Updated Results from a Phase Ⅱ Clinical Trial：Safety and Efficacy of Azacitidine and Chidamide Maintenance after Allogeneic Hematopoietic Stem Cell Transplantation for Patients with High-Risk Acute Myeloid Leukemia

Background

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is considered a potentially curative treatment for acute myeloid leukemia (AML), but the high recurrence rate after allo-HSCT of high-risk AML is a significant challenge. Effective and tolerable maintenance therapy is necessary, but options are limited. Chidamide, a histone deacetylase inhibitor, has been reported to elicit anti-tumor immune responses in mouse models and has been used for maintenance therapy in other hematological tumors in clinical practice. However, its use as maintenance therapy post allo-HSCT for AML patients has not been reported. Therefore, we conducted a multicenter, single-arm, phase II prospective study to investigate the safety and efficacy of combining azacitidine (AZA) with chidamide as maintenance therapy following allo-HSCT for high-risk AML patients(NCT05270200).

Methods

Patients aged 18-60 years with high-risk AML, defined by the European LeukemiaNet (ELN) 2017 adverse risk group, refractory, relapsed or secondary AML were enrolled. Maintenance therapy began 30 days after transplantation, with AZA administered at 100mg/day (days 1-5) for 6 cycles and chidamide 5mg daily (days 1-28) for up to 2 years. The AZA dose was adjusted to 50mg/m²/day (days 1-3) from Dec 23,2022 due to thrombocytopenia. If platelet(PLT) counts were below 50×10⁹/L or grade 3/4 non-hematological toxicity occured, maintenance was interrupted or delayed until PLT counts exceeded 75×10⁹/L or non-hematological toxicity resolved to ≦ grade 1. The primary endpoints were safety and one-year cumulative incidence of relapse. Secondary endpoints included relapse-free survival (RFS), overall survival (OS) and the incidence of acute and chronic graft-versus-host disease (GVHD).

Results

Eighteen patients were enrolled, with a median age of 46 years (range 26-60). Twelve (66.7%) were diagnosed with ELN 2017 adverse risk, seven (38.9%) had relapsed AML, three (16.7%) had secondary AML and one patient (5.5%) had refractory AML. All but two patients achieved bone marrow complete remission (CR) ,with ten patients (55.6%) being MRD negative and eight patient (44.4%) being MRD positive before transplantation. The median time from transplantation to the start of maintenance therapy was 79.5 days (range 30-182 days). Outcome data were updated as of June 30,2024. The median follow-up time was 7.8 months (range 1.3-28.5 months). Three patients relapsed, with a one-year cumulative incidence of relapse of 20.3% (95%CI, 0.57%-61.1%). One relapsed patient had extramedullary infiltration at 197 days post transplantation and died 11 months after transplant. The other two patients had active disease before transplantation and experienced bone marrow recurrence at 146 and 177 days post-transplantation, respectively. AZA/chidamide was well tolerated. The most common grade 3/4 hematological adverse events (AEs) were neutropenia (33.3%), thrombocytopenia (22.2%) and anemia (5.6%). The AZA dose was amended because platelet transfusion was required for 2 patients due to grade 4 thrombocytopenia; no further grade 4 thrombocytopenia occurred after dose adjustment. The most common non-hematological grade 3/4 AE was pneumonia (27.8%), followed by cGVHD(11.1%), hypopotassaemia (5.6%), nausea(5.6%), Hypoproteinemia(5.6%). No patients developed acute GVHD. Mild, moderate and severe chronic GVHD occurred in three (16.7%), one(5.6%) and one (5.6%) patient, respectively. Mild to moderate chronic GVHD resolved with immunosuppressive agents, while patient with severe chronic GVHD withdrew from the trial due to severe AEs. The median OS was not reached, with six months OS of 100%, one year OS of 85.7% (95%CI, 33.4%-97.9%). The median RFS was not reached, with six months RFS of 88.5% (95%CI, 61.389%-97.011%), one-year RFS of 79.7% (95%CI, 47.9%-93.2%).

Conclusions

Our results indicate that the combination of chidamide and azacitidine as a maintenance therapy for high-risk AML patients post allo-HSCT exhibits promising efficacy and is well-tolerated.

Disclosures

No relevant conflicts of interest to declare.