Ibrutinib in Waldenström's macroglobulinemia: revamping the landscape

Abstract

In The Lancet Oncology, Meletios Dimopoulos and colleagues 1 Dimopoulos MA Trotman J Tedeschi A et al. Ibrutinib monotherapy for patients with rituximab-refractory Waldenström's macroglobulinaemia (iNNOVATE): an open-label substudy of an international, multicentre, phase 3 trial. Lancet Oncol. 2016; (published online Dec 9.)http://dx.doi.org/10.1016/S1470-2045(16)30632-5 Google Scholar report that the activity of the BTK inhibitor, ibrutinib, in patients with rituximab-refractory Waldenström's macroglobulinemia is not only remarkable, but eclipses the other available treatment options. When attempting to place these results into perspective, a couple of adages regarding clinical trials come to mind. First, “the better the therapy, the less relevant the prognostic factors and the more important the predictive factors.” In almost all B-cell malignancies, including Waldenström's macroglobulinemia, an anti-CD20 antibody, generally rituximab, has become a standard component of most first-line treatment strategies because this drug improves progression-free survival and, often overall survival. Nonetheless, initial chemoimmunotherapy is associated with three potential outcomes: cure for the curable subtypes, such as diffuse large B-cell lymphoma, and for the remaining subtypes, either response with eventual relapse, in which case retreatment with a CD20-based regimen is reasonable, or the absence of a response where the role of additional rituximab is questionable. As such, rituximab refractoriness is considered highly unfavourable, and is traditionally associated with a poor outcome. Few drugs have provided exceptions to this rule. However, in the GADOLIN study, 2 Sehn LH Chua N Mayer J et al. Obinutuzumab plus bendamustine versus bendamustine monotherapy in patients with rituximab-refractory indolent non-Hodgkin's lymphoma (GADOLIN): a randomised, controlled, open-label, multicentre, phase 3 trial. Lancet Oncol. 2016; 17: 1081-1093 Summary Full Text Full Text PDF PubMed Scopus (232) Google Scholar , 3 Cheson BD Trneny M Bouabdallah K et al. Obinutuzumab plus bendamustine followed by obinutuzumab maintenance prolongs overall survival compared with bendamustine alone in patients with rituximab-refractory indolent non-Hodgkin lymphoma: updated results of the GADOLIN study. Blood. 2016; 128 (abstr).: 623 Google Scholar the use of the next generation anti-CD20 obinutuzumab prolonged not only progression-free survival but also overall survival in rituximab-refractory follicular and low-grade lymphoma. In the present study of patients with rituximab-refractory disease, the proportions of patients with a response were similar to those in another cohort 4 Treon SP Tripsas CK Meid K et al. Ibrutinib in previously treated Waldenström's macroglobulinemia. New Engl J Med. 2016; 372: 1430-1440 Crossref Scopus (655) Google Scholar who were not refractory to this drug, thus overcoming that adverse feature. Progression-free survival and overall survival results were also very promising. Traditional prognostic factors used in the International Waldenström Scoring System include age, serum IgM level, β-2 microglobulin, and presence of anaemia and thrombocytopenia. 5 Morel P Duhamel A Gobbi P et al. International prognostic scoring system for Waldenström macroglobulinemia. Blood. 2009; 113: 4163-4170 Crossref PubMed Scopus (280) Google Scholar Nevertheless, the activity of ibrutinib in the present study does not seem to be affected by any of those features. More importantly are the findings that suggest that mutations in MYD88 and CXCR4 are predictive of outcome. Although the present substudy enrolled a fairly small sample size (n=31) as part of a larger randomized trial of ibrutinib in this population, the quality of response seemed to be affected by MYD88 and CXCR4 mutational status; although these data must be interpreted with caution due to the small numbers. 4 Treon SP Tripsas CK Meid K et al. Ibrutinib in previously treated Waldenström's macroglobulinemia. New Engl J Med. 2016; 372: 1430-1440 Crossref Scopus (655) Google Scholar More data will be forthcoming on correlations between genotype and outcome after analysis of the main portion of the current study. Ibrutinib for patients with rituximab-refractory Waldenström's macroglobulinaemia (iNNOVATE): an open-label substudy of an international, multicentre, phase 3 trialThe sustained responses and median progression-free survival time, combined with a manageable toxicity profile observed with single-agent ibrutinib indicate that this chemotherapy-free approach is a potential new treatment choice for patients who had heavily pretreated, rituximab-refractory Waldenström's macroglobulinaemia. Full-Text PDF