What is the recommended chemotherapy regimen for mantle cell lymphoma (MCL) pleomorphic variant?

Chemotherapy for Mantle Cell Lymphoma Pleomorphic Variant

Treatment Approach Based on Patient Age and Fitness

For the pleomorphic variant of mantle cell lymphoma, treatment should follow the same intensive approaches used for blastoid MCL given its similarly aggressive biology, with younger fit patients receiving cytarabine-containing regimens followed by autologous stem cell transplantation, while older or less fit patients should receive bendamustine-rituximab (BR) or VR-CAP rather than R-CHOP alone. 1

Younger Patients (≤65 years, transplant-eligible)

The optimal induction regimen consists of rituximab-containing chemotherapy with high-dose cytarabine followed by autologous stem cell transplantation (ASCT). 1

• A randomized trial demonstrated that cytarabine-containing induction achieves significantly improved median time to treatment failure (P = 0.038) compared to regimens without cytarabine 1
• The recommended approach is R-CHOP alternating with high-dose cytarabine (HD-Ara-C) followed by ASCT consolidation 1
• R-HyperCVAD (rituximab with hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high-dose methotrexate/cytarabine) should NOT be used as standard therapy due to substantial toxicity, inability to deliver full doses, and unacceptably high stem cell collection failure rates 1

Older Patients (>65 years) or Transplant-Ineligible

Bendamustine-rituximab (BR) or VR-CAP (bortezomib, rituximab, cyclophosphamide, doxorubicin, prednisone) are the preferred first-line regimens; R-CHOP alone should NOT be used. 1

• BR demonstrated superior progression-free survival compared to R-CHOP (median PFS 35 vs 21 months) with better tolerability 1
• VR-CAP showed statistically significant improvement in PFS compared to R-CHOP (24.7 vs 14.4 months, P < .001) and received FDA approval for initial MCL treatment 1
• R-CHOP alone (without maintenance) should not be used as it produces relatively poor results 1

Novel Targeted Combination for Older Patients

Acalabrutinib plus bendamustine-rituximab (Acalabrutinib-BR) represents an FDA-approved option for previously untreated MCL patients ≥65 years who are transplant-ineligible. 2

• In the ECHO trial, acalabrutinib-BR demonstrated median PFS of 66.4 months vs 49.6 months for placebo-BR (HR 0.73, P = 0.016) 2
• The trial included 5.5% of patients with pleomorphic MCL histology 2
• Dosing: Acalabrutinib 100 mg orally twice daily starting Cycle 1 Day 1, bendamustine 90 mg/m² IV on Days 1-2 for 6 cycles, rituximab 375 mg/m² on Day 1 for 6 cycles 2
• For responders, continue acalabrutinib with maintenance rituximab every other cycle for up to 12 additional doses 2

Maintenance Therapy

Rituximab maintenance significantly improves both progression-free survival and overall survival and should be administered after induction therapy. 1

• After R-CHOP, rituximab maintenance provides PFS and OS benefit in patients ≥60 years 1
• After ASCT, rituximab maintenance shows significant PFS improvement (HR 0.48, P = 0.007) 1
• Rituximab maintenance is administered until disease progression 1

Critical Considerations for Pleomorphic Variant

The pleomorphic variant represents approximately 5% of MCL cases and behaves similarly to blastoid MCL with aggressive clinical features requiring intensive therapy approaches. 1, 2

• Pleomorphic MCL is classified alongside blastoid MCL as "transformed" MCL with high proliferation rates and complex karyotypes 1
• These aggressive variants require the same intensive treatment strategies as blastoid MCL rather than approaches used for classical MCL 1
• Avoid watch-and-wait strategies that might be considered for indolent classical MCL 1

Common Pitfalls to Avoid

• Do not use R-CHOP alone without maintenance or consolidation, as outcomes are suboptimal 1
• Do not use R-HyperCVAD outside specialized centers due to excessive toxicity and poor feasibility 1
• Do not use high-dose cytarabine alone as induction, as it achieves insufficient response rates 1
• Do not treat pleomorphic MCL with less intensive approaches used for indolent disease 1