Reduced chronic graft versus host disease after allogeneic HSCT with cryopreserved peripheral blood stem cell grafts: A CIBMTR analysis

Abstract During the COVID-19 pandemic, cryopreservation (cryo) of unrelated donor peripheral blood stem cells (PBSC) for allogeneic hematopoietic cell transplantation (allo-HCT) was performed to ensure graft availability. A prior single-institution analysis of patients receiving cryo versus fresh matched unrelated donor (MUD) PBSC observed a lower incidence of chronic graft-versus-host disease (cGVHD) with cryo but no difference in survival or relapse. We sought to validate these findings using data from the CIBMTR to assess the impact of cryo on cGVHD, as well as other key clinical outcomes such as survival, relapse rates, acute GVHD (aGVHD), and engraftment. We analyzed 7,983 adults (age ≥18 years) undergoing first allo-HCT between 2019-2022 at US centers for AML, ALL or MDS with an HLA-matched (8/8) or mismatched (7/8) unrelated donor PBSC. Patients were excluded from the study if GVHD prophylaxis information was missing or if they received in vivo T cell depletion/CD34 selection. Cox proportional hazards models were used to compare outcomes after cryo versus fresh PBSC grafts. Risk factors considered: patient age, donor age, donor type, ATG/Campath, Karnofsky score, conditioning regimen, GVHD prophylaxis, HCT-CI, refined disease risk index, donor-recipient CMV match, donor-recipient sex match, and year of HCT. Interactions between cryo status and adjusted covariates were tested at the significance level of 0.01. 3,339 patients received fresh PBSCs while 4,644 received cryo. The cohorts were similar in most key patient and transplant characteristics except more use of post-transplantation cyclophosphamide (PTCy) with cryo (39.7%) than fresh (30.8%). Median CD34+ cell dose was similar (7.0x106 cells/kg for fresh vs 6.8x106 cells/kg for cryo). In univariate analysis, recipients of cryo PBSCs had lower cumulative incidence of overall cGVHD (39.1% vs 45.8%, p<0.001) and moderate to severe cGVHD at 2 years (22.4% vs 28.6%, p<0.001). Cryo was not associated with a difference in incidence of relapse (28.1% vs 29.1%, p=0.53) or disease-free survival at 2 years (DFS, 53.7% vs 55.8%, p=0.08), but was associated with lower overall survival at 2 years (OS, 61.6% vs 65.1%, p=0.002) and higher treatment related mortality (TRM, 18.2% vs 15.1%, p=0.002) compared to fresh PBSCs. Receipt of cryo PBSCs was also associated with higher incidence of grade 2-4 aGVHD (37.5% vs 31.7%, p<0.001) and grade 3-4 aGVHD at 6 months (10.9% vs 9.6%, p=0.028). There were no major differences in the primary cause of death, with relapse, infection, and organ failure being most common in both cohorts. Multivariable modeling showed receipt of cryo PBSCs was associated with less overall cGVHD (HR 0.76, 95% CI 0.66-0.87, p=0.0001) and moderate to severe cGVHD (HR 0.79, 95% CI 0.70-0.89, p=0.0001) than fresh PBSC. However, cryo was associated with inferior OS (HR 1.17, 95% CI 1.08-1.27, p=0.0002), lower DFS (HR 1.17, 95% CI 1.07-1.28, p=0.004), and higher TRM (HR 1.25, 95% CI 1.10-1.41, p=0.0007) but no difference in incidence of relapse (HR 1.00, 95% CI 0.93-1.08, p=0.94). Recipients of cryo PBSCs had a higher risk of grade 2-4 acute GVHD (HR 1.29, 95% CI 1.15-1.46, p<0.0001), and a trend toward higher grade 3-4 acute GVHD (HR 1.23, 95% CI 1.03-1.48, p=0.02). There was no significant difference in GVHD-free, relapse-free survival (GRFS, HR 0.98, 95% CI 0.92-1.04, p=0.47). Patients who received cryo PBSCs had slower time to neutrophil (HR 0.82, 95% CI 0.76-0.87, p<0.0001) and platelet (HR 0.70, 95% CI 0.65-0.76, p<0.0001) recovery compared to recipients of fresh PBSCs. Sensitivity analyses excluding data from 2019 or limiting the cohort to patients who received PTCy yielded qualitatively similar results, although some did not reach statistical significance due to smaller sample sizes. This large registry study confirms our prior finding of reduced cGVHD among patients receiving cryo PBSCs compared to fresh. This is counterbalanced by higher TRM, acute GVHD 2-4, slower engraftment, and worse survival and DFS at 2 years post-HCT. These findings suggest that cryopreservation has a clinically significant negative impact on graft quality in terms of engraftment, NRM and survival despite a reduction in cGVHD. Further study is needed to understand the biological effect of cryopreservation on T cell function leading to reduced cGVHD.