AML-388: KDM6A Mutation in AML

Abstract

Introduction Loss of KDM6A expression has been reported as a potential drug resistance mechanism in AML. Here, we describe the clinical characteristics and treatment outcomes in our cohort of AML patients with KDM6A mutations. Methods We annotated a cohort of 293 AML patients who were treated at our center between Jan 2016 and Dec 2019. These cases were subjected to multiamplicon targeted deep NGS, including all ORFs of KDM6A and other recurrently mutated myeloid genes among a panel of 54 genes. Results Total of eleven patients (3.75%) were found to have KDM6A mutation. Median age at the time of mutation detection was 68 years. At the time of KDM6A mutation detection, three patients were newly diagnosed (2.6% of new diagnosis), three were in complete remission (CR), and the remaining five were in relapse stage (5.31% of relapsed patients). Missense mutation was the most common mutation type (five patients), followed by frameshift (three patients), splicing variant (two patients), and intronic mutation (one patient). Among eight patients who had active AML at the time of KDM6A mutation detection, five had adverse risk cytogenetics features, and seven had a co-existent mutation in other genes (most common in epigenetic regulator genes in five). Among three newly diagnosed patients, two patients died during induction; one patient required two cycles of daunorubicin and cytarabine before achieving CR, and at the time of relapse was noted to have the same mutation. Among five patients who were in relapse at the time of mutation detection, two of them were refractory to three different induction regimens at the time of initial diagnosis; both achieved CR after allogeneic stem cell transplant (ASCT), but relapsed after 13 and 98 months. None of the patients with relapse achieved CR with chemotherapy, but one with ASCT, and continues to be in remission at 22-month follow-up. Among three patients who were in CR at the time of KDM6A mutation detection, two of them have monoclonal plasma cells in bone marrow, and one patient had an allele frequency of 100%, likely germ cell origin. Conclusion KDM6A gene mutations are rare in AML and associated with poor response to chemotherapy.