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Persistent IDH mutations are not associated with increased relapse or death in patients with IDH-mutated acute myeloid leukemia undergoing allogeneic hematopoietic cell transplant with post-transplant cyclophosphamide

Bone Marrow Transplantation volume 59, pages 428–430 (2024)Cite this article

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In patients with acute myeloid leukemia (AML) there is considerable evidence that suggests that measurable residual disease (MRD) detection during and after treatment [1], and particularly before allogeneic hematopoietic cell transplantation (alloHCT), predicts subsequent relapse and inferior survival outcomes [2, 3]. ELN guidelines recommend the use of validated molecular tests for AML MRD where available, but the appropriate targets for such monitoring are incompletely defined [4]. Mutations in the epigenetic regulator Isocitrate Dehydrogenase (IDH) genes are observed in approximately 20% of patients diagnosed with AML [5]. AlloHCT may improve outcomes for such patients [6, 7]. To further investigate the utility of persistent IDH1 and IDH2 mutations as AML MRD markers, we screened for the detection of these variants at pre- and post-transplant remission timepoints in a cohort of AML patients undergoing alloHCT.

Consecutive adult patients between 2015 and 2020 with IDH-mutated AML who achieved complete remission (CR) and underwent non-myeloablative alloHCT with cyclophosphamide-based graft versus host disease prophylaxis at the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center were included in this study. Patient characteristics and outcomes for this cohort have been previously reported [8], although five patients were excluded because samples were not available (Supplementary Fig. 1). Written and informed consent was obtained from all patients and the study was approved by the internal ethics committee in accordance with the Declaration of Helsinki. Patients were followed up for a median of 1048 days post-alloHCT (range: 96–2413 days). Baseline and relapse bone marrow DNA samples were sequenced using the 75-gene VariantPlex myeloid panel (ArcherDx, Boulder, CO). Assessment for persistent IDH mutations was performed on pre- and post-alloHCT remission samples using droplet digital PCR (ddPCR) or a custom error-corrected targeted next-generation sequencing panel (ecNGS). Additional clinical and testing details are provided in Supplementary Data 1–5.

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Fig. 1: Overall survival, relapse-free survival, cumulative incidence of relapse, and a comparison of variants identified at baseline and at relapse for select patients.

Data availability

Datasets generated from this study are available on the Sequencing Reads Archive (https://www.ncbi.nlm.nih.gov/sra) using the following accession number: PRJNA998386.

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Acknowledgements

This work was supported by the Intramural Research Program of the National Heart, Lung, and Blood Institute and grants from the National Institutes of Health/National Cancer Institute (P01 CA225618, P30 CA06973). Sequencing was performed at the DNA Sequencing and Genomics core. The Center for Cancer Research Genomics core provided support for digital droplet PCR experiments.

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Author notes

  1. These authors contributed equally: Christopher S. Hourigan, Alexander J. Ambinder.

Authors and Affiliations

  1. Laboratory of Myeloid Malignancies, Hematology Branch, National Heart Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA

    Niveditha Ravindra, Laura W. Dillon, Gege Gui & Christopher S. Hourigan

  2. Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA

    Matthew Smith, Lukasz P. Gondek, Richard J. Jones & Alexander J. Ambinder

  3. Bio-Rad Laboratories, Digital Biology Group, 5731, W. Las Positias Blvd, Pleasanton, CA, USA

    Adam Corner

  4. Myeloid Malignancies Program, National Institutes of Health, Bethesda, MD, USA

    Christopher S. Hourigan

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  1. Niveditha Ravindra
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Contributions

NR designed the study, conducted the research, analyzed and interpreted the results, and wrote the manuscript. LWD designed the study, conducted the research, analyzed, and interpreted the results. GG performed the statistical analysis for outcomes. MS, LPG, and RJJ collected samples and clinical data and provided clinical input. AC aided in the design and interpretation of droplet digital PCR experiments. AJA and CSH conceived and designed the study, collected samples, reviewed the results, and provided clinical input. All authors reviewed and approved the final manuscript.

Corresponding author

Correspondence to Christopher S. Hourigan.

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Competing interests

The National Heart, Lung, and Blood Institute receives research funding for the laboratory of CSH from the Foundation of the NIH AML MRD Biomarkers Consortium. AC is an employee and shareholder in Bio-Rad Laboratories. All other authors report no relevant conflict of interest.

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Ravindra, N., Dillon, L.W., Gui, G. et al. Persistent IDH mutations are not associated with increased relapse or death in patients with IDH-mutated acute myeloid leukemia undergoing allogeneic hematopoietic cell transplant with post-transplant cyclophosphamide. Bone Marrow Transplant 59, 428–430 (2024). https://doi.org/10.1038/s41409-023-02189-9

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