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. 2024 Dec;71(12):e31302.
doi: 10.1002/pbc.31302. Epub 2024 Sep 19.

Comprehensive analysis of constitutional mismatch repair deficiency-associated non-Hodgkin lymphomas in a global cohort

Charlotte Rigaud  1 , Victoria J Forster  2 , Hiba Al-Tarrah  3 , Andishe Attarbaschi  4   5 , Vanessa Bianchi  2 , Amos Burke  6 , Birgit Burkhardt  7 , Chrystelle Colas  8 , Christine Devalck  9 , Melissa Edwards  2 , Sarah Elitzur  10 , Anne-Kathrin Garthe  7 , Yael Goldberg  11   12 , Léa Guerrini-Rousseau  1 , Sukanya Horpaopan  13 , Danuta Januszkiewicz-Lewandowska  14 , Edita Kabíčková  15 , Christian P Kratz  16 , Jan Loeffen  17 , Vanessa Pérez-Alonso  18 , Marta Pineda  19   20 , Véronique Minard-Colin  1 , Daniel Rueda  21 , Clara Ruiz-Ponte  22 , Amelie Trinquand  23 , Anne Uyttebroeck  24 , Katharina Wimmer  13 , Anne Auperin  25 , Uri Tabori  3 , Laurence Brugieres  1
Affiliations

Comprehensive analysis of constitutional mismatch repair deficiency-associated non-Hodgkin lymphomas in a global cohort

Charlotte Rigaud et al. Pediatr Blood Cancer. 2024 Dec.

Abstract

Background: Constitutional mismatch repair deficiency syndrome (CMMRD) is a rare childhood cancer predisposition syndrome associated with a broad spectrum of malignancies, including non-Hodgkin lymphomas (NHL). Most patients die due to cancer before the age of 20 years. Limited data exist on CMMRD-associated lymphomas and their outcome.

Methods: We conducted a retrospective study including all CMMRD-associated NHL patients registered before 2020 in the European and North American databases or reported by members of the European Intergroup for Childhood Non-Hodgkin Lymphoma (EICNHL). Events considered to define event-free survival included relapse/progression, second malignancy (SML), or death, whichever occurred first.

Findings: The analysis included 74 patients, with 20 having multiple metachronous NHL. The median age at diagnosis was 9.4 years. Previous malignancies were reported in 36% of the patients, café au lait spots in 96%, and consanguinity in 54%. The initial lymphoma subtypes were 53 T-cell lymphoblastic lymphomas (T-LBL), four B-lymphoblastic lymphomas, and 17 mature B-cell non-Hodgkin lymphoma (B-NHL). All patients were treated with curative intent, with current chemotherapy regimens adapted to their subtype. The median follow-up was 8.7 years. After the first lymphoma, the 5-year event-free and overall survival rates were, respectively, 23.5% [95% confidence interval (CI): 14.9-35.1] and 61.5% [95% CI: 49.6-72.1]. The 5-year cumulative risk of progression/relapse, SML or death as a first event was 20.8%, 52.9%, and 2.7%.

Interpretation: Standard treatments for sporadic NHL are effective in most CMMRD-associated NHL cases, but multiple malignancies, including lymphomas, impair prognosis. Future strategies should evaluate the potential of less genotoxic therapies, including immunotherapy, in preventing SMLs while maintaining effective control of NHL.

Keywords: CMMRD; genetic predisposition; lymphoblastic lymphomas; lymphomas; second malignancy.

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References

REFERENCES

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    1. Wimmer K, Kratz CP, Vasen HFA, et al. Diagnostic criteria for constitutional mismatch repair deficiency syndrome: suggestions of the European consortium ‘Care for CMMRD’ (C4CMMRD). J Med Genet. 2014;51(6):355‑365.
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