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Clonal evolution in patients developing therapy-related myeloid neoplasms following autologous stem cell transplantation

Bone Marrow Transplantation volume 57, pages 460–465 (2022)Cite this article

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Abstract

Clonal hematopoiesis (CH) denotes somatic mutations in genes related to myeloid neoplasms present at any variant allele frequency (VAF). Clonal hematopoiesis is associated with increasing age and with a factor 6 increase in the risk of developing therapy-related myeloid neoplasms (tMNs) following autologous stem cell transplantation (ASCT). However, the impact of specific mutations on progression from CH to tMN has yet to be unraveled, and it remains unclear whether mutations directly impact or even drive the development of tMN. We performed deep sequencing in longitudinal samples from a cohort of 12 patients with either multiple myeloma or lymphoma who developed tMN following ASCT. Nine patients had one or more mutations that could be tracked longitudinally. Seven patients had clonal expansion from time of ASCT to diagnosis of tMN. Of these, six patients had CH at VAF < 2% at baseline. The median VAF of non-DNMT3A clones increased from 1% (IQR 0.7%–10.0%) at time of ASCT to 37% (IQR 17%–47%) at tMN diagnosis (P = 0.002), while DNMT3A clones showed quiescent trajectories (P = 0.625). Our data provide evidence to support the hypothesis that the development of tMN following ASCT is likely instigated by CH present at VAFs as low as 0.5%, detectable years before tMN onset.

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Fig. 1: Mutations detected at time of ASCT and at tMN diagnosis.
Fig. 2: Clonal evolution of clones from time of ASCT until diagnosis of tMN.

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Acknowledgements

The authors thank Henriette Rugholm Petersen for expert technical assistance. This work was supported by grants from the Danish Cancer Society, the Health Research Foundation of Central Denmark Region, the Wørzner Memorial Foundation for Cancer research, the Agriculturalist of ‘Ølufgård’ - Peder Nielsen Kristensen’s Memorial Foundation and the Karen Elise Jensen Foundation.

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Author notes

  1. These authors contributed equally: Anne Stidsholt Roug and Maja Ludvigsen.

Authors and Affiliations

  1. Department of Hematology, Aarhus University Hospital, Aarhus, Denmark

    Johannes Frasez Soerensen, Anni Aggerholm, Carina Agerbo Rosenberg, Marie Bill, Lene Hyldahl Ebbesen, Marcus Høy Hansen, Anne Stidsholt Roug & Maja Ludvigsen

  2. Department of Pathology, Aarhus University Hospital, Aarhus, Denmark

    Gitte Birk Kerndrup

  3. Department of Clinical Medicine, Aalborg University, Aalborg, Denmark

    Anne Stidsholt Roug

  4. Department of Clinical Medicine, Aarhus University, Aarhus, Denmark

    Maja Ludvigsen

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Contributions

JFS, ASR and ML designed the study, interpreted the data and wrote the manuscript. JFS and ASR identified patients for the study. GBK revised the tMN biopsies. CR and MB designed and conducted the flow cytometric evaluations. AA, MHH and JFS performed and interpreted the NGS analyses. ASR and ML share the last authorship. All authors have critically read and approved the manuscript prior to publication.

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Correspondence to Johannes Frasez Soerensen.

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Soerensen, J.F., Aggerholm, A., Rosenberg, C.A. et al. Clonal evolution in patients developing therapy-related myeloid neoplasms following autologous stem cell transplantation. Bone Marrow Transplant 57, 460–465 (2022). https://doi.org/10.1038/s41409-022-01567-z

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