Sirolimus plus low-exposure calcineurin inhibitors as an alternative gvhd prophylaxis in CNI-intolerant recipients: A retrospective study

Abstract Introduction: Graft-versus-host disease (GvHD) remains a major obstacle to long-term survival after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Calcineurin inhibitors (CNIs) are the standard for GvHD prophylaxis, but intolerance due to comorbidities necessitates alternative approaches. Methods: This retrospective study included 16 patients with hematologic disorders who were intolerant to standard-dose CNIs and received sirolimus plus low-exposure CNIs between Dec 2023 and Feb 2025. We assessed GvHD incidence, infection rates, survival outcomes, relapse, and immune reconstitution. Results: The cohort (10 males, 6 females) had a median age of 22.5 years (range 5–60). The regimen was initiated a median of 27.5 days post-transplant (range –2 to 114) and continued for a median of 53 days. Five patients (31.2%) received sirolimus and low-dose CNI alone, 10 (62.5%) received additional mycophenolate mofetil (MMF), and 1 patient received MMF plus anti-CD25 antibody. Only one patient (6.3%) developed grade II aGvHD; no grade III–IV aGvHD or chronic GvHD was observed. After a median follow-up of 271 days (range 58–505), there was one non-relapse death and three relapses (18.7%) without relapse-related mortality. The regimen was well-tolerated, with CMV and EBV viremia observed in 2 (12.5%) and 1 (6.3%) patient(s), respectively. Immune reconstitution analyses revealed preserved T, B, and NK cell recovery during early post-transplant period. Conclution: This study presents the first clinical evidence supporting sirolimus plus low-exposure CNIs as a feasible and safe GvHD prophylaxis in CNI-intolerant allo-HSCT recipients. The regimen showed promising efficacy with low toxicity and preserved immune reconstitution. Larger prospective studies are warranted to validate these findings.