Exploration of Rituximab Plus Lenalidomide（R2）in Newly Diagnosed Diffuse Large B Cell Lymphoma with Adverse Prognostic Factors As Maintenance Therapy

Background: Approximately 40% of diffuse large B-cell lymphoma (DLBCL) experience relapse or refractory after R-CHOP treatment, with those relapsing within 2 years having worser prognosis. Maintenance therapy can sustain or deepen disease remission and prolong progression-free survival. Studies have shown that the R2 regimen effectively improves survival in elderly or chemotherapy-intolerant patients with relapsed/refractory DLBCL(Guido, G Blood 2023). Here, we report a single-center retrospective study on the efficacy and safety of first-line maintenance therapy with the R2 regimen in DLBCL patients with poor prognostic factors. Additionally, we explore the optimal administration of lenalidomide.

Methods: Newly diagnosed DLBCL Pts, from February 2019 to March 2024, aged ≥18 y, with at least one of the following adverse prognostic factors achieved CR or PR after R-CHOP/CHOP like therapy, entered maintenance therapy with the R2 regimen ( 28-day cycles of 25./20 mg oral lenalidomide from days 1 to 21 and 12-week cycles of IV rituximab 375 mg/m² on day 1.) as a maximum of 2-year maintenance therapy. Control Group were those from December 2005 to December 2022, DLBCL Pts with at least one adverse prognostic factors achieved CR or PR after first-line treatment did not receive maintenance therapy. The primary endpoint was progression-free survival (PFS) .Adverse prognostic factors: 1. IPI≥3 or aaIPI≥2 with at least one of the following factors：① Tumor diameter≥6.0 cm；② Extranodal involvement at ≥ 1 sites；③ Lymphoma involving at least one of the following special sites：central nervous system, testis, breast, adrenal gland, uterus；2. Immunohistochemistry showed double expression (Bcl-2≥50% and c-Myc≥40%) or P53 positive；3. FISH showed double-hit or triple-hit (MYC rearrangement, Bcl-2 and/or Bcl-6 rearrangement) or TP53 mutation.

Results: A total of 187 pts were enrolled, 35 pts received R2, 152 pts involved in control group. ① The R2 maintenance therapy group primarily consisted of elderly (77.1%). 83.3% were in the advanced stages (III-IV). Intermediate-high/high-risk patients accounted for 80%. Extranodal involvement at ≥1 site (97.1%) was a major characteristic. Involvement of special sites was present in 17.2% of the cases. Before maintenance therapy, 68.6% of the patients achieved CR. The non-maintenance group included 152 patients with baseline characteristics similar to the R2 maintenance group. ② The median follow-up time in R2 group was 33 months. The median DOR, PFS, and OS were not reached in. Compared to the control group, R2 maintenance therapy significantly improved DOR (1 year: 93.5% vs. 68.7%; 2 years: 83.9% vs. 60.0%, P=0.001), PFS (1 year: 96.9% vs. 70.8%; 2 years: 85.2% vs. 61.5%, P=0.001), and OS (1 year: 96.7% vs. 80.3%; 2 years: 84.2% vs. 71.4%, P=0.006). R2 maintenance therapy significantly improved PFS whether the disease achieved CR(P=0.030) or PR(P=0.045). ③ Subgroup analysis showed that patients who achieved CR before or during maintenance therapy had longer PFS (P=0.013) and OS (P=0.041). Additionally, in this study, 7 patients with PR converted to CR during R2 maintenance therapy, and their PFS (P=0.470) and OS (P=0.498) were not significantly different from those who achieved CR with first-line treatment. ④ Prognostic factor analysis using the COX proportional hazards regression model showed no significant difference in PFS (P=0.772) and OS (P=0.719) between double-expressor DLBCL receiving R2 and non-double-expressor. However, patients with involvement of special sites had significantly worse PFS (P=0.024) and OS (P=0.012) compared to those without such involvement. ⑤ The most common grade 3/4 adverse event was neutropenia (14.3%), with a higher incidence in patients with bone marrow involvement (37.5%). ⑥ Exploration of the optimal dosing regimen for lenalidomide: Patients tolerated best at the 20 mg dose. 20 mg dose with a 28-day cycle had similar efficacy to the 25 mg, but significantly fewer grade 3/4 adverse events.

Conclusion: In DLBCL patients with adverse prognostic factors, R2 maintenance therapy after first-line treatment could deepen disease remission (PR converting to CR) and provided significant survival benefits (PFS, OS). The recommended dose of lenalidomide in R2 is 20 mg on days 1-21 of a 28-day cycle. Special attention should be paid to neutropenia in patients with bone marrow involvement.