A Systematic Review of High-Dose Methotrexate for Adults with Primary Central Nervous System Lymphoma

SIMPLE SUMMARY: High-dose methotrexate (HDMTX) is the backbone of induction therapy for primary central nervous system lymphoma (PCNSL). There are numerous different protocols to treat PCNSL that incorporate a wide range of HDMTX doses and various combinations with other chemotherapeutic agents. This systematic review was conducted to summarize the various treatment regimens for PCNSL and determine outcomes among the different doses of HDMTX and combination regimens. The findings are intended to provide guidance on the optimal dose and regimen of HDMTX for the treatment of PCNSL. ABSTRACT: Primary central nervous system lymphoma (PCNSL) is a highly aggressive non-Hodgkin lymphoma that is confined within the CNS. Due to its ability to cross the blood–brain barrier, high-dose methotrexate (HDMTX) is the backbone for induction chemotherapy. This systematic review was conducted to observe outcomes among different HDMTX doses (low, <3 g/m(2); intermediate, 3–4.9 g/m(2); high, ≥5 g/m(2)) and regimens used in the treatment of PCNSL. A PubMed search resulted in 26 articles reporting clinical trials using HDMTX for PCNSL, from which 35 treatment cohorts were identified for analysis. The median dose of HDMTX used for induction was 3.5 g/m(2) (interquartile range IQR, 3–3.5); the intermediate dose was most frequently used in the studies examined (24 cohorts, 69%). Five cohorts used HDMTX monotherapy, 19 cohorts used HDMTX + polychemotherapy, and 11 cohorts used HDMTX + rituximab ± polychemotherapy. Pooled overall response rate (ORR) estimates for low, intermediate, and high dose HDMTX cohorts were 71%, 76%, and 76%, respectively. Pooled 2-year progression-free survival (PFS) estimates for low, intermediate, and high HDMTX dose cohorts were 50%, 51%, and 55%, respectively. Regimens that included rituximab showed a tendency to have higher ORR and 2-year PFS than those that did not include rituximab. These findings indicate that current protocols utilizing 3–4 g/m(2) of HDMTX in combination with rituximab provide therapeutic efficacy in PCNSL.