Emerging therapeutic options for Waldenström macroglobulinemia/lymphoplasmacytic lymphoma

Abstract

Lymphoplasmacytic lymphoma is an indolent B-cell, non-Hodgkin lymphoma (NHL), the majority of which are characterized by production of a monoclonal immunoglobulin M (IgM) protein and are known as Waldenström macroglobulinemia. Identification of highly recurrent activating somatic mutation in MYD88 has improved our understanding of the pathogenesis of Waldenström macroglobulinemia and has therapeutic implications. Here, we review novel therapeutic agents in Waldenström macroglobulinemia/lymphoplasmacytic lymphoma, which have emerged in the past decade and discuss their comparative efficacy and safety, with emphasis on a Bruton’s tyrosine kinase (BTK) inhibitor, which has been recently approved by the US FDA, specifically for Waldenström macroglobulinemia/lymphoplasmacytic lymphoma. Future research should focus on identifying targeted agents against activating mutations and long-term data for currently available novel agents should be critically evaluated, both in treatment-naïve and in relapsed/refractory settings.

Keywords:

• bendamustine
• BTK inhibitors
• HDAC inhibitors
• immunomodulators
• mTOR inhibitors
• MYD88L265P
• PI3K/AKT/PKC inhibitors
• proteasome inhibitors
• Waldenström macroglobulinemia

Financial & competing interests disclosure

M Gertz has affiliations with Novartis, Celgene, Millennium and Isis Pharmaceuticals. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Key issues

• MYD88L265P is a highly recurrent activating somatic mutation identified in 90% of patients with WM/LPL, which activates BTK, IRAK 1/4 and NF-κB signaling pathways, and can be detected by whole genome sequencing and peripheral blood allele-specific PCR.

• BTK inhibitor, an emerging therapeutic agent in WM, has been shown to produce an ORR of 100% in previously treated patients with MYD88L265P/CXCR4WT genotype. However, data in treatment-naïve patients are not available.

• Carfilzomib, a second-generation proteasome inhibitor, in combination with rituximab and dexamethasone, has been shown to produce stringent molecular complete remission in one patient, as front-line therapy.

• Lenalidomide, a potent immunomodulator, has been shown to be safe in low doses, and its use in other doses and combinations should be restricted to clinical trials, till further data are available.

• With the advent of orally available nonmyelotoxic and non-neurotoxic agents, long-term oral maintenance therapy will be possible with the potential decrease in incidence of second malignancies and transformation.

• Future clinical trials should address the impact of recurrent somatic mutations, including that of MYD88 and CXCR4, on response to novel agents.

• Preclinical candidates targeting downstream MYD88 signaling pathways should be tested in clinical trials in the future.