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Article: Ibrutinib Monotherapy in Symptomatic, Treatment-Naive Patients with Waldenstrom Macroglobulinemia

Abstract:

Purpose
Ibrutinib is active in previously treated Waldenstro¨m macroglobulinemia (WM). MYD88 mutations
(MYD88MUT) and CXCR4 mutations (CXCR4MUT) affect ibrutinib response. We report on a prospective
study of ibrutinib monotherapy in symptomatic, untreated patients with WM, and the effect
of CXCR4MUT status on outcome.
Patients and Methods
Symptomatic, treatment-na¨ıve patients withWMwere eligible. Ibrutinib (420 mg) was administered
daily until progression or unacceptable toxicity. All tumors were genotyped for MYD88MUT and
CXCR4MUT.
Results
A total of 30 patients with WM received ibrutinib. All carried MYD88MUT, and 14 (47%) carried
a CXCR4MUT. After ibrutinib treatment, median serum IgM levels declined from 4,370 to 1,513 mg/
dL, bone marrow involvement declined from 65% to 20%, and hemoglobin level rose from 10.3 to
13.9 g/dL (P , .001 for all comparisons). Overall (minor or more than minor) and major (partial or
greater than partial) responses for all patients were 100% and 83%, respectively. Rates of major
(94% v 71%) and very good partial (31 v 7%) responses were higher and time to major responses
more rapid (1.8 v 7.3 months; P = 0.01) in patients with wild-type CXCR4 versus those with
CXCR4MUT, respectively. With a median follow-up of 14.6 months, disease in two patients (both
with CXCR4MUT) progressed. The 18-month, estimated progression-free survival is 92% (95% CI,
73% to 98%). All patients are alive. Grade 2/3 treatment-related toxicities in . 5% of patients
included arthralgia (7%), bruising (7%), neutropenia (7%), upper respiratory tract infection (7%),
urinary tract infection (7%), atrial fibrillation (10%), and hypertension (13%). There were no grade 4 or
unexpected toxicities.
Conclusion
Ibrutinib is highly active, produces durable responses, and is safe as primary therapy in patients with
symptomatic WM. CXCR4MUT status affects responses to ibrutinib.

 

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