Page 49 - Haematologica Vol. 107 - September 2022

REVIEW ARTICLE - IgM monoclonal gammopathies of clinical significance J. Khwaja et al.
pathological characteristics of the circulating IgM rather than by the tumor itself. While deep suppression of the pathogenic IgM is typically required for response, achiev- ing long-term clonal eradication is challenging, as dem- onstrated by low complete response rates. Treatment inhibiting the pathogenic effects of IgM while not directed at the underlying clone has led to great success in CAD (complement inhibitors) and Schnitzler syndrome (cyto- kine inhibition), whereas the other treatments are cen- tered on eradicating the underlying clone. Treatment approaches in cryoglobulinemia and IgM-related periph- eral neuropathies are the least well developed. A multi- disciplinary approach is required particularly for IgM-related neuropathies and Schnitzler syndrome.
Due to the rarity of IgM MGCS, data are scant and collab- orative research is imperative to aid defining optimal treatment strategies. International registries may better define characteristics and assess treatment outcomes. Future work exploring clone-directed treatment options and pathogenic IgM-directed therapies is welcomed.
Disclosures
JK has no conflicts of interest to disclose. SD'S has re- ceived research funding, honoraria for advisory board work and conference support from Janssen and BeiGene, and
References
1. Swerdlow SH, Campo E, Pileri SA, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016;127(20):2375-2390.
2. Fermand JP, Bridoux F, Dispenzieri A, et al. Monoclonal gammopathy of clinical significance: a novel concept with therapeutic implications. Blood. 2018;132(14):1478-1485.
3. Owen RG, Treon SP, Al-Katib A, et al. Clinicopathological definition of Waldenstrom's macroglobulinemia: consensus panel recommendations from the Second International Workshop on Waldenstrom's Macroglobulinemia. Semin Oncol. 2003;30(2):110-115.
4. Castillo JJ, Advani RH, Branagan AR, et al. Consensus treatment recommendations from the tenth International Workshop for Waldenström Macroglobulinaemia. Lancet Haematol. 2020;7(11):e827-e837.
5. Kyle RA, Larson DR, Therneau TM, et al. Long-term follow-up of monoclonal gammopathy of undetermined significance. N Engl J Med. 2018;378(3):241-249.
6. Treon SP, Xu L, Yang G, et al. MYD88 L265P somatic mutation in Waldenström's macroglobulinemia. N Engl J Med. 2012;367(9):826-833.
7. Varettoni M, Zibellini S, Defrancesco I, et al. Pattern of somatic mutations in patients with Waldenström macroglobulinemia or IgM monoclonal gammopathy of undetermined significance. Haematologica. 2017;102(12):2077-2085.
8. Bazarbachi AH, Avet-Loiseau H, Szalat R, et al. IgM-MM is predominantly a pre-germinal center disorder and has a distinct genomic and transcriptomic signature from WM. Blood. 2021;138(20):1980-1985.
honoraria for advisory board work from Sanofi. MCM has provided speakers bureau services for Medscape and BMS, consultancy for Janssen-Cilag and Gilead Sciences Nether- lands B.V., sat on advisory boards for Janssen Phar- maceutica and Alnylam, and received hospitality support from Celgene. MJK has acted as a consultant for and re- ceived honoraria and travel support from Novartis and Mil- tenyi Biotec, has received research funding from Takeda and Celgene, has acted as a consultant for and received honoraria, travel support and research funding from Kite, a Gilead Company, and Roche, and has acted as a consul- tant for and received honoraria from BMS/Celgene. AW has provided consultancy services for Alexion, AstraZeneca Rare Diseases and Janssen, and has received honoraria from Celgene and Takeda, clinical trial funding from Caelum Bio- sciences, and research funding from Amgen. JMIV has re- ceived reimbursement of travel costs from Celgene, receives research funding from Beigene (institutional) and has participated in an advisory board as well as acted as a consultant for Sanofi (institutional honoraria)
Contributions
JK and JMIV wrote the first draft of the manuscript, SD’S, MCM, MJK, and AW equally reviewed and added critical dis- cussions throughout the writing of the review.
9. Jäger U, Barcellini W, Broome CM, et al. Diagnosis and treatment of autoimmune hemolytic anemia in adults: recommendations from the First International Consensus Meeting. Blood Rev. 2020;41:100648.
10. Berentsen S, Barcellini W, D'Sa S, et al. Cold agglutinin disease revisited: a multinational, observational study of 232 patients. Blood. 2020;136(4):480-488.
11. Berentsen S, Ulvestad E, Langholm R, et al. Primary chronic cold agglutinin disease: a population based clinical study of 86 patients. Haematologica. 2006;91(4):460-466.
12. Barcellini W, Fattizzo B, Zaninoni A, et al. Clinical heterogeneity and predictors of outcome in primary autoimmune hemolytic anemia: a GIMEMA study of 308 patients. Blood. 2014;124(19):2930-2936.
13. Röth A, Bommer M, Hüttmann A, et al. Eculizumab in cold agglutinin disease (DECADE): an open-label, prospective, bicentric, nonrandomized phase 2 trial. Blood Adv. 2018;2(19):2543-2549.
14. Randen U, Trøen G, Tierens A, et al. Primary cold agglutinin- associated lymphoproliferative disease: a B-cell lymphoma of the bone marrow distinct from lymphoplasmacytic lymphoma. Haematologica. 2014;99(3):497-504.
15. Małecka A, Trøen G, Delabie J, et al. The mutational landscape of cold agglutinin disease: CARD11 and CXCR4 mutations are correlated with lower hemoglobin levels. Am J Hematol. 2021;96(8):E279-E283.
16. Małecka A, Trøen G, Tierens A, et al. Frequent somatic mutations of KMT2D (MLL2) and CARD11 genes in primary cold agglutinin disease. Br J Haematol. 2018;183(5):838-842.
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