Optimizing the treatment of secondary central nervous system lymphoma (SCNSL) with intensive systemic and cns-targeted chemoimmunotherapy followed by autologous stem cell transplant (ASCT): A retrospective, single-center analysis of a modified ferreri protocol Free

Introduction Secondary central nervous system lymphoma (SCNSL) complicates the management of 5-15% of patients (pts) with aggressive B-cell lymphoma. Optimal management of SCNSL requires adequate treatment of both systemic and CNS disease. Prognosis remains poor, with historical cohorts reporting median overall survival (OS) of 30-60 months (mos) despite chemoimmunotherapy and autologous stem cell transplant (ASCT). To optimize treatment of both systemic and CNS disease, we adopted a modified protocol based on Ferreri et al (JCO, 2015) as our institutional approach to SCNSL. We report our single-center analysis of outcomes using the modified Ferreri (mFerreri) protocol.

Methods We conducted a retrospective study of adult SCNSL pts treated with mFerreri at the University of Colorado between January 1, 2015, and December 31, 2024. Treatment consisted of an initial cycle (C) of R-EPOCH (rituximab, etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin) plus intrathecal (IT) methotrexate (MTX) for systemic debulking. C2 and C3 consisted of intravenous (IV) MTX (3.5g/m² on day (D) 1), cytarabine (2g/m² every 12 hours on D2–3), and rituximab (500mg/m² on D3 and 11). C4 consisted of R-EPOCH plus IT MTX for further systemic therapy. C5 consisted of cytarabine (2g/m² every 12 hours on D1, 3, 5) and rituximab (500mg/m² on D3). Pts in complete (CR) or partial remission (PR) could proceed to ASCT with thiotepa-based conditioning. Primary outcome was OS. Progression-free survival (PFS) and CR rate were also assessed. Outcomes were evaluated using Kaplan-Meier analysis and Cox regression.

Results 39 pts with SCNSL were treated with mFerreri. Median age at diagnosis was 58 years (range, 26–83). 14 (36%) were female. ECOG was ≤1 at diagnosis in 37 (95%). Histologic subtypes included DLBCL (N=27, 69%), high-grade B-cell lymphoma (HGBL) in 9 pts (23%), including 7 (18%) with double-hit or triple-hit and 2 (5%) with HGBL-NOS. Burkitt and transformed lymphoma in 2 (5%) and 4 (10.3%) pts, respectively. Twenty pts (51.3%) had germinal center B-cell subtype. Most pts (97%) had stage III/IV at diagnosis. IPI score was ≥3 in 28 pts (73.7%). Of 39 pts, 25 had received 1^st line of therapy (LOT; R-CHOP, R-EPOCH, or polatuzumab + R-CHP) prior to mFerreri. The median time from 1^st LOT to progression was 7 mos (range, 5–13.2). Median number of mFerreri cycles was 3 (IQR 2-5); 16 pts received 2 or fewer cycles. In assessable pts, the systemic CR and PR rates were 67.1% (N=19) and 17.9% (N=5), respectively, and CNS CR and PR rates were 56.2% (N=18) and 15.6% (N=5), respectively.

After median follow-up of 28.9 mos, median OS was 64.6 mos (10.4-NA) and median PFS was 21.4 mos (3.9-NA). Notably, pts who proceeded to ASCT (N=16) had a 2-year OS and PFS of 100% (100-100) and 93.3% (81.5-100), respectively, whereas pts that did not proceed to ASCT had 2-year OS and PFS of 20.9% (8.8-50) and 10.2% (2.8-37.6), respectively. Pts with CNS involvement at initial diagnosis had significantly improved median PFS (64.6 mos, 64.6-NA) compared to patients with CNS disease first detected at relapse within 12 mos (4.0 mos; 1.1-NA) or >12 mos (21.4 mos 1.3-NA) from diagnosis (p=0.04). Of the 23 pts who did not proceed to ASCT, reasons were progressive disease (PD; 39%, N=9), pt preference (26%, N=6), poor performance status (22%, N=5), hospice (35%, N=8), and alternative therapy (26%, N=6).

In univariate analysis, variables associated with improved OS included ASCT (HR 0.05, CI: 0.006–0.35, p < 0.01), treatment with more cycles of mFerreri prior to ASCT (HR 0.3, CI: 0.2–0.5, p < 0.001), CNS involvement at diagnosis (vs at relapse; HR 0.3, CI: 0.09–0.9, p = 0.03), and non-GCB origin (HR 0.3, CI: 0.1–0.9, p = 0.04). In contrast, PD on PET (HR 17.1, CI: 3.0-98.1, p<0.01) or MRI (HR 14.3, CI: 3.4-60.2, p<0.001) after mFerreri, CNS relapse within 12 mos of 1^st LOT (HR 6.9, CI: 1.8–25.5, p < 0.01) and ECOG ≥2 (HR 13.5, CI: 1.9–93.5, p < 0.01) were associated with inferior OS. Similar findings were observed for PFS. Multivariate analysis was limited by sample size.

Conclusions Among fit pts with SCNSL, mFerreri demonstrates efficacy against both systemic and CNS disease, resulting in excellent outcomes in responders who proceed to ASCT. Additionally, pts with CNS disease detected at initial diagnosis experience improved survival, underscoring the importance of CNS staging in high-risk pts.