Preliminary Investigation of the Efficacy and Safety of Zanubrutinib in Combination with R-Chemo As First-Line Therapy Inpatients with Newly Diagnosed Mantle Cell Lymphoma

Background

Mantle Cell Lymphoma (MCL) is an uncommon lymphoma. The primary first-line therapeutic approach involves induction therapy with high-dose cytarabine, followed by autologous hematopoietic stem cell transplantation, with subsequent maintenance of rituximab. (Jain & Wang, 2019; Maddocks, 2018). Current research suggests that BTK inhibitors may offer enhancement of efficacy in high-risk MCL. However, evidence regarding their effectiveness in the initial treatment of newly diagnosed patients remains limited. Zanubrutinib, as an investigational next-generation BTK inhibitor, incorporates innovative structural modifications that notably enhance its specificity for the BTK target. This may potentially result in improved efficacy and safety in the management of newly diagnosed MCL patients(Song et al., 2020, 2022).

Aims

This ongoing phase II clinical trial (ChiCTR2200055483) aims to assess the efficacy and safety of zanubrutinib in combination with R-Chemo as a first-line therapeutic approach for newly diagnosed MCL. Herein, we report the preliminary results of the study.

Methods

Previously untreated patients diagnosed with MCL were enrolled in this study. The efficacy was evaluated after completion of 4 cycles of treatment. For patients achieving complete response (CR) or partial response (PR), the choices of subsequent treatment were zanubrutinib in combination with the R-Chemo regimen for an additional 2- 4 cycles as consolidation treatment followed by sequential zanubrutinib maintenance therapy or autologous hematopoietic stem cell transplantation. A follow-up period of 21 months will be implemented. The primary endpoint is CR rate (CRR), with secondary endpoints including progression-free survival, overall survival, and adverse events.

Results

As of 2023 and July 2024, a total of twelve patients were enrolled in the study. The cohort comprised 66.7%% males and 33.3% females. The median age was 57 (range: 47-76) years. A majority of patients (75.0%) presented with Ann Arbor stage III or higher. seven patients(58.3%) had a medium-high risk according to the MIPI score. Two cases exhibited blastocytic features, while ten cases were classified as classic. A significant proportion of patients (83.3) had Ki-67 levels ≥30%. Flow cytometry identified bone marrow involvement in five patients (41.7%).

As of July 20, 2024, 10 patients received 4 cycles of treatment and were efficacy evaluable. One patient opted out of the study after 3 cycles of treatment for personal reasons, so the efficacy was evaluated in advance. One patient received only two cycles of induction therapy and were not assessed for efficacy. Ten patients who achieved CR continued maintenance therapy with zanubrutinib monotherapy after chemotherapy ended. ORR and CRR are 100% and 90.9%, respectively. Eight patients achieved CR after four cycles of induction. Two patients achieved PR after four cycles of induction, and CR was obtained after four cycles of continuous treatment.

Bone puncture was performed in 5 patients to evaluate the efficacy. The bone marrow MRD negative CR rate was 100% (4/4) after induction therapy. One patient did not reach the evaluation time. Among evaluable patients (n=4), peripheral blood MRD detection showed complete consistency with bone marrow.

The most common treatment-related adverse events were hematologic toxicity in 4 patients, neutropenia in 2 patients, fatigue in 3 patients, and pulmonary infection during treatment in 1 patient. Other adverse events were not found.

Conclusion

The combination of zanubrutinib and R-Chemo regimen for induction therapy followed by zanubrutinib monotherapy maintenance in patients with newly diagnosed mantle cell lymphoma has shown excellent initial efficacy. This approach initially shows better efficacy, and its toxicity may be lower than that of induction therapy with high doses of cytarabine. However, the current data volume and the sample size are small, and the follow-up time is short, so the efficacy, toxicity, and MRD data of this regimen need to be supplemented and further evaluated.

No relevant conflicts of interest to declare.