Preliminary Exploration of Ibrutinib Combined with Methotrexate, Ifosfamide, Liposomal Doxorubicin and Methylprednisolone in the Treatment of Relapsed/Refractory Primary CNS Lymphoma

Background Primary central nervous system lymphoma (PCNSL) is a rare variant of extranodal non-Hodgkin lymphoma with an aggressive clinical course and poor outcomes. Although high-dose methotrexate (HD-MTX) based regimen significantly improves the outcome of the patients, approximately 10-35% of PCNSL patients are treatment refractory and 35-60% of patients eventually relapse. There is great unmet need in improving the prognosis of patients with relapsed/refractory PCNSL. In this study, we describe our institutional experience with I-MIDD regimen(ibrutinib combined with methotrexate, ifosfamide, liposomal doxorubicin and methylprednisolone) for patients with relapse/refractory PCNSL. Methods The clinical data of 18 relapse/refractory PCNSL patients treated from September 2017 to December 2019 were analyzed retrospectively. The doses and administration schedule were as follows: ibrutinib 560 mg/d for 21 consecutive days, methotrexate 3.5 g/m² on day 1, ifosfamide 1.5 g/m² on day 2, liposomal doxorubicin 25 mg/m² on day 3 and methylprednisolone 80 mg/d from day 1 to day 3. Every 21 days were as a course of treatment, and they were treated for 1-6 courses. The primary endpoint was complete response (CR) rate, and secondary endpoints included progression-free survival (PFS), overall survival (OS), overall response rate (ORR) and main adverse events (AEs). Results The median follow-up time of 18 patients was 13（3-27）months, 10 patients achieved complete remission, 5 achieved partial remission, 1 had stable disease and 2 had progression of disease. The ORR was 83.3%(5/18)．The median PFS was 6（1-27）months，the OS ranged from 3 to 27 months and the median OS was not achieved. The 1-year PFS and OS were 42.8% and 87.4% respectively. The AEs of chemotherapy were mainly bone marrow suppression. 17/69(24.6%) events was grade 3 to 4 leukopenia, neutropenia and thrombocytopenia in the course of the disease and was all manageable. No grade 4 non-hematologic AEs were observed. The only grade 3 non-hematologic toxicity was infectious disease which occurred in 2 cases, and one patient experienced fungal pneumonia with a favorable outcome. Conclusion I-MIDD regimen is a feasible and active combination for patients with relapse/refractory primary central nervous system lymphoma.