Abstract
Introduction CD19-directed chimeric antigen receptor T-cell therapy (CAR T) has significantly improved outcomes in relapsed/refractory (R/R) B-ALL. In registrational and real-world studies, patients (pts) with low disease burden had better outcomes and lesser CAR T related toxicity. We hypothesize that the administration of brexucel as consolidation therapy in frontline (FL) high-risk (HR) B-ALL or R/R B-ALL after cytoreduction could be more tolerable and lead to better outcomes and might eventually replace allogeneic stem cell transplantation (ASCT).
Methods We conducted a phase 2 clinical trial (NCT06287229) that included pts (³18 years) with FL HR B-ALL, defined by adverse genomics (KMT2A rearrangement [r], complex karyotype [CK] as per NCCN 2022, low hypoploidy/tetraploidy, CRLF2r, TP53 mutation) or persistent/recurrent MRD [MRD+ve] by flow cytometry [FCM] and/or next generation sequencing [NGS] at a LOD of at least 1 in 10-6; or R/R B-ALL. Pts with FL disease received 1-2 cycles of HCVAD or Mini-HCVD-inotuzumab (InO)-blinatumomab (blina) followed by leukapheresis and be in morphological remission. Leukapheresis could be followed by further chemo-immunotherapy and then standard lymphodepletion (LD) with fludarabine-cyclophosphamide before brexucel infusion. Pts in R/R cohort were to receive Mini-HCVD-ino-blina followed by leukapheresis and LD with/without further intervening chemoimmunotherapy. Pts in FL-MRD+ve cohort could proceed directly to leukapheresis. Primary objective was efficacy evaluated as event free survival (EFS). EFS endpoints included morphological relapse and death. Secondary objectives included overall survival (OS), rate of persistent MRD negativity (-ve) by FCM and NGS, and safety.
Results: From Dec 2024-July 31 2025, 28 pts have had leukapheresis,18 pts were infused and 14 pts with a follow-up (FU) >1 month post brexucel infusion were included in this report. The median age of the infused pts was 35 years (range 19-77), and 5 pts (36%) were ³60 years of age. Ten pts (71%) received brexcuel as FL consolidation therapy for adverse genomics, 3 FL pts (21%) had persistent (n=2)/recurrent (n=1) MRD, and 1 (7%) pt had R/R ALL. Among the 10 pts with FL adverse genomics, 5 pts had CRLF2r, 2 pts had CK, and 1 pt each had KMT2Ar, TP53 mutation and hypoploidy. The median time to brexucel from initial B-ALL diagnosis was 7.3 months (mos) (range 2.1-41.2). All pts had received prior blina (100%) and 13 pts (93%) had received prior InO. The median time from last blina to LD for brexucel was 22 days (range 9-58 days) and from InO was 38 days (range 9-1000).
At LD all pts (100%) were in morphological complete remission (CR), and 13 (93%) were MRD-ve by NGS (10/10 FL-adverse genomics; 2/3 FL-MRD+ve; 1/1 R-R). The maximum CAR T expansion was 14 cells/ul (range, 0-69) at a median of 8 days (range, 7-14) from infusion and 6 pts (43%) had ³20 cells/ul CAR T expansion. With a median FU up of 113 days from brexucel infusion (95% CI 65-170), 1 pt (FL- hypoploidy-TP53]) who proceeded to brexucel after 2 cycles of Mini-HCVD-InO-blina had a morphological relapse 145 days after CAR T infusion. Another FL-MRD+ve pt underwent ASCT 52 days post-brexucel and died in CR 60 days after ASCT from related complications. The median EFS was NR with a 4-month EFS rate of 88%. The 4-month OS and continuous NGS-MRD-ve rates were 88%. All 3 pts who received brexucel for FL-MRD+ve remained in NGS-MRD-ve CR at data cutoff; the only pt who had NGS-MRD+ve at LD initiation became MRD-ve post brexucel (167 to 0 cells/million) and maintains NGS-MRD-ve CR at 70 days follow-up. One FL-KMT2Ar pt who had an NGS-MRD relapse 140 days after brexucel underwent ASCT. Adverse events included cytokine release syndrome (CRS) in 8 (57%) pts (all grade 1); 3 pts needed single dose tocilizumab. The median duration of CRS was 1.5 days (range, 1-5). No pt had immune effector cell associated neurotoxicity (ICANS). No infectious complications were encountered. Among pts who encountered CRS, the median CAR T expansion was 21 cells/ul (range,6-30), compared to 5 cells (range, 0-69) in pts without a CRS, p=0.007. At the last FU, 11/14 pts are in NGS MRD-ve CR, 1 pt each had an NGS-MRD and morphological relapse and 1 pt died in CR from post-ASCT complication.
Conclusion he early prospective results of brexucel as consolidative therapy showed good tolerability with very limited CAR T specific toxicities and promising efficacy. The study continues to accrue pts.
