Zanubrutinib-rituximab followed by shortened chemoimmunotherapy as frontline treatment for mantle cell lymphoma (CHESS): a phase II trial.

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Journal: Nature communications

This phase II, single-arm study evaluated a chemotherapy-sparing frontline strategy for previously untreated mantle cell lymphoma (MCL). The regimen used zanubrutinib plus rituximab as induction, followed by abbreviated chemoimmunotherapy and BTK inhibitor maintenance.

Key design:

  • Population: 42 patients with stage II–IV MCL requiring treatment, no prior systemic therapy.
  • Induction (Part A): Up to 12 cycles of zanubrutinib plus rituximab.
  • Chemoimmunotherapy (Part B): Patients achieving complete response (CR) or progressing on Part A received 4 cycles of R‑DHAOx (rituximab, dexamethasone, cytarabine, oxaliplatin), i.e., a shortened intensive regimen.
  • Maintenance: Patients in CR after Part B received 1 year of zanubrutinib maintenance.
  • Primary endpoint: CR rate at completion of Part A.

Efficacy:

  • CR rate after zanubrutinib–rituximab induction: 88% (95% CI, 74–96).
  • CR rate at completion of the entire planned regimen (after R‑DHAOx when given): 86% (95% CI, 72–95).
  • Overall: These results indicate high depth of response with a BTK inhibitor–rituximab backbone and limited chemotherapy exposure.

Safety:

  • Toxicities were mainly hematologic.
  • Part A (zanubrutinib–rituximab): Most common grade 3–4 event was neutropenia (7%).
  • Part B (R‑DHAOx): High rates of grade 3–4 thrombocytopenia (77%) and neutropenia (49%), consistent with cytarabine-based intensive regimens.
  • Overall safety: Considered manageable.

Implications:

  • Frontline zanubrutinib–rituximab induction can achieve very high CR rates and permits a reduction in the number of intensive chemotherapy cycles, potentially lowering cumulative chemo-related toxicity.
  • The approach offers a targeted-therapy–first paradigm for fit MCL patients, with consolidation using a shortened high-dose cytarabine/oxaliplatin regimen and finite BTK inhibitor maintenance.
  • The findings support further evaluation in randomized controlled trials comparing this strategy to standard chemoimmunotherapy-based approaches (e.g., R‑CHOP/R‑DHAP–type regimens and/or autologous transplant).

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