Lowering Conditioning Intensity in Fit Adolescents and Adults with Lymphoblastic Leukemia without Residual Disease Undergoing Transplantation: A Proof of Concept
Authors: Gonzalez Alexia , Varela Constantino Ana Laura , Méndez-Ramírez Nereida , Medina-Olivares Fernando J , Fuentes-Chavez Eli , Salazar-Riojas Rosario , Gutierrez-Aguirre César Homero , Cantu Olga , Colunga-Pedraza Perla , Tarin-Arzaga Luz , Gonzalez Leal Xitlaly Judith , Gonzalez-López Elías Eugenio , Gomez-Almaguer David , Gomez-De Leon Andres 
Published: December 2024

Background
Myeloablative conditioning (MAC) is considered standard for fit persons with acute lymphoblastic leukemia (ALL) undergoing allogeneic transplantation (allo-HCT). Next generation flow cytometry allows for the detection of persons without measurable residual disease (MRD) who may not need MAC. Since 2019 Reduced-intensity conditioning (RIC) has been used for persons with undetectable MRD (MRDneg) regardless of their fitness or comorbidities. In this pre-post study we compare the outcomes of persons with ALL treated before and after the implementation of this strategy.
Methods
This was a prospective study including adolescents and adults with ALL from 2015-2024 in two institutions. Before 2019 patients received MAC based on cyclophosphamide 350 mg/m2 plus fludarabine 25 mg/m2 (CyFlu) for 3 days and melphalan 200 mg/m2 or busulfan (Bu)≥12 mg/kg if considered fit. After 2019 patients with pre-transplant MRDneg could receive RIC (CyFlu plus melphalan 100-140 mg/m2 or Bu 8-9 mg/kg with 2 Gy of total body irradiation), regardless of comorbidities or fitness in an effort to reduce short-term complications. MRD was centrally assessed using next generation flow cytometry using Euroflow protocols before conditioning. Peripheral blood was used in all cases. Donors included matched siblings or haploidentical. Graft-versus-host disease prophylaxis was based on post-transplant cyclophosphamide or calcineurin inhibitor plus methotrexate.The primary outcome was overall survival (OS). Secondary outcomes were the cumulative incidence of relapse (CIR), non-relapse mortality (NRM) and GVHD-relapse-free survival (GRFS).
Results
Eighty-eight patients received an allo-HCT for ALL during the study period, n=41 RIC and n=31 MAC, the remainder received alternative conditioning were excluded. The median age was 27 years (15-62), 66.7% were men, mostly with B-ALL (87.5%) without comorbidities (HCT-CI score 0; 84%) and a median of 2 treatment lines (range, 1-6). Fifty-seven had MRDneg, while 15 had detectable measurable residual disease (MRDpos), 16 were not assessed. Donors were haploidentical in n=56 and matched siblings in n=16. No differences were observed in the baseline characteristics of RIC-MRDneg vs MAC-MRDneg groups. The median follow-up was 35.6 months (range 2,7-134). Median day of neutrophil engraftment was longer in MAC-MRDneg (16 vs. 14 days; p=.016). No differences in platelet engraftment, graft failure, acute or chronic GVHD incidence or severity were observed. Three year OS in RIC-MRDneg was 77.1% vs. 54.3% for MAC-MRDneg (p=.2). The 2-year CIR was 44% in RIC-MRDneg (95% CI 22-64%) and 51% in MAC-MRDneg (95% CI 23-74%) (p=.6) with a trend towards worse cumulative incidence of 2-year NRM in MAC-MRDneg 9.8% (95% CI 1.6-27%) vs RIC-MRDneg 5.9% (95% CI 1-18%) (p=.06); 2 year GRFS RIC-MRDneg 40.4% and MAC-MRDneg 28.2%, 3-year GRFS was 34.6% in RIC-MRDneg and 28.2% in MAC-MRDneg(p=.5).
The 2-year OS in RIC-MRDpos 60% vs MAC-MRDpos 57.1%. Meanwhile the 2-year RIC-MRDpos CIR was 20% (95% CI 0.35-63%) and MAC-MRDpos CIR was 33% (6.2-64%). Also, the 2-year NRM in RIC-MRDpos was 20% (0.43-62%) and the 2-year NRM in MAC-MRDpos patients was 20% (95% CI 2.6-49%). In a multivariate analysis of OS, pre-transplant MRD was associated with OS (HR 2.9; 95% CI 1.4-5.8) but the intensity of conditioning did not.
Conclusion
For patients with ALL and MRDneg before transplant, RIC is an acceptable alternative and offers comparable outcomes to MAC. No differences in outcomes were observed, validating our strategy.