ABCL-198: Pre-Phase Rituximab and High-Dose Methotrexate Enables Reassessment of Intensive Treatment Eligibility in Frail Patients with Central Nervous System Lymphoma: A Multicenter Cohort Study

High-dose methotrexate (HD-MTX)-based induction followed by high-dose chemotherapy and autologous stem cell transplantation (HCT-ASCT) is the standard of care for patients with primary central nervous system lymphoma (PCNSL) and is also effective in secondary CNS lymphoma (SCNSL). However, many patients are deemed ineligible upfront due to age, poor performance status (PS), comorbidities, or prior therapies. Objective: We aimed to evaluate whether a pre-phase treatment with rituximab and HDMTX (R-MTX) could enable a reevaluation of treatment eligibility for intensive induction regimens and ultimately HCT-ASCT in frail patients with CNS lymphoma. This retrospective multicenter cohort study included 83 patients with PCNSL or SCNSL treated between 2017 and 2024 across three German tertiary referral centers. All patients received an R-MTX pre-phase due to questionable fitness for intensive induction, consisting of rituximab (375 mg/m2) and high-dose methotrexate (≥3 g/m2, adjusted for renal function). A combined frailty score (CFS; range, 0–5) was developed to stratify baseline vulnerability based on age, PS, comorbidities, renal function, and prior therapy. At a median follow-up of 13.5 months, 48 of 83 patients (58%) proceeded to intensive induction regimens, primarily MARTA and MATRix. Thirty (63%) ultimately underwent HCT-ASCT. No treatment-related deaths occurred during R-MTX. An additional 34% received non-intensive therapy, while 8% discontinued treatment. Notably, four patients initially receiving non-intensive therapy were later able to proceed to HCT-ASCT. Progression-free and overall survival were significantly improved in patients with low CFS ( P = 0.019 and P = 0.0004, respectively) and in those who ultimately received HCT-ASCT (both P < 0.0001). Pre-phase R-MTX represents a pragmatic and effective strategy to reassess treatment eligibility in patients initially deemed too frail for intensive therapy. These findings highlight the value of integrating dynamic treatment reassessment and structured frailty scoring to expand access to curative-intent regimens in CNS lymphoma. This approach has the potential to redefine how we manage vulnerable patients in routine clinical practice. Prospective validation is currently ongoing.