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. 2025 Feb;60(2):144-153.
doi: 10.1038/s41409-024-02449-2. Epub 2024 Oct 25.

Measurable residual mutated IDH2 before allogeneic transplant for acute myeloid leukemia

Gege Gui  1   2 , Niveditha Ravindra  3 , Pranay S Hegde  3 , Georgia Andrew  3 , Devdeep Mukherjee  3 , Zoë Wong  3 , Jeffery J Auletta  4   5 , Firas El Chaer  6 , Evan C Chen  7 , Yi-Bin Chen  8 , Adam Corner  9 , Steven M Devine  4 , Sunil G Iyer  10 , Antonio Martin Jimenez Jimenez  11 , Marcos J G De Lima  5 , Mark R Litzow  12 , Partow Kebriaei  13 , Wael Saber  14 , Stephen R Spellman  4 , Scott L Zeger  2 , Kristin M Page  14 , Laura W Dillon #  15 , Christopher S Hourigan #  16
Affiliations

Measurable residual mutated IDH2 before allogeneic transplant for acute myeloid leukemia

Gege Gui et al. Bone Marrow Transplant. 2025 Feb.

Abstract

Routine genetic profiling of acute myeloid leukemia (AML) at initial diagnosis has allowed subgroup specific prognostication, drug development, and clinical management strategies. The optimal approach for treatment response assessment for AML subgroups has not yet however been determined. A nationwide cohort of 257 adult patients in first remission (CR1) from AML associated with an IDH2 mutation (IDH2m) undergoing allogeneic transplant during the period 2013-2019 in the United States had rates of relapse and survival three years after transplantation of 24% and 71%, respectively. Pre-transplant clinical flow cytometry assessment was not useful in stratifying patients based on risk of post-transplant relapse or death. DNA-sequencing was performed on CR1 blood collected within 100 days before transplant. Persistent detection of IDH2m was common (51%) and associated with increased relapse and death compared to testing negative. Co-mutation at initial diagnosis with mutated NPM1 and/or FLT3-ITD was common in this cohort (41%) and use of these validated MRD markers provided superior stratification compared to IDH2m testing. Patients testing negative for IDH2m prior to transplant had low relapse-related death, regardless of conditioning intensity. Post-transplant relapse rates for those with persistently detectable IDH2m in pre-transplant remission were lower after the FDA approval of enasidenib in August 2017.

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Conflict of interest statement

Competing interests: The authors declare no competing interests. Ethics approval and consent to participate: Protected health information for research was collected and maintained in CIBMTR’s capacity as a public health authority under the Health Insurance Portability and Accountability Act (HIPAA) privacy rule. All patients provided written informed consent for participation in the National Marrow Donor Program institutional review board–approved CIBMTR database (NCT01166009) and repository (NCT04920474) research protocols. Research was performed in compliance with all applicable federal regulations pertaining to the protection of human research participants and with the approval of the CIBMTR observational research group.

Figures

Fig. 1
Fig. 1. Clinical outcomes of AML patients with IDH2 mutations at baseline and the association with MRD after allogeneic hematopoietic cell transplant.
Cumulative incidence of relapse (left) and overall survival (right) are shown for IDH2 mutated patients (a) for the entire cohort (b) based on the presence (Flow MRDpos) or absence (Flow MRDneg) of reported clinical flow cytometry measurable residual disease (MRD), and (c) based on the presence (IDH2 NGS MRDpos) or absence (IDH2 NGS MRD neg) of residual IDH2 variants by next generation sequencing (NGS) MRD assay.
Fig. 2
Fig. 2. Baseline characteristics for IDH2 mutated AML patients and the association with clinical outcomes after allogeneic hematopoietic cell transplant.
Cumulative incidence of relapse (left) and overall survival (right) are shown for IDH2 mutated patients by the presence (IDH2 NGS MRDpos) or absence (IDH2 NGS MRDneg) of residual IDH2 variants and by (a) age group below 60 years old, (b) age group 60 years or above, (c) different variant allele fraction (VAF) groups, and (d) by IDH2 mutation type.
Fig. 3
Fig. 3. Clinical outcomes for IDH2-mutated AML patients without baseline mutations in NPM1 or FLT3-ITD and the association with residual IDH2 variants.
Cumulative incidence of relapse on the left and overall survival on the right for patients based on the presence (IDH2 NGS MRDpos) or absence (IDH2 NGS MRDneg) of residual IDH2 variants.
Fig. 4
Fig. 4. Clinical outcomes of IDH2-mutated AML patients with co-mutated NPM1 or FLT3-ITD at baseline and the association with residual variants.
Cumulative incidence of relapse on the left and overall survival on the right for patients based on (a) the presence (IDH2 NGS MRDpos) or absence (IDH2 NGS MRDneg) of residual IDH2 variants or (b) the presence of residual NPM1 and/or FLT3-ITD variants (NPM1/FLT3-ITD NGS MRDpos), the presence of only residual IDH2 variants (IDH2 NGS MRDpos), or the absence of residual variants (NGS MRDneg).
Fig. 5
Fig. 5. Evaluation of conditioning intensity modifying the association of residual IDH2 mutations and clinical outcomes.
Cumulative incidence of relapse on the left and overall survival on the right for (a) the entire cohort of IDH2-mutated AML patients, and (b) those ≥60 years of age based on the presence (IDH2 NGS MRDpos) or absence (IDH2 NGS MRDneg) of residual IDH2 variants and conditioning intensity received. MAC myeloablative conditioning, Mel melphalan, RIC reduced intensity conditioning, NMA nonmyeloablative conditioning.
Fig. 6
Fig. 6. The association of enasidenib drug approval date and residual IDH2 mutations on clinical outcomes.
Cumulative incidence of relapse on the left and non-relapse related mortality (NRM) on the right for IDH2-mutated AML patients based on the date of transplant occurring before or after the approval date of enasidenib (August 2017) and the presence (IDH2 NGS MRDpos) or absence (IDH2 NGS MRDneg) of residual IDH2 variants.
See this image and copyright information in PMC

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