Consolidative Allogenic Hematopoietic Cell Transplantation Vs. Watch and Wait Strategy for B-Cell Acute Lymphoblastic Leukemia Patients with Early Loss of B-Cell Aplasia after Chimeric Antigen Receptor T-Cell Therapy
Authors: Camarillas Sergi , Alonso-Saladrigues Anna , Molinos Quintana Agueda , Navarro Víctor , Herrero-Velasco Blanca , Sánchez-Salinas Mario , González-Martínez Berta , Martin Lopez Ana Africa , Torrent Anna , Marsal Julia , Reguera Juan Luis , Iacoboni Gloria , Pérez-Martínez Antonio , Rives Susana , Barba Pere 
Published: December 2024

Introduction. Chimeric antigen receptor (CAR) T-cells provide a high remission rate in patients with relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL). However, relapses still occur in the majority of patients. Early loss of B cell aplasia (BCA) is a widely described risk factor for disease recurrence. The common practice is performing consolidative allogenic hematopoietic cell transplantation (allo-HCT) in patients with early loss of BCA, despite data comparing HCT versus other strategies in this setting is lacking. Our aim was to compare consolidative allo-HCT vs. a watch and wait (W&W) strategy in B-ALL patients with an early loss of BCA after CAR-T therapy.

Methods. We conducted a registry-based, retrospective, multicenter study in patients with R/R B-ALL treated with commercially available tisagenlecleucel from February 2019 to April 2023. Additional inclusion criteria included achieving complete response with (CR) or without hematological recovery after CAR T-cell therapy and loss of BCA during within the first 12 months after infusion. Patients receiving any maintenance therapy after BCA were excluded from the analysis. The primary objective was to compare the outcome of patients who underwent HCT with those managed with closing monitoring (W&W). Relapse-free survival (RFS) and overall Survival (OS) were calculated from the time of CAR-T infusion and were analyzed using Kaplan Meier method and Cox model.

Results. During the study period, 101 patients underwent lymphoapheresis and 95 patients received a CAR-T infusion. Of them, 80 patients (84.2%) achieved CR. During the follow up, 28 patients lost BCA within the first year after CAR T-cell infusion while in remission and constitute the study population. Of them, 10 patients (36%) received a consolidative allo-HCT while 18 patients were followed without subsequent treatment. Global median follow up time was 24.3 months (CI 95% 11.3-30.7).

In terms of baseline characteristics, median age at infusion was 14.5 years [IQR 7-22] and 68% were male. High-risk genetic disease represented 46% of cases and median number of prior lines was 2 [range 1-4]. Bridging therapy was administered in 24 (86%) patients. Baseline characteristics were balanced between the W&W and the allo-group except for a higher use of previous HCT (83% vs 20%; p=0.003) in the former. The median time to BCA loss was comparable between groups (median of 3 months [range 1-12]).

In the allo-HCT group, the most frequent donor type was matched related donor (n=9) and most of the patients received myeloablative conditioning. Seventy percent presented acute (median maximum grade 2 [range 1-3]) and 20% chronic (median maximum grade 2) graft versus host disease.

Focusing on efficacy endpoints, cumulative incidence of ALL relapse was 41% in the whole series, being higher in the W&W group compared with the allo-HCT group (59% vs 10%, p=0.08). Median time to relapse in the W&W group was 7.6 months (95% CI 3.1, 22.4) while in the allo-group was 19.44 (95% CI 5.1, 33.8). Median RFS of the full cohort was 33 months (95% CI 13, not reached (NR): 16 months in the W&W group and NR in the allo-HCT group (HR 0.42, 95% CI 0.23-4.56, p=0.2). Median OS was NR in both groups. 24-month OS was 75% (95%CI 56-100) in the W&W group and 80% (95%CI 59-100) in the allo-HCT group, p&gt;0.9. Despite low numbers, similar RFS and OS were also observed between both groups when focusing on patients losing BCA before and after the 6-month landmark. Seven patients died during follow-up, 3 in the allo-HCT and 4 in the W&W groups, all but 1 due to ALL relapse (1 patient died from non-relapse mortality in the allo-HCT group).

Conclusions.Consolidative allo-HCT is associated with lower risk of relapse after early loss of BCA after CAR T-cell therapy, but this benefit does not seem to translate into a survival benefit in patients with B-cell ALL.