Waldenström macroglobulinemia: genetics dictates clinical course

In this issue of Blood, Treon and colleagues provide strong evidence that mutations in MYD88 and CXCR4 dictate clinical presentation and survival in Waldenström macroglobulinemia (WM).¹ 

WM is a rare malignancy of immunoglobulin M–secreting B cells.²  Recent work identified recurrent somatically acquired activating mutations in MYD88 as well as in CXCR4 in WM patient samples.^3,4  In more than 90% of WM patient samples, the MYD88 L265P mutation is detectable. This aberration, which is also found in other lymphoma subtypes such as the activated B cell–like subtype of diffuse large B-cell lymphoma (ABC DLBCL) or mucosa-associated lymphoid tissue lymphoma, leads to constitutive activation of the oncogenic nuclear factor-κB signaling pathway.^5-7  CXCR4 is a chemokine receptor that promotes survival of WM cells.⁴  Different mutations affecting the C terminus of CXCR4 can be identified in roughly 30% of WM patients.⁴  Although these analyses provided important insights into the molecular pathogenesis of WM, it remained unclear if these genetic aberrations impact clinical presentation or survival of affected patients.

In this issue, Treon et al investigate the clinical implications of MYD88 and CXCR4 mutations in WM.¹  Virtually all patients harboring mutations in CXCR4 also exhibited mutated MYD88. Patient samples harboring CXCR4 mutations were further distinguished based on the mutation pattern (nonsense vs frameshift mutations). Interestingly, the mutation status of CXCR4 and MYD88 was associated with significant differences in clinical presentation and outcome (see figure).¹  Patients with mutated MYD88 and CXCR4 nonsense mutations exhibited bone marrow infiltration significantly more frequently, had higher serum immunoglobulin M levels, and presented with symptomatic disease, including hyperviscosity, syndrome more frequently. In contrast, patients with mutated MYD88 and CXCR4 frameshift or nonsense mutations presented less frequently with adenopathy. Finally, patients that were wild type for both MYD88 and CXCR4 were characterized by adverse survival compared with patients with mutated MYD88 alone or patients that harbored both mutations. Taken together, these results suggest that the MYD88 and CXCR4 mutation status determines clinical presentation and outcome of patients diagnosed with WM (see figure).¹ 

From a clinical standpoint, the results by Treon et al can potentially be highly relevant for WM treatment. A better understanding which oncogenic pathways are activated and used in WM is a prerequisite for the optimal utilization of novel therapeutic agents. To this end, the determination of the MYD88 and CXCR4 mutation status might help us identify novel subgroups of WM that differ with respect to clinical presentation and prognosis. Additionally, these subgroups might benefit differentially to novel therapeutic strategies. Bruton’s tyrosine kinase, which interacts with MYD88, is a promising target for the treatment of WM, and encouraging results were obtained by using the Bruton’s tyrosine kinase inhibitor ibrutinib in relapsed and refractory WM.⁸  Similarly, interleukin-1 receptor–associated kinase inhibitors that are being developed for clinical use hold promise for the treatment of WM because MYD88 coordinates the assembly of a signaling complex consisting of different members of the interleukin-1 receptor–associated kinase family.^5,6  Finally, the use of CXCR4 inhibitors such as plerixafor might be promising in WM patients with mutated CXCR4. Importantly, large and well-designed clinical trials with accompanying scientific programs are required to investigate if specific subtypes of WM respond preferentially to novel compounds. This approach will pave the way to more specific and less toxic treatment regimens for patients with WM.