Decitabine induction with myeloablative conditioning and allogeneic hematopoietic stem cell transplantation in high-risk patients with myeloid malignancies is associated with a high rate of infectious complications

Abstract

Patients with high-risk myelodysplastic syndrome or acute myeloid leukemia have an increased risk of death following allogeneic hematopoietic stem cell transplantation (allo-HSCT). Decitabine has minimal non-hematologic toxicity and proven efficacy in myeloid diseases, and post-transplant cyclophosphamide (PTCy) has reduced rates of graft-versus-host-disease (GVHD). We hypothesized that decitabine induction with allo-HSCT and PTCy would improve outcomes in a high-risk myeloid disease population. We performed a phase-II trial of decitabine at 20 mg/m2 for 10 days followed by allo-HSCT using a myeloablative regimen of fludarabine, IV busulfan and 4 Gy total body irradiation with PTCy for GVHD prophylaxis. Twenty patients underwent decitabine induction and 17 patients proceeded to transplant per protocol. Median overall survival from decitabine induction was 210 days (95 % CI 122-not reached). All patients developed grade 4 neutropenia after decitabine, eleven patients (55 %) developed grade 3-4 infections, and 5 cases were fatal. There were 5/20 (25 %) long-term survivors with a median follow-up of 3.6 years. Decitabine induction followed by myeloablative allo-HSCT in a high-risk population was associated with a high risk of infection and mortality related to enhanced immunosuppression. Further exploration of decitabine conditioning on reduced intensity platforms and improved infectious prophylaxis and screening may better mitigate toxicity (ClinicalTrials.gov (NCT01707004)).

Keywords: Allogeneic hematopoietic stem cell transplant; Clinical trial; Decitabine; High-risk myeloid disease; Immunosuppression; Infection.

Conflict of interest statement

CONFLICT OF INTEREST DECLARATION: Dr. Ryan Mattison served on a Pfizer editorial board in 2017. All other authors have no relevant conflicts of interest to disclose.

Copyright © 2020 Elsevier Ltd. All rights reserved.

Figures

Figure 1:. Treatment Schema

Treatment doses: Decitabine: 20 mg/m2 IV x 10 days for 1 cycle, Fludarabine: 50 mg/m2/day, Busulfan: 3.2 mg/kg/day age ≤60, Busulfan: 2.4 mg/kg/day age >60. Steady-state busulfan target levels listed above. Flu: fludarabine CTX: cyclophosphamide MMF: mycophenolate mofetil. TBI: total body irradiation.

Figure 2:. Subject Flowchart

Study flowchart for patient outcomes and reporting.

Figure 3:. Overall and Non-Relapse Survival

A: Overall survival (OS) from time of transplant for those undergoing transplant on protocol (n=17). B: OS from initiation of decitabine for all patients enrolled (n=20). Shaded area represents the 95% confidence interval for the K-M estimates. C: Incidence of non-relapse mortality using death from disease as a competing risk from day of transplant (n=17 evaluable).