Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

LYMPHOMA

Clonal hematopoiesis is associated with hematological toxicity during lenalidomide-based therapy for MCL

Leukemia volume 36, pages 2912–2916 (2022)Cite this article

Subjects

Lenalidomide is widely used to treat mantle cell lymphoma (MCL) and multiple myeloma (MM). It is however associated with development of serious adverse events, mainly in the category of hematological toxicities [1, 2]. Dose-reductions due to grade 3/4 cytopenia, limiting treatment efficacy, are generally seen in more than 50% of lymphoma patients treated with single-agent lenalidomide. It is unclear how lenalidomide affects the hematopoietic system in patients with lymphoma.

Large clinical trials have tested the addition of lenalidomide to standard immunochemotherapy regimens [2, 3], but cytopenias has been a major obstacle for optimal dosing. There is need for a biomarker to identify patients who develop severe hematological toxicity during lenalidomide treatment. It is furthermore unknown why lenalidomide infers a small, but significant risk of therapy-related leukemia (t-AML/MDS) in patients with lymphoproliferative cancers [4].

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Characteristics of clonal hematopoiesis and its relation to hematological toxicity in MCL patients treated with lenalidomide-based therapy.
Fig. 2: Survival of patients grouped by size of CH clones and evolution of CH during lenalidomide-based therapy.

Data availability

Data on genetic alterations supplied in Supplementary material. Due to European Union GDPR law, data directly linking clinical annotation and genetics cannot be reposited in publicly available databases. Please contact the corresponding author for inquiries regarding data sharing.

References

  1. Ruan J, Martin P, Shah B, Schuster SJ, Smith SM, Furman RR, et al. Lenalidomide plus rituximab as initial treatment for mantle-cell lymphoma. N Engl J Med. 2015;373:1835–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Nowakowski GS, Hong F, Scott DW, Macon WR, King RL, Habermann TM, et al. Addition of lenalidomide to R-CHOP Improves outcomes in newly diagnosed diffuse large B-cell lymphoma in a randomized phase II US Intergroup Study ECOG-ACRIN E1412. J Clin Oncol. 2021;39:1329–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Tilly H, Morschhauser F, Casasnovas O, Molina TJ, Feugier P, Gouill SL, et al. Lenalidomide in combination with R-CHOP (R2-CHOP) as first-line treatment of patients with high tumour burden follicular lymphoma: a single-arm, open-label, phase 2 study. Lancet Haematol. 2018;5:e403–e410.

    Article  PubMed  Google Scholar 

  4. Musto P, Anderson KC, Attal M, Richardson PG, Badros A, Hou J, et al. Second primary malignancies in multiple myeloma: an overview and IMWG consensus. Ann Oncol J Eur Soc Med Oncol. 2017;28:228–45.

    Article  CAS  Google Scholar 

  5. Mouhieddine TH, Sperling AS, Redd R, Park J, Leventhal M, Gibson CJ, et al. Clonal hematopoiesis is associated with adverse outcomes in multiple myeloma patients undergoing transplant. Nat Commun. 2020;11:2996.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Chitre S, Stölzel F, Cuthill K, Streetly M, Graham C, Dill C, et al. Clonal hematopoiesis in patients with multiple myeloma undergoing autologous stem cell transplantation. Leukemia. 2018;32:2020–4.

    Article  PubMed  Google Scholar 

  7. Boyle EM, Williams L, Blaney P, Ashby C, Bauer M, Walker BA, et al. Improving prognostic assignment in older adults with multiple myeloma using acquired genetic features, clonal hemopoiesis and telomere length. Leukemia. 2022;36:221–4.

    Article  PubMed  Google Scholar 

  8. Wudhikarn K, Padrnos L, Lasho T, LaPlant B, Kumar S, Dispenzieri A, et al. Clinical correlates and prognostic impact of clonal hematopoiesis in multiple myeloma patients receiving post-autologous stem cell transplantation lenalidomide maintenance therapy. Am J Hematol. 2021;96:E157–E162.

    Article  CAS  PubMed  Google Scholar 

  9. Jerkeman M, Eskelund CW, Hutchings M, Räty R, Wader KF, Laurell A, et al. Ibrutinib, lenalidomide, and rituximab in relapsed or refractory mantle cell lymphoma (PHILEMON): a multicentre, open-label, single-arm, phase 2 trial. Lancet Haematol. 2018;5:e109–e116.

    Article  PubMed  Google Scholar 

  10. Eskelund CW, Husby S, Favero F, Klausen TW, Rodriguez-Gonzalez FG, Kolstad A et al. Clonal hematopoiesis evolves from pre-treatment clones and stabilizes after end of chemotherapy in patients with MCL. Blood. 2020. https://doi.org/10.1182/blood.2019003539.

  11. Gibson CJ, Lindsley RC, Tchekmedyian V, Mar BG, Shi J, Jaiswal S, et al. Clonal hematopoiesis associated with adverse outcomes after autologous stem-cell transplantation for lymphoma. J Clin Oncol. 2017;35:1598–605.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Husby S, Favero F, Nielsen C, Sørensen BS, Bæch J, Grell K, et al. Clinical impact of clonal hematopoiesis in patients with lymphoma undergoing ASCT: a national population-based cohort study. Leukemia. 2020. https://doi.org/10.1038/s41375-020-0795-z.

  13. Sperling AS, Guerra VA, Kennedy JA, Yan Y, Hsu JI, Wang F et al. Lenalidomide promotes the development of TP53-mutated therapy-related myeloid neoplasms. Blood. 2022. https://doi.org/10.1182/blood.2021014956.

  14. Jädersten M, Saft L, Smith A, Kulasekararaj A, Pomplun S, Göhring G, et al. TP53 mutations in low-risk myelodysplastic syndromes with del(5q) predict disease progression. J Clin Oncol. 2011;29:1971–9.

    Article  PubMed  Google Scholar 

  15. Santini V, Fenaux P, Giagounidis A, Platzbecker U, List AF, Haferlach T, et al. Impact of somatic mutations on response to lenalidomide in lower-risk non-del(5q) myelodysplastic syndromes patients. Leukemia. 2021;35:897–900.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

We thank all patients and study sites for participating in the clinical trial.

Funding

The research was supported by Rigshospitalets Research Foundation and the Novo Nordisk Foundation (Novo Nordisk Foundation Center for Stem Cell Biology, DanStem; grant NNF17CC0027852). The project is part of the Danish Research Center for Precision Medicine in Blood Cancers funded by the Danish Cancer Society grant no. R223-A13071 and Greater Copenhagen Health Science Partners. The clinical trial was investigator-initiated and supported by Janssen and Celgene.

Author information

Authors and Affiliations

  1. Department of Hematology, Rigshospitalet, Copenhagen, Denmark

    Simon Husby, Cecilie Bæch-Laursen, Christian W. Eskelund, Martin Hutchings, Lone Bredo Pedersen, Carsten U. Niemann & Kirsten Grønbæk

  2. Biotech Research and Innovation Center (BRIC), University of Copenhagen, Copenhagen, Denmark

    Simon Husby, Cecilie Bæch-Laursen, Christian W. Eskelund, Francesco Favero, Jakob Schmidt Jespersen, Joachim Weischenfeldt & Kirsten Grønbæk

  3. Finsen Laboratory, Rigshospitalet, Copenhagen, Denmark

    Francesco Favero, Jakob Schmidt Jespersen & Joachim Weischenfeldt

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

    Carsten U. Niemann & Kirsten Grønbæk

  5. Department of Hematology, Helsinki University Central Hospital, Helsinki, Finland

    Riikka Räty

  6. Department of Hematology, Odense University Hospital, Odense, Denmark

    Thomas Stauffer Larsen

  7. Centre for Cellular Immunotherapy of Haematological Cancer Odense (CITCO), Odense University Hospital, Odense, Denmark

    Thomas Stauffer Larsen

  8. Department of Oncology, Innlandet Hospital, Lillehammer, Norway

    Arne Kolstad

  9. Department of Oncology, Lund University Hospital, Lund, Sweden

    Mats Jerkeman

Authors
  1. Simon Husby
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Cecilie Bæch-Laursen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Christian W. Eskelund
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Francesco Favero
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jakob Schmidt Jespersen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Martin Hutchings
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Lone Bredo Pedersen
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Carsten U. Niemann
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Joachim Weischenfeldt
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Riikka Räty
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Thomas Stauffer Larsen
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Arne Kolstad
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Mats Jerkeman
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Kirsten Grønbæk
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Contribution: SH, TSL, MJ, and KG study idea and design; CBL, SH, CWE, and JSP sequencing; FF, CWE, and SH bioinformatic analysis and variant curation; LBP, CUN supplied patient material, MJ, AK, TSL, RR, CG, MH, and CWE supplied clinical data; SH, KG, MJ, AK, CWE, TSL, and CUN, data interpretation; SH, MJ, and KG writing; all authors manuscript review.

Corresponding author

Correspondence to Simon Husby.

Ethics declarations

Competing interests

TSL: Research Support: Roche. Advisory Board: Roche, Novartis, Gilead and BMS. CUN: Research support, consultancy fees, or travel grants from Abbvie, Gilead, Janssen, Roche, CSL. MH: Consulting or Advisory Role: Takeda, Roche, Genmab. Research Funding: Celgene, Genmab, Roche, Takeda, Novartis.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Husby, S., Bæch-Laursen, C., Eskelund, C.W. et al. Clonal hematopoiesis is associated with hematological toxicity during lenalidomide-based therapy for MCL. Leukemia 36, 2912–2916 (2022). https://doi.org/10.1038/s41375-022-01725-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41375-022-01725-8

Search

Advanced search

Quick links