Impact of Conditioning Intensity on Outcomes after Allogeneic Related Donor HCT with Post-Transplant Cyclophosphamide-Based Gvhd Prophylaxis in Acute Leukemia and Myelodysplastic Syndromes
Authors: Mushtaq Muhammad Umair , Kasaeian Amir , Amin Muhammad Kashif , Ur Rehman Aqeeb , Khavandgar Naghmeh , Alemi Hediyeh , Chaudhary Sibgha Gull , Anwar Iqra , McGuirk Matthew , Abdelhakim Haitham , Singh Anurag K. , Hamadani Mehdi , McGuirk Joseph P. , Shahzad Moazzam 
Published: December 2024

Background: Allogeneic hematopoietic cell transplantation (allo-HCT) is a curative therapy for patients with acute leukemia (AL) and myelodysplastic syndromes (MDS). The intensity of the conditioning regimen before transplantation, myeloablative versus reduced intensity or non-myeloablative conditioning, can significantly impact post-transplant outcomes. We aimed to investigate the impact of conditioning intensity on post-transplant outcomes in AL/MDS patients undergoing related donor allo-HCT with post-transplant cyclophosphamide (PT-Cy)-based graft-versus-host disease (GVHD) prophylaxis.

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 2012 to 2017 using P5737 data by Ustun 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), grade 2-4 acute GVHD (aGVHD), chronic GVHD (cGvHD), and GvHD-free relapse-free survival (GRFS). Patient-, disease- and transplant-related factors were compared between groups using the Chi-square test for categorical variables and the Wilcoxon two-sample test for continuous variables. The median follow-up duration was estimated using the reverse Kaplan-Meier method. Cox proportional hazards regression was used for outcomes, including OS, DFS, GRFS, aGVHD, cGVHD, relapse, and NRM. The hazard ratios (HR) with 95% confidence intervals (CI) were calculated. Variables with p-values &lt;0.2 in univariable analysis and the clinically relevant variables were included in the multivariable models. A significance level of 0.05 was used throughout. Statistical analyses were conducted using Stata version 18.

Results: We included 865 allo-HCT patients, 370 (43%) of whom underwent myeloablative conditioning (MAC), while 495 (57%) had reduced intensity or non-myeloablative conditioning (RIC/NMAC). The median age at the time of transplant was 46.6 years in the myeloablative cohort and 62.5 years in the RIC/NMAC cohort (p&lt;0.001). Fifty-nine percent (n=514) were men. Ethnicities were Caucasian (64%), African American (18%), Hispanic (10%), and Asian and others (8%). The primary disorders included acute myeloid leukemia (54%), MDS (26%), and acute lymphoblastic leukemia (20%). Patients received either haploidentical (haplo, 64%) or matched sibling donor (MSD, 36%) transplants. Graft sources were peripheral blood stem cells (65%) and bone marrow (35%). All patients received PT-Cy-based GVHD prophylaxis. Fifty percent of patients had a Karnofsky performance score of 90% or higher, and 20% had a comorbidity index of 0. The median follow-up time was 3.61 (3.14-3.88) years. Univariate regression analyses revealed that patients who underwent RIC/NMAC had a significantly inferior OS(Median 1.88 years RIC/NMAC vs. 5.07 years MAC; HR 1.38, 95% CI 1.14-1.68, p=0.001) and DFS(Median 0.67 years RIC/NAMC vs. 2.05 years MAC; OR 1.57, 95% CI 1.31-1.87, p&lt;0.001) and higher risk of relapse(51% RIC/NMAC vs. 31% MAC; HR 1.95, 95% CI 1.56-2.43, p&lt;0.001), while a lower risk of grade II-IV aGvHD (33% RIC/NMAC vs. 40% MAC; HR 0.76, 95% CI 0.60-0.94, p=0.014) was observed with RIC/NMAC. Conditioning intensity did not impact GRFS, NRM, and cGvHD. In multivariate regression analyses, RIC/NMA was associated with a significantly higher risk of relapse (HR 1.60, 95% CI 1.01-2.54, p=0.045) but did not significantly impact other transplant outcomes.

Conclusion: Our study demonstrates the potential benefits of myeloablative conditioning in reducing the relapse rate after haploidentical and matched sibling donor hematopoietic cell transplantation with post-transplant cyclophosphamide-based graft-versus-host disease prophylaxis and should be considered in eligible patients.