Ibrutinib Is Highly Active in Previously Treated Waldenström’s Macroglobulinemia
In a study reported in The New England Journal of Medicine, Treon et al found that ibrutinib (Imbruvica) was highly active and produced durable responses in patients with previously treated Waldenström’s macroglobulinemia. Response rates were highest in patients with MYD88 mutation and wild-type CXCR4 and those with both MYD88 and CXCR4 mutations. MYD88 and CXCR4 mutations are common in the disease; the MYD88 L265P mutation triggers tumor cell growth through Bruton’s tyrosine kinase, which is targeted by ibrutinib, and CXCR4 WHIM mutations are associated with in vitro resistance to ibrutinib.
Study Details
In the study, 63 symptomatic patients (43 from Dana-Farber Cancer Institute, 10 from Memorial Sloan Kettering Cancer Center, and 10 from Stanford University Medical Center) who had received at least one previous treatment received ibrutinib 420 mg/d until disease progression or development of unacceptable toxicity.
Patients had received a median of two prior treatments (range = 1–9), with the most common being a monoclonal antibody (90%), glucocorticoids (67%), proteasome inhibitors (52%), and alkylating agents (51%). International Prognostic Scoring System (IPSS) score was low in 22%, intermediate in 43%, and high in 35%. Both MYD88 and CXCR4 were wild-type in 7 patients, 34 had MYD88 L265P mutation/wild-type CXCR4, and 21 had both MYD88 L265P and CXCR4 WHIM mutations.
Response Rates
Among all patients, median serum IgM levels decreased from 3,520 to 880 mg/dL, hemoglobin increased from 10.5 to 13.8 g/dL, and bone marrow involvement decreased from 60% to 25% (P < .01 for all). Median time to at least minor response was 4 weeks.
Among all patients, the overall response rate was 90.5%, and the major response rate was 73.0%. Overall and major response rates were 100% and 91.2% in those with MYD88 L265P mutation and wild-type CXCR4, 85.7% and 61.9% in those with MYD88 L265P and CXCR4 WHIM mutation, and 71.4% and 28.6% in those with wild-type MYD88 and CXCR4.
At 24 months, progression-free survival was 69.1% (95% confidence interval [CI] = 53.2%–80.5%), and overall survival was 95.2% (95% CI = 86.0%–98.4%) among all patients. Among patients with disease progression, median time to progression was 9.6 months. In subgroup analysis, high IPSS score, more than three previous treatment regimens, and wild-type MYD88 and CXCR4 genotype were associated with poorer progression-free survival.
Adverse Events
The most common treatment-related grade 3 or 4 adverse events were neutropenia (15%, 10% grade 3) and thrombocytopenia (13%, 10% grade 3), with most of them occurring in patients who had received more than three prior therapies. No other treatment-related grade 3 or 4 adverse events occurred in more than 2% of patients. Among other adverse events, postprocedural bleeding occurred in 3%, epistaxis associated with the use of fish-oil supplements occurred in 3%, and atrial fibrillation associated with a history of arrhythmia occurred in 5%.
The investigators concluded: “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.”
Steven P. Treon, MD, PhD, of Dana-Farber Cancer Institute, is the corresponding author of The New England Journal of Medicine article. M. Lia Palomba, MD, of Memorial Sloan Kettering Cancer Center, and Ranjana H. Advani, MD, of Stanford University Medical Center, contributed equally to The New England Journal of Medicine article.
The study was funded by Pharmacyclics and others. For full disclosures of the study authors, visit www.nejm.org.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
