-Author name in bold denotes the presenting author
-Asterisk * with author name denotes a Non-ASH member
Clinically Relevant Abstract denotes an abstract that is clinically relevant.

PhD Trainee denotes that this is a recommended PHD Trainee Session.

Ticketed Session denotes that this is a ticketed session.

4343 Inflammatory Waldenström Macroglobulinemia Is Associated with Clonal Hematopoiesis: A Multicentric Cohort

Program: Oral and Poster Abstracts
Session: 621. Lymphomas: Translational – Molecular and Genetic: Poster III
Hematology Disease Topics & Pathways:
Research, Translational Research
Monday, December 9, 2024, 6:00 PM-8:00 PM

Pierre-Edouard Debureaux, MD1,2, Stephanie Poulain, MD3*, Marie Passet, Pharm.D. / Ph.D.4*, Marie Temple5*, Chloé Friedrich5*, Nathalie Forgeard, MD6*, Dikelele Elessa, MD4*, William Plas4*, Laureen Chat4*, Gregory Lazarian, PharmD7*, Lise Willems8*, Bruno Royer, MD6*, Alexis Talbot4*, Tristan Vaugeois, MD6*, Floriane Theves4*, Alexandre Terre9*, Anne Brignier, MD4*, Marion Malphettes4*, Daphne Krzisch, MD10*, Laurent Frenzel, MD, PhD11*, Frederic Davi12*, Clothilde Bravetti12*, Florence Nguyen-Khac, MD, PhD12*, Jehan Dupuis, MD13*, Wendy Cuccuini, MD, PhD4*, Didier Bouscary, MD, PhD14*, Olivier Hermine, MD, PhD11, Damien Roos-Weil15*, Olivier Kosmider, PharmD, PhD16*, Emmanuelle Clappier, Pharm.D., Ph.D.4,17*, Marion Espeli2*, Karl Balabanian, PhD2* and Bertrand Arnulf, MD18

1Immuno-Hematology Unit, Saint Louis Hospital, APHP, Paris, France
2U1160, IRSL, Paris, France
3CHRU de Lille, Lille, FRA
4Saint Louis Hospital, Paris, France
5Hôpital Cochin, Paris, France
6Department of Immuno-hematology, Hôpital Saint Louis, APHP, Paris, France
7GHUPSSD Hôpital Avicenne AP-HP, PARIS, France
8Service d'hématologie clinique, Hôpital Cochin, Université de Paris, APHP, Paris, France
9Tenon Hospital, Paris, France
10Hopital Saint Louis, Assistance Publique - Hopitaux de Paris, Paris, France
11Hematology, Necker Hospital, Greater Paris University Hospitals (AP-HP), Paris, France
12Hopital Pitie-Salpetriere, Paris, France
13APHP, Creteil, Creteil, FRA
14Hematology, Cochin Hospital, Greater Paris University Hospitals (AP-HP), Paris, France
15Hôpital Pitié-Salpétrière, Paris, FRA
16Laboratory of Hematology, Université Paris Cité and Assistance Publique-Hôpitaux de Paris. Centre, Hôpital Cochin, Paris, France
17INSERM U944/CNRS UMR7212, Institut de Recherche Saint- Louis, Université Paris Cité, Paris, France
18Immuno-hematology, Saint Louis Hospital, Paris Cedex 10, France

Introduction

Waldenström Macroglobulinemia (WM) is a chronic B-cell lymphoma prevalent in elderly patients, characterized by lymphoplasmacytic cells infiltrating the bone marrow and monoclonal immunoglobulin M production. The disease commonly features a gain-of-function mutation in MYD88 (90%) and other genetic anomalies like CXCR4 mutations and chromosome 6 deletions (del6q). Recently, a subset of WM, termed inflammatory WM (iWM), has been identified in approximately one-third of symptomatic patients, marked by elevated C-reactive protein (CRP ≥ 20 mg/L) associated with more del6q and less CXCR4 mutation. This inflammation has been linked to a shorter time to the next treatment with immunochemotherapy and longer response to Bruton tyrosine kinase inhibitors (BTKi, Debureaux et al. Hematologica 2024).

Clonal hematopoiesis (CH) involves the clonal expansion of hematopoietic stem cells, typically increasing with age and potentially progressing to myeloid malignancies. CH is also associated with non-malignant inflammatory conditions and increased mortality. To explore the role of CH in iWM, we conducted a multicentric study involving WM patients from seven French centers.

Methods

Patients with a confirmed diagnosis of WM and with myeloid NGS data on bulk bone marrow (BM) or peripheral blood (PB) samples were included between 2007 and 2024 in seven French centers. CH mutations were detected using NGS of a panel of 62 genes involved in myeloid malignancies, with a cut-off of Variant Allele Frequency (VAF) ≥ 2%.

Results

Our analysis included 107 patients after excluding those with concurrent myeloid neoplasms, active solid cancers, isolated TP53 mutations, or unconfirmed WM diagnoses. Among these, 46 had iWM, characterized by at least two CRP measurements ≥ 20 mg/L. We identified 63 CH mutations in 42 patients (39%), predominantly in DNMT3A, TET2, and ASXL1 genes (68%). Notably, iWM patients showed a significantly higher prevalence of CH mutations compared to non-iWM patients (67% vs. 28%, p<0.001), particularly in DTA mutations (43% vs. 20%, p=0.01).

CRP levels at the time of NGS were higher in patients with CH (median: 25 mg/L) compared to those without CH (median: 10 mg/L, p=0.01). CH was associated with older age but not with other clinical or demographic features. Interestingly, there was no correlation between CH mutation presence and del6q, a chromosomal deletion previously linked to iWM. Investigating the interaction between iWM, del6q, and CH, CRP levels were higher in patients with both del6q and CH compared to patients with only del6q or CH (p=0.005).

Discussion

This study is the first to associate CH, especially DTA mutations, with iWM, highlighting a novel aspect of the disease's pathophysiology. Our findings also suggest a potential synergistic effect between del6q and CH in contributing to inflammation in WM patients, possibly involving pro-inflammatory cytokines like IL-1b and IL-6. This interaction may influence the effectiveness of BTKi, which are known to inhibit inflammasome activity in myeloid cells and reduce pro-inflammatory cytokine production. Our results underline the need for prospective studies to investigate further the role of CH in WM and its impact on treatment outcomes.

Disclosures: Lazarian: JANSSEN: Honoraria; AsrtraZeneca: Honoraria. Frenzel: BioMarin: Consultancy; Pfizer: Consultancy, Research Funding; CSL Behring: Consultancy, Research Funding. Hermine: Alexion: Research Funding; Roche: Research Funding; Inatherys: Consultancy, Current equity holder in publicly-traded company, Patents & Royalties, Research Funding; MSD Avenir: Research Funding; AB Science: Consultancy, Current equity holder in publicly-traded company, Patents & Royalties, Research Funding; BMS: Research Funding. Arnulf: BMS, janssen, amgen, Sanofi: Consultancy, Honoraria.

*signifies non-member of ASH