Mantle cell lymphoma in 2022—A comprehensive update on molecular pathogenesis, risk stratification, clinical approach, and current and novel treatments

Abstract The field of mantle cell lymphoma (MCL) has witnessed remarkable progress due to relentless advances in molecular pathogenesis, prognostication, and newer treatments. MCL consists of a spectrum of clinical subtypes. Rarely, atypical cyclin D1‐negative MCL and in situ MCL neoplasia are identified. Prognostication of MCL is further refined by identifying somatic mutations (such as TP53 , NSD2 , KMT2D ), methylation status, chromatin organization pattern, SOX‐11 expression, minimal residual disease (MRD), and genomic clusters. Lymphoid tissue microenvironment studies demonstrated the role of B‐cell receptor signaling, nuclear factor kappa B (NF‐kB), colony‐stimulating factor (CSF)‐1, the CD70‐SOX‐11 axis. Molecular mechanism of resistance, mutation dynamics, and pathogenic pathways (B‐cell receptor (BCR), oxidative phosphorylation, and MYC) were identified in mediating resistance to various treatments (bruton tyrosine kinase (BTK) inhibitors [ibrutinib, acalabrutinib]. Treatment options range from conventional chemoimmunotherapy and stem cell transplantation (SCT) to targeted therapies against BTK (covalent and noncovalent), Bcl2, ROR1, cellular therapy such as anti‐CD19 chimeric antigen receptor therapy (CAR‐T), and most recently bispecific antibodies against CD19 and CD20. MCL patients frequently relapse. Complex pathogenesis and the management of patients with progression after treatment with BTK/Bcl2 inhibitors and CAR‐T (triple‐resistant MCL) remain a challenge. Next‐generation clinical trials incorporating newer agents and concurrent translational and molecular investigations are ongoing.