Upfront maintenance therapy improves the prognosis of patients with diffuse large B-cell lymphoma in the era of novel agents: A multicenter retrospective study

Abstract Introduction Current first-line R-CHOP therapy achieves a cure in only 50–70% of diffuse large B-cell lymphoma (DLBCL) patients, with 20–30% relapsing after achieving complete remission. Prolonging progression-free survival (PFS) remains a key clinical challenge. Rituximab maintenance shows limited efficacy in R-CHOP-treated patients, and lenalidomide improves PFS only in elderly populations without enhancing overall survival (OS). The role of novel agents such as bruton's tyrosine kinase inhibitors (BTKi) in maintenance therapy remains underexplored. This study aimed to assess the prognostic impact of upfront maintenance therapy in patients with DLBCL. Methods We retrospectively analyzed data from DLBCL patients receiving upfront maintenance therapy (MT) across four hospitals in Beijing (Beijing Tongren Hospital, China-Japan Friendship Hospital, Beijing Tsinghua Changgung Hospital, and Beijing Luhe Hospital) between January 2019 and August 2024, with follow-up through May 2025. Patients received rituximab, lenalidomide, or BTKi for up to two years as maintenance therapy after 6-8 cycles of R-CHOP±X (X mainly indicated BTKi or lenalidomide) treatment. The patients who had not received maintenance treatment in the publicly available REMoDL-B trial database were selected as the control group. The propensity score matching (PSM) method was used to match the two groups. The analysis focused on clinical characteristics, PFS, OS, and prognostic factors. Results There were 106 cases in the MT group. The median age was 69 years. The median follow-up time was 25.4 months. 2-year PFS and 2-year OS rates were 90% and 98%, respectively. In the high-risk group of IPI (IPI score ≥3), 2-year PFS rate was 87.0%. Multivariate analysis confirmed immune-privileged site involvement (P=0.013), Ki-67≥85% (P=0.025), and duration of maintenance (DOM) <12 months (P=0.012) as independent risk factors for PFS. There was no significant difference in PFS between patients achieving CR versus PR at the end of induction therapy. After PSM analysis, the baseline data of the MT group was balanced with the control group. The PFS and OS of the MT group were significantly better than those of the control group (P=0.024, P=0.008). Multivariate analysis revealed that MT (P=0.019) was independent risk factor for PFS. The MT regimens mainly included BTKi (73.6%), rituximab (24.5%), and lenalidomide (1.9%). For patients receiving BTKi, the 2-year PFS and 2-year OS rates were 87.6% and 97.2%, respectively. The PFS and OS were significantly better than those of the control group (P=0.048, P=0.024). 43.6% patients had high central nervous system (CNS)- IPI risk, yet no CNS recurrences occurred. There is no statistical difference between the two types of covalent BTKi (zanubrutinib or orelabrutinib ). MCD/A53 subtypes showed worse prognosis. These two groups of patients predominantly received BTKi, with the A53 subtype showing a shorter PFS. Conclusions In the era of novel agents, upfront maintenance therapy remains a promising strategy for improving outcomes in DLBCL. We recommend more proactive consideration of maintenance therapy for high-risk DLBCL patients and for those achieving only PR, with a recommended duration of at least one year. BTKi maintenance may be a suitable option for the MCD molecular subtype. Future prospective studies in larger cohorts are warranted to evaluate a broader range of maintenance strategies. Keywords diffuse large B-cell lymphoma, maintenance therapy, survival