FDA Approves Ibrutinib Plus Rituximab for Waldenström’s Macroglobulinemia


The U.S. Food and Drug Administration (FDA) has approved ibrutinib (Imbruvica) plus rituximab (Rituxan) for the treatment of adult patients with Waldenström's macroglobulinemia (WM). With this approval, the ibrutinib prescribing information now includes combination use with rituximab, representing the first and only chemotherapy-free combination treatment specifically indicated for the disease. Ibrutinib— a first-in-class Bruton's tyrosine kinase (BTK) inhibitor—was first approved as a single agent therapy for WM in January 2015.

WM is a rare, slow-growing and incurable form of non-Hodgkin lymphoma with limited treatment options. WM typically affects older adults and is primarily found in the bone marrow, although lymph nodes and the spleen also may be affected. In the United States, there are about 2,800 new cases of WM each year.


The approval is supported by data from the phase III iNNOVATE trial, which evaluated ibrutinib in combination with rituximab vs rituximab alone in 150 patients with previously untreated and relapsed/refractory WM. 

Patients were randomized to receive intravenous rituximab 375 mg/m2 once weekly for 4 consecutive weeks, followed by a second four-weekly rituximab course following a 3-month interval. All patients received either ibrutinib 420 mg or placebo once daily continuously until criteria for permanent discontinuation were met. The primary endpoint was progression-free survival (PFS), with secondary endpoints including overall response rate, hematological improvement measured by hemoglobin, time to next treatment, overall survival, and number of participants with adverse events as a measure of safety and tolerability within each treatment arm.

At a median follow up of 26.5 months, the study demonstrated a significant improvement in PFS with ibrutinib plus rituximab compared to rituximab alone (30-month PFS rates were 82% vs 28%, respectively). Patients taking ibrutinib plus rituximab also experienced an 80% reduction in relative risk of disease progression or death than those only treated with rituximab (hazard ratio = 0.20; confidence interval = 0.11–0.38, P < .0001). These data were recently presented by Dimopoulos et al at the 2018 ASCO Annual Meeting (Abstract 8003) and simultaneously published in The New England Journal of Medicine.

“The iNNOVATE study demonstrated persuasive clinical evidence supporting the efficacy of ibrutinib plus rituximab in Waldenström's macroglobulinemia,” said Meletios A. Dimopoulos, MD, Professor and Chairman of the Department of Clinical Therapeutics, National and Kapodistrian University of Athens School of Medicine, Athens, Greece, and lead iNNOVATE study investigator. “This approval is a significant milestone for the WM community who have limited treatment options.”

“Ibrutinib has significantly advanced the treatment of Waldenström's macroglobulinemia. The approval of ibrutinib and rituximab has added a new option for many Waldenström's patients,” said Steven P. Treon, MD, PhD, Director of the Bing Center for Waldenström's Macroglobulinemia at the Dana-Farber Cancer Institute, Associate Professor at Harvard Medical School, and lead investigator of the ibrutinib phase II clinical trial which served as the basis for its January 2015 FDA approval.

The most common adverse reactions (occurring in 20% or more of patients) of all grades in patients treated with ibrutinib plus rituximab in the iNNOVATE study were bruising (37%), musculoskeletal pain (35%), hemorrhage (32%), diarrhea (28%), rash (24%), arthralgia (24%), nausea (21%), and hypertension (20%).

In combination with rituximab or as a single agent, the recommended dose of ibrutinib for adults with WM is 420 mg taken orally once daily until disease progression or unacceptable toxicity. When administering ibrutinib in combination with rituximab, consider administering ibrutinib prior to rituximab when given on the same day.

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®.