Clinical Characteristics and Prognostic Analysis of Patients with Aggressive Mantle Cell Lymphoma：a Single-Center Real-World Study in China
Authors: Huang Ying , Zhu Yanan , Zhang Xiang , Zhang Xuewu , Wei Juying , Ye Xingnong , Lou Yinjun , Yang Min , Yang Chunmei , Xie Wanzhuo , Meng Haitao , Jin Jie , Tong Hongyan , Yu Wenjuan 
Published: December 2024

Background: Aggressive variant mantle cell lymphoma (AV-MCL), encompassing blastoid and pleomorphic subtypes, is characterized by its aggressive nature and grim prognosis, posing a significant therapeutic challenge. Although constituting 10-15% of all MCL cases, there is currently no standardized treatment approach.

Methods: This study retrospectively analyzed 66 AV-MCL patients hospitalized at the Department of Hematology, First Affiliated Hospital of Zhejiang University, from January 2010 to March 2024. All patients were diagnosed using pathological histological sections and immunohistochemistry. Clinical features, treatment strategies, and survival data were assessed. Kaplan-Meier estimates predicted progression-free survival (PFS) and overall survival (OS), while the Cox risk model was utilized for multifactorial analysis. Chi-square tests compared groups.

Results: The study included 66 patients with B-MCL (n=44) or P-MCL (n=22), with a median age of 66 years and a male predominance of 78.7%. Most patients presented at Ann Arbor stage III+IV (85.9%). A minority, 12%, had AV-MCL transformed from classic MCL, whereas 88% were de novo cases. Notably, 25.8% of cases were CD5 negative, 94.4% were MYC positive, and 78.8% showed SOX-11 positive expression. The median Ki-67 was 70%, with 71.1% falling into the high-risk MIPI category and 58.6% exhibiting LDH levels above normal. Next-generation sequencing (NGS) in 21 patients revealed P53 mutations in 57.1%, CCND1 in 47.6%, and ATM in 42.9%. High-risk MIPI scores correlated with a higher incidence of P53 mutations (P=0.028). Extranodal involvement was present in 93.3% of cases, with 70.1% involving two or more organs and 68.3% involving bone marrow.

As of June 30, 2024, 28 patients (45.2%) were alive, 34 (54.8%) had deceased, and 4 (6.1%) were lost to follow-up. With a median follow-up of 12.5 months, the median PFS (mPFS) was 14.2 months and median OS (mOS) was 20.3 months. The 3-year PFS and OS rates were 32.9% and 38.8%, respectively. The presence of P53 mutations significantly lowered OS, with a mOS of 6.5 months compared to undetermined mOS in those without. The best response to induction was complete response in 27 patients (45.8%), partial response in 13 (22.0%), and stable disease or progression in 19 (32.2%). The median remission length was 10.1 months. Post-relapse survival was shorter, with a mOS of 8.5 months. Primary refractory disease was fatal for 17 patients (28.8%), with a mOS of 6.5 months.

Therapy varied: R-CHOP was used in 31 patients, CHOP in 6, R-HyperCVAD in 6, BR in 5, and 4 received an R-CHOP/R-DHAP alternating regimen. First-line BTKi was added for 13 patients. The BTKi group showed a mOS of 17.4 months, contrasting with 32.5 months for the non-BTKi group. The 2-year OS rates were 50% for BTKi and 56.5% for non-BTKi (P=0.631). The mPFS was 15.0 months for BTKi and 23.1 months for non-BTKi, with POD12 at 57.1% and 58.9%, respectively (P=0.48). Intense chemotherapy did not improve OS or PFS but correlated with a higher CR rate (P=0.027). The R-CHOP group exhibited superior OS and PFS compared to non-R-CHOP (P=0.006, P=0.013). Maintenance therapy post-PR or CR significantly improved both OS and PFS (P=0.006, P=0.046).

Only 12% of AV-MCL cases converted from the classic subtype, with a median conversion time of 11.0 months and a post-conversion follow-up of 4.8 months. Transformed AV-MCL showed inferior OS (P=0.036) and significantly lower PFS (P&lt;0.001). Initial treatment non-responders were more prone to CNS recurrence (P=0.001), as were those with extranodal involvement of ≥4 sites (P=0.033) or Ki-67 ≥90% (P=0.048). Primary refractory disease was the sole multivariate factor enhancing CNS recurrence risk (P=0.027).

Conclusion: AV-MCL represents a high-risk MCL subtype with a poor clinical prognosis, exacerbated by P53 mutations.Initial treatment non-response is linked to higher CNS recurrence risks. Despite the lack of significant survival benefits from early BTKi use combined with R-regimen, traditional R-CHOP regimens remain beneficial, particularly when followed by maintenance therapy for responders. The overall prognosis for AV-MCL remains challenging, highlighting an urgent need for novel therapeutic strategies and clinical investigations.