Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Clinical Trial
. 2025 Apr 22;9(8):1805-1815.
doi: 10.1182/bloodadvances.2024014948.

Large clones of clonal hematopoiesis affect outcome in mantle cell lymphoma: results from the FIL MCL0208 clinical trial

Simone Ragaini  1   2 , Anna Galli  3   4 , Elisa Genuardi  1 , Martina Gandossini  3   4 , Beatrice Alessandria  1 , Aurora Maria Civita  1 , Andrea Evangelista  5 , Enrico Amaducci  1   2 , Vittorio Stefoni  6 , Federica Cavallo  1   2 , Filippo Ballerini  7 , Benedetta Puccini  8 , Daniele Vallisa  9 , Mariagrazia Michieli  10 , Anna Pascarella  11 , Angelo Palmas  12 , Caterina Patti  13 , Elisa Lucchini  14 , Maria Grazia Careddu  15 , Michele Merli  16 , Massimiliano Postorino  17 , Carola Boccomini  18 , Monica Balzarotti  19 , Vittorio Ruggero Zilioli  20 , Maria Gomes da Silva  21 , Benedetto Bruno  1   2 , Ettore Rizzo  22 , Marco Ladetto  23   24 , Luca Malcovati  3   4 , Simone Ferrero  1   2
Affiliations
Clinical Trial

Large clones of clonal hematopoiesis affect outcome in mantle cell lymphoma: results from the FIL MCL0208 clinical trial

Simone Ragaini et al. Blood Adv. .

Abstract

Although recent evidence suggests that myeloid clonal hematopoiesis (M-CH) may influence lymphoma clinical outcome, its impact in mantle cell lymphoma (MCL) remains unclear. Here, we report a comprehensive next-generation sequencing-based analysis of the M-CH mutational landscape at baseline and follow-up in patients enrolled in the Fondazione Italiana Linfomi MCL0208 phase 3 trial, evaluating lenalidomide maintenance vs observation after chemoimmunotherapy and autologous stem cell transplantation (ASCT) in untreated young patients with MCL. Overall, 254 of 300 (85%) enrolled patients (median age, 57 years [range, 32-66]) had a baseline sample available for CH analysis. Using stringent criteria, at least 1 mutation involving M-CH candidate genes was described in 34 patients (13%), with DNMT3A being the most frequently mutated gene (54%). After a median follow-up of 7 years, the presence of large CH clones (variant allele frequency of ≥10%) predicted worse progression-free survival (hazard ratio [HR], 2.93; 95% confidence interval [CI] 1.36-6.31; P = .006) and overall survival (HR, 3.02 [1.21-7.55]; P = .018) compared with patients with CH. Importantly, the competing risks analysis demonstrates that the worse clinical outcome associated with M-CH large clones is linked to MCL progression (P < .05). Moreover, large M-CH clones showed longer time to hematological recovery after ASCT than the remaining cohort (P = .026). In conclusion, we showed for the first time that large CH clones might associate with unfavorable clinical impact in patients with MCL. This trial was registered at www.clinicaltrialsregister.eu as EudraCT (2009-012807-25) and www.ClinicalTrials.gov as #NCT02354313.

PubMed Disclaimer

Conflict of interest statement

Conflict-of-interest disclosure: V.R.Z. serves on the advisory board of Kite/Gilead and Takeda; is a consultant for Roche; received research funding from Kite/Gilead; is a member of the speakers bureau for Janssen, Lilly, and Takeda; and received travel support from BeiGene, Janssen, Roche, and Takeda. M.G.d.S. received research grants from Gilead Sciences and AstraZeneca; serves on the advisory board of Janssen, Roche, Gilead Sciences, Lilly, and Takeda; received institutional payments from Janssen and AbbVie; and received travel support from Roche, AbbVie, Janssen, Gilead, and Takeda. M.L. reports consulting fees from AstraZeneca, BeiGene, Janssen, and Lilly; reports honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AstraZeneca, BeiGene, Janssen, and Lilly; and reports participation on a data safety monitoring board with Acerta. S.F. is a consultant for Janssen, EUSA Pharma, AbbVie, and Sandoz; serves on the advisory board of Janssen, EUSA Pharma, Recordati, Incyte, Roche, Astra Zeneca, and Italfarmaco; received speaker’s honoraria from Janssen, EUSA Pharma, Recordati, Lilly, BeiGene, Gilead, and Gentili; and received research funding from Gilead, BeiGene, and Morphosys. E.R. owns shares in enGenome s.r.l. The remaining authors declare no competing financial interests.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
Overview of M-CH mutations detected at MCL diagnosis. M-CH mutational landscape of patients with an available sample at MCL diagnosis. M-CH mutations were detected at baseline in 34 of 254 patients (13.4%).
Figure 2.
Figure 2.
Prevalence and mutational profile of M-CH clones in MCL patients at diagnosis and after ASCT. Comparison of M-CH prevalence stratified by age group and M-CH mutation types in MCL patients at diagnosis (A-B) and after ASCT (C-D).
Figure 3.
Figure 3.
A 10% M-CH VAF cutoff identifies patient with different PFS and OS. (A) PFS. (B) OS.
Figure 4.
Figure 4.
Patients who wereM-CH+ with a VAF of ≥10% at baseline have increased incidence of relapse mortality when compared with other patients. At 84 months of median follow-up, patients who were M-CH+ with a VAF of >10% compared with who were M-CH+ with a VAF between 2% and 10% or who were M-CH– presented higher incidence of relapse mortality (P < .05). n.s., not significant.
See this image and copyright information in PMC

References

    1. Arber DA, Orazi A, Hasserjian RP, et al. International Consensus Classification of myeloid neoplasms and acute leukemias: integrating morphologic, clinical, and genomic data. Blood. 2022;140(11):1200–1228. - PMC - PubMed
    1. Jaiswal S, Ebert BL. Clonal hematopoiesis in human aging and disease. Science (1979) 2019;366(6465) - PMC - PubMed
    1. Genovese G, Kähler AK, Handsaker RE, et al. Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N Engl J Med. 2014;371(26):2477–2487. - PMC - PubMed
    1. Jaiswal S, Fontanillas P, Flannick J, et al. Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med. 2014;371(26):2488–2498. - PMC - PubMed
    1. Zink F, Stacey SN, Norddahl GL, et al. Clonal hematopoiesis, with and without candidate driver mutations, is common in the elderly. Blood. 2017;130(6):742–752. - PMC - PubMed

Publication types

Associated data