Post-Transplantation Cyclophosphamide Following Busulfan and Fludarabine Myeloablative Conditioning Prevents Severe Acute and Chronic Graft-Versus-Host Disease and Minimizes Duration Of Immunosuppression: Results Of a Multi-Institutional Trial In Patients With High-Risk Hematologic Malignancies

Allogeneic blood or marrow transplantation (alloBMT) involves a multi-faceted platform with each component having significant implications for the overall success of the transplant. However, the optimal transplantation platform is unknown. We combined two promising approaches, intravenous (IV) busulfan (Bu)/fludarabine (Flu) myeloablative conditioning and high-dose, post-transplantation cyclophosphamide (PTCy) graft-versus-host disease (GVHD) prophylaxis, in a multi-institutional trial for patients receiving HLA-matched related or unrelated bone marrow allografts. We hypothesized that this transplantation platform could prevent severe acute and chronic GVHD, while shortening the duration of post-grafting immunosuppression, having low treatment-related toxicity, and providing effective disease control.

Busulfan was given in daily IV doses which were adjusted based on measured pharmacokinetics. Fludarabine was given at 40 mg/m²/day. PTCy (50 mg/kg/day in IV daily dosing) was administered as sole GVHD prophylaxis on days +3 and +4 after infusion of unmanipulated bone marrow. Forty-five (49%) patients received HLA-matched related allografts, while 47 (51%) received HLA-matched unrelated allografts. Seventy-three (79%) patients were transplanted for myeloid diseases, including 53 (58%) with acute myelogenous leukemia and 13 (14%) with myelodysplastic syndrome. Fifteen (16%) patients had acute lymphocytic leukemia. Sixty-seven (73%) patients were in morphologic complete remission (CR) at the time of alloBMT, and the remaining twenty-five (27%) patients had active disease. Eighteen (20%) patients had evidence of minimal residual disease. Twenty-five (27%) patients were males who received allografts from females. The primary endpoint of the study was the cumulative incidence of grade III-IV acute GVHD. Pre-defined secondary endpoints included chronic GVHD, non-relapse mortality, event-free and overall survival, and use and duration of systemic immunosuppressants beyond the originally planned two days of PTCy. GVHD was scored centrally by an independent reviewer.

The median follow-up was 595 days (1.6 years) for all patients and 794 days (2.2 years) for patients who were alive at last follow-up. The cumulative incidence (CI) of grade II-IV and III-IV acute GVHD were 51% and 15%, respectively, at two years. The CI of chronic GVHD was 14% at two years. Thirty-five percent of all patients and 39% of patients alive at last follow-up never required immunosuppression for any reason beyond day +4 post-transplant. Corticosteroid use occurred in 61% of all patients and 60% of patients alive at last follow-up. A median 98 days (range 10-1221) elapsed from first initiation to final cessation of corticosteroids. Immunosuppression beyond corticosteroids was used for 50% of all patients and 52% of patients alive at last follow-up. A median 167.5 days (range 1-1156) elapsed from first initiation to final cessation of secondary immunosuppression. A calcineurin inhibitor was required for any reason in 45% of patients. Only 16% of patients required additional immunosuppression beyond corticosteroids and/or a second systemic immunosuppressant. Seventy-two percent of patients alive at last follow-up were off all immunosuppression at one year.

Non-relapse mortality was 9% and 16% at 100 days and one year, respectively. Event-free survival and overall survival were 62% and 67% at two years and were 80% and 79% at two years for patients in CR without MRD at the time of alloBMT. Multivariate Bayesian analysis showed that having an unrelated donor, being in CR without MRD, and having a higher nucleated cell count all had beneficial effects on EFS.

Myeloablative IV Bu/Flu conditioning followed by single-agent GVHD prophylaxis with PTCy results in low rates of severe acute and chronic GVHD and effective disease control for patients with high-risk hematologic malignancies undergoing HLA-matched alloBMT even from unrelated donors. Moreover, the use of post-grafting immunosuppression beyond day +4 was not required in a significant subset of patients and was rapidly tapered in others. This study confirms the efficacy of PTCy after myeloablative conditioning and provides further support for future randomized studies comparing PTCy against other GVHD prophylactic approaches.

Off Label Use: post-transplantation cyclophosphamide as graft-versus-host disease prophylaxis. Luznik:Otsuka Pharmaceutical: Research Funding.