THE 5‐YEAR FOLLOW‐UP RESULTS OF THE C5R PROTOCOL WITH RITUXIMAB AND INTRATHECAL LIPOSOMAL CYTARABINE FOR PRIMARY CNS LYMPHOMA: A PROSPECTIVE PHASE 2 STUDY OF THE LYSA

Abstract

Introduction: We developped in the LNHCP93 trial an intensive highdose methotrexate and cytarabine containing chemotherapy (CT) derived from CT regimens used for Burkitt lymphomas (C5R protocol) (Figure Presented) followed by brain radiotherapy (RT) showing favorable long-term survival in PCNSL patients younger than 60 years. We prospectively evaluated the addition of intravenous rituximab and intrathecal (IT) liposomal cytarabine to the C5R protocol before RT for 18 to 60 years old immunocompetent patients with a confirmed CD20 positive diffuse large B-cell lymphoma PCNSL. We present the updated results of this multicentric prospective phase 2 study from the LYSA with a median follow-up 59 months (min: 1.1-max: 77.8). Method(s): Fifty-three patients included between August 2007 and September 2011 received two courses of methotrexate, cyclophosphamide, doxorubicin, vincristine, prednisone (COPADEM) followed by two courses of methotrexate, cytarabine (CYM) administred at 21-day intervals from day 1 to day 21. At each day 1, intravenous rituximab 375 mg/m2 and at each day 3 IT liposomal cytarabine 50 mg were infused. After immuno-CT, a brain RT was planned for all patients. The primary objective of this study was the complete and unconfirmed complete response rate (CR/CRu) after immuno-CT, according to IPCG response criteria. Neurotoxicity was evaluated by a Mini-Mental State Examination (MMSE) test. Result(s): The median age of the 53 PCNSL patients was 55 years (range, 36-60), 57% were male, 42% had a performance status (PS) > 1, 55% had an involvement of deep structures of brain, 45% a high CSF protein level and 36% a high LDH level. Fortyfive patients (85%) completed the fourth cycles of immune-CT, and three patients (5.7%) died of acute toxicity. Forty-two patients (79%) underwent RT. We showed an improvement of the CR/CRu after immuno-CT from 33% in the LNHCP93 to 66% in the R-C5R protocol (P < 0.001). We showed no additional severe toxicities with the addition of intravenous rituximab and IT liposomal cytarabine. The 5-year progression-free survival (PFS) rate of whole cohort was 53% (95%CI, 38% to 66%) (Figure). For patients with 0-1 and 2-4 adverse IELSG prognostic scores, the 5-year PFS rates were 69% and 46%, respectively (P = 0.13). The 5-year overall survival (OS) rate for whole cohort was 65% (95%CI, 50% to 77%) (Figure). For patients with 0-1 and 2-4 adverse IELSG prognostic scores, the 5-year OS rates were 91% and 54%, respectively (P = 0.02). From baseline to 6-12 months, the median MMSE improved from 26 (3-30) (N = 42) to 29 (23-30) (N = 13) and was at 30 (29-30) (N = 3) at the last follow-up (54-60 months). Conclusion(s): R-C5R protocol provided high CR/CRu rates (66%) and favorable long-term outcomes with a 5-year PFS and OS of 53% and 65%, respectively. These results compared favorably with historical controls of LNHCP93 trial who presented a 5-year PFS and OS of 31% and 42%, respectively.