Abstract
Mantle cell lymphoma (MCL) is a rare but aggressive B-cell hemopathy characterized by the translocation t(11;14)(q13;q32) that leads to the overexpression of the cell cycle regulatory protein cyclin D1. This translocation is the initial event of the lymphomagenesis, but tumor cells can acquire additional alterations allowing the progression of the disease with a more aggressive phenotype and a tight dependency on microenvironment signaling. To date, the chemotherapeutic-based standard care is largely inefficient and despite the recent advent of different targeted therapies including proteasome inhibitors, immunomodulatory drugs, tyrosine kinase inhibitors, relapses are frequent and are generally related to a dismal prognosis. As a result, MCL remains an incurable disease. In this review, we will present the molecular mechanisms of drug resistance learned from both preclinical and clinical experiences in MCL, detailing the main tumor intrinsic processes and signaling pathways associated to therapeutic drug escape. We will also discuss the possibility to counteract the acquisition of drug refractoriness through the design of more efficient strategies, with an emphasis on the most recent combination approaches.
Highlights
Physiopathology of Mantle Cell LymphomaMantle cell lymphoma (MCL) is a rare B-cell lymphoma that represents 5–10% of all non-Hodgkin lymphomas (NHLs), with an incidence of 0.8 cases per 100,000 persons [1]
Mantle cell lymphoma (MCL) is a rare but aggressive B-cell hemopathy characterized by the translocation t(11;14)(q13;q32) that leads to the overexpression of the cell cycle regulatory protein cyclin D1
In transplant-ineligible patients with untreated, newly diagnosed MCL, a phase 3 trial demonstrated that frontline bortezomib plus rituximab, cyclophosphamide, doxorubicin, and prednisone (VR-CAP regimen) was associated with a survival benefit over rituximab to CHOP (R-CHOP), with a median overall survival (OS) of 90.7 months, significantly longer that the value observed in the R-CHOP group
Summary
Mantle cell lymphoma (MCL) is a rare B-cell lymphoma that represents 5–10% of all non-Hodgkin lymphomas (NHLs), with an incidence of 0.8 cases per 100,000 persons [1]. It develops primarily among elderly individuals with a median age of approximately 67 years and a male-to-female ratio of 2–3:1. 70% of patients or more have disseminated disease (stage III or IV), with lymphadenopathy (75%), hepato-splenomegaly (35–60%), bone marrow (>60%) and peripheral blood (13–77%) involvement [2]. The clinical evolution is usually very aggressive, and despite overall response rates above 70% with standard immunochemotherapeutic schemes (see Section 1.3), few patients can be cured [4]
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