Exploration of optimal high-dose methotrexate-based therapy for patients with primary CNS lymphoma: A real-world study in China Free

Primary CNS lymphoma (PCNSL) is a rare and highly aggressive extranodal non-Hodgkin lymphoma, with a dismal outcome in untreated patients (J Clin Oncol 2017:35:2410-2418). The prognosis of PCNSL has significantly improved during the last decades with the introduction and widespread use of high-dose methotrexate (HD-MTX; Blood 2022:140: 971-979). Currently, first-line HD-MTX-based polychemotherapy is widely considered the standard-of-care for fit PCNSL patients (Nat Rev Dis Primers 2023:9:29). Recent insights into incorporating novel agents (e.g., rituximab, BTK inhibitors, and immunomodulatory agents) have demonstrated promising efficacy in this disease (ESMO Open 2021:6:100213). Despite this progress, no uniform consensus on the optimal treatment regimen exists currently (JNCCN 2020;18:1571-1578). In this context, our study investigated four HD-MTX-based combinations to identify a potentially optimal treatment strategy.

This retrospective study included patients with PCNSL who received HD-MTX-based regimens as first-line induction therapy. Patient baseline characteristics (e.g., age, sex, IELSG risk, and cell of origin), treatment regimens, response data, and survival outcomes were obtained retrospectively from the electronic medical record system. Tumor response was compared among the cohorts using the chi-square test or Fisher's exact test; survival (progression-free survival [PFS] and overall survival [OS]) was performed using Kaplan-Meier estimates and compared using the Log-rank test or Breslow test. p < 0.05 was considered statistically significant.

From August 2012 to August 2024, a total of 110 patients were included in this study. Among them,19 patients were treated with rituximab (R) plus HD-MTX (HD-MTX±R); 8 patients were administered R, HD-MTX, and cytarabine (R-MA); 50 patients received R, lenalidomide, and HD-MTX (R2-MTX); and 33 patients received pomalidomide plus orelabrutinib and R followed by sequential HD-MTX (POR/ROM). The mean age of all patients was 56.9 years; 52.7% of the patients were male, and the majority had an IELSG score of ≥2 (2-3, 56.4%; 4-5, 24.6%). Most baseline characteristics were well balanced across the four cohorts, with the exception of cerebrospinal fluid involvement (p=0.004). After induction therapy, 28 patients received autologous stem cell transplantation (21.1% vs. 37.5% vs. 14% vs. 42.4%; p=0.026), and 56 received maintenance therapy (26.3% vs. 75% vs. 70% vs. 30.3%; p<0.001) among all patients. At the interim analysis, the POR/ROM and R2-MTX cohorts showed a comparable complete response rate (CRR; 54.6% vs. 56.0%), both of which were significantly higher than the R±MTX (21.1%%) and R-MA (12.5%) cohorts (p<0.001). The overall response rates (ORR) were 31.6%, 62.5%, 90%, and 81.8% at each cohort (p=0.010), respectively. At the end of treatment, response outcomes exhibited a comparable pattern, with CRR of 26.3%, 25%, 60%, and 72.7% across the four cohorts (p=0.003), and ORR of 47.4%, 75.0%, 86.0%, and 78.8% (p=0.011). At data cutoff, the median follow-up was 42 months. Regarding the long-term efficacy, both PFS (p=0.0239) and OS (p=0.0037) differed significantly among the four cohorts. The POR/ROM and R2-MTX cohorts showed similar outcomes, with POR/ROM demonstrating superior survival compared to the R-MA and R±MTX cohorts. Furthermore, treatment regimens that incorporated small-molecule targeted agents (POR/ROM and R2-MTX) were associated with significantly better survival outcomes compared to other regimens (R±MTX and R-MA), with a median PFS of 49.7 months versus 17.9 months (p=0.025) and a trend toward longer OS (median not reached vs. 36.6 months, p=0.0051). By multivariate Cox regression analysis, patients who achieved overall response during first-line treatment were found to have improved PFS and OS (both p<0.001). Treatment strategies were identified as an independent prognostic factor for PFS (p=0.032), while the use of maintenance therapy was associated with prolonged OS (p=0.014). The safety profiles were comparable across the four cohorts.

HD-MTX-based treatments demonstrated encouraging efficacy, particularly among patients who received POR/ROM or R2-MTX. These findings support adding small molecular target drugs to HD-MTX as a viable first-line treatment option for patients with PCNSL. Prospective studies are warranted to confirm these results.