OS04.6.A MULTICENTER RANDOMIZED PHASE II STUDY OF R-MPV-A CHEMOIMMUNOTHERAPY WITH OR WITHOUT LOW-DOSE WHOLE-BRAIN RADIOTHERAPY FOR NEWLY DIAGNOSED PRIMARY CNS LYMPHOMA: NRG/ RTOG 1114

Abstract BACKGROUND Methotrexate-based chemoradiotherapy is effective in primary central nervous system lymphoma (PCNSL), but carries a risk of severe neurotoxicity. In a single-arm study, a chemotherapy regimen with methotrexate, procarbazine, vincristine and cytarabine was combined with rituximab (R-MPV-A) and substantially reduced doses of whole-brain radiotherapy (LD-WBRT), resulting in excellent progression-free survival (PFS) and overall survival (OS). Because R-MPV-A had never been tested without radiation, we conducted a randomized study to determine if this low radiotherapy dose was relevant for disease control, and to characterize the neurotoxicity of this approach. MATERIAL AND METHODS Patients were randomized to receive R-MPV-A alone (Chemo arm) or combined with LD-WBRT (ChemoRT arm), given at 2,340 cGy (180cGy X13). Methotrexate dose was 3.5g/m2 in 2-hour infusions. Primary endpoint was intent-to-treat (ITT) PFS. A sample size of 89 would provide 80% power to detect a hazard ratio (HR) of 0.63 (one-sided alpha=0.15). The study was supported by grants U10CA180868 (NRG Oncology Operations) and U10CA180822 (NRG Oncology SDMC) from the National Cancer Institute (NCI). RESULTS A total of 91 patients were randomized, and 44 were analyzed in the ChemoRT arm and 46 in the Chemo arm. Median age was 66 and 59.5, respectively. R-MPV-A was well tolerated with high overall response rate (ORR) in both arms; radiographic complete response rate was 92.3% (ChemoRT) and 76.3% (Chemo). After median follow-up of 4.6 years, median PFS was not reached (ChemoRT) vs 2.1 years (Chemo), HR=0.47 (p=0.007). The 2-year PFS was 78.7% vs 54%, respectively. OS favored ChemoRT but differences were not statistically significant (HR 0.71; p=0.33). Comprehensive neuropsychological evaluation showed no differences in cognitive outcomes, with several tests favoring ChemoRT, possibly reflecting more relapses and salvage treatments in the Chemo arm. CONCLUSION The study met the primary endpoint, demonstrating the addition of LD-WBRT to chemoimmunotherapy with R-MPV-A significantly improves PFS in newly-diagnosed PCNSL, with favorable neurocognitive outcomes.