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MYELODYSPLASTIC SYNDROME

Differential prognostic impact of IDH1 and IDH2 mutations in chronic myelomonocytic leukemia

Leukemia volume 36, pages 1693–1696 (2022)Cite this article

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Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem cell neoplasm characterized by sustained peripheral blood (PB) monocytosis with an inherent risk of acute myeloid leukemia (AML) transformation [1]. CMML is associated with ageing, usually occurring on the background of clonal hematopoiesis [2]. In most patients, TET2 mutations are founder events, occurring in the hematopoietic stem and progenitor cells, with second-order mutations involving TET2 (biallelic) and/or SRSF2 biasing hematopoiesis towards monocytosis [3]. The subsequent acquisitions of ASXL1, DNMT3A, SF3B1, RUNX1 and SETBP1 mutations confer a dysplastic CMML phenotype, while JAK2V617F, NRAS, KRAS, CBL and PTPN11 confer a proliferative CMML phenotype [3, 4]. Of interest, due to the recent development and approval of pharmacological inhibitors, are mutations involving IDH1 and IDH2, seen in <10% of CMML patients [5]. IDH1 and IDH2 mutations confer neomorphic activity in the mutant proteins resulting in the conversion of α ketoglutarate (αKG) to an oncometabolite D-2-hydroxyglutarate (2-HG) [6]. The subsequent accumulation of 2-HG in cells, results in epigenetic dysregulation via inhibition of histone and DNA demethylases, especially TET enzymes [6]. This relationship also makes IDH and TET mutations synergistically lethal and near mutually exclusive [7]. IDH mutations occur in 5–12% of MDS patients and in 20% of AML patients, with Ivosidenib and Enasidenib, being two commercially available IDH1 and IDH2 inhibitors for the management of relapsed/refractory AML [8, 9]. We carried out this study to assess phenotypic and prognostic impacts of IDH1 and IDH2 mutations in a large molecularly annotated cohort of CMML patients.

Institutional Review Board approval was obtained at participating institutions (Mayo Clinic, Rochester, Minnesota and Moffitt Cancer Center, Tampa, Florida) and patients with a diagnosis of CMML, as defined by the 2016 World Health Organization criteria, were included [1]. Bone marrow (BM) biopsy, cytogenetic analysis, and next-generation sequencing were completed at time of diagnosis or first referral (usually within 6 months of diagnosis). Disease and treatment-related data were collected retrospectively. Response assessment was documented as per the 2015 International Working Group (IWG) overlap neoplasm response criteria [10]. Overall survival (OS) and AML-free survival (AML-FS) survival curves were prepared by Kaplan Meier method and compared by log-rank test. OS was defined from date of diagnosis to date of death or loss of follow up. AML-FS was defined from date of diagnosis to date of death, loss to follow-up, or transformation to AML. Cox proportional hazard regression model was used for multivariable analysis. P-values less than 0.05 were considered significant. All statistical calculations were carried out using BlueSky statistical software.

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Fig. 1: Overall and AML-free survival outcomes of IDH1/2 mutated CMML patients, along with detailed phenotypic features of TET2 and IDH co-mutated CMML patients.

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Acknowledgements

We would like to acknowledge the “Henry J. Predolin Leukemia Foundation” at Mayo Clinic for supporting the CMML biobank and all the patients at both institutions for participating in research studies.

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Authors and Affiliations

  1. Alix School of Medicine, Mayo Clinic, Rochester, MN, USA

    Connor Walsh

  2. Division of Hematology and Oncology, Moffitt Cancer Center, Tampa, FL, USA

    Anthony Hunter

  3. Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA

    Terra Lasho, Christy Finke, Ayalew Tefferi, Abhishek Mangaonkar, Naseema Gangat, Aref Al-Kali & Mrinal M. Patnaik

  4. Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA

    Rhett Ketterling & Matthew Howard

  5. Deparmenent of Malignant Hematology, Moffitt Cancer Center, Tampa, FL, USA

    Rami Komrokji, Najla Al Ali & Eric Padron

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  1. Connor Walsh
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Contributions

CW and AH helped with data collection and analysis. TL and CF helped with sequencing. MH helped with pathology review. NAA helped with data statistics. AT, NG, AM, RK, EP and MP helped with manuscript writing and editing.

Corresponding authors

Correspondence to Eric Padron or Mrinal M. Patnaik.

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Competing interests

MP has received research funding from Kura Oncology and Stem Line Pharmaceuticals. The remaining authors declare no competing interests.

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Walsh, C., Hunter, A., Lasho, T. et al. Differential prognostic impact of IDH1 and IDH2 mutations in chronic myelomonocytic leukemia. Leukemia 36, 1693–1696 (2022). https://doi.org/10.1038/s41375-022-01551-y

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