A Retired Teacher With a Constant Headache and Vomiting

Amanda L. Blackmon, DO, MS; Lauren Pinter-Brown, MD


January 05, 2022

Clinically, mantle cell lymphoma has a wide range of presenting symptoms. Patients may be asymptomatic, with monoclonal MCL-type lymphocytosis. Some patients have extranodal disease and present with gastrointestinal symptoms. Other patients have B symptoms; cytopenias; splenomegaly; and, rarely, neurologic symptoms with central nervous system (CNS) involvement. Most classical, nodal forms of mantle cell lymphoma are more advanced and symptomatic at the time of diagnosis and require up-front treatment with systemic therapy. Mantle cell lymphoma can also transform from one variant to another, usually classical to blastoid.

The current method used for prognostication includes the Mantle Cell Lymphoma International Prognostic Index (MIPI) risk score, which takes into account performance status, age, LDH level, and white blood cell count, with or without Ki67; on the basis of the number of positive risk factors, a risk category is assigned. Our patient has a simplified MIPI score of 4, making him intermediate-risk, with 58 months as a likely median survival and 35% 5-year overall survival (OS). Ki-67 is reported as a percentage, which is a marker of cell division, with higher numbers associated with more aggressive disease; > 30% is often used as a cutoff for more aggressive disease, although the percentage remains subjective on the numbers of cells that stain positive.[6] This patient's Ki-67 percentage was not increased on his initial bone marrow biopsy at the time of diagnosis.

Other factors that have been associated with worse clinical outcomes include complex karyotype, TP53 mutations or overexpression, MYC translocation or overexpression, and unmutated IgVH status. Additional prognostic factors that have been proposed include minimal residual disease testing, circulating tumor DNA, and specific mutations (eg, CDKN2A, ATM, MYC, NOTCH1, NOTCH2, BIRC3, BTK), as well as sequencing panels used to determine a prognostic score.[4,7] Some of these factors may also be correlated to response to certain systemic treatments.[4] Clot and colleagues[7] describe a molecular assay along with genomic complexity that may accurately predict the subtype of mantle cell lymphoma and aid in prognosis.

At the time of diagnosis, patients usually have advanced disease and are symptomatic, with widespread lymphadenopathy. The mainstay of treatment has been induction with chemoimmunotherapy with or without radiation. Regimens include the following:

  • Bendamustine plus rituximab (BR)

  • Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP)/rituximab plus cyclophosphamide, vincristine, and prednisone (R-CVP)

  • Rituximab plus fractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone (R-hyperCVAD)

  • Rituximab plus dexamethasone, cytarabine, and cisplatin (R-DHAP)

  • NORDIC protocol (especially in younger, healthier patients who can endure the side effects of myelosuppression, associated infections, development of myelodysplastic syndrome, and other toxicities)

The BRIGHT study compared BR with R-CHOP and found similar efficacy and less toxicity in the BR group; however, a higher rate of secondary cancers was observed in the BR group.[8] Autologous and allogenic hematopoietic stem cell transplant (HSCT) are often considered, with the hope of a more durable remission. In patients who are not eligible for transplant, rituximab maintenance every 8 weeks for 3 years is used, on the basis of a European trial with longer progression-free survival and OS compared with interferon.[9,10]

These induction treatments are often difficult for elderly patients. Martin and colleagues[11] reviewed nonchemotherapy strategies in mantle cell lymphoma. Several studies of these agents in a first-line setting are under way, and predictive markers are being evaluated to determine which patients may benefit more from these treatments. Avoiding chemotherapy is not recommended at this time, although better treatment regimens are clearly needed.

Other than the induction chemotherapy regiments mentioned above, other agents are often used as second-line treatments. These include bortezomib-rituximab, lenalidomide-rituximab, and temsirolimus. The BTK inhibitors ibrutinib and acalabrutinib and the BCL-2 inhibitor venetoclax have also been used. CD19 CAR-T clinical trials are under way for patients with disease that is refractory to other treatment; however, patients with CNS involvement are generally excluded owing to the neurotoxicity associated with treatment.

A subset of patients may be able to pursue a watchful waiting strategy; these are usually patients with good performance status who are asymptomatic, do not have B symptoms, have normal LDH levels, have non-nodal disease, and have low Ki-67 percentages. This observation strategy was studied by a Canadian group that evaluated 440 patients, 75 of whom were observed for 3 or more months.[12] The median time to treatment was 35 months, and the OS in this group was longer than that in the early treatment group.


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