Factors Associated with Graft-Versus-Host Disease after Related Donor Allogeneic Hematopoietic Cell Transplantation with Post-Transplant Cyclophosphamide-Based GvHD Prophylaxis

Background: Graft versus host disease (GvHD) remains a significant complication after allogeneic hematological cell transplantation (allo-HCT), adversely impacting quality of life and leading to high morbidity and mortality post-transplant. Several studies have reported the factors affecting the development of GvHD, but data is limited in post-transplant cyclophosphamide (PT-Cy)-based GvHD Prophylaxis. This study aimed to explore factors associated with acute GvHD (aGvHD) and chronic GvHD (cGvHD) following related donor allo-HCT with PT-Cy-based GvHD prophylaxis.

Methods: In this multicenter retrospective study, we included the first related donor allo-HCT recipients from 2012 to 2017 who received PT-Cy-based GvHD prophylaxis, in the publicly available Center for International Blood and Marrow Transplant (CIBMTR) dataset (P-5737, Ustun et al). Patient-, disease- and transplant-related factors were compared using the Chi-square test for categorical variables and the Wilcoxon two-sample test for continuous variables. Logistic regression analyses were performed for acute and chronic GvHD, and odds ratios (OR) with 95% confidence intervals (CI) were calculated. Variables with p-values <0.2 in univariable analysis and the clinically relevant variables were included in the multivariable models. Statistical analyses were conducted using Stata version 18, and significance was defined as p<0.05.

Results: We included 865 allo-HCT recipients, including 64% (n=550) haploidentical (haplo) and 36% (n=315) matched sibling donor (MSD) transplants. The median age was 57 years, and 59.5% were male. Caucasians were most common (64%), followed by African Americans (18%), Hispanics (10%), and others (8%). Hematologic diagnoses included acute myeloid leukemia (AML, 54.5%), myelodysplastic syndromes (MDS, 26%), and acute lymphoblastic leukemia (ALL, 19.5%). Myeloablative conditioning was performed in 43% of recipients. The graft source was peripheral blood stem cells (PBSC) in 65% and bone marrow (BM) in 35% of patients. The median donor age was 38 years, and 63% were male. The Karnofsky performance status (KPS) was 90% or higher in 50% of patients and the comorbidity index (HCT-CI) was less than 3 in 51% of patients. The median follow-up time was 3.6 years. Grade II-IV acute GvHD was observed in 310 (35.8%) and chronic GvHD was noted in 290 (33.5%) patients. Significant correlates of lower grade II-IV acute GvHD included hematologic diagnosis (ALL or MDS compared to AML, p=0.006), ethnicity (Asians compared to Caucasians, p<0.001), reduced intensity conditioning (p=0.027), and no use of growth factors (p=0.004) while significant correlates of lower chronic GvHD included bone marrow graft (p<0.001), ethnicity (Asians compared to Caucasians, p=0.018), lower CD34 cell dose (p=0.007) and no history of acute GvHD (p<0.001). In multivariate analyses for grade II-IV acute GvHD, ALL (OR 0.56, 95% CI 0.33-0.96, p=0.035) or MDS (OR 0.27, 95% CI 0.08-0.97, p=0.044) compared to AML and Asian ethnicity compared to Caucasians (OR 0.23, 95% CI 0.10-0.54, p=0.001) predicted a lower risk while the use of growth factors predicted a higher risk (OR 1.97, 95% CI 1.17-3.30, p=0.011) of acute GvHD. In multivariate analyses for chronic GvHD, Asian ethnicity compared to Caucasians (OR 0.35, 95% CI 0.16-0.75, p=0.007) predicted a lower risk while the PBSC graft (OR 2.41, 95% CI 1.54-3.76, p<0.001) predicted a higher risk of chronic GVHD. In multivariate analyses for acute or chronic GvHD, MDS (OR 0.21, 95% CI 0.06-0.70, p=0.012) compared to AML and Asian ethnicity compared to Caucasians (OR 0.28, 95% CI 0.14-0.53, p<0.001) predicted a lower risk while the use of growth factors (OR 1.57, 95% CI 1.00-2.47, p=0.048) and PBSC graft (OR 1.66, 95% CI 1.11-2.48, p=0.013) predicted a higher risk of developing either acute or chronic GvHD.

Conclusion: In this multi-center registry study of MSD and haplo HCT with PT-Cy-based GvHD prophylaxis, MDS or ALL diagnosis compared to AML and Asian ethnicity predicted a lower risk while the use of growth factors and PBSC graft predicted a higher risk of developing GvHD. Other patient- and transplant-related factors did not have a significant association.