Marginal-zone lymphoma (MZL) is a malignancy that arises from B-lymphocytes in the marginal zone of lymphoid tissue. This slow-growing indolent B-cell lymphoma represents approximately 12% of all cases of non-Hodgkin lymphoma (NHL) in adults.1 MZL is divided into 3 subtypes, including mucosa-associated lymphoid tissue (MALT), nodal MZL, and splenic MZL.1
MALT lymphoma, the most common of these subtypes, occurs in the stomach, intestines, salivary glands, thyroid, eyes, and lungs.1 In contrast to the spleen and lymph nodes, the body’s organs normally lack lymphoid tissue. However, in MALT lymphoma, autoimmune processes or chronic infection cause B cells to accumulate.2,3 Helicobacter pylori is 1 of at least 6 microbial species associated with lymphoproliferation in gastric MALT lymphoma.3
Short-term antibiotic therapy is the initial treatment of gastric MALT lymphoma and is effective in approximately 70% to 90% of patients.1
Because the other types of MZL can appear in several areas of the body, their treatment is based on the location and the extent of disease spread. Lung, breast, or spleen surgery can be considered, or radiation therapy, with or without chemotherapy.1 First-line chemotherapy regimens for advanced MZL include bendamustine plus rituximab, and the R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) regimen.1
Active surveillance is appropriate for patients with asymptomatic MZL.2 MZL usually has a favorable outcome; the 5-year overall survival rates for patients with MALT lymphoma exceed 85% in the majority of the cases.2
Although several agents and chemotherapy-based regimens are being evaluated in clinical trials for MZL, none is approved by the US Food and Drug Administration (FDA) for use in this patient population.Ibrutinib Approved for MZL
On January 19, 2017, the FDA accelerated the approval of a new indication for ibrutinib (Imbruvica; Pharmacyclics) for the treatment of patients with MZL who require systemic therapy and who have received at least 1 previous anti-CD20–based therapy (eg, rituximab).4 This is the fifth indication for ibrutinib in the United States.4,5 This approval was granted based on overall response rate (ORR) data.4,5
In 2013, ibrutinib received accelerated approval for mantle-cell lymphoma in patients who had received at least 1 previous therapy.5 This was followed by new indications for chronic lymphocytic leukemia or small lymphocytic lymphoma, and for Waldenström’s macroglobulinemia in patients who had received at least 1 previous therapy.5,6Mechanism of Action
Ibrutinib is a small-molecule inhibitor of Bruton’s tyrosine kinase, a signaling molecule of the B-cell antigen receptor and cytokine receptor pathways.5 Preclinical studies have demonstrated that ibrutinib prevents the activation of downstream pathways affected by Bruton’s tyrosine kinase, inhibits cell proliferation, and promotes apoptosis of cancer cells.7 Ibrutinib is the first FDA-approved drug designed to target Bruton’s tyrosine kinase, a protein necessary for the growth and survival of B-cells.5Dosing and Administration
In patients with MZL, the recommended dose and schedule for ibrutinib is 560 mg orally once daily. Ibrutinib should be administered at the same time each day, and should be swallowed whole with water. The capsules should not be opened, broken, or chewed.5Ibrutinib Distribution
Ibrutinib can be accessed through several specialty pharmacies and distributors, including ASD Healthcare, Avella Specialty Pharmacy, Biologics, Diplomat Specialty Pharmacy, McKesson Plasma and Biologics, McKesson Specialty Health, Onco360, and Oncology Supply.8The Pivotal Clinical Trial
The approval of ibrutinib for MZL was based on the phase 2, open-label, multicenter PCYC-1121 clinical trial of 63 patients with previously treated MZL.4,5,9 This study involved patients with MALT (N = 32), nodal MZL (N = 17), or splenic MZL (N = 14).4 The primary end point was ORR, as assessed by an independent review committee.5,9
Ibrutinib was given orally, 560 mg once daily, until disease progression or until unacceptable toxicity.5
The majority (92%) of patients (median age, 66 years) in the study had an Eastern Cooperative Oncology Group performance status 0 or 1. The majority of patients were female (59%) and white (84%).5 The median time since diagnosis of MZL was 3.8 years, and patients had received a median of 2 previous therapies (range, 1-9) for MZL.5
After a median follow-up of 19.4 months, the ORR was 46% (95% confidence interval, 33.4-59.1; Table).5 The duration of response was not reached at the time of the FDA approval, and ranged from 16.7 months to “not reached.”5 Overall, response rates were 46.9% for MALT lymphoma, 41.2% for nodal MZL, and 50% for splenic MZL.5Adverse Reactions
The most common (≥20%) adverse reactions in patients with MZL included thrombocytopenia (49%), diarrhea (43%), neutropenia (22%), fatigue (44%), bruising (41%), hemorrhage (30%), anemia (43%), rash (29%), peripheral edema (24%), arthralgia (24%), upper respiratory tract infection (21%), cough (22%), dyspnea (21%), musculoskeletal pain (40%), and nausea (25%).5
Treatment-emergent grade ≥3 adverse events were reported in 67% of patients, with anemia (14%), pneumonia (8%), and fatigue (6%) being the most common events.9 Diarrhea was the most common (3%) adverse reaction that led to the discontinuation of ibrutinib in patients with MZL.5
Ibrutinib has no contraindication.5Drug Interactions
Ibrutinib should not be used with strong or moderate cytochrome (CY) P3A inhibitors, and its dose should be reduced if a moderate CYP3A inhibitor must be used.5 Ibrutinib should also not be used with strong CYP3A inducers.5Selected Warnings
Bleeding events of any grade occurred in approximately 50% of patients who received ibrutinib. The mechanism responsible for the bleeding events is not well-understood. Because ibrutinib can increase the risk for hemorrhage in patients receiving antiplatelet or anticoagulant therapies, patients should be monitored for signs of bleeding.5
Fatal and nonfatal infections, including cases of progressive multifocal leukoencephalopathy, have occurred in clinical trials of ibrutinib.5
Severe cytopenias were reported with ibrutinib. Complete blood cell counts should be monitored monthly.5
Atrial fibrillation and atrial flutter have occurred in 6% to 9% of patients who received ibrutinib. If persistent atrial fibrillation is noted, dose modification or discontinuation of ibrutinib should be considered.5
Second malignancies (3%-16%), including nonskin carcinomas (1%-4%), have occurred with ibrutinib. Nonmelanoma skin cancer is the most common (2%-13%) second malignancy.5
Patients using ibrutinib can have tumor lysis syndrome and should be monitored closely.5Use in Specific Populations
Because ibrutinib can cause fetal harm, women of reproductive potential should avoid pregnancy while taking ibrutinib and for up to 1 month after ending treatment. Men should avoid fathering a child while taking ibrutinib and for up to 1 month after ending treatment.5
Anemia and grade ≥3 pneumonia have been observed more often in older patients who received ibrutinib compared with younger patients.5
Exposure to ibrutinib increases in patients with liver failure, and its use is not recommended for patients with moderate or severe liver disease. Patients who receive ibrutinib should be monitored for signs of liver toxicity.5Conclusion
Ibrutinib, a first-in-class inhibitor of Bruton’s tyrosine kinase, is the first drug approved in the United States specifically for patients with MZL, a rare and indolent subtype of NHL. This once-daily oral drug demonstrated efficacy and acceptable toxicity in patients with MZL.
The information in this article is current as of August 2017 and was derived from publicly available sources and the drug manufacturer’s website and prescribing information. The Publisher is not responsible for inaccurate information resulting from ongoing updates. Readers should refer to the drug manufacturer’s website for the most current information.
- Lymphoma Research Foundation. Marginal zone lymphoma. www.lymphoma.org/site/pp.asp?c=bkLTKaOQLmK8E&b=6554677. Accessed May 22, 2017.
- Zinzani PL. The many faces of marginal zone lymphoma. Hematology Am Soc Hematol Educ Program. 2012; 2012:426-432.
- Zucca E, Bertoni F. The spectrum of MALT lymphoma at different sites: biological and therapeutic relevance. Blood. 2016;127:2082-2092.
- Johnson & Johnson. IMBRUVICA® (ibrutinib) approved by FDA for marginal zone lymphoma (MZL) patients who require systemic therapy and have received at least one prior anti-CD20-based therapy. Press release. January 19, 2017. www.jnj.com/media-center/press-releases/imbruvica-ibrutinib-approved-by-fda-for-marginal-zone-lymphoma-mzl-patients-who-require-systemic-ther apy-and-have-received-at-least-one-prior-anti-cd20-based-therapy. Accessed May 22, 2017.
- Imbruvica (ibrutinib) capsules [prescribing information]. Sunnyvale, CA: Pharmacyclics; Horsham, PA: Janssen Biotech; January 2017.
- US Food and Drug Administration. FDA expands approved use of Imbruvica for rare form of non-Hodgkin lymphoma: first drug approved to treat Waldenström’s macroglobulinemia. Press release. January 29, 2015. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm432123.htm. Accessed May 22, 2017.
- Akinleye A, Chen Y, Mukhi N, et al. Ibrutinib and novel BTK inhibitors in clinical development. J Hematol Oncol. 2013;6:59.
- Pharmacyclics; Janssen Biotech. Imbruvica (ibrutinib): prescribing resources: specialty pharmacy & distributor list. www.imbruvicahcp.com/mcl/support-and-resources/prescribing-resources. Accessed May 22, 2017.
- Noy A, de Vos S, Thieblemont C, et al. Targeting Bruton tyrosine kinase with ibrutinib in relapsed/refractory marginal zone lymphoma. Blood. 2017;129:2224-2232.