The epiCMIT (epigenetically determined Cumulative MIToses) mitotic clock traces B-cell mitotic history via DNA methylation changes in heterochromatin and H3K27me3-containing chromatin. While high scores correlated with poor outcomes in CLL and MCL, its prognostic significance in SMZL remains unknown. Derived from 142 SMZL cases using DNA methylation microarrays, epiCMIT values were correlated with genomic, transcriptomic, and clinical data. EpiCMIT as a continuous variable was significantly higher in females (p=0.02), patients with IGHV1-2*04 allele usage (p<0001), intermediate IGHV somatic hypermutation load (97-99.9% identity, p=0.04), elevated mutational burden (25 vs. 17 mut/Mb, p=0.001), driver gene mutations [KLF2 (p<0.001), NOTCH2 (p<0.01), TP53 (p=0.01), KMT2D (p<0.001)], and del(7q) (p=0.01). Negative correlation between epiCMIT and telomere length (r=-0.29 p<0.001) supported the association between cumulated proliferation and telomere attrition. While univariate analysis highlighted epiCMIT as robust predictor of shorter treatment-free survival (TFS), multivariate analysis confirmed epiCMIT as an independent marker for shorter TFS. In summary, our matched multi-omic datasets facilitate the clinico-biological characterization of SMZL and introduces epiCMIT as a strong prognostic marker, identifying high-risk patients and predicting reduced treatment-free survival, hence providing a new tool for risk-adapted patient management.

R.R. had received honoraria from AbbVie, AstraZeneca, Illumina, Janssen and Roche. L.S. had received consultancy from AbbVie, AstraZeneca, BeiGene, Janssen and Lilly. P.G had received honoraria , consultancy and research funding from AbbVie, AstraZeneca, BeiGene, BMS, Lilly, Janssen, MSD and Roche. D.R. had received honoraria and research funding from AbbVie, AstraZeneca, BeiGene, BMS, Gilead, Janssen, Lilly and Kyte. M.A had received research funding from Pfizer. F.F had received honoraria from AbbVie, AstraZeneca, BeiGene and Janssen. R.W had received honoraria from AbbVie, AstraZeneca, BeiGene, Janssen and Secura bio. C.T. had received honoraria and/or consultancy from BMS, Janssen, Novartis, Roche, Abbvie, Gilead, Hospira, Amgen, Cellectis, Kyte, Takeda, Incyte, Bayer. All other authors have declared no competing interests.

The study was funded by research grants from the Kay Kendall Leukemia Fund (873, 1104), and Cancer Research UK (ECRIN-M3 accelerator award C42023/A29370). MDF is supported by a postdoctoral grant from the Spanish Association Against Cancer. R.R is supported by grants from the Swedish Cancer Society, the Swedish Research Council, Region Stockholm, and Radiumhemmets Forskningsfonder, Stockholm.

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NHS South Central- Hampshire B Research ethics committee granted ethical approval for this work

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