What are the treatment options for patients with relapsed or refractory mantle cell lymphoma?

Treatment Options for Relapsed and Refractory Mantle Cell Lymphoma

For relapsed/refractory mantle cell lymphoma, ibrutinib is the preferred first-line salvage agent achieving the highest single-agent efficacy with overall response rates of 68-72%, while CAR-T therapy with brexucabtagene autoleucel should be strongly considered for patients progressing on BTK inhibitors. 1

Treatment Selection Algorithm

Early Relapse (<12-24 months) or Refractory Disease

Prioritize targeted agents over chemotherapy in this setting:

• Ibrutinib achieves the highest response rates among registered compounds with ORR 68-72% and median PFS of 13.9-14.6 months, making it the preferred initial salvage option 2, 1
• Alternative BTK inhibitors include acalabrutinib and zanubrutinib, which differ primarily in toxicity profiles and dosing schedules rather than efficacy 3
• Lenalidomide (preferably combined with rituximab) is the preferred alternative when ibrutinib is contraindicated, particularly in patients with high bleeding risk 2
• Temsirolimus and bortezomib remain effective but should preferably be applied in combination with chemotherapy based on phase II/III data 2

Late Relapse (>12-24 months)

Non-cross-resistant chemotherapy regimens are appropriate:

• Bendamustine-based regimens or high-dose cytarabine-containing combinations (e.g., R-BAC: rituximab, bendamustine, cytarabine) after prior CHOP, or vice versa 2
• Add rituximab if the previous antibody-containing scheme achieved >6 months duration of remission 2

After BTK Inhibitor Failure

This represents the highest-risk population with median OS of only 6-10 months:

• CAR-T therapy with brexucabtagene autoleucel is now FDA-approved and achieves highly effective responses in this setting 3, 4
• Venetoclax has been used off-label, though data are limited specifically following BTK inhibitor treatment 3
• Clinical trial enrollment should be strongly pursued for patients with TP53 mutations, as conventional treatments yield poor outcomes 1

Consolidation and Maintenance Strategies

• Rituximab maintenance has Level I evidence for prolonging both PFS and OS in relapsed disease with favorable safety profile 2
• However, second-line maintenance has not been investigated in patients relapsing after front-line maintenance 2
• Radioimmunotherapy (RIT) consolidation extends remission durations, especially in elderly patients with comorbidities not eligible for dose intensification 2

Role of Transplantation in Relapsed Disease

Autologous Stem Cell Transplant (ASCT)

• May be considered in patients who relapsed after conventional first-line therapy, but the benefit appears marginal 2
• No role exists for a second autograft at relapse 2

Allogeneic Stem Cell Transplant (AlloSCT)

• Potentially curative in younger patients, achieving long-term remissions even following early relapse and refractory disease 2
• Dose-reduced conditioning is appropriate given the advanced age of most patients 2
• Haploidentical transplantation achieves high response rates but remains experimental 2

Historical Context: Pre-Targeted Therapy Era

While largely superseded by targeted agents, understanding historical options provides context:

• Bortezomib was the first FDA-approved agent for relapsed MCL based on the PINNACLE trial, achieving ORR 33% (CR 8%) with median duration of response 9 months 2
• Cladribine as single agent achieved ORR 46% (CR 21%) with median PFS 5 months in recurrent MCL 2
• Fludarabine-based combinations (R-FCM, FMR) showed activity with CR rates up to 90% in small studies 2

Critical Pitfalls to Avoid

• Do not delay targeted therapy in early relapse or refractory disease—outcomes with conventional chemotherapy are poor (CR rates generally <30%) 2
• Obtain repeat biopsy at relapse to identify prognostically important features including Ki-67 proliferation and TP53 mutations 2
• Do not use single-agent chemotherapy when combination regimens or targeted agents are available—combination approaches consistently produce higher response rates 5
• Recognize BTK inhibitor failure early—median OS after progression on BTKi is only 6-10 months, requiring immediate transition to CAR-T or clinical trial 4, 6