IDH2 Clonal Hematopoiesis and IKAROS Loss Cooperate in a B-ALL Subtype after Lenalidomide Therapy for Multiple Myeloma

Lenalidomide, a maintenance treatment in multiple myeloma first-line therapy, increases the risk of secondary malignancies, including B-cell precursor acute lymphoblastic leukemia (B‑ALL). We present a comprehensive molecular characterization of 57 patients with lenalidomide-associated B-ALL (LenB-ALL), revealing three mutational subgroups: (1) TP53mt (30%), (2) IDH2mt (p.R140Q) (23%) and (3) other, including NRAS/KRASmt. Remarkably, IDH2 R140Q mutations were highly enriched in LenB-ALL compared to primary B-ALL (p<0.001). Furthermore, IKZF1 intragenic deletions - often subclonal and likely RAG-mediated - were observed in 54% (7/13) of IDH2mt LenB-ALL cases. IDH2 mutations were not restricted to the leukemic clone: they persisted during MRD-negative remission and were identified in lymphoid as well as myeloid cell populations using fluorescence-activated cell sorting and single-cell RNA sequencing. This indicates a preleukemic origin of the IDH2 mutation within the context of clonal hematopoiesis. Transcriptomic and DNA methylation analyses revealed a distinct gene expression profile and a DNA hypermethylation phenotype in IDH2mt LenB-ALL, including IDH2mt-specific as well as lenalidomide-associated features. We propose that lenalidomide promotes expansion of IDH2-mutated clonal hematopoiesis and, via IKAROS downregulation, induces a maturation arrest at the B-cell precursor stage. Subsequent genetic or epigenetic alterations render leukemogenesis independent of ongoing lenalidomide exposure. Altogether, these data define IDH2mt B-ALL as a distinct molecular subtype that is markedly overrepresented after lenalidomide treatment and highlight clonal hematopoiesis as a key contributing factor in the development of LenB-ALL.

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Journal
Blood
Published
2026-03-13
DOI
https://doi.org/10.1182/blood.2025031047
Primary Topic
Acute Myeloid Leukemia Research
Type
article
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0.00

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article

IDH2 Clonal Hematopoiesis and IKAROS Loss Cooperate in a B-ALL Subtype after Lenalidomide Therapy for Multiple Myeloma

Raúl F. Pérez, Krischan Braitsch, Thomas Beder, Felix Klingler et al.
Blood
Acute Myeloid Leukemia Research
article

IDH2 Clonal Hematopoiesis and IKAROS Loss Cooperate in a B-ALL Subtype after Lenalidomide Therapy for Multiple Myeloma

Raúl F. Pérez, Krischan Braitsch, Thomas Beder, Felix Klingler, Johanna Horns, Snjezana Janjetovic, M. Neumann, Mayukh Mondal, Michaela Kotrová, Lorenz Bastian, Stefan Schwartz, Sonja Bendig, Malwine Barz, W. Fiedler, Aeint-Steffen Ströh, Boris Böll, Lars Velten, Klaus Wethmar, Katharina Iben, B. Steffen, Lennart Lenk, Maher Hanoun, Hauke Busch, Christoph Faul, Cecilia Bozzetti, Wiebke Weßels, V Bücklein, J Duell, Guranda Chitadze, Christoph Röllig, Axel Künstner, Nikos Darzentas, Monika Brüggemann, Stefan Knop, Bernd M Spriewald, José-Ignacio Martín-Subero, Nicola Gökbuget, Claudia D Baldus
article en

Abstract

Lenalidomide, a maintenance treatment in multiple myeloma first-line therapy, increases the risk of secondary malignancies, including B-cell precursor acute lymphoblastic leukemia (B‑ALL). We present a comprehensive molecular characterization of 57 patients with lenalidomide-associated B-ALL (LenB-ALL), revealing three mutational subgroups: (1) TP53mt (30%), (2) IDH2mt (p.R140Q) (23%) and (3) other, including NRAS/KRASmt. Remarkably, IDH2 R140Q mutations were highly enriched in LenB-ALL compared to primary B-ALL (p<0.001). Furthermore, IKZF1 intragenic deletions - often subclonal and likely RAG-mediated - were observed in 54% (7/13) of IDH2mt LenB-ALL cases. IDH2 mutations were not restricted to the leukemic clone: they persisted during MRD-negative remission and were identified in lymphoid as well as myeloid cell populations using fluorescence-activated cell sorting and single-cell RNA sequencing. This indicates a preleukemic origin of the IDH2 mutation within the context of clonal hematopoiesis. Transcriptomic and DNA methylation analyses revealed a distinct gene expression profile and a DNA hypermethylation phenotype in IDH2mt LenB-ALL, including IDH2mt-specific as well as lenalidomide-associated features. We propose that lenalidomide promotes expansion of IDH2-mutated clonal hematopoiesis and, via IKAROS downregulation, induces a maturation arrest at the B-cell precursor stage. Subsequent genetic or epigenetic alterations render leukemogenesis independent of ongoing lenalidomide exposure. Altogether, these data define IDH2mt B-ALL as a distinct molecular subtype that is markedly overrepresented after lenalidomide treatment and highlight clonal hematopoiesis as a key contributing factor in the development of LenB-ALL.

Blood
Goethe University Frankfurt (DE), Universität Hamburg (DE), Friedrich-Alexander-Universität Erlangen-Nürnberg (DE), LMU Klinikum (DE), Hochschule für Angewandte Wissenschaften Kiel (DE), Christian-Albrechts-Universität zu Kiel (DE), Universitätsklinikum Tübingen (DE), University Hospital Münster (DE), University Medical Center Hamburg-Eppendorf (DE), University Hospital Schleswig-Holstein (DE), Essen University Hospital (DE), University Cancer Center Hamburg (DE), Universitätsklinikum Würzburg (DE), University Hospital Frankfurt (DE), Centre for Genomic Regulation (ES), University Hospital Cologne (DE), Helios Hospital Berlin-Buch (DE), Consorci Institut D'Investigacions Biomediques August Pi I Sunyer (ES), Clinical Research Center Kiel (DE), Technische Universität Dresden (DE), Charité - Universitätsmedizin Berlin (DE), Ludwig-Maximilians-Universität München (DE), University of Lübeck (DE)
Amgen, Pfizer, Deutsche Forschungsgemeinschaft, José Carreras Leukämie-Stiftung, Servier, Science and Engineering Research Board
Good health and well-being
Openalex Percentile: Top 22%
Acute Myeloid Leukemia Research
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