FDA Approves Ibrutinib in Relapsed/Refractory Marginal Zone Lymphoma

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On January 19, the U.S. Food and Drug Administration (FDA) approved ibrutinib (Imbruvica) for the treatment of patients with marginal zone lymphoma who require systemic therapy and have received at least one prior anti–CD20-based therapy. Accelerated approval was granted for this indication based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

Marginal zone lymphoma is a slow-growing B-cell lymphoma occurring in lymphocytes at the edges of lymph nodes and various tissues, including the stomach, salivary glands, thyroid gland, eyes, lungs, and spleen. Marginal zone lymphoma accounts for approximately 12% of all cases of non-Hodgkin lymphoma in adults.

“Patients with relapsed/refractory marginal zone lymphoma are in critical need of treatment options to manage living with this rare, serious blood cancer,” said Ariela Noy, MD, hematologic oncologist at Memorial Sloan Kettering Cancer Center and lead investigator of the study on which the approval is based. “This approval of ibrutinib represents a welcome new oral option for the marginal zone lymphoma community and is the first approved therapy for these patients.” 


The approval is based on results from the multicenter, open-label, single-arm, phase II PCYC-1121 trial assessing the safety and efficacy of ibrutinib in 63 patients with marginal zone lymphoma who received at least 1 prior therapy, including all 3 subtypes: mucosa-associated lymphoid tissue (n = 32), nodal marginal zone lymphoma (n = 17), and splenic marginal zone lymphoma (n = 14).

The responses were assessed by an independent review committee using criteria adopted from the International Working Group criteria for malignant lymphoma and demonstrated a 46% overall response rate (95% confidence interval [CI] = 33.4%–59.1%), with 3.2% of patients achieving complete responses and 42.9% achieving partial responses. Efficacy was observed across all three marginal zone lymphoma subtypes (overall response rate = 46.9%, 41.2%, and 50.0% for mucosa-associated lymphoid tissue , nodal, and splenic subtypes, respectively).

The median duration of response was not reached (range, 16.7 months to not reached), with median follow-up of 19.4 months. The median time to initial response was 4.5 months (range, 2.3–16.4). These data were presented at the 58th Annual American Society of Hematology (ASH) Meeting and Exposition in December 2016 (Abstract 1213).1

Warnings and Adverse Events

Warnings and precautions for ibrutinib include hemorrhage, infections, cytopenias, atrial fibrillation, hypertension, second primary malignancies, tumor-lysis syndrome, and embryo­fetal toxicity.

The most common (> 20%) adverse events of all grades included thrombocytopenia (49%), fatigue (44%), anemia (43%), diarrhea (43%), bruising (41%), musculoskeletal pain (40%), hemorrhage (30%), rash (29%), nausea (25%), peripheral edema and arthralgia (24% each), neutropenia (22%), cough (22%), and dyspnea and upper respiratory tract infection (21% each). The most common (> 10%) grade 3 or 4 adverse events were decreases in hemoglobin and neutrophils (13% each) and pneumonia (10%). ■


1. Noy A, de Vos S, Thieblemont C, et al: Single-agent ibrutinib demonstrates efficacy and safety in patients with relapsed/refractory marginal zone lymphoma: A multicenter, open-label, phase 2 study. 2016 ASH Annual Meeting. Abstract 1213. Presented December 5, 2016.