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Lymphoma

Clinical impact of clonal hematopoiesis in patients with lymphoma undergoing ASCT: a national population-based cohort study

Leukemia volume 34, pages 3256–3268 (2020)Cite this article

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Abstract

Clonal hematopoiesis of indeterminate potential (CHIP) is suspected of being a risk factor for patients with cancer. This study aimed to assess the clinical consequences of CHIP in patients with lymphoma intended for high-dose chemotherapy and autologous stem-cell transplantation (ASCT) in a population-based setting. We identified 892 lymphoma patients who had undergone stem cell harvest at all transplant centers in Denmark. A total of 565 patients had an available harvest sample, which was analysed for CHIP by next-generation sequencing, and the median follow-up was 9.1 years. Of the patients who were intended for immediate ASCT, 25.5% (112/440) carried at least one CHIP mutation. In contrast to previous single-center studies CHIP was not associated with inferior overall survival (OS) in multivariate analyses. However, patients with mutations in genes of the DNA repair pathway (PPM1D, TP53, RAD21, BRCC3) had a significant inferior OS (HR after 1 year of follow-up 2.79, 95% confidence interval 1.71–4.56; p < 0.0001), which also was evident in multivariate analysis (p = 0.00067). These patients had also increased rates of therapy-related leukemia and admission to intensive care. Furthermore, in patients who did not undergo immediate ASCT, a significant inferior OS of individuals with DNA repair mutations was also identified (p = 0.003).

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Fig. 1: CONSORT diagram of the study cohort.
Fig. 2: Spectrum of CHIP mutations in patients intended for immediate ASCT.
Fig. 3: Overall and event-free survival by CHIP mutation and DNA repair pathway mutation.
Fig. 4: Association between risk variables and outcomes.
Fig. 5: Overall survival by mutation characteristics.
Fig. 6: Cumulative incidences of therapy-related myeloid neoplasms and severe infections by mutation status.
Fig. 7: Overall survival in patients intended for ASCT with low frequency DNA repair pathway mutations.

References

  1. Philip T, Guglielmi C, Hagenbeek A, Somers R, Van der Lelie H, Bron D, et al. Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin’s lymphoma. N Engl J Med. 1995;333:1540–5.

    Article  CAS  Google Scholar 

  2. Horning SJ, Chao NJ, Negrin RS, Hoppe RT, Long GD, Hu WW, et al. High-dose therapy and autologous hematopoietic progenitor cell transplantation for recurrent or refractory Hodgkin’s disease: analysis of the Stanford University results and prognostic indices. Blood. 1997;89:801–13.

    Article  CAS  Google Scholar 

  3. Gisselbrecht C, Glass B, Mounier N, Gill DS, Linch DC, Trneny M, et al. Salvage regimens with autologous transplantation for relapsed large B-cell lymphoma in the rituximab era. J Clin Oncol. 2010;28:4184–90.

    Article  Google Scholar 

  4. Wang ML, Rule S, Martin P, Goy A, Auer R, Kahl BS, et al. Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. N Engl J Med. 2013;369:507–16.

    Article  CAS  Google Scholar 

  5. Gopal AK, Kahl BS, de Vos S, Wagner-Johnston ND, Schuster SJ, Jurczak WJ, et al. PI3Kδ inhibition by idelalisib in patients with relapsed indolent lymphoma. N Engl J Med. 2014;370:1008–18.

    Article  CAS  Google Scholar 

  6. Davids MS, Roberts AW, Seymour JF, Pagel JM, Kahl BS, Wierda WG, et al. Phase I first-in-human study of venetoclax in patients with relapsed or refractory non-Hodgkin lymphoma. J Clin Oncol. 2017;35:826–33.

    Article  CAS  Google Scholar 

  7. Ansell SM, Lesokhin AM, Borrello I, Halwani A, Scott EC, Gutierrez M, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. N Engl J Med. 2015;372:311–9.

    Article  Google Scholar 

  8. Neelapu SS, Locke FL, Bartlett NL, Lekakis LJ, Miklos DB, Jacobson CA, et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med. 2017;377:2531–44.

    Article  CAS  Google Scholar 

  9. Jaiswal S, Fontanillas P, Flannick J, Manning A, Grauman PV, Mar BG, et al. Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med. 2014;371:2488–98.

    Article  Google Scholar 

  10. Genovese G, Kähler AK, Handsaker RE, Lindberg J, Rose SA, Bakhoum SF, et al. Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N Engl J Med. 2014;371:2477–87.

    Article  Google Scholar 

  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  Google Scholar 

  12. Wong TN, Miller CA, Jotte MRM, Bagegni N, Baty JD, Schmidt AP, et al. Cellular stressors contribute to the expansion of hematopoietic clones of varying leukemic potential. Nat Commun. 2018;9:455.

    Article  Google Scholar 

  13. Coombs CC, Zehir A, Devlin SM, Kishtagari A, Syed A, Jonsson P, et al. Therapy-related clonal hematopoiesis in patients with non-hematologic cancers is common and associated with adverse clinical outcomes. Cell Stem Cell. 2017;21:374–.e4.

    Article  CAS  Google Scholar 

  14. Olszewski AJ, Chorzalska AD, Kim AS, Quesenberry PJ, Lopresti ML, Fenton MA, et al. Clonal haematopoiesis of indeterminate potential among cancer survivors exposed to myelotoxic chemotherapy. Br J Haematol. 2019. https://doi.org/10.1111/bjh.15861.

  15. Weber-Lassalle K, Harter P, Hauke J, Ernst C, Kommoss S, Marmé F, et al. Diagnosis of Li-fraumeni syndrome: differentiating TP53 germline mutations from clonal hematopoiesis: results of the observational AGO-TR1 trial. Hum Mutat. 2018;39:2040–6.

    Article  CAS  Google Scholar 

  16. Li H, Durbin R. Fast and accurate long-read alignment with Burrows-Wheeler transform. Bioinformatics. 2010;26:589–95.

    Article  Google Scholar 

  17. Garrison E, Marth G. Haplotype-based variant detection from short-read sequencing. 2012. http://arxiv.org/abs/1207.3907.

  18. Lai Z, Markovets A, Ahdesmaki M, Chapman B, Hofmann O, McEwen R, et al. VarDict: a novel and versatile variant caller for next-generation sequencing in cancer research. Nucleic Acids Res. 2016;44:e108.

    Article  Google Scholar 

  19. Steensma DP, Bejar R, Jaiswal S, Lindsley RC, Sekeres MA, Hasserjian RP, et al. Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes. Blood. 2015;126:9–16.

    Article  CAS  Google Scholar 

  20. Lindsley RC, Saber W, Mar BG, Redd R, Wang T, Haagenson MD, et al. Prognostic mutations in myelodysplastic syndrome after stem-cell transplantation. N Engl J Med. 2017;376:536–47.

    Article  CAS  Google Scholar 

  21. Duncavage EJ, Jacoby MA, Chang GS, Miller CA, Edwin N, Shao J, et al. Mutation clearance after transplantation for myelodysplastic syndrome. N Engl J Med. 2018;379:1028–41.

    Article  CAS  Google Scholar 

  22. Takahashi K, Wang F, Kantarjian H, Doss D, Khanna K, Thompson E, et al. Preleukaemic clonal haemopoiesis and risk of therapy-related myeloid neoplasms: a case-control study. Lancet Oncol. 2017;18:100–11.

    Article  Google Scholar 

  23. Gillis NK, Ball M, Zhang Q, Ma Z, Zhao Y, Yoder SJ, et al. Clonal haemopoiesis and therapy-related myeloid malignancies in elderly patients: a proof-of-concept, case-control study. Lancet Oncol. 2017;18:112–21.

    Article  Google Scholar 

  24. Zink F, Stacey SN, Norddahl GL, Frigge ML, Magnusson OT, Jonsdottir I, et al. Clonal hematopoiesis, with and without candidate driver mutations, is common in the elderly. Blood. 2017;130:742–52.

    Article  CAS  Google Scholar 

  25. Tanaka TN, Bejar R MDS overlap disorders and diagnostic boundaries. Blood. 2019. https://doi.org/10.1182/blood-2018-10-844670.

  26. Young AL, Challen GA, Birmann BM, Druley TE. Clonal haematopoiesis harbouring AML-associated mutations is ubiquitous in healthy adults. Nat Commun. 2016;7:12484.

    Article  CAS  Google Scholar 

  27. Abelson S, Collord G, Ng SWK, Weissbrod O, Mendelson Cohen N, Niemeyer E, et al. Prediction of acute myeloid leukaemia risk in healthy individuals. Nature. 2018;559:400–4.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors thank Emil Druedahl Toft Jakobsen for sample preparations and all technicians at the respective departments of Clinical Immunology. Stine Kjær Morthorst is thanked for proof-reading the manuscript. This study was supported by a grant from Region Hovedstadens’ Research Foundation and PhD-scholarship (SH) from Rigshospitalets’ Research Foundation. Jacob Madsen og Hustru Olga Madsens Foundation provided funding for automated sample processing. KG is funded by a center grant from The Danish Cancer Society (Danish Research Center for Precision Medicine in Blood Cancer; grant 223-A13071-18-S68), from the Novo Nordisk Foundation (Novo Nordisk Foundation Center for Stem Cell Biology, DanStem; grant NNF17CC0027852) and from Greater Copenhagen Health Science Partners (Clinical Academic Group in Blood Cancers).

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Authors and Affiliations

  1. Department of Hematology, Rigshospitalet, Copenhagen, Denmark

    Simon Husby, Jakob W. Hansen, Bente Arboe, Peter Brown & Kirsten Grønbæk

  2. Biotech Research & Innovation Centre (BRIC), , University of Copenhagen, Copenhagen, Denmark

    Simon Husby, Francesco Favero, Jakob W. Hansen, Francisco G. Rodriguez-Gonzalez, Joachim Weischenfeldt & Kirsten Grønbæk

  3. Finsen Laboratory, Rigshospitalet, Copenhagen, Denmark

    Francesco Favero, Francisco G. Rodriguez-Gonzalez & Joachim Weischenfeldt

  4. Department of Clinical Immunology, Odense University Hospital, Odense, Denmark

    Christian Nielsen

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

    Christian Nielsen & Thomas S. Larsen

  6. Department of Clinical Immunology, Aarhus University Hospital, Aarhus, Denmark

    Betina S. Sørensen

  7. Department of Clinical Immunology, Aalborg University Hospital, Aalborg, Denmark

    John Bæch

  8. Section of Biostatistics, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark

    Kathrine Grell

  9. Department of Pediatrics and Adolescent Medicine, Rigshospitalet, Copenhagen, Denmark

    Kathrine Grell

  10. Novo Nordisk Foundation Center for Stem Cell Biology, DanStem, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark

    Jakob W. Hansen & Kirsten Grønbæk

  11. Department of Clinical Immunology, Rigshospitalet, Copenhagen, Denmark

    Eva K. Haastrup & Anne Fischer-Nielsen

  12. Department of Clinical Immunology, Herlev University Hospital, Herlev, Denmark

    Pernille Andersen

  13. Department of Clinical Immunology, Zealand University Hospital, Næstved, Denmark

    Susanne G. Sækmose

  14. Department of Hematology, Zealand University Hospital, Roskilde, Denmark

    Per B. Hansen

  15. Department of Hematology, Aalborg University Hospital, Aalborg, Denmark

    Ilse Christiansen & Tarec C. El-Galaly

  16. Department of Pathology, Rigshospitalet, Copenhagen, Denmark

    Erik Clasen-Linde

  17. Department of Hematology, Herlev University Hospital, Herlev, Denmark

    Lene Meldgaard & Pär Josefsson

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

    Lene H. Ebbesen, Erik K. Segel & Michael Thorsgaard

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

    Thomas S. Larsen

Authors
  1. Simon Husby
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  2. Francesco Favero
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Contributions

SH and KG initiated the study and obtained funding. SH, PB, JW, TCEG, TSL, and KG designed the study. SH and FGGM performed the sequencing. FF did bioinformatic analysis. SH and KaG did the statistical survival analysis and prepared the figures. CN, BS, JB, EVK, AFN, LPA, and SGS gathered patient samples. SH, BA, PBH, IC, LM, EKS, LHE, PJ, MT, TCEG, PB, TSL, and KG collected clinical data and provided clinical interpretation. All authors participated in interpretation of data, manuscript writing, and review of the manuscript.

Corresponding author

Correspondence to Kirsten Grønbæk.

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Conflict of interest

SH received grant funding from Rigshospitalet and Danish Capital Regions Research Fond. KG received grant funding from The Danish Cancer Society, the Novo Nordisk Foundation, and Greater Copenhagen Health Science Partners. KG serves on the advisory boards for Celgene and Otsuka Pharmaceutical, and has received travel grants from Celgene. TCEG was employed by F. Hoffmann–La Roche, Ltd, Basel, Switzerland from January 2019. TCEG has received travel funding from Roche (2016) and Takeda (2017). TSL has served on advisory boards for Takeda and Roche. PB has served on advisory boards for Celgene and Roche. All other authors declare no conflict of interest.

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Husby, S., Favero, F., Nielsen, C. et al. Clinical impact of clonal hematopoiesis in patients with lymphoma undergoing ASCT: a national population-based cohort study. Leukemia 34, 3256–3268 (2020). https://doi.org/10.1038/s41375-020-0795-z

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