Ibrutinib Is Active in Refractory Waldenström Macroglobulinemia

Waldenström macroglobulinemia is an indolent B-cell malignancy distinguished by lymphoplasmacytic cell hyperproliferation and increased immunoglobulin M (IgM) secretion. Although Waldenström macroglobulinemia is treatable, it is incurable, and most patients ultimately experience disease progression. Clinical responses to ibrutinib were observed among a small number of patients with Waldenström macroglobulinemia included in a phase I trial of ibrutinib in B-cell malignancies, prompting Treon and colleagues to initiate a prospective, multicenter study to evaluate the safety and efficacy of ibrutinib in a larger cohort of 63 patients with refractory Waldenström macroglobulinemia and assess the impact of MYD88 and CXCR4 mutation status on response. Activating mutations in MYD88 and CXCR4 are common in patients with Waldenström macroglobulinemia, but whereas MYD88 activation promotes Bruton tyrosine kinase (BTK)–dependent cell proliferation and confers sensitivity to the BTK inhibitor ibrutinib in preclinical studies, CXCR4 mutations have been shown to promote cell survival and resistance to ibrutinib. Ibrutinib showed significant clinical activity in this patient population, with an overall response rate of 90.5% and major responses (a 50% or greater reduction in serum IgM) seen in 73% of patients. The highest overall and major response rates (100% and 91.2%) were seen in patients with a MYD88-mutant, CXCR4–wild-type genotype, followed by the MYD88-mutant, CXCR4-mutant (85.7% and 61.9%) and MYD88–wild-type, CXCR4–wild-type (71.4% and 28.6%) genotypes. The estimated progression-free survival among all patients was 69.1% at 2 years. The most common treatment-related adverse events, neutropenia and thrombocytopenia, were reversible, and few infections were observed. The safety and efficacy of ibrutinib in this study suggest that ibrutinib may be a useful salvage therapy for some patients with refractory Waldenström macroglobulinemia. The effect of CXCR4 mutation status on ibrutinib response also raises the possibility that CXCR4 antagonists may be effective in combination with ibrutinib in patients with CXCR4 mutations.

Treon SP, Tripsas CK, Meid K, Warren D, Varma G, Green R, et al. Ibrutinib in previously treated Waldenström's macroglobulinemia. N Engl J Med 2015 Apr 9 [Epub ahead of print].