Interim Results of a Phase I/II Study of Intermediate-Dose Post-Transplantation Cyclophosphamide after Reduced Intensity Conditioned HLA-Matched Bone Marrow Transplantation for Older or Infirm Patients

Introduction Effective new therapies have allowed older/unfit patients to achieve disease remission, but allogeneic hematopoietic cell transplantation (HCT) remains the only potential cure for most. The curative potential of HCT is limited by graft-versus-host disease (GVHD), prolonged immunosuppression, and organ toxicity. High dose post-transplantation cyclophosphamide (PTCy) is now a standard of care due to its ability to reduce severe forms of GVHD without compromising relapse or survival, but the optimal dose of PTCy has not been defined. In a recent study of myeloablative (MAC) HLA-haploidentical bone marrow transplantation (BMT) at the National Institutes of Health (NIH, NCT03983850) intermediate dose PTCy 25 mg/kg/day on days +3/+4 resulted in low toxicity, protected against acute GVHD (aGVHD) (no grade II-IV events), and improved immune reconstitution. However, it is unknown if these results apply to other platforms. Methods This is a phase I/II study conducted at the NIH and University of Pennsylvania (NCT04959175). The primary endpoint is grade III-IV aGVHD. Eligible patients are 1) ≥60 years, or 2) <60 years, but unfit for MAC. All patients received RIC with Cy, fludarabine, and total body irradiation (400 cGy), followed by 10/10 HLA-matched BMT. Immunosuppression included intermediate-dose PTCy 25 mg/kg/day on days +3/+4, mycophenolate mofetil (days +5-35), and sirolimus (days +5-60). Results Phase I was completed for both cohorts; phase II is enrolling. To date, 13 of 40 planned patients have undergone HCT from HLA-matched donors (7 related and 6 unrelated) with a median follow-up of 215 (range 19-719) days. All patients engrafted. Median times to neutrophil and platelet engraftment are 14 (11-23) and 22 (11-101) days. In the first 30 days, the median number of RBC and platelet transfusions were 1 (range 0-8) and 5 (range 0-16) units, respectively. The incidence of mucositis was low with 2 patients developing grade 2 and no cases of grade 3 mucositis. One patient had grade IV aGVHD; no other patients developed grades II-IV aGVHD to date. By day 60, 83% of patients discontinued all immunosuppression. Thus far, one patient has had mild chronic GVHD (cGVHD) resolving with topical therapy with no moderate or severe cGVHD cases. The 1-year cumulative incidences of relapse and NRM are 22.2% (95% CI: 2.3 - 54.8%) and 8.3% (95% CI: 0.41 - 32.44%). 1-year estimates for OS, DFS, and GRFS are 76.4% (95% CI: 30.9-94%), 69.4% (95% CI: 29.7-89.6%), and 69.4% (95% CI: 29.7-89.6%). Conclusion In an older and unfit population, intermediate-dose PTCy is associated with low toxicity, while providing effective protection against GVHD and allowing early discontinuation of immunosuppression. Relapse and NRM were low for this high-risk cohort 38% of whom had disease detectable at HCT and >50% of whom had high co-morbidity indices. Complete enrollment is needed to confirm these favorable results.