Lymphoma

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

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.

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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).

Author information

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.

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 (2020). https://doi.org/10.1038/s41375-020-0795-z

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