IBRUTINIB IN RELAPSE OR REFRACTORY PRIMARY CNS AND VITREO-RETINAL LYMPHOMA. RESULTS OF THE PRIMARY END-POINT OF THE I LOC PHASE II STUDY FROM THE LYSA AND THE FRENCH LOC NETWORK.

Primary CNS lymphoma (PCNSL) is a diffuse large B-cell lymphoma (DLBCL), predominantly of non-germinal center (non-GC) subtype, with a constitutive activation of the NF-kB pathway. Mutations in B cell receptor (BCR) pathway (CD79B) and mutation of MYD 88 and TBL1XR1 play an important role in PCNSL. Ibrutinib is an inhibitor of BCR signaling, with a significant therapeutic activity in relapsed or refractory non-CNS non-GC DLBCL. This prospective, multicenter, open-label phase II, was designed for immuno-competent patients over 18 with a refractory or relapse of PCNSL or primary vitreo-retinal lymphoma (PVRL) of DLBCL type. The treatment consisted in ibrutinib monotherapy given orally at 560 mg daily until disease progression or unacceptable toxicity. Additional corticosteroids treatment was allowed during the first 4 weeks of treatment in case of a threatening or symptomatic edema. The primary objective of the study was the disease control (DC) rate (CR + CRu + PR + SD) after two months of treatment. Patients were evaluable for response if they received ≥90% of the expected dose during the first month of treatment. A total of 35 evaluable patients were required for the final analysis (P0 < 10%; P1 hypotheses >30%). Results of the interim analysis were encouraging with a DC achieved in 15/18 patients (83%, IC 95%, [59-96%]) after two months of treatment. NCT02542514. Between September 2015 and June 2016, 52 patients were recruited in 10 French centers of the French LOC network for PCNSL. Forty-three patients (24 females; 19 males) are evaluable for response (median age: 70 y, range 52-81). Initial diagnoses were PCNSL (n = 30) and PVRL (n = 13). Patients were included in the study for a relapse (n = 31) or a progressive disease (n = 12). At time of inclusion in the study, disease status was PCNSL (n = 29) and PVRL or isolated intra-ocular relapse of a PCNSL (n = 14). Four patients had a concomitant meningeal involvement. ECOG performance status was 0, 1 and 2 in 11, 22 and 10 patients respectively. All the patients had previously received high-dose methotrexate-based chemotherapy. Six patients had previously received high-dose chemotherapy followed by autologous stem cell transplantation. Patients had received ≥2 prior treatments in 25 cases. Twenty-seven patients prematurely interrupted ibrutinib treatment between cycle 2 and cycle 15 (median time: 3 months, range, 0.9-13 months), because of a progressive disease (n = 22), toxicity (n = 1, grade 3 hyphema), other (n = 4). Among the 52 patients included in the study, two patients experienced a pulmonary aspergillosis with a favorable (n = 1) and a fatal outcome (n = 1). Ibrutinib was detectable in the CSF (> 0.15 ng/ml) in all the samples tested (n = 26). Thirteen patients are currently on treatment ≥6 months, including 8 patients ≥12 months. The analysis of the primary end-point of the 43 evaluable patients is ongoing and results will be presented. Keywords: ibrutinib; primary CNS lymphoma (PCNSL).