Infection Burden in Mismatched Unrelated Donor Hematopoietic Cell Transplantation Using Standard-Dose Post-Transplantation Cyclophosphamide As Graft-Versus-Host Disease Prophylaxis: Insights from the NMDP-Sponsored, CIBMTR-Led ACCESS Trial

ACCESS (NCT04904588), a multi-center phase II trial, was designed to assess safety and efficacy of HLA-mismatched unrelated donor (MMUD) peripheral blood allografts in adult patients with high-risk hematologic malignancies receiving myeloablative (MAC) or non-myeloablative/reduced-intensity conditioning (NMA/RIC) and standard-dose post-transplantation cyclophosphamide (SD PTCy) as graft-versus-host disease (GvHD) prophylaxis. One-year overall survival (75%) was similar irrespective of conditioning intensity and degree of donor HLA MM (Al Malki et al., JCO 2025). However, 56% MAC and 64% RIC adult recipients experienced at least one Common Terminology Criteria for Adverse Events (CTCAE) grade (Gr) ≥2 infection within the first 100 days of transplant (D100). Herein, we describe infection burden in ACCESS patients within one year after transplant. CTCAE Gr≥2 infections were analyzed by time after transplant (Days 0-30, 31-100, 101-180, 181-365), conditioning intensity, degree of donor HLA MM (HLA 7/8 vs. <7/8), pathogen type, and post-MMUD HCT outcomes (Gr2-4 acute GvHD, moderate/severe chronic GvHD, and American Society for Transplantation and Cellular Therapy (ASTCT) Gr≥2 cytokine release syndrome. Infection density was calculated as number of infections per 100 days at risk for enrolled patients. Infection data were summarized with standard descriptive statistics. Infection density with 95% confidence intervals (CI) were estimated using Poisson regression models; p<0.05 was considered statistically significant. Median (range) ages for 268 patients receiving MAC (n=75) and RIC/NMA (n=193) were 49.8 (20.4-65.6) and 64.4 (24.3-77.9) years, respectively. CTCAE Gr≥2 infections occurred in 183 (69%) patients: 49 (65%) MAC and 134 (69%) RIC/NMA recipients. Days 0-30 infection densities for Gr2-5 and Gr3-5 infections were higher relative to infection densities at other post-transplant periods and irrespective of conditioning intensity ( Fig. 1A ) and degree of donor HLA MM ( Fig. 1B ). When comparing infection densities by conditioning intensity, patients receiving RIC/NMA had higher infection densities at Days 31-180 for Gr3-5 infections ( Fig. 1A ). When comparing infection densities by degree of donor HLA MM, significant differences were noted only at Days 181-365 in the RIC stratum ( Fig. 1B ). Similar distribution of pathogen types by conditioning intensity were noted early ( Fig. 1C ) and late ( Fig. 1D ) post-transplant, with predominantly gram-positive bacteria and non-respiratory viruses, respectively. Finally, pathogen type frequencies by clinical outcomes were indistinct ( Fig. 1E ). In the MMUD PBSC transplant setting, SD PTCy associates with significant infection burden. These findings provide insights into potential interventions to prevent infection or augment immune response after MMUD transplant.