Ibrutinib in previously treated Waldenström's macroglobulinemia.

Abstract

BACKGROUND:

MYD88(L265P) and CXCR4(WHIM) mutations are highly prevalent in Waldenström's macroglobulinemia. MYD88(L265P) triggers tumor-cell growth through Bruton's tyrosine kinase, a target of ibrutinib. CXCR4(WHIM) mutations confer in vitro resistance to ibrutinib.

METHODS:

We performed a prospective study of ibrutinib in 63 symptomatic patients with Waldenström's 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 MYD88(L265P)CXCR4(WT) (with WT indicating wild-type) (100% overall response rate and 91.2% major response rate), followed by patients with MYD88(L265P)CXCR4(WHIM) (85.7% and 61.9%, respectively) and patients with MYD88(WT)CXCR4(WT) (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 Waldenström's macroglobulinemia. MYD88 and CXCR4 mutation status affected responses to this drug. (Funded by Pharmacyclics and others; ClinicalTrials.gov number, NCT01614821.).

• Authors: Steven P Treon, Christina K Tripsas, Kirsten Meid, Diane Warren, Gaurav Varma, Rebecca Green, Kimon V Argyropoulos, Guang Yang, Yang Cao, Lian Xu, Christopher J Patterson, Scott Rodig, James L Zehnder, Jon C Aster, Nancy Lee Harris, Sandra Kanan, Irene Ghobrial, Jorge J Castillo, Jacob P Laubach, Zachary R Hunter, Zeena Salman, Jianling Li, Mei Cheng, Fong Clow, Thorsten Graef, M Lia Palomba, Ranjana H Advani
• Journal: The New England journal of medicine (N Engl J Med) Vol. 372 Issue 15 Pg. 1430-40 (Apr 09 2015) ISSN: 1533-4406 [Electronic] United States
• PMID: 25853747 (Publication Type: Clinical Trial, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)

Chemical References

• CXCR4 protein, human
• Hemoglobins
• Immunoglobulin M
• MYD88 protein, human
• Myeloid Differentiation Factor 88
• Piperidines
• Protein Kinase Inhibitors
• Pyrazoles
• Pyrimidines
• Receptors, CXCR4
• ibrutinib
• Protein-Tyrosine Kinases
• Agammaglobulinaemia Tyrosine Kinase
• Adenine

Topics

• Adenine (analogs & derivatives)
• Adult
• Agammaglobulinaemia Tyrosine Kinase
• Aged
• Aged, 80 and over
• Disease-Free Survival
• Female
• Hemoglobins (analysis)
• Humans
• Immunoglobulin M (blood)
• Kaplan-Meier Estimate
• Male
• Middle Aged
• Mutation
• Myeloid Differentiation Factor 88 (genetics)
• Piperidines
• Prospective Studies
• Protein Kinase Inhibitors (adverse effects, therapeutic use)
• Protein-Tyrosine Kinases (antagonists & inhibitors)
• Pyrazoles (adverse effects, therapeutic use)
• Pyrimidines (adverse effects, therapeutic use)
• Receptors, CXCR4 (genetics)
• Survival Rate
• Waldenstrom Macroglobulinemia (blood, drug therapy, genetics)