Impact of Graft Cell Dose on Outcomes after Haploidentical Peripheral Blood Stem Cell Transplantation with Post-Transplant Cyclophosphamide-Based Gvhd Prophylaxis
Authors: Mushtaq Muhammad Umair , Kasaeian Amir , Chaudhary Sibgha Gull , Amin Muhammad Kashif , Anwar Iqra , Alemi Hediyeh , Khavandgar Naghmeh , Mohsin Aleenah , McGuirk Matthew , Abhyankar Sunil , Hamadani Mehdi , McGuirk Joseph P. , Shahzad Moazzam 
Published: December 2024

Background: CD34+ cell dose in the peripheral blood stem cell (PBSC) graft may significantly affect outcomes after haploidentical PBSC transplantation (haplo-PBSCT). However, the data is limited and heterogeneous. We aimed to investigate the impact of CD34+ graft cell dose on outcomes following haplo-PBSCT with post-transplant cyclophosphamide (PT-Cy)-based graft-versus-host disease (GVHD) prophylaxis.

Methods: In this retrospective study, we included all patients undergoing haplo-PBSCT (n=266) from 2013 to 2018 in the publicly available Center for International Blood and Marrow Transplant (P-5737 dataset, Ustun et al). Outcomes included overall survival (OS), disease-free survival (DFS), relapse, non-relapse mortality (NRM), acute and chronic GVHD, and GVHD-free relapse-free survival (GRFS). Baseline characteristics were compared using the Chi-square test for categorical variables and the Kruskal-Wallis test for continuous variables. The median follow-up duration was estimated using the reverse Kaplan-Meier method. Cox proportional hazards regression analyses were performed and 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. Statistical analyses were conducted using Stata version 18, and significance was defined as p&lt;0.05.

Results: We included 266 patients who received a Haplo-PBSCT with PT-Cy-based GVHD prophylaxis. The median recipient age was 58 years, and 57% of patients were male. The graft cell dose was categorized as low dose (LD): 0-2 million CD34+ cells/kg (8%, n=22), intermediate-dose (ID): over 2 to 5 million CD34+ cells/kg (31%, n=82), and high dose (HD): over 5 million CD34+ cells/kg (61%, n=162) CD34+ cells/kg. Myeloablative and reduced-intensity conditioning were performed in 126 (47%) and 140 (53%) recipients. Hematologic diagnoses included acute myeloid leukemia (n=152, 57.5%), acute lymphoblastic leukemia (n=40, 15%), and myelodysplastic syndrome (n=73, 27.5%). The Karnofsky performance score was 90% or higher in 43% of patients. The HCT-specific comorbidity index of less than three was noted in 45% of patients. Growth factor was used in 86.5% (n=230) of patients. All baseline characteristics were balanced between the groups. Median follow-up time was 3.69 (95% CI 3.10-3.90) years. Median OS was 2.85 years (LD: 0.53 yrs, 95%CI 0.30-0.87; ID: 2.46 yrs, 95% CI 0.63-Not reached/NR; HD: 4.48 yrs, 95% CI 1.94-NR). Median DFS was 0.95 years (LD: 0.37 yrs, 95% CI 0.20-0.77; ID: 1.21 yrs, 95% CI 0.63-NR; HD: 1.05 yrs; 95% CI 0.61-2.44). Median GRFS was 0.25 years (LD: 0.20 yrs, 95% CI 0.07-0.40; ID: 0.24 yrs, 95% CI 0.13-0.38; HD: 0.26 yrs; 95% CI 0.22-0.39). No statistically significant differences were noted in the incidence of relapse (LD: 54.5%, ID: 33%, HD: 39.5%; p=0.172), grade II-IV acute GVHD (LD: 36%, ID: 39%, HD: 38%; p=0.966) or chronic GVHD between the two groups. Adjusted multivariate regression analyses showed that graft cell dose of over 2 to 5 million cells/kg was associated with significantly superior OS (HR 0.34, 95% CI 0.18-0.63, p=0.001), superior DFS (HR 0.35, 95%CI 0.19-0.64, p=0.001), lower relapse risk (HR 0.17, 95% CI 0.07-0.39, p&lt;0.001), while no significant association was observed with GRFS (HR 0.67, 95% CI 0.39-1.14, p=0.139), NRM (HR 0.59, 95% CI 0.25-1.39, p=0.225), grade II-IV acute GVHD (HR 0.91, 95% CI 0.41-2.02, p=0.825) or chronic GVHD (HR 1.12, 95% CI 0.45-2.82, p=0.806). In adjusted multivariate regression analyses, graft cell dose of over 5 million cells/kg was associated with significantly superior OS (HR 0.31, 95% CI 0.17-0.55, p&lt;0.001), superior DFS (HR 0.38, 95% CI 0.22-0.65, p&lt;0.001), superior GRFS (HR 0.57, 95% CI 0.34-0.96, p=0.033), and lower relapse risk (HR 0.24, 95% CI 0.12-0.51, p&lt;0.001), while no significant association was observed with GRFS (HR 0.67, 95% CI 0.39-1.14, p=0.139), NRM (HR 0.47, 95% CI 0.21-1.03, p=0.059), grade II-IV acute GVHD (HR 0.76, 95% CI 0.36-1.62, p=0.482) or chronic GVHD (HR 0.75, 95% CI 0.31-1.81, p=0.519).

Conclusion: Higher CD34+ graft cell dose leads to improved outcomes after haploidentical peripheral blood stem cell transplantation. The data strongly supports the use of over 2 million CD34+ cells/kg, with the optimal cell dose potentially exceeding 5 million CD34+ cells/kg, to achieve superior survival and lower relapse rates.