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Evaluating ibrutinib in the treatment of symptomatic Waldenstrom's macroglobulinemia.

ABSTRACT: Waldenstrom's macroglobulinemia (WM) is a rare lymphoplasmacytic lymphoma with indolent course and prolonged disease course. The first-in-class Bruton's tyrosine kinase inhibitor, ibrutinib, has shown significant activity and a distinct adverse event profile among both newly diagnosed and relapsed/refractory WM patients. Interestingly, clinical responses to ibrutinib have been shown to be dependent on patients' MYD88 and CXCR4 mutational status. The recent outcomes of the Phase III iNNOVATE trial showed that the combination of ibrutinib with rituximab resulted in a significantly prolonged progression-free survival compared with rituximab monotherapy, which provides a novel therapeutic option in the clinical practice especially for the rituximab-refractory WM patients. However, the need for continuous drug administration along with the unique toxicity manifestations may render the patient management challenging. Furthermore, our understanding of the underlying resistant mechanisms to ibrutinib is currently being evolved.

SUBMITTER: Papanota AM

PROVIDER: S-EPMC6717707 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Evaluating ibrutinib in the treatment of symptomatic Waldenstrom's macroglobulinemia.

Papanota Aristea-Maria AM Ntanasis-Stathopoulos Ioannis I Kastritis Efstathios E Dimopoulos Meletios A MA Gavriatopoulou Maria M

Journal of blood medicine 20190827

Waldenstrom's macroglobulinemia (WM) is a rare lymphoplasmacytic lymphoma with indolent course and prolonged disease course. The first-in-class Bruton's tyrosine kinase inhibitor, ibrutinib, has shown significant activity and a distinct adverse event profile among both newly diagnosed and relapsed/refractory WM patients. Interestingly, clinical responses to ibrutinib have been shown to be dependent on patients' MYD88 and CXCR4 mutational status. The recent outcomes of the Phase III iNNOVATE tria ...[more]

PMID: 31695539

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Project description:PurposeWe report the long-term findings and final analysis of a pivotal multicenter trial of ibrutinib monotherapy in previously treated patients with Waldenström macroglobulinemia (WM).Patients and methodsSixty-three symptomatic patients with median prior therapies of two (range, one to nine therapies), of whom 40% were refractory to their previous therapy, received ibrutinib at 420 mg/d. Dose reduction was permitted for toxicity.ResultsThe median follow-up was 59 months, and overall and major response rates were 90.5% and 79.4%, respectively. At best response, median serum immunoglobulin M declined from 3,520 to 821 mg/dL, bone marrow disease involvement declined from 60% to 20%, and hemoglobin rose from 10.3 to 14.2 g/dL (P < .001 for all comparisons). Responses were impacted by mutated (Mut) MYD88 and CXCR4 status. Patients with MYD88Mut, wild-type (WT) CXCR4 showed higher major (97.2% v 68.2%; P < .0001) and very good partial (47.2% v 9.1%; P < .01) response rates and a shorter time to major response (1.8 v 4.7 months; P = .02) versus patients with MYD88MutCXCR4Mut. Conversely, four patients who had MYD88WT disease showed no major responses. The median 5-year progression-free survival (PFS) rate for all patients was not reached, and was 70% and 38% for those with MYD88MutCXCR4WT and MYD88MutCXCR4Mut WM, respectively (P = .02). In patients with MYD88WT, the median PFS was 0.4 years (P < .01 for three-way comparisons). The 5-year overall survival rate for all patients was 87%. Grade ≥ 3 adverse events in more than one patient at least possibly related included neutropenia (15.9%), thrombocytopenia (11.1%), and pneumonia (3.2%). Eight patients (12.7%) experienced atrial arrhythmia, and seven of the eight continued therapy with medical management.ConclusionIbrutinib is highly active and produces long-term disease control in previously treated patients with WM. Treatment is tolerable. Response depth, time to major response, and PFS are impacted by MYD88 and CXCR4 mutation status.

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Evaluating ibrutinib in the treatment of symptomatic Waldenstrom's macroglobulinemia.

Publications

Evaluating ibrutinib in the treatment of symptomatic Waldenstrom's macroglobulinemia.

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