Ibrutinib for the treatment of Waldenström macroglobulinemia

Abstract

Waldenström macroglobulinemia (WM) is a B-cell non-Hodgkin lymphoma (NHL) characterized by IgM monoclonal gammopathy and bone marrow infiltration by lymphoplasmacytic cells. Until recently, there was no drug specifically approved for WM by the US FDA, leading to wide variations in therapeutic strategies across the globe. Ibrutinib, an oral Bruton tyrosine kinase (BTK) inhibitor, is the first drug approved specifically for WM by the FDA after a clinical trial showed impressive response in previously treated WM. Ibrutinib is a non-stem cell toxic and non-neurotoxic option and suitable for long-term oral maintenance therapy, with the potential of improving survival in WM. With identification of novel genetic mutations impacting response to ibrutinib, it would be possible to individualize therapy based on MYD88 and CXCR4 genotypes. However, long-term safety and efficacy data are required, and cost-effectiveness needs to be addressed before ibrutinib can gain widespread acceptance for front-line therapy of WM.

Keywords:

• bruton tyrosine kinase
• ibrutinib
• immunoglobin M
• lymphoplasmacytic lymphoma
• Waldenström macroglobulinemia

Financial & competing interests disclosure

M Gertz has received support from Millenium Celgene Binding Site Onyx Med Learning Group Research to Practice. 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

• A highly prevalent somatic mutation MYD88 L265P that activates Bruton’s tyrosine kinase (BTK) and drives B-cell receptor signaling pathways has been identified in Waldenström macroglobulinemia (WM).

• Ibrutinib, a potent, irreversible BTK inhibitor leads to decreased BTK-MYD88 complexing and has shown an impressive overall response rate of 90.5% in previously treated WM.

• Success of ibrutinib, a non-stem cell toxic and non-neurotoxic option for WM has the potential to improve survival by allowing long-term oral maintenance therapy.

• Although safety and efficacy data of ibrutinib monotherapy in WM are limited, promising results in WM as well as other B-cell receptor signaling pathway-dependent lymphomas, namely chronic lymphocytic leukemia, mantle cell lymphoma, activated B-cell type diffuse large B-cell lymphoma and follicular lymphoma serve as catalysts for assessment of effective combination of this recently approved monotherapy in WM.

Notes