What is the current treatment for Mantle Cell Lymphoma (MCL)?

Treatment of Mantle Cell Lymphoma per Current Guidelines

The treatment of mantle cell lymphoma (MCL) should be based on disease stage, patient age, fitness level, and risk factors, with cytarabine-containing regimens followed by autologous stem cell transplantation (ASCT) recommended for younger fit patients, and less intensive immunochemotherapy regimens such as bendamustine-rituximab (BR) for elderly patients. 1

Initial Assessment and Stratification

• MCL is typically diagnosed at advanced stages and has historically carried a poor prognosis with median overall survival of 4-5 years 2
• The Mantle Cell Lymphoma International Prognostic Index (MIPI-c) should be used for risk stratification, incorporating ECOG performance status, age, leukocyte count, LDH, and Ki-67 proliferation index 1
• SOX11 negativity may help identify indolent cases, while additional TP53 mutations can cause aggressive clinical evolution even in otherwise indolent-appearing disease 1

Treatment Approach by Disease Presentation

Indolent MCL

• For asymptomatic patients with indolent features (leukemic non-nodal presentation, splenomegaly, low tumor burden, Ki-67 <10%), a "watch and wait" approach under close observation is appropriate 1
• SOX11 negativity with hypermutated IGHV helps confirm truly indolent disease 1

Limited Stage Disease (Stage I-II)

• For the small proportion of patients with limited non-bulky stages I-II, a shortened conventional chemotherapy induction followed by consolidation radiotherapy (30-36 Gy) is recommended 1
• In stage I-II patients with large tumor burden or adverse prognostic features, systemic therapy as indicated for advanced stages should be applied 1

Advanced Disease (Stage III-IV)

Younger Fit Patients (<65 years)

• Intensive induction with cytarabine-containing regimens followed by ASCT is the standard of care for younger fit patients 1
• Options include:
  • R-CHOP/R-DHAP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone alternating with rituximab, dexamethasone, high-dose cytarabine, cisplatin) followed by ASCT 1
  • R-hyperCVAD/MTX-Ara-C (rituximab with hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone alternating with high-dose methotrexate and cytarabine) 1, 3
• A randomized trial confirmed that cytarabine-containing induction achieves significantly improved median time to treatment failure (p=0.038) 1
• Total body irradiation (TBI) before ASCT is beneficial only in partial response patients 1

Elderly Patients (≥65 years)

• Less intensive immunochemotherapy regimens are recommended for elderly patients who are not candidates for intensive therapy 1
• Preferred regimens include:
  • Bendamustine-rituximab (BR) - demonstrated superior PFS (35 vs 21 months) compared to R-CHOP 1, 4
  • R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) 1
  • VR-CAP (bortezomib, rituximab, cyclophosphamide, doxorubicin, prednisone) - showed improved PFS (31 vs 16 months) compared to R-CHOP 1
• For very elderly or frail patients, less intensive approaches such as rituximab-chlorambucil may be considered 5

Consolidation and Maintenance Therapy

• Rituximab maintenance significantly improves progression-free survival (PFS) and overall survival (OS) after R-CHOP and should be administered 1
• Maintenance rituximab is given every 2 months for up to 3 years following induction therapy 3
• Radioimmunotherapy (RIT) consolidation also prolongs PFS after chemotherapy but appears inferior to rituximab maintenance 1

Relapsed/Refractory Disease

• Treatment approach depends on the duration of prior response, patient fitness, and prior therapies 1
• For late relapses (>12-24 months), repeating the previous effective therapy may be considered 1
• For early relapses or refractory disease, targeted approaches are recommended 1:
  • Ibrutinib (BTK inhibitor) - achieves highest response rates in relapsed/refractory setting 1, 6, 4
  • Lenalidomide (immunomodulatory agent) 1, 7
  • Temsirolimus (mTOR inhibitor) - the only agent registered for relapsed MCL in the EU based on a randomized trial 1
  • Bortezomib (proteasome inhibitor) - preferably in combination with chemotherapy 1, 7
• Rituximab maintenance prolongs PFS and OS in relapsed disease 1
• Allogeneic stem cell transplantation may be considered for younger patients with chemosensitive disease 1, 2

Special Considerations

• BTK inhibitors appear to mitigate the negative influence of del17p/TP53-mutated MCL 4
• Blastoid variant MCL has particularly poor outcomes and may benefit from more intensive approaches 4
• Novel approaches including CAR-T cell therapy show promise in heavily pretreated patients 7

Common Pitfalls to Avoid

• Antibody monotherapy (rituximab alone) achieves only moderate response rates and is not recommended as primary therapy 1
• Induction based on high-dose cytarabine alone achieves insufficient response rates 1
• Failure to consider maintenance rituximab after successful induction therapy significantly reduces long-term outcomes 1, 4
• Underutilization of ASCT consolidation in eligible younger patients 4