What is the best course of action for a patient with mantle cell lymphoma who is stable but shows signs of progression while on current treatment, such as rituximab (Rituxan) maintenance, bendamustine-rituximab, or a Bruton's tyrosine kinase (BTK) inhibitor like ibrutinib (Imbruvica) or acalabrutinib (Calquence)?

Management of Stable Mantle Cell Lymphoma with Disease Progression

For a patient with mantle cell lymphoma showing progression while stable on current treatment, you should switch to second-line therapy with a BTK inhibitor (acalabrutinib or ibrutinib) as monotherapy, or consider alternative salvage regimens based on prior treatment and patient eligibility for transplant. 1

Immediate Treatment Decision Algorithm

If Currently on Rituximab Maintenance or Bendamustine-Rituximab

Switch to BTK inhibitor monotherapy:

• Acalabrutinib 100 mg orally every 12 hours until disease progression is the preferred option based on FDA approval and demonstrated efficacy in relapsed/refractory MCL 2
• Ibrutinib is an alternative BTK inhibitor option with established efficacy in second-line therapy 1
• Among registered compounds for relapsed/refractory disease, ibrutinib achieves the highest response rates and can produce long-term remissions in some cases 1

If Currently on a BTK Inhibitor (Ibrutinib or Acalabrutinib)

This represents BTK inhibitor failure and requires alternative salvage therapy:

• Consider non-cross-resistant chemotherapy regimens: bendamustine-based regimens (if not previously used) or high-dose cytarabine-containing regimens such as R-BAC (rituximab, bendamustine, cytarabine) 1
• Lenalidomide preferably combined with rituximab is an option when BTK inhibitors are contraindicated or have failed, achieving 57% response rates 1
• Temsirolimus or bortezomib preferably in combination with chemotherapy based on phase II/III data 1

Key Treatment Principles for Relapsed Disease

Timing Considerations

• For early relapses (<12-24 months): Use non-cross-resistant schemes - bendamustine or high-dose cytarabine-containing regimens after CHOP, or vice versa 1
• Add rituximab if the previous antibody-containing scheme achieved >6 months duration of remission 1

Transplant-Eligible Patients

• Patients with relapsed disease after complete response to induction, partial response only, or progressive disease are appropriate candidates for clinical trials involving high-dose therapy with autologous stem cell transplant (HDT/ASCT) or allogeneic HSCT 1
• Allogeneic HSCT is potentially curative and has achieved long-term remissions even in patients with early relapse and refractory disease, particularly in younger patients 1
• Dose-reduced conditioning is appropriate based on advanced age of most patients 1

Maintenance After Salvage Therapy

• Rituximab maintenance has a favorable safety profile and prolongs both progression-free survival and overall survival in relapsed disease 1
• However, second-line maintenance approaches have not been investigated in patients relapsing after front-line maintenance 1

Recent Evidence Supporting BTK Inhibitors

Acalabrutinib demonstrates superior outcomes when added to bendamustine-rituximab:

• In the recent phase 3 trial of 598 patients aged ≥65 years, acalabrutinib plus bendamustine-rituximab achieved median progression-free survival of 66.4 months versus 49.6 months with placebo plus bendamustine-rituximab (hazard ratio 0.73, P=0.0160) 3
• Overall response rate was 91.0% with complete response rate of 66.6% in the acalabrutinib arm 3
• Grade 3 or greater adverse events were comparable between arms (88.9% vs 88.2%), demonstrating manageable toxicity 3

Common Pitfalls to Avoid

Do not continue ineffective therapy:

• Progression on current treatment mandates switching to a different mechanism of action rather than dose escalation or continuation 1

Obtain repeat biopsy at relapse:

• A repeated biopsy is recommended to identify important prognostic features and potential transformation 1

Consider clinical trial enrollment:

• The optimal approach to relapsed or refractory disease remains to be defined, making clinical trial participation highly appropriate 1

Avoid second autograft at relapse:

• There is no role for a second autologous transplant at relapse; the benefit is marginal in this setting 1

When contraindications exist for ibrutinib:

• Particularly with high bleeding risk, alternative agents like lenalidomide with rituximab should be prioritized 1