Intermediate-Dose Post-Transplantation Cyclophosphamide for Myeloablative HLA-Haploidentical Bone Marrow Transplantation
Researchers from the National Cancer Institute (NCI), USA, have demonstrated that intermediate-dose post-transplantation cyclophosphamide (ID-PTCy) at 25 mg/kg/day administered on days 3 and 4 after myeloablative HLA-haploidentical bone marrow transplantation effectively prevents acute graft-versus-host disease (aGVHD) while providing additional clinical benefits compared to traditional high-dose cyclophosphamide (HD-PTCy) (50 mg/kg/day). In their phase I/II trial, involving 35 patients predominantly from ethnic/racial minority backgrounds (89%), no grade II-IV aGVHD occurred among the 23 patients receiving ID-PTCy. The 2-year cumulative incidences of chronic GVHD requiring systemic immunosuppression, non-relapse mortality, and relapse were 13%, 17%, and 22%, respectively, with overall survival and GVHD-free/relapse-free survival at 61% and 52%.
Traditionally, HD-PTCy is the standard-of-care for GVHD prophylaxis but has drawbacks, including delayed immune recovery and increased infectious complications. Given preclinical studies indicating superior GVHD control with intermediate dosing, researchers sought to evaluate the efficacy and safety of reducing PTCy dosing. The phase I part of the trial assessed two reduced dosing schedules (25 mg/kg/day on days +3/+4 and day +4 only), with grade III-IV aGVHD as the primary endpoint. Due to better tolerability, the schedule of 25 mg/kg/day on days +3/+4 proceeded to phase II, combined with sirolimus and mycophenolate mofetil as additional immunosuppression.
Results from the trial indicated substantial clinical benefits from ID-PTCy. Compared with HD-PTCy, ID-PTCy led to significantly faster neutrophil (median 14 vs. 19 days, p = 0.0004) and platelet engraftment (median 22 vs. 33 days, p = 0.0097), fewer transfusions (median 2 vs. 8 units, p = 0.015), reduced mucositis severity, and shorter symptomatic BK virus-associated cystitis duration (median 7 vs. 51 days for BK hemorrhagic cystitis, p = 0.006). Pharmacokinetic analysis showed 4-hydroxycyclophosphamide (4HCY) exposure correlated significantly with these outcomes, emphasizing the potential of tailored dosing strategies. These findings suggest ID-PTCy could become an optimized, safer GVHD prophylactic approach in haploidentical transplantation pending further validation.
Reference:
Hyder M, Dimitrova D, Sabina R, et al. Intermediate-Dose Post-Transplantation Cyclophosphamide for Myeloablative HLA-Haploidentical Bone Marrow Transplantation. Blood Advances. 2025.