The Phase II multicenter clinical trial (CHESS chemo-less, NCT04624958) aims to explore the efficacy and safety of zanubrutinib combined with rituximab followed by a short course of cytarabine-based chemotherapy, then maintained with zanubrutinib in newly diagnosed mantle cell lymphoma (MCL) patients. The 2024 American Society of Clinical Oncology (ASCO) Annual Meeting was grandly held in Chicago from May 31 to June 4. The study results of "Zanubrutinib Combined with Rituximab Followed by Short Course R-DHAOx Therapy in MCL Patients: Phase II CHESS Clinical Trial" were presented as a poster. Hematology Frontier invited the first author of the study, Professor Qingqing Cai from Sun Yat-sen University Cancer Center, to interpret the study and share insights into the progress in MCL diagnosis and treatment.

Hematology Frontier: At this conference, you presented the results of the Phase II CHESS clinical trial. Could you comment on the unique advantages this study offers for MCL treatment?

Professor Qingqing Cai: Since the widespread application of rituximab, the value of high-dose cytarabine in MCL has been confirmed. Previous clinical trials have shown that adding cytarabine to the first-line treatment of MCL significantly improves response rates and prolongs response duration. Therefore, the NCCN guidelines recommend cytarabine-containing combination chemotherapy as a high-intensity induction regimen for first-line MCL, with hematopoietic stem cell transplantation consolidation for patients achieving complete remission (CR).

At the 2019 ASH meeting, Professor Michael Wang from MD Anderson Cancer Center first reported the results of the Window-1 study. It used ibrutinib combined with rituximab as a “chemo-free” induction (Part A), followed by short-term R-HyperCVAD/R-MA consolidation chemotherapy (Part B, 4 courses) in previously untreated young MCL patients (≤65 years). Among 131 enrolled patients, the best CR rate after Part A was 88%, and the CR rate after Part B was 94%. The 3-year progression-free survival (PFS) and overall survival (OS) rates were 85% and 97%, respectively, with toxicity far lower than the previously reported full 8-course R-HyperCVAD/R-MTX, offering a promising window to improve efficacy and reduce toxicity for patients.

However, high-intensity R-HyperCVAD/R-MA induction chemotherapy, although providing survival benefits, has significant side effects that can be a double-edged sword, particularly for Chinese patients. These side effects often lead to delayed or reduced chemotherapy doses, with some patients unable to complete all courses, affecting treatment efficacy and lowering their quality of life. Additionally, a high proportion of MCL patients are elderly, often unsuitable for high-dose chemotherapy and stem cell transplantation.

Based on this, we designed the Phase II CHESS clinical trial to explore the efficacy and safety of zanubrutinib combined with rituximab (ZR) followed by short-term R-DHAOx chemotherapy and subsequent zanubrutinib maintenance in newly treated MCL patients. The innovations of this study include: 1) using the new-generation high-efficiency, low-toxicity BTK inhibitor zanubrutinib; 2) replacing R-HyperCVAD with the relatively lower-intensity R-DHAOx chemotherapy, more suitable for Chinese patients; 3) halving the cytarabine dose for patients over 65; 4) using zanubrutinib maintenance instead of hematopoietic stem cell transplantation.

This study has completed enrollment of all 42 patients. Among the 37 patients who completed treatment and underwent PET evaluation, the best CR rate after ZR induction therapy was 91.9% (34/37), with 94.1% (32/34) of patients achieving CR after 2-4 courses of ZR treatment. The median follow-up time was 11.6 months, with 1-year PFS and OS rates of 90.1% and 96.7%, respectively. The safety profile during ZR treatment was good, with grade 3-4 adverse events including neutropenia (n=3), fatigue (n=2), and elevated transaminases (n=1). This study offers a new “chemo-less” treatment strategy for newly treated MCL patients.

Hematology Frontier: Can you provide an overview of the recent diagnosis and treatment progress in MCL? What important advancements should we focus on, and what directions should future research explore?

Professor Qingqing Cai: MCL is a special type of B-cell non-Hodgkin lymphoma, diagnosed based on typical histological features, immunophenotype, and/or t(11:14)/CCND1 abnormality. Over 80% of patients are diagnosed at stage III or IV, with generally poor prognosis and a median survival of about 3-5 years. Currently, MCL is considered an incurable disease, but with the advent of new targeted drugs such as BTK inhibitors (e.g., ibrutinib, zanubrutinib, acalabrutinib), proteasome inhibitors (e.g., bortezomib), and immunomodulatory drugs (e.g., lenalidomide), the prognosis for MCL patients has significantly improved, and treatment modalities have evolved.

Particularly noteworthy is the growing presence of “chemo-free” regimens based on BTK inhibitors in first-line MCL treatment. A Phase II study exploring ibrutinib combined with rituximab (IR) as first-line treatment in elderly MCL patients (≥65 years) showed a best overall response rate (ORR) of 96% (46/48), with a CR rate of 71% (34/48). The 3-year PFS and OS rates were 87% and 94%, respectively. The IMCL2015 study, using the IR regimen as first-line treatment for indolent MCL patients, reported an ORR of 84% and a CR rate of 80% after 12 cycles. At the 2023 Lugano meeting, acalabrutinib combined with rituximab achieved a 90% CR rate in elderly MCL patients, indicating that BTK inhibitor and rituximab combinations are feasible and effective for elderly or indolent MCL patients, greatly reducing toxic side effects.

Additionally, the 2022 ASH meeting reported a Phase II study using zanubrutinib, obinutuzumab, and BCL-2 inhibitor venetoclax (BOVen) as first-line treatment for TP53-mutated MCL, showing a best ORR of 95% and a CR rate of 88%. This suggests that combining multiple targeted drugs may offer better treatment efficacy for MCL patients with poor prognostic factors, such as TP53 mutations and blastoid/pleomorphic variants.

For relapsed/refractory MCL patients, besides the widely used BTK inhibitors, various new targeted therapies and cell therapies show promising efficacy, including BCL-2 inhibitors (venetoclax and BGB-11417), PI3K inhibitors (idelalisib), CDK4/6 inhibitors (palbociclib), anti-CD20/CD3 bispecific antibodies (mosunetuzumab), ROR1×CD3 bispecific T-cell engagers (NVG-111), anti-CD19 CAR-T cells (brexu-cel), and bispecific CD20/CD19 lentiviral CAR-T cells (LV20.19). Numerous new drug clinical trials are underway, potentially offering more treatment options for MCL patients in the future.

Many targeted drugs have shown good antitumor activity in MCL, and future research can leverage high-throughput sequencing technology to identify specific molecular targets for MCL and develop new targeted therapies. Exploring new drug combinations with synergistic effects could also provide more treatment options for patients. Additionally, since different patients have different genetic characteristics, not all patients benefit from new drugs. Finding effective biomarkers to identify patients suitable for specific targeted/immunotherapies will be a key focus of future research.