Non-Hodgkin Lymphoma (NHL) is 1 of the 10 most common malignancies, accounting for approximately 3% to 4% of cancer cases worldwide.1
Over 30 different subtypes of NHL have been identified.2
Of these, B-cell lymphomas make up the majority of cases in the United States and worldwide, accounting for approximately 85% of cases.3,4
The 5-year survival rate associated with B-cell lymphomas, which varies by subtype, ranges from 83% to 91% for patients with marginal zone lymphoma, and between 44% and 48% for those with plasma cell neoplasms.5
Some B-cell lymphomas, such as mantle cell lymphoma (MCL), are associated with a particularly grim prognosis due an aggressive disease course.5
Bruton tyrosine kinase (BTK) plays a central role in the development of several types of B-cell malignancies. Upon antigen binding to the B-cell receptor (BCR), a host of signaling mechanisms are activated, which eventually result in BTK activation.6 BTK is known to have a prominent role in B-cell development and in regulating BCR communication with the microenvironment.6
B-cell malignancies characteristically co-opt BCR signaling as a survival and proliferation mechanism via 1 or more known mechanisms: activating mutations in BCR signaling domains, antigen-dependent BCR activation, and/or ligand-independent, autonomous BCR pathway activation.6
The mechanism by which this process unfolds has relevance for how strongly BTK is involved.
Treatment of B-cell malignancies is largely based on chemotherapy-based regimens at induction. Although response is variable in subsequent lines of therapy, growth of subclonal cell populations that lead to recurrence and relapse is possible in some instances. Owing to the recognition of the central role of BTK in clonal B-cell survival, a new class of targeted therapies that inhibit BTK activity has emerged, demonstrating significant improvements in animal models, in vitro, in vivo, and in humans.6
The most mature data are associated with the BTK inhibitor ibrutinib, which has been studied in clinical trials of patients with MCL, chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma, and Waldenström macroglobulinemia.
These studies have helped elucidate the multiple mechanisms by which BTK inhibition may lead to reduction in disease activity. Fundamentally, ibrutinib interferes with migration and adhesion of CLL and MCL cells, thereby permitting redistribution of the B-cell population.6
Correspondingly, continuous therapy with ibrutinib has been shown to result in normalization of lymphocyte counts and remissions in a majority of patients.6
Similar to experiences with other tyrosine kinase inhibitor therapy approaches utilized in other forms of cancers, both primary and secondary resistance to BTK inhibition has been noted. As a result, the potential role of second-generation BTK inhibitors in ibrutinib-resistant CLL and MCL, and in combinatorial approaches in other settings, is being evaluated.
Reviewing the epidemiology, etiology, and pathophysiology of MCL and CLL, with emphasis on the fundamental role of BTK, this article provides context and background for consid- eration of how the BTK inhibitors ibrutinib and acalabrutinib may impact treatment paradigms for these and potentially other B-cell malignancies.
Mantle Cell Lymphoma
MCL is a rarely occurring but clinically aggressive entity that accounts for approximately 2% to 10% of all NHLs.1,7,8
Annual incidence of MCL in the United States is estimated to be approximately 0.51 to 0.55 per 100,000 persons, which is similar to rates observed with marginal zone lymphoma, lymphoplasmacytic lymphoma, and Burkitt lymphoma.1 MCL is more common among males and individuals over the age of 60 and rarely occurs among those individuals who are younger than 30 years.1
Some studies have suggested a rising incidence in the past 2 decades, although the contribution of improved diagnosis may artificially inflate the number of cases. As MCL was only formally categorized as a B-cell NHL subtype in 1992,9
there is limited historical data for comparison.1
The underlying cause of MCL has not been fully elucidated. The contribution of various environmental factors (ie, infectious entities, autoimmune disease, and/or lifestyle) and family history of hematopoietic malignancies have each been associated with increased risk but not confirmed.1
Although body mass index, history of cigarette smoking, and alcohol consumption are generally associated with an increased risk of NHL, these have not been implicated as risk factors for MCL.1,2
Meanwhile, occupational exposure to pesticides and solvents has likewise been noted to contribute to B-cell lymphoma pathogenesis, although these risk factors have not been extensively studied in the context of MCL.1,2