Management of Relapsed/Refractory Marginal Zone Lymphoma: Focus on Ibrutinib

Abstract: Marginal zone lymphomas (MZLs) consist of a diverse family of malignancies, which are derived from B-cells. The disease subtypes are recognized extranodal, nodal, and splenic MZLs. The disease characteristics, clinical course, and treatment vary considerably based on the site of involvement. In 2017, the US Food and Drug Administration approved ibrutinib, a first in class Bruton’s tyrosine kinase inhibitor that revolutionized the care of chronic lymphocytic leukemia patients; for, the treatment of relapsed/refractory MZL based on pivotal open-label Phase II trial demonstrated an overall response rate of 48%, with a complete response rate of 3%, median progression-free survival of 14.2 months, and median overall survival not yet reached at a median follow-up of 19.4 months. In this review, we aim to summarize the current conundrums in the management of MZL and the evolving role of ibrutinib in the treatment of MZL.

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Keywords: non-Hodgkin’s lymphoma, marginal zone, ibrutinib 

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INTRODUCTION

Marginal zone lymphoma (MZL) is the third most common lymphoma, accounting for 8%–12% of all B-cell non-Hodgkin’s lymphomas (NHL).^1,2 MZL originates from memory B lymphocytes harbored in the marginal zone of secondary lymphoid follicles present in the spleen, mucosa-associated lymphoid tissues, and rarely lymph nodes.³ The development of MZL is associated with chronic antigen-mediated B-cell receptor (BCR) activation in most cases.^4–7 The Surveillance, Epidemiology, and End Results (SEER) data have shown that MZL occurs in adults with a median age of 67 years, but with a slight female predominance.^8–10 Based on the involved sites and characteristic molecular findings, the World Health Organization classified MZL into 3 specific subtypes, each with its own unique epidemiology, clinical presentation, and therapeutic options.¹ These subtypes include extranodal marginal zone lymphoma (EMZL), also called mucosa-associated lymphatic tissue (MALT) lymphoma; splenic MZL (SMZL); and nodal MZL (NMZL).¹

Over the past 5–7 years, a greater understanding of the disease biology, including genetic and molecular characterization, has changed the therapeutic landscape of MZL. Novel pharmaceutical engineering approaches focusing on intracellular signaling pathways have resulted in targeted therapies that have improved efficacy and tolerable toxicity profiles. There has been a growing evidence on the role played by the BCR signaling pathway in the pathogenesis of B-cell lymphoproliferative disorders, including MZL.^11–13 In many of these malignancies, small molecule kinase inhibitors targeting BCR signaling, such as the Bruton’s tyrosine kinase (BTK) inhibitor (ibrutinib), seem to provide new avenues of therapeutic strategies.¹² Here, we provide a brief overview of the various subtypes of MZL, discuss in detail the management of MZL, and focus on the emerging role of ibrutinib in this realm.

MZL – a heterogeneous disease entity: epidemiology and presentation

EMZL

Epidemiology of EMZL

EMZL, also called MALT lymphoma, is the most common subtype of MZL, accounting for ~70% of all MZLs.¹⁴ Median age at diagnosis is 50–60 years.¹⁵ EMZL can originate at virtually any extranodal site and arises in organs that normally lack lymphoid tissue (eg, stomach, intestine, thyroid, lung, and skin). Pathogenesis of EMZL involves continued proliferation of B cells and persistent stimulation of the BCR signaling pathway. The latter seems to be induced by chronic inflammation^16–21 as a result of both infectious and autoimmune causes. Examples of infectious and EMZL correlative relationships include gastric EMZL arising from Helicobacter pylori, MZL localized to the skin and Borrelia burgdorferi, the ocular adnexa and Chlamydophila psittaci, the small intestine and Campylobacter jejuni, and possibly the lung with Achromobacter xylosoxidans. The most frequently affected organ in EMZL is the stomach, and there is compelling evidence for a causal relationship between H. pylori and gastric EMZL.^5–7,22 Chronic hepatitis C viral (HCV) infection has been implicated in the pathogenesis of all MZL subtypes^21,23–26 and mainly affects the non-gastric sites, often the salivary or lacrimal glands in EMZL. Autoimmune diseases also increase the risk of non-gastric EMZL at various anatomical sites; for example, primary Sjogren’s syndrome results in a greatly increased risk for salivary gland EMZL, and Hashimoto’s thyroiditis has been implicated in the development of thyroid EMZL.^27–31

Presentation of EMZL

EMZL most commonly presents as extranodal disease and is limited to the site of origin (Ann Arbor stage IE); peripheral lymph node and bone marrow (BM) involvement is uncommon.³² Diagnosis is made by tissue biopsy, with confirmation of diagnosis by an expert hematopathologist to avoid overtreatment of benign reactive conditions or other lymphoma entities.³³ Clinical signs and symptoms of EMZL may vary according to the site of primary location.³³ Gastric EMZL is most common, accounting for one-third of all sites of localization and frequently presents with early-stage localized disease, while disseminated disease is more common with primary non-gastric sites.^34–38

SMZL

Epidemiology of SMZL

SMZL arises predominantly from the marginal zone memory B-cells located in the follicles of the spleen, splenic hilar lymph nodes, BM, and the peripheral blood.³⁹ SMZL accounts for ~20% of all MZLs,^1,40 and the median age of occurrence is 69 years.⁴¹ The pathogenesis of SMZL has yet to be fully understood; similar to other subtypes of MZL, it likely involves the persistent stimulation of BCR signaling pathway, with increasing proliferation and survival of malignant B cells.¹³ Though the association between HCV infection and SMZL has been described, there seems to be some geographic difference given the variation in seroprevalence from one series to the other.^42–44

Presentation of SMZL

Most SMZL patients are asymptomatic at the time of presentation with anemia, thrombocytopenia, or lymphocytosis incidentally found on routine blood test. Subsequent referral to the hematologist and further workup then may reveal SMZL. Advanced stage SMZL, however, can present with massive splenomegaly, abdominal pain, and early satiety. Symptomatic cytopenias may be present, and imaging may show splenic hilar lymphadenopathy.⁴⁵ Up to 20% of patients also present with autoimmune manifestations, including hemolytic anemia, immune thrombocytopenia, and acquired coagulation disorders.^42,46 Definitive diagnosis can be made from histopathologic evaluation of the spleen, which shows a nodular lymphoid proliferation with a biphasic appearance effacing the white pulp, involving the red pulp in a patchy fashion, and infiltrating the vessel wall. If histopathologic evaluation of the spleen is unavailable, diagnosis can be made by immunophenotyping of peripheral blood cells coupled with the histopathologic evaluation of the BM showing intrasinusoidal infiltration of CD20+ cells.^1,47,48

NMZL

Epidemiology of NMZL

NMZL is the least common subtype of MZL, representing <2% of all NHL and ~10% of all MZLs.¹ The median age of patients diagnosed with NMZL is between 50 and 60 years.⁴⁹ The molecular pathogenesis of NMZL is still incompletely described but likely involves constitutive BCR signaling, resulting in proliferation and survival of malignant B cells.⁵⁰

Presentation of NMZL

Similar to other indolent nodal lymphomas, such as small lymphocytic lymphoma and follicular lymphoma (FL), the majority of patients with NMZL present with non-bulky disseminated peripheral, abdominal, and thoracic lymph node involvement.^51,52 B symptoms are rare, and diagnosis requires exclusion of splenic and other organ involvement to distinguish it from other subtypes of MZL. Though involvement of BM can occur in about one-third of patients, peripheral blood involvement and cytopenias are rare.^51,53