Research in context
Evidence before this study
Despite progress in understanding the pathophysiology of Waldenström macroglobulinemia and improved treatment options, Waldenström macroglobulinemia remains an incurable disease with substantial mortality. Bruton tyrosine-kinase is a validated target based on clinical activity of ibrutinib, an inhibitor of bruton tyrosine-kinase, in Waldenström macroglobulinemia. Bruton tyrosine-kinase could be of increased importance in Waldenström macroglobulinemia because of the high prevalence of the MYD88L265P (Leu265Pro) mutation, which activates NFκB through bruton tyrosine-kinase. Before the start of the enrolment of this study in September 2014, bruton tyrosine-kinase inhibition with ibrutinib was reported to trigger cell death of Waldenström macroglobulinemia cells with MYD88L265P in vitro and showed clinical activity in patients with Waldenström macroglobulinemia in a phase 1 study. This activity was validated in later phase clinical trials. Ibrutinib, however, has additional kinase targets beyond bruton tyrosine-kinase, including EGFR, ErbB2, Src, and interleukin 2–inducible T-cell kinase, which could contribute to adverse events, such as diarrhoea, rash, bleeding, and atrial fibrillation. These adverse events could lead to discontinuation of an effective treatment and support the development of alternative bruton tyrosine-kinase inhibitors for the treatment of Waldenström macroglobulinemia to overcome these issues. Acalabrutinib is a bruton tyrosine-kinase inhibitor that is more potent and selective than ibrutinib, as indicated by kinase selectivity profiling against 395 human kinases. In patients with treatment naive and relapsed or refractory chronic lymphocytic leukaemia, acalabrutinib has shown efficacy and acceptable safety. Here we report the activity and safety results of acalabrutinib treatment in patients with Waldenström macroglobulinemia.
Added value of this study
To our knowledge, this is the first clinical analysis of acalabrutinib in patients with Waldenström macroglobulinemia, expanding existing literature of clinical activity and safety with bruton tyrosine-kinase inhibition in Waldenström macroglobulinemia by using a highly selective bruton tyrosine-kinase inhibitor.
Implications of all the available evidence
An effective bruton tyrosine-kinase inhibitor monotherapy with a differentiate safety profile would offer another viable therapeutic option for patients with Waldenström macroglobulinemia.