Although modern therapeutic approaches for adults with B-cell acute lymphoblastic leukemia (B-ALL) achieve high rates of first complete remission, relapse remains a common and devastating experience for affected patients. Bispecific and antibody-drug conjugates are critically important salvage options for relapsed disease; however, responses are not particularly durable. Prior to late 2024, two CD19-directed chimeric antigen receptor T-cell (CAR-T) therapies were commercially available in the U.S. for relapsed/refractory (R/R) B-ALL. Tisagenlecleucel (tisa-cel) was approved for patients aged 25 and below in second or later relapse,1 while brexucabtagene autoleucel (brexu-cel) was approved for patients aged 18 and older with R/R B-ALL, including those in first relapse. The approval of brexu-cel on October 1, 2021, came on the heels of the ZUMA-3 trial results, which reported a 71% remission rate among 55 infused patients.2 Rates of grade 3 to 4 cytokine release syndrome (CRS) and grade 3 to 4 immune effector cell-associated neurotoxicity syndrome (ICANS) were high at 24% and 25%, respectively, a finding that was replicated in analyses of real-world ALL patients treated with this therapy.3 Importantly, durable remissions occurred in 48% at one year, an encouraging outcome that reinforced enthusiasm for CAR-T therapies in R/R B-ALL.
On November 8, 2024, based on results of the phase Ib/II FELIX trial (described below), the U.S. Food and Drug Administration approved a third CD19-directed autologous CAR-T therapy, obecabtagene autoleucel (obe-cel), which now joins the therapeutic toolbox for adults with R/R B-ALL. Like tisa-cel, obe-cel incorporates a 4-1BB costimulatory domain. In contrast, brexu-cel uses a CD28 costimulatory domain, which accounts for differing expansion kinetics. Obe-cel contains a proprietary “fast-off” binding domain that is intentionally designed to have lower affinity for CD19. It has been postulated that this design will improve CAR-T persistence in vivo and enable a favorable toxicity profile.4,5
In Brief
The FELIX trial began in June 2020, conducted at 34 sites across the U.K., U.S., and Spain. The trial’s pivotal phase IIA cohort included patients with R/R morphologic (>5% marrow lymphoblasts) B-ALL; additional cohorts included patients with limited measurable residual disease or extramedullary disease. Obe-cel was infused as a split dose (day 1 and day 10) after fludarabine-cyclophosphamide lymphodepletion (LD), with dosing strategy determined by pre-LD bone marrow disease burden. Of 153 patients enrolled in the phase Ib/II trial, 127 (83%) were infused (94 in cohort 2A), with median vein-to-vein time of 21 days. The overall remission rate was 78% (77% in cohort 2A). With a median follow-up of 21.5 months, the estimated six- and 12-month event-free survival (EFS) rates among all infused patients were 65.4% and 49.5%, respectively. Both EFS and overall survival correlated with bone marrow disease burden prior to LD; patients with less than 5% blasts pre-LD (typically achieved with successful bridging therapy) had superior outcomes. Notably, high-grade toxicity was infrequent, with grade 3 to 4 CRS or grade 3 to 4 ICANS occurring in 2.4% and 7.1%, respectively.
The data published by Claire Roddie, MD, PhD, and colleagues on behalf of the FELIX investigators are exciting. If these early results hold, we can anticipate that obe-cel may lead to durable remissions in most patients, especially when administered in a low disease-burden state. Few patients in the FELIX trial received allogeneic hematopoietic cell transplantation (HCT) after obe-cel. Thus, the paradigm of consolidating CAR responses with HCT in adult B-ALL may shift towards CAR T cells as a standalone, definitive therapy in HCT-naive patients. With an array of commercially available, highly effective options, how should we choose? Building on the approaches outlined in lymphoma,6 ALL clinicians will now have an opportunity to establish personalized selection of CAR-T therapies to fit patient-, disease-, and therapy-related features.
Disclosure Statement
Drs. Roloff and Muffly have both provided advisory support for Autolus, the manufacturer of obe-cel.
