Editor's Note: Mantle Cell Lymphoma (MCL) is a type of B-cell non-Hodgkin lymphoma (B-NHL) characterized by both the rapid progression of aggressive lymphomas and the incurability of indolent lymphomas, resulting in generally poor prognosis. At the recent "2024 Nanjing Lymphoma Forum," Professor Zhitao Ying from the Cancer Hospital of the Chinese Academy of Medical Sciences delivered an enlightening lecture titled "Advances in Diagnosis and Treatment of Mantle Cell Lymphoma." This article aims to provide a comprehensive overview of the current treatment landscape and emerging strategies for improving outcomes in MCL, as presented by Professor Ying.Mantle Cell Lymphoma (MCL): A Poor Prognosis B-NHL with Steadily Increasing Incidence
MCL is a subtype of non-Hodgkin lymphoma (NHL) originating from mature B cells, accounting for 6% to 8% of NHL cases. It combines the aggressiveness of invasive lymphomas with the incurability of indolent lymphomas. A population-based study, which included 5,796 lymphoma patients diagnosed between 2004 and 2012 and followed up until March 2014, aimed to evaluate the incidence and survival rates of over 20 lymphoma subtypes classified as Hodgkin lymphoma (HL) or NHL. The results showed that MCL had the lowest 5-year overall survival (OS) and 5-year relative survival (RS) rates, at 25.0% (95% CI: 18.8–31.6) and 31.4% (95% CI: 23.6–39.5), respectively. Another study on MCL incidence from the SEER database and the Texas Cancer Registry (TCR) from 1995 to 2013 indicated a steady increase in MCL incidence.
Significant Improvement in MCL Patient Survival with Evolving Treatment Regimens
The treatment of MCL has evolved through different phases, including chemotherapy, autologous stem cell transplantation (ASCT), and new drugs. Since the application of ASCT in MCL treatment in 1991, patient prognosis has significantly improved, with median survival increasing from 3–4 years to 5–8 years. After 2010, the introduction of new drugs such as proteasome inhibitors, immunomodulators, and Bruton tyrosine kinase (BTK) inhibitors has further improved median survival. However, MCL remains incurable.
Current Status and Exploration Directions in MCL Treatment
The standard first-line treatment for MCL is rituximab combined with chemotherapy. Currently, young MCL patients usually receive high-dose cytarabine-containing regimens plus rituximab, with ASCT and maintenance therapy to extend remission and reduce relapse. In contrast, elderly MCL patients require reduced chemotherapy intensity and toxicity, considering maintenance therapy to prolong remission duration. Exploration directions in young MCL patients include: (1) combining targeted drugs with intensive chemotherapy to increase complete remission (CR) depth; (2) avoiding transplantation; (3) avoiding chemotherapy. For elderly MCL patients, directions include: (1) adding targeted drugs to improve efficacy and prolong survival; (2) replacing conventional chemotherapy with chemotherapy-free regimens based on targeted drugs.Previous studies have shown that RDHAOx (rituximab, dexamethasone, cytarabine, oxaliplatin) induction therapy for ASCT achieved a CR rate of 77%.
A multicenter phase II single-arm clinical study presented at the 2023 ASH meeting included 44 newly diagnosed MCL patients, with a median age of 59 years, ECOG 0-1 in 98%, stage IV in 84%, sMIPI intermediate-high risk in 50%, and Ki-67>30% in 68%, with 9% of patients having blastoid/pleomorphic variants. The results showed that after two cycles of acalabrutinib and rituximab (AR) treatment, the objective response rate (ORR) and CR were 93% and 57%, respectively, with an MRD negativity rate of 18%. After AR sequential RDHAOx treatment, the ORR and CR were 95% and 88%, with an MRD negativity rate of 94%, indicating that the acalabrutinib sandwich regimen achieved a high remission depth in newly diagnosed MCL. Additionally, this regimen demonstrated good efficacy and safety, with a 2-year progression-free survival (PFS) rate of 73.3% and a 2-year overall survival (OS) of 79.3%. Grade 3–4 adverse events (AEs) were mainly hematological, and the incidence of grade 3 or higher AEs during AR induction therapy was low.
The 2023 ASH meeting presented the Rectangle study, a phase II study of acalabrutinib combined with R-CHOP in newly diagnosed young MCL patients. Among the 53 patients who completed six cycles of acalabrutinib + R-CHOP induction therapy, 48 underwent ASCT, and 46 received AR maintenance therapy. The results showed that with a median follow-up of 14.2 months, the ORR and CR rates of induction therapy were 98% and 92%, respectively, with 12-month PFS and OS rates of 95.4% and 97.2%. Both induction and maintenance therapies were safe and tolerable.
The WINDOW-1 study, a single-center phase II clinical study, included 131 newly diagnosed MCL patients aged ≤65 years, with a median age of 56 years (range: 49–60 years). The sMIPI risk was low in 80% and high in 8%, with Ki-67 ≥30% in 49.5%, and 11% had blastoid/pleomorphic variants. The results showed that after induction therapy with ibrutinib and rituximab (IR), the ORR and CR were 98% and 87%, respectively. After IR + R-HCVAD/R-MTX consolidation, the ORR and CR were 90% and 89%, indicating that IR induction could shorten the R-HCVAD/R-MTX consolidation cycle, achieving sustained remission. The long-term follow-up (median follow-up 71 months) results presented at the 2023 ASH meeting confirmed that the IR induction followed by R-HCVAD/R-MTX regimen in first-line MCL achieved long-term survival. The WINDOW-2 study, presented at the 2023 ICML meeting, involved IRV (ibrutinib, rituximab, venetoclax) induction therapy followed by risk-stratified sequential R-Hyper CVAD/MTX-AraC. The results showed that IRV triple induction therapy achieved sustained deep remission, with a best ORR of 96% and CR of 92% in 48 patients receiving IRV induction therapy. After the second phase, the best ORR and CR remained consistent at 96% and 92%, respectively, with a median follow-up of 40.7 months. The median PFS and OS were not reached, and there were no significant differences in PFS and OS between MIPI scores and TP53 mutation categories.
Summary
MCL is a highly aggressive NHL with rapid progression and high relapse rates. The overall survival of MCL patients has significantly improved in the era of new drugs.
Both domestic and international guidelines recommend that young newly diagnosed MCL patients receive high-dose cytarabine regimens plus ASCT standard treatment. Induction therapy should include new drugs, with maintenance therapy post-ASCT. Future directions include removing ASCT or adopting chemotherapy-free regimens. For elderly MCL patients, first-line treatment is primarily lower-intensity immunochemotherapy, with new drugs potentially further improving efficacy. Clinical practice should focus on high-risk MCL patients, considering R-BAC500, BOVEN regimens, etc.
The SYMPATICO study reached its primary endpoint, with ibrutinib combined with venetoclax challenging single-agent BTKi’s status in R/R MCL. CAR-T therapy has shown high response rates with acceptable safety. New treatments such as ROR1xCD3 T-cell engagers, CDK4/6 inhibitors, dual BTKis, BTK degraders, and dual-target CAR-T cells bring new hope for MCL patients.
