Ibrutinib for Waldenström’s Macroglobulinemia

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Expanded Indication for Ibrutinib

In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.


On January 29, 2015, the U.S. Food and Drug Administration (FDA) approved ibrutinib (Imbruvica) for treatment of patients with the B-cell malignancy Waldenström’s macroglobulinemia.1,2 The drug has previously been approved by FDA to treat mantle cell lymphoma and chronic lymphocytic leukemia.

Supporting Study

The approval was based on demonstration of durable responses in a single-arm, multicenter trial in which 63 patients with previously treated disease received ibrutinib at 420 mg once daily.2 Patients had a median age of 63 years (range = 44–86 years), 76% were male, 95% were white, and all had Eastern Cooperative Oncology Group performance status of 0 or 1. Median time since diagnosis was 74 months, median number of prior treatments was two (range = 1–11), and median serum IgM level was 3.5 g/dL (range = 0.7–8.4 g/dL).

The response rate was 61.9% (95% confidence interval = 48.8%–73.9%), including a very good partial response in 11.1% and a partial response in 50.8%. Median time to response was 1.2 months and median response duration was not reached (range = 2.8+ to 18.8+ months).

How It Works

Ibrutinib is a small-molecule inhibitor of Bruton’s tyrosine kinase, a signaling molecule of the B-cell antigen receptor and cytokine receptor pathways. Bruton’s tyrosine kinase activity via signaling through the B-cell surface receptor results in activation of pathways necessary for B-cell trafficking, chemotaxis, and adhesion. Ibrutinib forms a covalent bond with a cysteine residue in the Bruton’s tyrosine kinase active site, leading to inhibition of Bruton’s tyrosine kinase enzymatic activity. Preclinical studies have shown that ibrutinib inhibits malignant B-cell proliferation and survival in vivo and cell migration and substrate adhesion in vitro.

How It Is Given

The recommended dosage of ibrutinib in Waldenström’s macroglobulinemia is 420 mg orally once daily. Ibrutinib treatment should be interrupted for grade 3 or higher nonhematologic toxicities, grade 3 or higher neutropenia with fever, and grade 4 hematologic toxicities. With resolution of toxicity to grade 1 or baseline status, treatment can be reinitiated at the starting dose. The dose may be reduced to 280 mg and then to 140 mg for recurrent toxicity.

Coadministration of ibrutinib with strong or moderate CYP3A inhibitors (eg, clarithromycin, grapefruit juice, indinavir, ketoconazole) should be avoided. If a strong inhibitor is to be used for ≤ 7 days, interruption of ibrutinib during this period should be considered. If a moderate inhibitor must be used, the ibrutinib dose should be reduced to 140 mg. Patients taking concomitant strong or moderate CYP3A inhibitors should be monitored more closely for signs of ibrutinib toxicity.

Since ibrutinib is metabolized in the liver, significant increases in exposure are expected in patients with hepatic impairment, and patients with aspartate transaminase or alanine transaminase levels ≥ 3.0 times the upper limit of normal were excluded from clinical trials. Use of ibrutinib should be avoided in patients with hepatic impairment; there are insufficient data to recommend a dose in such patients. Ibrutinib exposure is not altered in patients with creatinine clearance > 25 mL/min; there are no data in patients with severe renal impairment or on dialysis.

Safety Profile

In the supporting trial, the most common nonhematologic adverse events of any grade were diarrhea (37%), rash (22%), nausea (21%), fatigue (21%), and muscle spasms (21%). Grade 3 or 4 adverse events consisted of pneumonia in 6% and skin infection in 2%. Grade 3 or 4 hematologic toxicities consisted of thrombocytopenia in 13% (43% any grade), neutropenia in 19% (44% any grade), and anemia in 8% (13% any grade).

Ibrutinib carries warnings/precautions for hemorrhage, infection, cytopenias, atrial fibrillation, second primary malignancies (including skin cancers and other carcinomas), tumor lysis syndrome, and embryo-fetal toxicity. Patients must be monitored for bleeding, fever and infection, and atrial fibrillation. Complete blood cell counts should be monitored monthly. Women must be advised of potential fetal risk and counseled to avoid pregnancy while taking ibrutinib. ■


1. U.S. Food and Drug Administration: Ibrutinib. Available at Accessed February 5, 2015.

2. Imbruvica® (ibrutinib) capsules prescribing information, Pharmacyclics, Inc, 2015. Available at Accessed February 5, 2015.


Report Adverse Events

Health-care professionals should report all serious adverse events suspected to be associated with the use of any medicine or device to FDA’s MedWatch Reporting System by completing a form online at, by faxing (800-FDA-0178), by mailing the postage-paid address form provided online, or by telephone (800-FDA-1088).