QUESTIONING CONVENTION-IS INTRATHECAL CHEMOTHERAPY (ITC) NECESSARY FOR PATIENTS WITH NEWLY DIAGNOSED PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA (PCNSL): COMBINED RESULTS FROM THREE INDEPENDENT COHORTS

Abstract Background Despite beguiling responses to initial therapy in many patients, PCNSL remains a therapeutic challenge. Relapse is common, cures are elusive for most patients, and overall response are disappointing compared to other diffuse large B-cell lymphomas. High-dose methotrexate-based therapies have become the standard of care, with many variations, but there is no consensus, and very little data regarding the role of ITC in the initial treatment of patients with PCNSL. Material and Methods We collected study-level and where possible, patient-level data from three independent clinical trials comparing adults with newly diagnosed PCNSL treated with regimens that differed based on the use of ITC. Patient characteristics, overall (OS) and progression-free survival (PFS), and characteristics of relapse were examined. The frequency of lymphomatous meningitis at diagnosis based on the location of CSF sampling - ventricular vs. lumbar - was also investigated. Complete data retrieval for this updated analysis has allowed us to combine data from the three studies and calculate summary statistics using a random effects model and inverse variance technique. In addition, predictors of OS and PFS were modeled using a Cox proportional hazards technique. Results The three cohorts were treated with: HD MTX/rituximab/ifosfamide followed by either HD MTX/cytarabine/ifosfamide (group Ia), or cytarabine/thiotepa and autologous stem cell transplant (group Ib) (n=80); HDMTX/vinca alkaloids/ifosfamide/cytarabine (group II) (n=83); or HD MTX/rituximab (group III) (n=49). ITC consisted of MTX/cytarabine/prednisolone (group Ia only, n=43); MTX/cytarabine/prednisolone (group II, n=65); or liposomal cytarabine (group III, n=21). One- and two-year OS was better in the ITC chemotherapy compared to the no-ITC group (RR 1.25 [1.16-1.34] and 1.20 [1.14-1.26] respectively, p< 0.001 for both comparisons). One-year PFS was also improved in the ITC group (RR 1.12 [1.01-1.25], p=0.031). Two-year PFS was not statistically different between groups (RR 1.20 [0.90-1.59], p=0.220). Relapse involving the CSF was more frequent in the non-IT chemotherapy group (RR 2.31 [2.03-2.62], p< 0.001). CSF cytology was positive in 81% of ventricular specimens vs 14.3% of lumbar specimens (p< 0.001). Conclusion This analysis of three independent cohorts of adults with newly diagnosed PCNSL suggests (when ventricular rather than lumbar CSF is sampled) that lymphomatous meningitis is dramatically more frequent, and perhaps universal. Including ITC as part of the initial treatment regimen increased both OS and PFS substantially. A randomized controlled trial is urgently required.