Effect of rhG-CSF Combined with Decitabine Prophylaxis on Relapse in High-Risk Acute Myeloid Leukemia Patients after Hematopoietic Stem Cell Transplantation: An Open-Label, Multicenter, Randomized, Controlled, Phase 2 Trial

Background: Recurrence is a major cause of treatment failure after allogeneic hematopoietic stem cell transplantation (allo-HSCT) for high-risk acute myeloid leukemia (HR-AML). Recent studies have indicated that granulocyte colony-stimulating factor (G-CSF) and DNA methyltransferase inhibitor Decitabine (Dec) have regulatory effects on T/B/NK lymphocytes and could help enhance the graft versus leukemia (GVL) effect after allo-HSCT. The aim of this study was to prove G-CSF combined with minimal-dose Dec could effectively prevent AML relapse after allo-HSCT. Methods: We did an open-label, multicenter, randomized, controlled, phase 2 trial. 204 HR-AML patients 60-100 days after allo-HSCT were randomized 1:1 to either rhG-CSF combined with minimal-dose decitabine (G-Dec: G-Dec group: 100 µg/m2 of rhG-CSF subcutaneous injection on days 0-5 and 5 mg/m2 of Dec infusion on days 1-5) or no intervention (non-G-Dec) groups. The primary outcome of the trial was relapse after transplantation, and the secondary outcomes were chronic graft-versus-host disease (cGVHD), the safety of the treatment, leukemia-free survival and overall survival. Findings: Between Apr 1, 2016, and Mar 21, 2019, 220 patients from 12 transplant centers were included in the clinical study, and 204 patients were randomly assigned to the study groups (102 patients in the G-Dec group and 102 patients in non-G-Dec group). Median follow-up was 30 months (IQR 6-38). Of 204 evaluable patients, the estimated cumulative incidence of 2-year relapse in the G-Dec group was 15.1 (95% CI 8.0-22.2) %, compared with 38.3 (95% CI 28.9-47.7) % in the non-G-Dec group (P<0.001). There was no difference between the two groups in the incidence of cGVHD without relapse (23.8[95% CI 15.4-32.2] % and 25.6[95% CI 16.2-35.0] %, p=0.844). The most common treatment-emergent adverse event (TEAE) was hypoleukocytosis. After rhG-CSF combined with minimal-dose Dec maintenance, increasing numbers of NK, CD8+ T and regulatory T (Treg) cells were observed. Interpretation: Our findings suggest that rhG-CSF combined with minimal-dose Dec maintenance after allo-HSCT can reduce the incidence of relapse, accompanied by changes in the numbers and subtypes of lymphocytes, leading to the acquisition of graft-versus-leukemia and immune tolerance. Trial Registration: This study is registered with www.chictr.org.cn, number ChiCTR-IIR-16008182. Funding Statement: This research was supported by the National Key Research and Development Program of China (2016YFA0202104 and 2017YFA0105504), the Chinese National Natural Science Foundation (No. 81370593, No. 81570131 and No. 81570097), the Chongqing Social Undertakings, People's Livelihood Guarantee and Technology Innovation Foundation (cstc2016shms-ztzx10003), the Chongqing Key Project of Basic and Frontier Research Program (cstc2015jcyjBX0077), the Chongqing National Natural Science Key Foundation (cstc2019jcyj-zdxmX0023), the Research Fund from the Clinical Foundation of Army Medical University (2018JSLC0034) and Xinqiao Hospital (2018YQYLY007). Declaration of Interests: All authors have agreed to the submission of this manuscript and have no conflicting financial interests to disclose. Ethics Approval Statement: The protocol and all amendments were approved by the China Registered Clinical Laboratory Ethics Committee and the institutional review boards at each of the 12 participating institutions.