Safety and Efficacy of Azacitidine and Chidamide Maintenance after Allogeneic Hematopoietic Stem Cell Transplantation for Patients with High-Risk Acute Myeloid Leukemia: Interim Analysis of a Prospective, Multicenter, Single-Arm, Phase Ⅱ Clinical Trial

Abstract

Background Although allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the potentially curative therapy for AML, the relapse rate after HSCT is high with 30-60% for patients with high-risk AML. Maintenance therapy with efficacy and low toxicity is needed to mitigate relapse. It has been reported that histone deacetylases inhibitor chidamide exhibits anti-tumor activity against AML cells, and is able to elicit anti-tumor immune response in mouse models. However, efficacy and safety of chidamide as maintenance therapy following allo-HSCT for patients with AML have not been reported. Therefore, we designed a multicenter, single arm, phase II clinical trial for high-risk AML patients to use azacitidine combined with chidamide as maintenance therapy post allo-HSCT to prevent relapse. Methods In this multicenter, single arm, phase II clinical trial, patients aged 18-60 years with high-risk AML, defined as the European LeukemiaNet (ELN) 2017 adverse risk group, refractory, relapsed or secondary AML were given AZA and chidamide as maintenance therapy after 60 days post transplantation (NCT05270200). AZA was given at 100mg/day (days 1-5) for 6 cycles and chidamide 5mg daily (days 1-28) with a cycle of 28 days for up to 2 years. The dose of AZA was amended at 50mg/m 2/day (days 1-3) from Dec 23,2022 due to occurrence of thrombocytopenia. If PLT was below 50×10 9/L or grade 3/4 non-hematological toxicity occurs, maintenance should be interrupted or delayed until PLT count was greater than 75×10 9/L or the non-hematological toxicity resolved to ≦ grade 1. Primary objectives were safety and one year cumulative incidence of relapse. Secondary objections were relapse-free survival (RFS), overall survival (OS) and incidence of severity of acute and chronic graft-versus-host disease (GVHD). Results From February 12,2022 to June 30,2023, seven patients were enrolled, with a median age of 46 years（28-60), four patients (57%) were female. One patient (14%) received matched sibling donor transplantation, six patients (86%) received haploidentical donor transplantation. Five patients (71%) received myeloablative and 2/7 (29%) reduced intensity conditioning regimen. Six (86%) were in ELN 2017 adverse risk with three patients harboring KMT2A rearrangement, one patient with TP53 mutation, one patient with -7, one patient with RUNX1 mutation, while one patient (14%) was diagnosed as secondary AML with broad extramedullary infiltration. All but one patients entered transplant in CR, while five patients (83%) were MRD negative and one patient (17%) were positive. The baseline patient characteristics are summarized in Table1. Outcome data were updated as of June 30,2023 (Figure1). The median time to start maintenance therapy after transplantation was 77 days (range 64-80). The median follow-up time was 9.9 months, only one patient relapsed and the accumulative incidence of relapse of one year was 16.7%（95%CI,0.4%-64.1%). The relapsed patient diagnosed with MLL-AF10 rearrangement had extramedullary infiltration of left tonsil, gum and neck lymph nodes at 197 days post transplantation while bone marrow remained in MRD negative remission. AZA/chidamide were well tolerated, with no severe adverse event was recorded. Two grade 3/4 non-hematologic adverse events were observed, with one increased bilirubin due to cGVHD and one pneumonia. Two patients (29%) experienced grade4 thrombocytopenia requiring platelet transfusion. After amendment of AZA dose, no grade4 thrombocytopenia was recorded. No one discontinued treatment due to toxicity. During follow-up, none of patients had aGVHD. Three patients (43%) experienced mild or moderate cGVHD, no severe cGVHD was observed. The median OS was not reached, with six months and one year OS both of 100%. The median RFS is not reached, with six months and one year RFS of 100% and 83.3%(95%CI,35.9%-99.6%). Conclusions Preliminary results suggest that maintenance of AZA combined with chidamide post allo-HSCT in patients with high-risk AML exhibits promising efficacy and well-tolerated. Recruitment of patients with high-risk AML post allo-HSCT for this trial is ongoing. Disclosures No relevant conflicts of interest to declare.