“Real World” Outcome of Hematopoietic Stem Cell Transplantation after CAR19 T Cell Therapy in Children and Adults with B-ALL: A Gocart Coalition Study on Behalf of the PDWP, ALWP, and Ctiwp of the EBMT
Authors: Ottaviano Giorgio , Alonso-Saladrigues Anna , Ortiz-Maldonado Valentin , Galimard Jacques-Emmanuel , Farhan Shatha Y. , Vuyyala Sowjanya , Michel Eva , Imran Fizza , Martinez-Cibrian Nuria , Ryhänen Samppa , Attarbaschi Andishe , Mielke Stephan , Kuball Jurgen , Perez Martinez Antonio , Beguin Yves , Nagler Arnon , Sirvent Anne , Petersen Soeren Lykke , Barba Pere , Marsal Julia , Delgado Julio , Kalwak Krzysztof , Ciceri Fabio , Ruggeri Annalisa , Giebel Sebastian , Rives Susana , Balduzzi Adriana 
Published: December 2024

Introduction:
Despite the success of anti-CD19 Chimeric Antigen Receptor T cells (CART19) in patients with B-cell acute lymphoblastic leukemia (B-ALL), an allogeneic haematopoietic stem cell transplantation (HSCT) might rescue patients with disease recurrence. However, in patients at high risk of relapse, indication and timing of HSCT are challenging. Whether waiting for detectable disease or proceeding to consolidative HSCT in remission, is still controversial. This GoCART Coalition registry study aimed at investigating the outcome of patients who received HSCT after CART19.
Methods:
We retrieved data from the EBMT registry on adults and children with B-ALL who received autologous CART19 from 2016 and 2023. Baseline, previous treatment, bridging therapy, CART19 therapy, B cell aplasia duration, outcome, disease status at follow-up were collected. Kaplan Meier estimates were used for overall survival (OS), leukemia-free survival (LFS) and non-relapse mortality (NRM) from date of HSCT, whereas cumulative incidence was used for relapse after HSCT. The relapse was defined as molecular or hematologic recurrence of the disease. Relapse and NRM were mutually competing events.
Results:
Of 345 patients (173 adults and 172 children) infused with CART19 (Tisagenlecleucel in 65.2%, Varnimcabtagene autoleucel 25.8%, brexucabtagene autoleucel 5.5%, and others 3.5%), 113 subsequently received an HSCT (37 adults and 76 children; median age 13.5 years, IQR 8.2-22.2) at a median of 6.2 months (3.7-11.8) after CART19 infusion. Median follow-up was 1.6 years (95%CI 1.1-1.9). Overall, 67/113 (59.3%) patients were transplant-naive (17 adults; 50 children). 78.2% received a myeloablative conditioning, 36.8% were grafted from a mismatched related donor. Most of the patients (64.2%) were transplanted in CR3 or more. Disease status at HSCT was relapsed disease for 9% of the patients, whereas among patients in CR with reported MRD 26/95 (27%) received HSCT with MRD positivity (MRD+). Among the patients with disease recurrence after CART19, 19/60 (32%) detected a CD19-negative clone.
Indication for the subsequent HSCT was reported for 110 patients, as follow: (I) Rescue HSCT in 68 (62%) patients with molecular/morphological disease after CAR-T (including one patient with MDS post CAR-T); (II) Pre-emptive HSCT in 22 (20%) patients with B-cell aplasia loss with no signs of disease recurrence; (III) ConsolidativeHSCT in the 20 patients (18%) who were transplanted for the high risk of relapse, despite ongoing B cell aplasia and no disease recurrence. Median time elapsed between CART19 and HSCT was 9.5, 4.4 and 3.4 months in the three groups, respectively.
The 2-yr OS was 71.1% (95%CI 59.8-79.7) and 2-yr LFS was 53.5% (41.9- 63.8), relapse incidence was 32.7% (22.4-43.5), while NRM was 11.6% (6.1-19.1). The 2-years LFS was 59.6% (45.2-71.4) vs 42% (19.2-63.4), for patients transplanted with negative or positive MRD, respectively. 5/11 patients transplanted with overt disease (including one with MDS) relapsed or died, the 6 survivors free of disease had follow-up inferior to 2 years. Children compared with adults showed better OS (76.8%, 62.1-86.4; 59.9%; 40.8-74.6; p=0.02), and better LFS (64.3%, vs. 36.4%; p= 0.02). Patients receiving a rescue HSCT for MRD+ or overt relapse had a significant lower LFS (43.6% and 33.2%), as compared to pre-emptive (77.3%) and consolidative HSCT (83.6%, p= 0.001). In univariate analysis, no significant differences in OS (74.5% vs 65.6%, p=0.32), LFS (54.3% vs 52.4%, p=0.75) and NRM (10.7% vs 12.9%, p=0.68) were reported for those patients having a previous HSCT before CART19.
Conclusion:
To the best of our knowledge this is the largest cohort of transplanted patients after CART19. In this “real-world” registry-based study we found that patients transplanted without disease recurrence had a better LFS, also accounting for MRD. For those who experienced molecular or overt relapse, achieving MRD negativity appeared to be relevant for a better outcome. The low NRM, with no differences between pre-transplanted and transplant naive patients, suggest that HSCT after CART19 is well tolerated, and represent a valid strategy to reduce the risk of relapse. As it remains unclear for which patients autologous CART19 cells remains a stand-alone treatment, future studies should focus on strategies for early identification of patients at higher risk of treatment failure.