursuing strategies to address antigen escape following CAR-T cell therapy directed against a previously targeted antigen.