Chidamide in HR-AML

Overview

Acute myeloid leukemia (AML) patients with fusion gene-positive including core binding factor (CBF), mixed-lineage leukemia (MLL) gene rearrangement have a high incidence of relapse if they have continuously positive measurable residual disease (MRD) or ELN 2022-high risk chromosome abnormality and could not be bridged to allogenetic heamatopoitic stem cell transplantation (allo-HSCT). Histone deacetylase (HDAC) is known to abnormally recruit in these fusion gene-positive AML, and has been proven to be a promising therapy target. Whether HDAC inhibitor chidamide could be used as a maintenance therapy in these AML patients remains unknown. This study aims to evaluate the efficacy and safety of chidamide in the maintenance therapy of high-risk acute myeloid leukemia (AML) patients with core binding factor (CBF) and measurable residual disease (MRD) positivity, or ELN 2022-high risk fusion gene positive.

Despite the above data providing positive signals for the application of chidamide in fusion gene AML, particularly in high-risk patients, there remain significant gaps in the evidence: 1) most supportive data come from combination therapy in relapsed/refractory settings or post-transplant interventions, and systematic studies on its use as a post-remission maintenance therapy after initial induction are still lacking; 2) existing studies related to maintenance therapy are mostly small-sample retrospective analyses, lacking supportive data from prospective, or multi-center, or large scale designs; 3) for the definition of 'high-risk,' especially incorporating 'MRD-positive' as a strong prognostic indicator in patient selection criteria and evaluating the value of maintenance therapy accordingly, research is still insufficient. Based on the clinical dilemma of high relapse risk after remission in high-risk fusion gene AML patients, and the scientific rationale of chidamide exerting anti-leukemia effects through multiple mechanisms such as correcting epigenetic abnormalities, inducing differentiation, and modulating immunity, combined with its efficacy and safety signals in R/R and post-transplant settings, we propose conducting clinical research on chidamide as maintenance therapy in high-risk fusion gene-positive AML. This study aims to focus on the high-risk patient group who have completed standard induction and consolidation therapy, achieved morphological remission but remain MRD-positive (including CBF-AML and MLL-r AML), who are at extremely high risk of relapse under current standard treatment, and may be unable or not planning to undergo allo-HSCT due to age, comorbidities, or lack of suitable donors. Evaluating whether chidamide as maintenance therapy can effectively clear MRD, reduce relapse rates, prolong disease-free survival and overall survival, and clarify its safety profile in this specific population has significant clinical and scientific value, and is expected to provide a new and effective maintenance therapy option for this high-risk AML population, improving their long-term prognosis. Therefore, conducting this study is an important exploration responding to urgent clinical needs, continuing the chain of evidence from basic and preclinical studies, and striving to fill the gap in the field of maintenance therapy for high-risk AML.