Genomic Landscape of Waldenström Macroglobulinemia and Its Impact on Treatment Strategies

Abstract

Next-generation sequencing has revealed recurring somatic mutations in Waldenström macroglobulinemia (WM), including MYD88 (95%-97%), CXCR4 (30%-40%), ARID1A (17%), and CD79B (8%-15%). Deletions involving chromosome 6q are common in patients with mutated MYD88 and include genes that modulate NFKB, BCL2, Bruton tyrosine kinase (BTK), and apoptosis. Patients with wild-type MYD88 WM show an increased risk of transformation and death and exhibit many mutations found in diffuse large B-cell lymphoma. The discovery of MYD88 and CXCR4 mutations in WM has facilitated rational drug development, including the development of BTK and CXCR4 inhibitors. Responses to many agents commonly used to treat WM, including the BTK inhibitor ibrutinib, are affected by MYD88 and/or CXCR4 mutation status. The mutation status of both MYD88 and CXCR4 can be used for a precision-guided treatment approach to WM.

FIG 1.

Prosurvival signaling mediated by mutated MYD88. Mutated MYD88 triggers assembly of the Myddosome, which includes activated BTK and IRAK4/IRAK1 that transactivate NFKB. Mutated MYD88 also transcriptionally upregulates and transactivates through interleukin (IL)-6 the SRC family member HCK, which triggers activation of BTK itself, as well as AKT and ERK. Mutated MYD88 also mediates cross talk through LYN-activated SYK, which activates STAT3 and AKT prosurvival signaling. Deletions in chromosome 6q result in the loss of important regulators of MYD88 signaling, including inhibitor of BTK (IBTK) and the NFKB regulators HIVEP2 and TNFAIP3. Waldenström macroglobulinemia cells also export mutated MYD88 via extracellular vesicles to induce signaling cascades in mast cells and macrophages that provide a supportive proinflammatory microenvironment. BCR, B-cell receptor; mTOR, mammalian target of rapamycin; TLRs, Toll-like receptors.

FIG 2.

Genomic-based treatment algorithm for symptomatic, treatment-naïve patients with Waldenström macroglobulinemia. Rituximab should be held for serum immunoglobulin M (IgM) ≥ 4,000 mg/dL to prevent symptomatic IgM flare. Bendamustine and rituximab (Benda-R) should be considered as primary choice in patients with bulky adenopathy or extramedullary disease. Proteasome inhibitor (PI)–based regimens should be considered in patients with symptomatic amyloidosis, with autologous stem-cell transplantation as possible consolidation. Rituximab alone or with ibrutinib if MYD88 is mutated or bendamustine may be considered in patients with IgM peripheral neuropathy (PN) depending on severity and pace of progression. Cyclophosphamide-based therapy such as dexamethasone, cyclophosphamide, and rituximab (DRC) represents an alternative to Benda-R but may be less effective. Maintenance rituximab may be considered in patients responding to rituximab-based regimens. BTK-I, Bruton tyrosine kinase inhibitor; CAGG, cold agglutinemia; CRYOS, cryoglobulinemia; HV, hyperviscosity; Mut, mutated; WT, wild type (not mutated).

FIG 3.

Genomic-based treatment algorithm for symptomatic, previously treated or refractory patients with Waldenström macroglobulinemia. Rituximab should be held for serum immunoglobulin M (IgM) ≥ 4,000 mg/dL to prevent symptomatic IgM flare. Bendamustine and rituximab (Benda-R) should be considered as primary choice in patients with bulky adenopathy or extramedullary disease. Proteasome inhibitor (PI)–based regimens should be considered in patients with symptomatic amyloidosis, with autologous stem-cell transplantation (ASCT) as possible consolidation. Rituximab alone or with ibrutinib if MYD88 is mutated or bendamustine may be considered in patients with IgM peripheral neuropathy (PN) depending on severity and pace of progression. Rituximab combined with cyclophosphamide and dexamethasone (DRC) represents an alternative to Benda-R, although it may be a potentially less effective option. Maintenance rituximab may be considered in patients responding to rituximab-based regimen. (^a) Nucleoside analogues (NA) should be avoided in younger patients and candidates for ASCT. ASCT may be considered in patients with multiple relapses and chemotherapy-sensitive disease. BTK-I, Bruton tyrosine kinase inhibitor; CAGG, cold agglutinemia; CRYOS, cryoglobulinemia; HV, hyperviscosity; Mut, mutated; WT, wild-type (not mutated).