학술논문
Ibrutinib in Previously Treated Waldenströmʼs Macroglobulinemia
Document Type
Academic Journal
Author
Treon, Steven P.; Tripsas, Christina K.; Meid, Kirsten; Warren, Diane; Varma, Gaurav; Green, Rebecca; Argyropoulos, Kimon V.; Yang, Guang; Cao, Yang; Xu, Lian; Patterson, Christopher J.; Rodig, Scott; Zehnder, James L.; Aster, Jon C.; Harris, Nancy Lee; Kanan, Sandra; Ghobrial, Irene; Castillo, Jorge J.; Laubach, Jacob P.; Hunter, Zachary R.; Salman, Zeena; Li, Jianling; Cheng, Mei; Clow, Fong; Graef, Thorsten; Palomba, Lia M.; Advani, Ranjana H.
Source
The New England Journal of Medicine. Apr 09, 2015 372(15):1430-1440
Subject
Language
English
ISSN
0028-4793
Abstract
BACKGROUND: MYD88 and CXCR4 mutations are highly prevalent in Waldenströmʼs macroglobulinemia. MYD88 triggers tumor-cell growth through Brutonʼs tyrosine kinase, a target of ibrutinib. CXCR4 mutations confer in vitro resistance to ibrutinib. METHODS: We performed a prospective study of ibrutinib in 63 symptomatic patients with Waldenströmʼs macroglobulinemia who had received at least one previous treatment, and we investigated the effect of MYD88 and CXCR4 mutations on outcomes. Ibrutinib at a daily dose of 420 mg was administered orally until disease progression or the development of unacceptable toxic effects. RESULTS: After the patients received ibrutinib, median serum IgM levels decreased from 3520 mg per deciliter to 880 mg per deciliter, median hemoglobin levels increased from 10.5 g per deciliter to 13.8 g per deciliter, and bone marrow involvement decreased from 60% to 25% (P<0.01 for all comparisons). The median time to at least a minor response was 4 weeks. The overall response rate was 90.5%, and the major response rate was 73.0%; these rates were highest among patients with MYD88CXCR4 (with WT indicating wild-type) (100% overall response rate and 91.2% major response rate), followed by patients with MYD88CXCR4 (85.7% and 61.9%, respectively) and patients with MYD88CXCR4 (71.4% and 28.6%). The estimated 2-year progression-free and overall survival rates among all patients were 69.1% and 95.2%, respectively. Treatment-related toxic effects of grade 2 or higher included neutropenia (in 22% of the patients) and thrombocytopenia (in 14%), which were more common in heavily pretreated patients; postprocedural bleeding (in 3%); epistaxis associated with the use of fish-oil supplements (in 3%); and atrial fibrillation associated with a history of arrhythmia (5%). CONCLUSIONS: Ibrutinib was highly active, associated with durable responses, and safe in pretreated patients with Waldenströmʼs macroglobulinemia. MYD88 and CXCR4 mutation status affected responses to this drug. (Funded by Pharmacyclics and others; ClinicalTrials.gov number, NCT01614821.)