Impact of Graft Cell Dose on Outcomes after Matched Sibling Donor Peripheral Blood Stem Cell Transplantation with Post-Transplant Cyclophosphamide-Based Gvhd Prophylaxis

Background: CD34+ graft cell dose may be essential in determining the outcomes after matched sibling donor peripheral blood stem cell transplantation (MSD-PBSCT). The existing literature on the effect of graft cell dose on outcomes after MSD-PBSCT is heterogeneous and limited. We investigated the impact of graft cell dose on the outcomes following MSD-PBSCT with post-transplant cyclophosphamide (PT-Cy)-based graft-versus-host disease (GVHD) prophylaxis.

Methods: A retrospective multicenter analysis was conducted, including MSD-PBSCT patients in the publicly available Center for International Blood and Marrow Transplant (CIBMTR) registry from 2012 to 2017 using the P5737 dataset by 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. Cox proportional hazards regression analyses were performed, and hazard ratios (HR) 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 171 MSD-PBSCT recipients. The median age was 50.1 years, and 59% were male. Most patients were Caucasian (69%). Hematologic diagnoses included acute myeloid leukemia (62%), acute lymphoblastic leukemia (18%), and myelodysplastic syndromes (20%). Myeloablative conditioning was performed in 53% of recipients. The Karnofsky performance score was 90% or higher in 52% of patients. The HCT-specific comorbidity index was less than 3 in 47% of patients. Growth factor was used in 51.5% (n=88) of patients. The graft cell dose was categorized as low dose (LD): 0-2 million CD34+ cells/kg (10%, n=17), intermediate-dose (ID): over 2 to 5 million CD34+ cells/kg (38%, n=65), and high dose (HD): over 5 million CD34+ cells/kg (52%, n=89) CD34+ cells/kg. The median follow-up time was 3.14 (3.02-3.77) years. Median OS was not reached/NR (LD: 0.98 yrs, 95%CI 0.31-NR; ID: 2.28 yrs, 95% CI 1.37-NR; HD: NR). Median DFS was 1.40 years (LD: 0.93 yrs, 95% CI 0.24-NR; ID: 1.30 yrs, 95% CI 0.50-1.99; HD: 3.85 yrs; 95% CI 0.77-NR). Median GRFS was 0.26 years (LD: 0.47 yrs, 95% CI 0.23-0.93; ID: 0.15 yrs, 95% CI 0.13-0.33; HD: 0.32 yrs; 95% CI 0.20-0.44). Incidence of grade II-IV acute GVHD was higher with a higher CD34+ cell dose (LD: 12%, ID: 48%, HD: 38%; p=0.025), but no statistically significant differences were noted in the risk of relapse (LD: 53%, ID: 43%, HD: 33%; p=0.184) or chronic GVHD (LD: 29.4%, ID: 41.5%, HD: 38%; p=0.654) between the two groups. Adjusted multivariate regression analyses showed that graft cell dose of over 2 to 5 million cells/kg was associated with a higher incidence of grade II-IV acute GVHD (HR 7.01, 95% CI 1.60-30.64, p=0.010) while no significant association was observed with OS (HR 0.65, 95% CI 0.28-1.55, p=0.333), DFS (0.93, 95% CI 0.40-2.18, p=0.872), GRFS (HR 1.39, 95% CI 0.71-2.70, p=0.334), relapse (HR 0.46, 95% CI 0.18-1.19, p=0.110), NRM (HR 1.15, 95% CI 0.22-6.04, p=0.872) or chronic GVHD (HR 1.35, 95% CI 0.51 -3.60, p=0.543). In adjusted multivariate regression analyses, graft cell dose of over 5 million cells/kg was associated with significantly superior OS (HR 0.33, 95% CI 0.14-0.82, p=0.016) and a higher incidence of grade II-IV acute GVHD (HR 5.27, 95% CI 1.24-22.47, p=0.025) while no significant association was observed with DFS (HR 0.58, 95% CI 0.24-1.38, p=0.216), GRFS (HR 1.10, 95% CI 0.56-2.15, p=0.786), relapse (HR 0.40, 95% CI 0.15-1.07, p=0.068), NRM (HR 0.61, 95% CI 0.11 -3.30, p=0.566), or chronic GVHD (HR 1.10, 95% CI 0.42-2.90, p=0.844).

Conclusion: Our study revealed that a graft cell dose of over 5 million CD34+ cells/kg was linked to superior survival rates, albeit with a higher risk of acute GVHD, following matched sibling donor peripheral blood stem cell transplantation with PT-Cy-based GVHD prophylaxis. However, no significant association was found with other outcomes. These findings suggest that a CD34+ dose lower than 2 million cells/kg might be acceptable for successful transplantation when using MSD PBSC graft and PT-Cy for GVHD prophylaxis.

Mushtaq:Iovance Biotherapeutics: Research Funding. Abhyankar:CSL Behring, Miltenyi Biotec.: Research Funding; Incyte: Consultancy. Hamadani:Forte Biosciences: Consultancy; Caribou: Consultancy; Autolus: Consultancy; Kite Pharma: Consultancy, Speakers Bureau; Astellas Pharma: Research Funding; Omeros: Consultancy; Myeloid Therapeutics: Speakers Bureau; AbbVie: Consultancy; Spectrum Pharmaceuticals: Research Funding; ADC Therapeutics: Consultancy, Research Funding, Speakers Bureau; Genmab: Consultancy; Sanofi Genzyme: Speakers Bureau; AstraZeneca: Speakers Bureau; BMS: Consultancy; Genentech: Speakers Bureau; CRISPR: Consultancy; Allovir: Consultancy; BeiGene: Speakers Bureau; Byondis: Consultancy; CRISPR: Speakers Bureau; DMC, Inc: Speakers Bureau; Takeda: Research Funding.