Multi-institutional study of post-transplantation cyclophosphamide as single-agent graft-versus-host disease prophylaxis after allogeneic bone marrow transplantation using myeloablative busulfan and fludarabine conditioning

Abstract

Purpose: The clinical safety and efficacy of intravenous busulfan and fludarabine (IV Bu/Flu) myeloablative conditioning as well as graft-versus-host disease (GVHD) prophylaxis with high-dose, post-transplantation cyclophosphamide (PTCy) have been demonstrated independently in several single-institutional studies. We hypothesized that combining these two promising approaches in a multi-institutional study of human leukocyte antigen (HLA) -matched bone marrow transplantation would provide low rates of severe acute and chronic GVHD, low toxicity, and effective disease control.

Patients and methods: Ninety-two adult patients (median age, 49 years; range, 21 to 65 years) with high-risk hematologic malignancies were enrolled at three centers (clinical trial No. NCT00809276). Forty-five patients received related allografts, and 47 received unrelated allografts. GVHD prophylaxis was solely with PTCy at 50 mg/kg/day on post-transplantation days +3 and +4.

Results: The cumulative incidences of grades 2 to 4 acute, grades 3 to 4 acute, and chronic GVHD were 51%, 15%, and 14%, respectively. Nonrelapse mortality (NRM) at 100 days and 1 year were 9% and 16%, respectively. With a median follow-up period of 2.2 years, the 2-year disease-free survival (DFS) and overall survival (OS) rates were 62% and 67%, respectively. Donor relatedness did not affect NRM, DFS, or OS. Patients in complete remission (CR) without evidence of minimal residual disease (MRD) had markedly better DFS (80%) and OS (80%) than patients in CR with MRD or with active disease at the time of transplantation (DFS, P = .0005; OS, P = .019).

Conclusion: This multi-institutional study demonstrates that PTCy can be safely and effectively combined with IV Bu/Flu myeloablative conditioning and confirms PTCy's efficacy as single-agent, short-course GVHD prophylaxis for both acute and chronic GVHD after bone marrow transplantation from HLA-matched donors.

Fig 1.

Transplantation platform. The treatment schema is shown. No additional graft-versus-host disease prophylaxis was administered after post-transplantation cyclophosphamide on days +3 and +4. (*) Busulfan dosing was adjusted based on measured pharmacokinetics, which at Johns Hopkins Hospital and MD Anderson Cancer Center used a test dose and at Fred Hutchinson Cancer Research Center used busulfan targeting in real time. IV, intravenously.

Fig 2.

Transplantation outcomes for nonrelapse mortality and graft-versus-host disease (GVHD) by donor type. Cumulative incidences are shown for (A) nonrelapse mortality; (B) grades 2 to 4 acute GVHD; (C) grades 3 to 4 acute GVHD; and (D) chronic GVHD.

Fig 3.

Disease-free and overall survival. Disease-free and overall survival probabilities are shown for (A and B) all patients, (C and D) patients by donor type, and (E and F) patients by disease status at the time of transplantation. (A and B) Dashed lines represent 95% CIs. AD, active disease; CR, complete remission without MRD; MRD, minimal residual disease.