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Review
. 2023 Nov:62:101129.
doi: 10.1016/j.blre.2023.101129. Epub 2023 Aug 26.

Current approach to Waldenström macroglobulinemia

Prashant Kapoor  1 , S Vincent Rajkumar  2
Affiliations
Review

Current approach to Waldenström macroglobulinemia

Prashant Kapoor et al. Blood Rev. 2023 Nov.

Abstract

Waldenström macroglobulinemia (WM) is a unique CD20+, B-cell non-Hodgkin lymphoma, characterized by lymphoplasmacytic infiltration of the bone marrow and circulating monoclonal immunoglobulin M. The clinical manifestations and outcomes of patients are highly variable. High-level evidence supports integration of monoclonal anti-CD20 antibody, rituximab, to the chemotherapy backbone to treat WM. However, its contemporary management has become more nuanced, with deeper understanding of the pathophysiology and incorporation of Bruton's tyrosine kinase (BTK) inhibitors to the treatment paradigm. Prior knowledge of the patients' MYD88L265P and CXCR4 mutation status may aid in the treatment decision-making. Currently, the two frequently utilized approaches include fixed-duration chemoimmunotherapy and BTK inhibitor-based continuous treatment until progression. Randomized trials comparing these two vastly divergent approaches are lacking. Recent studies demonstrating efficacy of B cell lymphoma-2 (BCL2) inhibitors and non-covalent BTK inhibitors in patients, previously exposed to a covalent BTK inhibitor, are a testament to the rapidly expanding options against WM.

Keywords: BTK inhibitor; CXCR4; Chemoimmunotherapy; IgM monoclonal gammopathy; Lymphoplasmacytic lymphoma; MYD88.

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Conflict of interest statement

Declaration of Competing Interest Prashant Kapoor, MD is the principal investigator of trials for which Mayo Clinic has received research funding from Amgen, Regeneron, Bristol Myers Squibb, Loxo Pharmaceuticals, Ichnos, Karyopharm, Sanofi, AbbVie and GlaxoSmithKline. Prashant Kapoor has served on the Advisory Boards of BeiGene, Pharmacyclics, X4 Pharmaceuticals, Kite, Oncopeptides, Angitia Bio, GlaxoSmithKline, AbbVie and Sanofi. S. Vincent Rajkumar, MD has no conflict of interest to declare.

Figures

Figure 1:
Figure 1:. Genomics of Waldenström Macroglobulinemia
MYD88, an adapter protein downstream of Toll-Like Receptor (TLR), is critical for TLR signaling. TLRs recognize highly conserved motifs, DNA, RNA, and polysaccharides that are shared by pathogens. MYD88 is essential for induction of the downstream NFKB and MAP kinase activity. The N terminus of the MYD88 protein has a death domain (DD) that allows MYD88 oligomerization and interaction with IRAK4-IRAK1, forming Myddosome, a multimeric complex. Mutated MYD88 transactivates the SRC family member, HCK, cross talks with LYN-activated SYK, and spontaneously triggers the Myddosome assembly, with activated BTK and IRAK4 and IRAK1, which in turn activate NFKB. B-cell receptor (BCR) Is a transmembrane receptor, with a crucial role in B-cell development from early precursor to plasma cell differentiation. It also recognizes a variety of antigens, with a critical role in the adaptive immune response. The BCR signaling is mediated by coupling its immunoglobulin component with the heterodimerized signal transduction unit consisting of CD79A and CD79BBTK, a member of the TEC family plays a central role in the proximal BCR signal transduction pathway, and its absence can block maturation of cells at the pre-B cell stage. Loss of critical regulators of MYD88 signaling, IBTK and the NFKB regulators, TNFAIP3 and HIVEP2 occurs with the deletion of the long arm of chromosome 6.
Figure 2:
Figure 2:
Evolution of Treatment in Waldenström Macroglobulinemia Regimens: Flu Fludarabine; 2CDA Cladrabine; Chl Clhorambucil; R Rituximab; FCR: Fludarabine, Cyclophosphamide, Rituximab; V Bortezomib; DRC Dexamethasone, Cyclophosphamide, Rituximab, BR Bendamustine, Rituximab; VDR Bortezomib, dexamethasone, Rituximab; CaRD Carfilzomib, Rituximab, Dexamethasone; I Ibrutinib; O Ofatumumab; IR Ibrutinib, Rituximab; Ixa-RD Ixazomib Dexamethasone Rituximab; Ven Venetoclax; P Pirtobrutinib; VDRC Bortezomib, Dexamethasone, Cyclophosphamide, Rituximab
Figure 3:
Figure 3:
Our Approach to the Management of Waldenström Macroglobulinemia
Figure 4:
Figure 4:
Targets in Waldenström Macroglobulinemia
See this image and copyright information in PMC

References

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