Key points:

●      Mantle cell lymphoma (MCL) is a relatively rare B‐cell lymphoma subtype (2%–10% of all lymphomas), with a higher incidence among males and a median age of 70 years at diagnosis.

●      MCL is characterized by clinically diverse behavior, from indolent disease to extremely aggressive, related to the presence of biological risk factors such as proliferation rate and TP53 mutations.

●      The diagnosis of MCL requires a mature B cell phenotype, often with co‐expression of CD5, and the demonstration of cyclin D1 expression and/or CCND1 rearrangement. SOX11 is expressed in conventional MCL (cMCL). Its detection may also recognize uncommon cyclin D1‐negative MCL, which carry CCND2 or CCND3 rearrangements. Most cMCL have IGHV with high level of identity with the germline (≥97%).  High‐risk histological features in MCL are blastoid/pleomorphic morphology and high number of Ki‐67‐positive cells (≥30%).

●      A leukemic nonnodal MCL (nnMCL) subtype has been recognized with bone marrow involvement and frequent splenomegaly. These cases are SOX11 negative (<10%), carry high levels of IGHV somatic hypermutations (>3%), and usually follow a more indolent clinical course.

○      Although in most tumors SOX11 expression and IGHV mutational status distinguished conventional and nnMCL, some cases may have borderline values of these parameters and the distinction between cMCL and nnMCL may be uncertain.

●      Routine staging for MCL includes computed tomography (CT) scan of the neck, thorax, abdomen, and pelvis, bone marrow aspirate, and biopsy.

●      In suspected limited stage I–II disease, positron emission tomography‐CT scan and gastrointestinal endoscopy are recommended.

●      Most often, patients present with disseminated disease, necessitating systemic treatment. Immunochemotherapy has historically been the mainstay of treatment, but recent data indicate that addition of novel agents, especially covalent Bruton tyrosine kinase inhibitors (cBTKi), may substantially improve outcome in younger and older patients, although a curative approach remains to be shown. See Figure 1 in original article.

○      Asymptomatic MCL patients with low‐risk features managed by a watch‐and‐wait strategy should be monitored initially every 3 months, and then every 3–6 months by physical examination, imaging (as clinically required), blood counts, and biochemistry.

○      In low‐risk (MCL International Prognostic Index: MIPI) disease (stage I, without risk factors), observation or involved site radiotherapy (24-36 Gy) can be offered.

○      In patients with intermediate risk/tumor load, a shortened systemic therapy, followed by radiation, may be considered. For patients with stage II, bulky disease, and/or high‐risk MIPI, systemic treatment may lead to better long‐term disease control.

○      Although prospective evidence is scarce, the authors advise that patients with high‐risk biology (blastoid morphology, Ki67 > 30%, TP53 mutations/deletions) should receive systemic treatment as per advanced‐ stage disease.

○      Fit younger patients should be treated with R‐CHOP‐Ibrutinib/R‐DHAP or R‐DHAOx induction, followed by 2 years of ibrutinib and 3 years of rituximab maintenance.

○      Consider discussing autologous stem cell transplantation (ASCT) in selected patients if high‐risk features are present.

○      If cBTKi are not available in the first‐line treatment, rituximab and high‐dose cytarabine‐containing induction and ASCT consolidation may be applied, followed by 3 years of rituximab maintenance.

○      In patients in complete response with molecular remission by the next-generation sequencing‐based assay postinduction, ASCT can be omitted. 

●      In elderly patients, the standard of care is still immunochemotherapy such as rituximab‐bendamustine, although this may be challenged by non‐chemotherapeutic options, such as rituximab plus cBTKi.

●      For patients with relapsed or refractory disease, treatment options are developing rapidly, including chimeric antigen receptor (CAR) T-cell therapy, novel BTK targeting agents, BCL2 inhibitors, and T‐cell engagers. See Figure 2 in original article.

○      Treatment options post anti‐CD19 CAR T therapy include pirtobrutinib or immunochemotherapy.

○      Treatment options post‐pirtobrutinib include anti‐CD19 CAR T therapy or immunochemotherapy.

○      Allogeneic stem cell transplantation should be considered in younger, fit patients with relapsed MCL in cases where anti‐CD19 CAR T therapy is unavailable or has failed.