Impact of Conditioning Intensity on Allogeneic Hematopoietic Stem Cell Transplant Outcomes in Patients with Acute Leukemia and Myelodysplastic Syndromes

Background: Allogeneic hematopoietic cell transplantation (allo-HCT) is a crucial therapeutic option for patients with acute leukemias and myelodysplastic syndromes (MDS). The intensity of the conditioning regimen before transplantation can significantly impact post-transplant outcomes. We aim to evaluate the effect of conditioning intensity, myeloablative versus reduced-intensity/non-myeloablative conditioning, on the post-allo-HCT outcomes.

Methods: A retrospective multicenter analysis was conducted, including allo-HCT patients in the publicly available Center for International Blood and Marrow Transplant (CIBMTR) registry from 2013 to 2018 using P5646 data by Ramathan et al. We examined the impact of conditioning intensity on post-transplant outcomes, including overall survival (OS), disease-free survival (DFS), relapse, non-relapse mortality (NRM), acute graft-versus-host disease (aGVHD), and chronic graft-versus-host disease (cGVHD), and neutrophil and platelet engraftment. The hazard ratios (HR) with 95% confidence intervals (CI) were calculated using multivariate Cox or logistic regression analyses for OS, DFS, relapse, NRM, aGVHD, cGVHD, and platelet and neutrophil engraftment. Statistical analysis was conducted using R version 4.16, with statistical significance defined as p <0.05.

Results: We included 7545 allo-HCT recipients. Of these, 4004 (53%) had myeloablative conditioning (MAC), while 3541(47%) had non-myeloablative conditioning (NMAC) or reduced-intensity conditioning (RIC). The median age at the time of transplant was 56 years, 58% of the patients were men, and the majority were Caucasian (76%), Hispanic (8%), African American (6%), Asian (5%), and others/not available (5%). The primary disorders included acute myeloid leukemia (AML, 47%), myelodysplastic syndromes (MDS, 34%), and acute lymphoblastic leukemia (ALL, 18%). Donor types were matched unrelated (50%), matched related (34%), and cord blood (16%). Graft sources were peripheral blood stem cells (68%), umbilical cord blood (16%), and bone marrow (15%). GVHD prophylaxis regimens included post-transplant tacrolimus or cyclosporine-based (87%), cyclophosphamide-based (9%), CD34 selection (2%), and others (2%). Univariate regression analyses revealed that MAC was associated with a superior OS(HR 0.76, 95% CI 0.71-0.81, p<0.01) and DFS (HR 0.67, 95% CI 0.61-0.73, p<0.01), lower rates of relapse (HR 0.77, 95% CI 0.72-0.83, p<0.01), NRM(OR 0.75, 95% CI 0.67-0.84, p<0.01) and chronic GVHD (HR 0.92, 95% CI 0.86-0.99, p<0.05), and faster neutrophil (HR 0.93, 95% CI 0.89-0.97, p=0.002) and platelet engraftment (HR 0.79, 95% CI 0.75- 0.83, p<0.01) while a higher risk for acute GVHD grades II-IV(HR 1.23, 95% CI 1.14-1.32, p<0.01) was noted. Multivariate regression analyses, adjusted for minimal residual disease (MRD) status, age, gender, graft type, comorbidity index, performance status and GVHD prophylaxis, showed that MAC carries a lower risk of relapse(HR 0.91, 95% CI 0.83-1.00, p=0.049); however, an inferior OS(HR 1.09, 95% CI 1.001-1.180, p=0.048), higher acute GVHD(HR 1.42, 95% CI 1.30-1.55, p<0.01) and chronic GVHD (HR 1.25, 95% CI 1.14-1.36, p<0.01), and delayedneutrophil engraftment (HR 1.24, 95% CI 1.17-1.32, p<0.01) were noted. Within the MRD-positive group (n=1343), MAC was associated with higher acute GVHD (HR 1.32, 95% CI 1.08-1.61, p=0.008) and delayed neutrophil engraftment(HR 1.27, 95% CI 1.11-1.46, p=0.001) but not with other outcomes in the multivariate analyses. Within the MRD-negative group (n=5085), MAC was associated with lower risk for relapse (HR 0.85, 95% CI 0.76-0.96, p=0.008), but higher acute GVHD (HR 1.43, 95% CI 1.28-1.60, p<0.01) and NRM (OR 1.27, 95% CI 1.06-1.54, p=0.011), and delayed neutrophil engraftment(HR 1.25, 95% CI 1.16-1.34, p<0.01) but not with other outcomes in the multivariate analyses.

Conclusion:

Myeloablative conditioning reduces relapse rate but leads to inferior overall survival, higher incidence of acute and chronic GVHD, and delayed neutrophil engraftment. These findings highlight the need for a prospective studyto evaluate the role of conditioning intensity and the optimal conditioning regimen in patients with acute leukemia and myelodysplastic syndromes undergoing allo-HSCT.

Abdelhakim:Iovance Biotherapeutics: Research Funding. Hamadani:Kite Pharma: Consultancy, Speakers Bureau; Spectrum Pharmaceuticals: Research Funding; Allovir: Consultancy; DMC, Inc: Speakers Bureau; Genmab: Consultancy; Genentech: Speakers Bureau; ADC Therapeutics: Consultancy, Research Funding, Speakers Bureau; CRISPR: Speakers Bureau; Omeros: Consultancy; Byondis: Consultancy; AstraZeneca: Speakers Bureau; Sanofi Genzyme: Speakers Bureau; AbbVie: Consultancy; Caribou: Consultancy; Astellas Pharma: Research Funding; CRISPR: Consultancy; BeiGene: Speakers Bureau; Forte Biosciences: Consultancy; Autolus: Consultancy; BMS: Consultancy; Myeloid Therapeutics: Speakers Bureau; Takeda: Research Funding. McGuirk:Sana technologies: Consultancy; Legend biotech: Consultancy; CRISPR therapeutics: Consultancy; Caribou bio: Consultancy; NEKTAR therapeutics: Consultancy; Autolus: Consultancy; Envision: Consultancy; Allo Vir: Consultancy; Novartis: Consultancy; Kite: Consultancy; BMS: Consultancy. Mushtaq:Iovance Biotherapeutics: Research Funding.