Background: The combination therapy of Bruton's tyrosine (BTK) inhibitor and rituximab has shown favourable clinical efficacy and safety data as first-line therapy in mantle cell lymphoma (MCL). The idea of "chemo-less” is becoming an important treatment strategy for MCL. Zanubrutinib is a next-generation, selective BTK inhibitor. In this multicenter phase II clinical trial (CHESS - Chemo-less), we attempted to investigate the efficacy and toxicity of zanubrutinib and rituximab (ZR) combination followed by short course cytarabine-based chemotherapy, then maintenance with zanubrutinib monotherapy as frontline therapy in newly-diagnosed MCL patients. Here we report the preliminary result of this study.

Methods: Previously untreated MCL patients who need immediate therapy are eligible for this study. Included patients received induction therapy of ZR until achieving complete remission (CR) or to a maximum of 12 cycles, and followed by 4 cycles of R-DHAOx regimen (rituximab, dexamethasone, cytarabine and oxaliplatin). Patients ≥ 65 years receive dose-reduced cytarabine (1000mg/m2). Patients achieving CR after chemotherapy would receive maintenance therapy with zanubrutinib for a maximum of 1 year. The primary endpoint was CR rate after induction therapy with ZR regimen. Adverse events were evaluated according to CTCAE version 5. Among evaluable samples of bone marrow and/or peripheral blood, we evaluated the minimal residual disease (MRD) by flow cytometry at baseline and after every 2 cycles of treatment. This trial is registered in ClinicalTrials.gov (identifier number: NCT04624958).

Results: From Oct 2020 to Apr 2022, a total of 17 patients were enrolled in this study. Among included patients, over 80% of patients were males, median age was 60 years (range, 26-70), and 88.2% were advanced stages. More than half of the patients had intermediate or high risk simplified MIPI score. Pathologically, 2 patients were blastoid subtype and 52.9% with Ki67 ≥ 30%. Fifteen patients (88.2%) had initial bone marrow involvement by flow cytometry. Among 13 patients who performed peripheral blood flow cytometry before treatment, the results were identical to bone marrow. With a median follow up of 11.6 months (range, 1.93-20.03), the median number of ZR cycles was 4 (range, 2-7). After 4 cycles of ZR regimen, the CR rate was 88.2% (15/17) and all patients responded to the treatment. The best CR rate during ZR was 94.1% (16/17). All the 4 patients over 65 years old achieved CR. At the time of last follow-up (June 2022), only 1 male patient with blastoid MCL experienced progressive disease after a best response of partial remission. A new lesion was found after 5 cycles of ZR regimen, with a progression-free survival of 4.03 months. The bone marrow MRD negative CR rate was also 88.2% (15/17) after induction of ZR. Among evaluable patients (n=10), peripheral blood MRD detection showed complete consistency with bone marrow. Grade 3-4 adverse events on ZR regimen were neutropenia (n=1) and fatigue (n=2). The most common grade 1-2 adverse events were rash (17.6%), neutropenia (17.6%), and subcutaneous hemorrhage (17.6%). None had grade 3-4 atrial fibrillation or hemorrhage. During chemotherapy, grade 3-4 thrombocytopenia was observed in 76.9% of patients.

Conclusion: Outstanding preliminary responses were observed by "chemo-less” treatment strategy - induction treatment with ZR followed by short-course R-DHAOx chemotherapy. This approach might reduce the toxicity of cytarabine-based chemotherapy without weakening the therapeutic efficacy. Moreover, both bone marrow and peripheral blood MRD was highly consistent with imaging evaluation, indicating its potential value as a predictor. However, the efficacy, toxicity and MRD data were immature, which needs to be complemented and further evaluated at the completion of this trial.

No relevant conflicts of interest to declare.

Author notes

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Asterisk with author names denotes non-ASH members.

© 2022 by The American Society of Hematology
2022
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