Abstract LB180: Isocitrate dehydrogenase (IDH) isoform switch confers resistance to ivosidenib in myelodysplastic neoplasm

Abstract Introduction: Myelodysplastic neoplasms (MDS) are clonal myeloid malignancies characterized by ineffective hematopoiesis and heterogeneous genetic drivers. Mutations in isocitrate dehydrogenase (IDH1/2) occur in a subset of patients and lead to accumulation of the oncometabolite 2-hydroxyglutarate, resulting in epigenetic dysregulation and impaired cellular differentiation. Ivosidenib, a selective IDH1 inhibitor, is approved for IDH1-mutant acute myeloid leukemia and is under investigation in MDS. While responses to IDH inhibition have been observed, acquired resistance is increasingly recognized. Isoform switching between IDH1 and IDH2 has been described as a mechanism of resistance in AML but has not previously been documented in MDS. Methods: We performed longitudinal clinical, hematologic, morphologic, and molecular analysis of an MDS patient with IPSS-R very-low-risk/IPSS-M low-risk disease harboring an IDH1 R132H mutation treated with single-agent ivosidenib. Serial peripheral blood and bone marrow samples were analyzed using targeted next-generation sequencing of myeloid-associated genes to assess clonal dynamics over the course of therapy. Results: The patient achieved a marked hematologic response to ivosidenib, including improvement in neutropenia, anemia, and thrombocytopenia. Early-on-treatment next-generation sequencing demonstrated the stability of the IDH1-mutant clone. With continued therapy, serial molecular profiling revealed a progressive decline in IDH1 variant allele frequency concurrent with the emergence and subsequent expansion of an IDH2 R140Q mutant subclone. This molecular evolution temporally correlated with loss of hematologic response and worsening cytopenia’s, consistent with acquired resistance mediated by IDH isoform switching. Ivosidenib was subsequently discontinued, and the patient was managed with close clinical and molecular surveillance. This clinical report represents the first reported instance of acquired resistance to ivosidenib in MDS mediated by an IDH1-to-IDH2 isoform switch, extending observations previously limited to acute myeloid leukemia. These findings highlight shared mechanisms of clonal evolution across myeloid malignancies, underscore the importance of longitudinal molecular monitoring during IDH inhibitor therapy, and support consideration of dual IDH1/2 inhibition as a rational strategy to mitigate isoform-switch-associated resistance. Citation Format: Nicole Lux, Patrick R. Gonzales, Stephen D. Hyter, Shivani Golem, Wei Cui, Ramesh Balusu, Abdulraheem Yacoub. Isocitrate dehydrogenase (IDH) isoform switch confers resistance to ivosidenib in myelodysplastic neoplasm [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr LB180.