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LYMPHOMA

Circulating tumor cells in Waldenström macroglobulinemia

Leukemia volume 38, pages 903–907 (2024)Cite this article

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Waldenström macroglobulinemia (WM) is a rare mature B-cell neoplasm defined by the association of a serum monoclonal IgM gammopathy and bone marrow (BM) infiltration by lymphoplasmocytic lymphoma [1]. Differential diagnosis with other indolent B-cell lymphomas, including marginal zone lymphoma (MZL), is sometimes difficult, due to overlapping clinico-biological features. Indeed, detection of a monoclonal IgM component is common in MZL, and the MYD88 L265P mutation, a hallmark of WM, can also be detected in a proportion of MZL cases [2, 3], whereas splenomegaly and lymphocytosis, though more commonly associated with MZL, is sometimes observed in WM. Although WM patients with cytologically detectable circulating lymphoplasmocytes have been described, the exact proportion of WM patients who present with circulating tumor cells (CTCs) and the potential correlation with clinico-biological characteristics is not known. Molecular features may influence the presence and level of CTCs, notably CXCR4 mutations that have been shown to increase medullar homing of CXCR4-mutated B-cells [4, 5]. This could be also relevant for prognosis, since the detection of CTCs in other lymphoid neoplasms (such as follicular lymphoma or myeloma) has been recently shown to confer a poorer prognosis [6, 7]. We therefore aimed in a large cohort of WM patients to evaluate the presence of detectable CTCs by flow cytometry (FCM) at diagnosis, their potential correlation with clinico-biological features and outcomes.

Among 270 patients diagnosed from 2000 to 2021 and followed up in Pitié-Salpêtrière hospital (Paris, France), 187 patients had peripheral blood (PB) FCM analysis performed at diagnosis and were included in this retrospective study. Criteria for diagnosis, treatment initiation and response followed the WHO classification and recommendations from the eleventh IWWM [8]. All patients underwent BM biopsy and IgM-MGUS cases were excluded. CTC counts were assessed by multiparameter FCM analysis (see details in Supplementary methods and Table S1), allowing for the detection of phenotypically aberrant clonal CD19+ B-cells harboring light-chain restriction in line with patient-specific IgM monotype. Briefly, FCM analyses were performed on erythrocyte-lysed blood samples. Several monoclonal antibodies panels were used regarding the period of analyses (Supplementary Table S1). After washing serum Ig, a stain-and-then-lyse direct immunofluorescence technique was used to evaluate all surface markers. Data were acquired on FACSCanto™ II cytometer (BD Biosciences) (with a target of 10, 000 CD19+ events stored), processed and analyzed on FACSDivaTM (BD Biosciences). Markers were evaluated in mature B cells identified as CD19+/SSC low cells. An example of gating strategy is described in details in Supplementary Fig. S1. CTC counts were expressed as absolute numbers in giga per liter (x109/L). Routine cytogenetic analyzes and allele-specific PCR for MYD88 L265P and CXCR4 S338X were performed for 133, 132 and 127/187 respectively (see Supplementary methods and ref. [9]), in bone marrow samples. Additionally, targeted NGS of 21 genes (MYD88, CXCR4, TP53, MLL2, ARID1A, CARD11, CD79A, CD79B, SPI1, TNFAIP3, PRDM1, EZH2, IKZF3, NOTCH2, KLF2, NFKBIE, HIST1H1E, CREBBP, TBL1XR1, ETV6 and IRF4) was performed for 127 patients for whom DNA material was sufficient (see Supplementary Table S2 for genomic coordinates of targeted regions). The study was conducted in accordance with the declaration of Helsinki and with ethical approval from national (CNIL 2212382) and local (CPP Ile-De-France 05212014) ethics committees. Time to first treatment (TFT) was analyzed in asymptomatic patients, progression-free survival (PFS) in symptomatic patients and overall survival (OS) in the entire cohort as well as specifically in those of asymptomatic or symptomatic patients. Additional information regarding genetic and statistical analyses is available in Supplementary methods.

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Fig. 1: Circulating tumor cells (CTC) counts and correlation with clinical and biological characteristics.

Data availability

The data that support the findings of this study are available from the corresponding author, DRW, upon reasonable request.

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Acknowledgements

This study was supported by grants from INCA-DGOS-Inserm_12560 (SiRIC CURAMUS is financially supported by the French National Cancer Institute, the French Ministry of Solidarity and Health and Inserm with financial support from ITMO Cancer AVIESAN), Fondation ARC and Ligue contre le Cancer (to DRW).

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Author notes

  1. These authors contributed equally: Clémentine Boccon-Gibod, Elise Sourdeau, Pierre Morel.

  2. These authors jointly supervised this work: Magali Le Garff-Tavernier, Marine Baron, Damien Roos-Weil.

Authors and Affiliations

  1. Sorbonne Université, Service d’Hématologie Clinique, Hôpital Pitié-Salpêtrière, APHP, Paris, France

    Clémentine Boccon-Gibod, Véronique Morel, Nicolas Gauthier, Adrien Grenier, Inès Boussen, Sylvain Choquet, Véronique Leblond, Marine Baron & Damien Roos-Weil

  2. Sorbonne Université, Service d’Hématologie Biologique, Hôpital Pitié-Salpêtrière, APHP, Paris, France

    Elise Sourdeau, Elise Chapiro, Florence Nguyen-Khac, Clotilde Bravetti, Frédéric Davi & Magali Le Garff-Tavernier

  3. CHU Amiens Hôpital Sud, Amiens, France

    Pierre Morel

  4. Drug Resistance in Hematological Malignancies, Centre de Recherche des Cordeliers, UMRS 1138, INSERM, Sorbonne Université, Université Paris Cité, F-75006, Paris, France

    Elise Chapiro, Florence Nguyen-Khac, Clotilde Bravetti, Frédéric Davi, Magali Le Garff-Tavernier & Damien Roos-Weil

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  1. Clémentine Boccon-Gibod
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Contributions

CBG, ES, MLT, MB and DRW designed the research, analysed data and wrote the manuscript. CBG, ES, PM, EC, FNK, CB, FD, MLT, MB and DRW performed experiments. CBG, PM, VM, NG, AG, IB, VL, SC, MB and DRW recruited patients. All authors reviewed and approved the manuscript.

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Correspondence to Clémentine Boccon-Gibod or Damien Roos-Weil.

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Boccon-Gibod, C., Sourdeau, E., Morel, P. et al. Circulating tumor cells in Waldenström macroglobulinemia. Leukemia 38, 903–907 (2024). https://doi.org/10.1038/s41375-024-02156-3

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