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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. Disclosures No relevant conflicts of interest to declare.

High-dose methotrexate (HD-MTX) based chemotherapy is the standard treatment for patients with newly diagnosed primary central nervous system lymphoma (PCNSL). The role of rituximab is controversial because as a large protein limits its penetration to blood brain barrier (BBB). We aimed to investigate the efficacy and tolerability of adding rituximab to methotrexate-cytarabine-dexamethasone combination therapy (RMAD regimen). We retrospectively analyzed 60 immunocompetent patients with newly diagnosed PCNSL from Beijing Tiantan Hospital, Capital Medical University. Twenty-four patients received 3-6 courses of methotrexate 3.5 g/m2 on day 1, cytarabine 0.5-1 g/m2 on day 2 and dexamethasone 5-10 mg on days 1, 2 and 3. Thirty-six patients received the same combination plus rituximab 375 mg/m2 on day 0. All patients repeated the treatment every 3 weeks. Patients who obtained a complete remission (CR) after induction chemotherapy received consolidation chemotherapy, and those with partial remission (PR), stable disease (SD) or progression disease (PD) received rescue whole brain radiotherapy (WBRT). After induction chemotherapy, patients treated with rituximab plus methotrexate-cytarabine-dexamethasone had a CR rate of 66.7%, compared with 33.3% of those treated with methotrexate-cytarabine-dexamethasone alone (p=.011). Seven anaphylaxis and 1 interstitial pneumonitis occured in patients with rituximab. The most common grade 1-3 adverse events were similar in the two groups including neutropenia, anaemia, thrombocytopenia, aminotransferases elevated and gastrointestinal reaction. None of the patients in the two groups experienced any grade 4 toxicity. On multivariate analysis, rituximab was associated with longer progression-free survival (PFS, hazard ratio: 5.23, 95% CI: 1.64-16.70, p=.005). Elevated serum lactate dehydrogenase (LDH) was associated with shorter OS (hazard ratio: 0.06, 95% CI: 0.00-0.97, p=.048) and PFS (hazard ratio: 0.10, 95% CI: 0.03-0.37, p=.001). HD-MTX based chemotherapy with rituximab had a higher rate of CR, and without serious toxicity. PFS but not OS benefited from addition of rituximab. LDH as an independent prognostic factor which predicted poor outcome. Disclosures No relevant conflicts of interest to declare.

Primary central nervous system lymphoma (PCNSL) is aggressive and confined to the central nervous system, including the brain parenchyma, leptomeninges, spinal cord, eyes or cranial nervous. Morphologically, approximately 95% of these tumors are DLBCL according to the new World Health Organization (WHO) classification. However, PCNSL has treatment outcome distinct from those of systemic DLBCL, as well as dismal prognosis than systemic DLBCL. Our goal was to determine the immunohistochemical profile and prognostic significance for 132 Chinese PCNSL cases. The expression of CD20, CD10, BCL-6, MUM1, CD138, BCL-2, and Ki67 antigens were observed by immunohistochemical method. All cases expressed CD20. CD10, BCL-6, and MUM1 were positive in 15.2% (20/132), 86.4% (114/132), 90.2% (119/132). CD138 was negative in 100% (39/39). BCL-2 was positive in 89.3% (108/121). The Ki67 antigen, a proliferative index, ranging from 1% to 100% (median 85.3%) and 76.5% (101/132) PCNSLs showed Ki67 ≥ 90%. Among 132 cases, 25 (18.9%) were classified as germinal center B-cell-like (GCB); 107 (81.1%) were classified as activated B-cell-like (ABC). The Ki67 index in 25 GCB was similar to that in 107 ABC (p=0.663>0.05). No significant correlation was found between Ki67 index and BCL-2 (p=0.225>0.05). Significant positive correlation was found between Ki67 index and BCL-6 expression (p=.000 Table 1. Clinical characteristics. Characteristics Patients, n (%) Age (years); n=132 ≥60 y, n=53; 2 84 (63.6) Involvement of deep structures; n=132 Absence 43 (32.6) Presence 89 (67.4) Table 2. Hans classification. CD10 BCL-6 MUM1 Immunoprofile PCNSL, n (%) + + + GCB 16 (12.1) + + - GCB 3 (2.3) + - + GCB 0 (0) + - - GCB 1 (0.7) - + - GCB 5 (3.8) - + + Non-GCB 90 (68.2) - - + Non-GCB 12 (9.1) - - - Non-GCB 5 (3.8) Table 3. Chang classification. CD10 BCL-6 MUM1 Immunoprofile PCNSL, n (%) + + - GCB (Pattern A) 3 (2.4) + - - GCB (Pattern A) 1 (0.8) - + - GCB (Pattern A) 5 (3.9) + + + activated GCB (Pattern B) 16 (12.6) + - + activated GCB (Pattern B) 0 (0) - + + activated GCB (Pattern B) 90 (70.9) - - + activated non-GCB (Pattern C) 12 (9.4) Figure 1. Immunohistochemical labeling. Figure 1. Immunohistochemical labeling. Figure 2. Kaplan-Meier curve shows clinical prognostic variables and their relationship to OS and/or PFS. Figure 2. Kaplan-Meier curve shows clinical prognostic variables and their relationship to OS and/or PFS. Figure 3. T1 axial, post-gadolinium magnetic resonance imaging of PCNSL. Figure 3. T1 axial, post-gadolinium magnetic resonance imaging of PCNSL. Disclosures No relevant conflicts of interest to declare.