Mantle cell lymphoma: from pathogenesis to treatment for 2024 and beyond

Mantle cell lymphoma (MCL) is a rare B-cell non-Hodgkin lymphoma with multiple subtypes including classical mantle cell lymphoma (cMCL), the leukemic variant of mantle cell lymphoma (LV-MCL), and in situ mantle cell neoplasia (ISMCN). Their clinical presentations differ significantly and range from indolent to very aggressive. The defining genetic feature and chief oncogenic mechanism of MCL involves the t(11;14)(q13;q32) translocation, which results in a fusion of the gene that encodes cyclin D1 (CCND1) and the immunoglobulin heavy chain gene (IGH). As a result of significant variation between subtypes, treatment approaches and prognoses of this disease vary drastically. Current treatment options for MCL range from observation to conventional chemotherapy with or without subsequent stem cell transplantation, to targeted immunotherapies against key molecular targets. The role of stem cell transplant has become more debatable for frontline consolidation therapy. Earlier incorporation of Bruton's tyrosine kinase (BTK) inhibitors is being strongly considered for frontline therapy. Chimeric antigen receptor therapy (CAR-T) therapies have become established treatment options for relapsed/refractory disease. Ongoing frontiers involve optimal management of TP53 mutated MCL and those relapsing with CNS involvement. Novel therapeutic approaches including the development of non-covalent BTK inhibitors and bispecific antibody therapy carry significant promise to further improve outcomes across all subtypes of this disease.