Editor's Note: The 29th Annual Meeting of the Chinese Society of Clinical Oncology (CSCO) was held in Jinan from September 16 to 19, 2026, bringing together oncology experts from around the world to explore advances in precision diagnosis and treatment. During the lymphoma session, Professor Wenyu Li of Guangdong Provincial People's Hospital delivered a presentation entitled “Current Treatment Landscape and Controversies in Newly Diagnosed Mantle Cell Lymphoma (MCL).” Drawing on the 2025 EHA–EU MCL Network guidelines, the 2026 CSCO guidelines, and several pivotal clinical studies, Professor Li examined three major controversies in first-line MCL treatment: whether transplant-eligible patients still require autologous stem cell transplantation (ASCT) in the BTK inhibitor (BTKi) era; treatment options for older or transplant-ineligible patients; and precision treatment strategies for high-risk patients, including those with TP53 mutations. This article summarizes the key points of the presentation.Disease Background and Evolution of the Treatment Landscape
MCL is a B-cell non-Hodgkin lymphoma that combines the aggressive behavior of aggressive lymphomas with the incurable nature of indolent lymphomas. Its management has long been challenged by persistent relapse, progressively shorter remission durations, and frequent chemotherapy resistance.
In the BTKi era, both failure-free survival (FFS) and overall survival (OS) have improved significantly among transplant-eligible patients with newly diagnosed MCL. A pooled analysis of six randomized phase III clinical trials conducted between 1996 and 2020, involving 2,541 patients, showed that among 1,763 transplant-eligible patients with previously untreated MCL, median OS increased from 4.9 years in 1996–2000 to 13.8 years in 2004–2014, while the five-year OS rate rose from 49% to 84%.
Nevertheless, real-world data from China indicate that disease progression remains common after first-line treatment. The multicenter Chinese retrospective CHOICE cohort included 1,261 patients with newly diagnosed MCL, of whom 48% developed relapsed or refractory disease. Patients with early relapse (within 24 months) or primary refractory disease had poor outcomes. Prognosis deteriorated with each subsequent line of treatment: median OS after first-, second-, third-, and fourth-line treatment was 9.7 years, 41.1 months, 25.2 months, and 14.4 months, respectively.
Controversy 1: Is ASCT Still Necessary for Transplant-Eligible Patients in the BTKi Era?
The TRIANGLE study was a randomized, open-label, three-arm phase III trial involving 870 previously untreated patients with stage II–IV MCL who were aged 65 years or younger and eligible for high-dose cytarabine and ASCT. It compared three treatment strategies:
- Group A: Standard immunochemotherapy followed by ASCT.
- Group A+I: Ibrutinib plus immunochemotherapy, followed by ASCT and ibrutinib maintenance.
- Group I: Ibrutinib plus immunochemotherapy, followed by ibrutinib maintenance without ASCT.
At 4.5 years of follow-up, the four-year FFS rates were 82% in the A+I group and 81% in the I group, both higher than the 70% observed in the standard-treatment group. The corresponding four-year OS rates were 88%, 90%, and 81%, respectively. Both ibrutinib-containing regimens significantly outperformed standard treatment.
These findings suggest that incorporating a BTKi into first-line therapy can achieve superior long-term outcomes without relying on ASCT-based intensification, supporting BTKi-containing immunochemotherapy as a preferred option for younger, transplant-eligible patients.
Subgroup analyses showed a trend toward benefit with the A+I regimen among patients with blastoid morphology, Ki-67 expression of at least 30% (and even at least 50%), or high p53 expression. However, the small sample sizes mean that these findings should be considered hypothesis-generating rather than definitive.
The EA4151 study provides additional randomized evidence. This international, open-label, randomized phase III trial enrolled 650 patients with MCL in first remission. Patients who achieved complete remission (CR) and undetectable MRD at a sensitivity of (10^{-6}) (uMRD6) were randomized to receive either autologous hematopoietic cell transplantation (auto-HCT) plus rituximab maintenance or rituximab maintenance alone.
After a median follow-up of approximately 2.7 years, the three-year OS rates were 82.1% and 82.7%, respectively, while the three-year PFS rates were 76.6% and 77.4%. The study did not demonstrate a significant OS or PFS benefit from ASCT, and the results crossed the prespecified futility boundary.
Modern evidence therefore reframes the central question: Can ASCT further improve outcomes when highly effective targeted agents have already been incorporated into first-line treatment? Long-term results from TRIANGLE suggest that, for most patients, the answer may be no.
Other studies have explored strategies that preserve the option of avoiding transplantation. The CARIBOU study investigated an ASCT-sparing approach using acalabrutinib plus VR-CAP or R-HDAC. The complete metabolic response (CMR) rate was 85.3%, the 18-month PFS rate was 76.7%, and the 18-month OS rate was 95.5%.
The CHESS study evaluated zanubrutinib plus rituximab induction followed by a shortened course of R-DHAOx. The CR rate was 88%, the MRD-negativity rate was 79%, the two-year PFS rate was 85%, and the two-year OS rate was 90%.
Controversy 2: How Should Immunochemotherapy and BTKi-Containing Regimens Be Selected for Older or Transplant-Ineligible Patients?
For older or transplant-ineligible patients, the SHINE study showed that adding ibrutinib to BR improved PFS but did not confer an OS benefit. The ENRICH study found no significant difference between ibrutinib plus rituximab and BR, while the R-CHOP regimen performed substantially worse.
The ECHO study provides important randomized evidence in older patients with MCL. It compared acalabrutinib plus BR (ABR) with placebo plus BR (PBR) in 598 patients aged 65 years or older with newly diagnosed MCL. After a median follow-up of 60.8 months, median PFS was 72.5 months in the ABR group versus 47.8 months in the PBR group, corresponding to a 32% reduction in the risk of disease progression or death.
The benefit was more pronounced in high-risk subgroups. Among patients with blastoid or pleomorphic histology, ABR reduced the risk of progression or death by 41%, with an approximately 24-month difference in median PFS between the treatment groups. Long-term follow-up also showed that ABR reduced the need for third-line treatment by 24%.
The ZBR study evaluated zanubrutinib plus bendamustine and rituximab in older or high-risk patients with newly diagnosed MCL. The overall response rate (ORR) was 91.3%, and the complete response rate (CRR) was 82.6%. Outcomes were similar in patients with TP53 mutations and those with wild-type TP53, and the regimen was generally well tolerated.
A study of orelabrutinib plus BR in intermediate- or high-risk patients with MCL who were ineligible for transplantation reported an ORR of 97.4% and a CR rate of 94.9%, significantly higher than those achieved with BR alone.
The MANGROVE study compared zanubrutinib plus rituximab with BR in 500 patients aged 60 years or older with newly diagnosed MCL. The zanubrutinib–rituximab regimen reduced the risk of disease progression or death by 43%. However, its open-label design and the absence of maintenance therapy in the control group should be considered when interpreting the findings.
At present, BTK inhibitors have not been approved in China for first-line MCL treatment. In clinical practice, physicians must therefore weigh efficacy against toxicity, financial burden, and drug accessibility.
Controversy 3: What Is the Optimal Treatment Strategy for High-Risk MCL, Including TP53-Mutated Disease?
The BOVen regimen, comprising zanubrutinib, obinutuzumab, and venetoclax, uses an MRD-guided, fixed-duration treatment strategy. Among 25 patients with previously untreated, TP53-mutated MCL, the median follow-up was 39 months. Median PFS was 45 months, the three-year PFS rate was 64%, the three-year OS rate was 76%, and the three-year disease-specific survival (DSS) rate was 95%.
Among the 18 patients who completed 24 treatment cycles, 77.8% remained in CR. Of those who achieved uMRD6 CR, 91% maintained CR after treatment discontinuation.
The MAVO study evaluated acalabrutinib plus venetoclax and obinutuzumab in previously untreated high-risk MCL. In the high-risk treatment-naïve cohort, the overall response rate at the end of induction (EOI ORR) was 88%, the CR rate was 83%, the two-year PFS rate was 79%, and the two-year OS rate was 92%.
The TrAVeRse study investigated acalabrutinib plus venetoclax and rituximab in previously untreated MCL. Among 106 patients, 93% of those who completed induction achieved MRD-negative CR, and the CR rate was 94%. Patients with TP53 mutations benefited to a similar extent as the overall population: the MRD-negative CR rates were 100% versus 93%, and the ORRs were 100% versus 94%. Safety was manageable, with no new safety signals reported.
The GLOVe study evaluated glofitamab plus lenalidomide and venetoclax in previously untreated high-risk MCL. Among 27 patients, 24 of 25 evaluable patients (97%) achieved CR as their best response, and 23 of 24 evaluable patients (96%) achieved uMRD. The PFS and OS rates at six months or later were both 89%. Grade 3 or higher adverse events were primarily hematologic toxicities. One patient experienced grade 3 CRS, and no grade 4 or 5 CRS events were reported.
Future Perspectives: From Risk Stratification to MRD-Guided Individualized Treatment
First-line MCL treatment is moving toward greater precision, less chemotherapy, and reduced reliance on transplantation. An expert panel on individualized MCL treatment reported that most experts support incorporating novel targeted agents, such as BTK inhibitors, into first-line treatment research. The clinical role of ASCT continues to decline, and it may eventually be used only rarely or even be eliminated from routine practice.
Six major areas for future investigation have been identified:
- MRD-guided treatment.
- Optimization of chemotherapy backbones.
- Combining chemotherapy backbones with targeted agents.
- Redefining the role of ASCT.
- Improving maintenance therapy.
- Developing chemotherapy-free regimens.
The first-line treatment landscape for MCL is shifting from a uniform treatment approach toward individualized, risk-adapted care.
For younger, transplant-eligible patients, BTK inhibitors are reshaping the first-line paradigm and challenging the routine use of ASCT. Transplantation should no longer be regarded as the default option for every patient. Instead, decisions should be individualized according to high-risk biological features, depth of MRD response, and patient-specific factors.
For older or transplant-ineligible patients, treatment is moving away from conventional immunochemotherapy toward a chemotherapy backbone plus a BTK inhibitor. BTKi plus BR has delivered clinically meaningful and sustained PFS benefits while reducing the need for subsequent treatment. However, access remains constrained by the limited availability of first-line BTKi indications in China. Physicians must carefully balance efficacy, toxicity, affordability, and access to treatment.
Patients with high-risk disease, particularly those with TP53 mutations, have the greatest unmet need and should be prioritized for clinical trials and novel mechanism-based combinations. Conventional immunochemotherapy and ASCT have limited ability to overcome their adverse prognosis. Chemotherapy-free triplet regimens combining a BTK inhibitor, a BCL-2 inhibitor, and an anti-CD20 monoclonal antibody have demonstrated high CR and uMRD rates, along with early signals of durable remission. However, the current evidence comes largely from single-arm and early-phase studies and requires validation through longer follow-up and randomized trials.
Looking ahead, individualized first-line MCL treatment will increasingly be guided by risk stratification and MRD status. The goal will extend beyond improving CR rates and PFS to exploring treatment de-escalation, fixed-duration therapy, and the possibility of omitting ASCT or chemotherapy once deep MRD negativity has been achieved. For patients with persistent MRD positivity or high-risk disease, early treatment intensification or a change in therapeutic strategy may be necessary.
As additional prospective data accumulate, the treatment landscape for MCL is expected to become increasingly refined, with the potential to further improve long-term patient outcomes.
Expert Profile
Professor Wenyu Li
Guangdong Provincial People’s Hospital
- MD; Chief Physician; Master’s Supervisor
- Administrative Director, Department of Lymphoma, Guangdong Provincial People’s Hospital Cancer Hospital
- Chair, Lymphoma Committee, Guangdong Women Physicians Association
- Chair, Lymphoma Committee, Guangdong Primary Healthcare Association
- Vice Chair, Hematology Committee, Guangdong Women Physicians Association
- Vice Chair, Medical Oncology Branch, Guangdong Medical Association
- Vice Chair, Hematologic Oncology Committee, Guangzhou
- Standing Committee Member, Lymphoma Committee, Guangzhou Anti-Cancer Association
