Background.Most patients with primary CNS lymphoma (PCNSL), an aggressive extranodal lymphoma confined to the CNS, have a poor prognosis in spite of development of chemotherapy regimens. First-line treatment consists of high-dose methotrexate-based (HD-MTX) regimen followed by consolidation with autologous stem cell transplantation or whole brain radiotherapy. Given that this tumor manifests predominantly in older patients with median age of 65 years, many patients are unable to tolerate intensive chemotherapy. Moreover, most patients eventually present with relapsed or refractory (r/r) disease. Relapse or refractory (r/r) PCNSL has a poor prognosis with median overall survival not exceeding 3.5 months (Langner-Lemercier et al, 2016) and these patients should be offered a clinical trial whenever possible. These groups are in need of safe, tolerable and effective therapeutic approaches. Primary testicular lymphoma (PTL) shares biological and clinical similarities with PCNSL and often present with CNS involvement. Such patients are also in need of new approaches, especially if they are refractory or not suitable to HD-MTX. Given high PD-1/PD-L1 expression in tumor microenvironment (Berghoff, 2014), immune checkpoint inhibitors were successfully tested in r/r PCNSL and PTL setting. However, data are still scarce and limited to case series (Nayak et al., 2017; Graber et al. 2020). Here we present Pavlov University experience of the treatment of PCNSL and PTL with CNS involvement with PD-1 inhibitor nivolumab. Methods.Eight patients, 2 men and 6 women, with PCNSL and one patient with PTL with CNS involvement treated at the Pavlov University between 2017 and 2020 were included into analysis. Median age at a diagnosis was 62 (28-66) years. Two patients (22%) had ECOG score 3-4 and therefore could not be considered for intensive MTX containing frontline treatment. In all of the cases the tumor histological type was diffuse large B-cell lymphoma. All patients had parenchymal involvement: 7 patients had multifocal disease; deep structures were involved in 2 patients. One patient had leptomeningeal involvement. Nivolumab was used in a first-line setting in 2 patients (22%). In 7 (78%) patients with relapsed/refractory disease, the median number of treatment lines prior to nivolumab was 1 (1-7). Nivolumab was given every 2 weeks in the 100 mg dose. Adverse events were defined according to NCI CTC-AE 5.0. Results.At the time of analysis, the median follow-up was 18 (3-44) months. Median number of nivolumab cycles was 10 (2-23). Seven (78%) patients had an objective response: complete response in 3 patients (33.3%) and partial response in 4 patients (44.4%). Two patients (22.2%) were refractory to treatment. Two-year overall survival (OS) was 44% with median OS of 12 months. Two-year progression-free survival (PFS) was 26% with median of PFS 12 months. Оne responder had a moderate increase of tumor volume on MRI after two months of therapy followed by complete disappearance of brain lesions on sequential imaging at 4 months after treatment initiation. Nivolumab therapy appeared safe with only one patient (11%) having severe adverse event, namely grade 3 alanine aminotransferase and aspartate aminotransferase increase. Conclusion.Nivolumab appears to be safe and effective therapy in PCNSL and PTL with CNS involvement both in first-line and r/r setting. However, in our cohort majority of patients relapsed that suggest that consolidation therapy after remission induction with nivolumab may be crucial for long-term remissions. We also demonstrate that pseudoprogression might be also observed in PCNSL during immunotherapy. Large-scale trials are needed to generate strong evidence for the use of PD-1 inhibitors in PCNSL. Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: Nivolumab is an anti-PD-1 inhibitor approved for classical Hodgkin lymphoma. There is early clinical data suggesting the efficiency of nivolumab in PCNS lymphoma (Nayak, 2017)

Background:Primary central nervous system lymphoma (PCNSL) and CNS involvement in primary testicular lymphoma (PTL) are two biologically closely related entities that carry suboptimal prognosis. Recent insights into the biology of this neoplasms provided a rationale for exploiting targeted therapy and immunotherapy. Given that these tumors express high levels of PD‐1 and PD‐1L, targeting this pathway with immune checkpoint inhibitors such as nivolumab is of particular interest. There is a little evidence regarding feasibility of checkpoint inhibitors use in these malignancies with the only paper of Nayak et al. (Blood, 2017) to be illustrative of efficacy and safety of this therapeutic modality. Here we report case series of 5 PCNSL patients and one patient with PTL with CNS involvement treated with nivolumab either in monotherapy or in combination with other agents.Aims:to report efficacy and safety of checkpoint inhibitor immunotherapy using nivolumab in patients with PCNSL and CNS involvement in PTL.Methods:5 patients diagnosed with primary CNS DLBCL and 1 patient diagnosed with PTL with CNS involvement were treated in First Pavlov State Medical University of Saint‐Petersburg between January 2017 and February 2019. Median age at a diagnosis was 55 (30‐65) years. Median age at the start of treatment with nivolumab was 56 (33‐66) years. At the treatment initiation, median Karnofsky performance status (KPS) was 70 (40‐90) and Eastern Cooperative Oncology Group (ECOG) status – 1,5 (1‐3). Four pts had multifocal lesions and 3 had involvement of deep structures (basal ganglia, brainstem and cerebellum). All patients had brain parenchyma disease and no ocular involvement. One patient had leptomeningeal disease as well. Nivolumab was used as first‐line therapy in one patient with poor performance status who was not candidate for methotrexate (MTX)‐based regimen. In the rest patients, nivolumab was used in relapsed/refractory setting with 1 to 6 previous therapy lines. Three patients received nivolumab as monotherapy and 3 in combination with other agents (rituximab in 1 case, high‐dose MTX with cytarabine and rituximab in the other, and ibrutinib in case of PTL patient). Nivolumab dosing were as follows: 3 pts – 3 mg/kg, 3 pts – 100 mg regardless of body weight. Response to treatment was assessed according to standardized guidelines for response assessment in PCNSL (Abrey et al., 2005).Results:At the time of analysis, median follow‐up was 7,5 (0,5‐24) months. In all patients the treatment was well tolerated with no reported immune related adverse events. Among patients with assessed response 2 pts achieved a complete response (CR), 1 patient had stable disease as best response to the treatment and 2 pts experienced progression. Later, one patient with PCNSL relapsed after CR. Retreatment with nivolumab, rituximab and intrathecal MTX, cytarabine, dexamethasone allowed to obtain CR again. Median progression‐free survival was 7 months (0,5‐24) with 4 pts still alive at the time of analysis.Summary/Conclusion:Nivolumab containing regimens may be efficient treatment option in patients with relapsed/refractory primary CNS lymphoma and primary testicular lymphoma or in patients who are not candidates for standard intensive chemotherapy regimen. The place of nivolumab in the treatment of PCNSL and PTL should be further determined in prospective clinical trials.

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primary endpoint was objective response rate (ORR) per Lugano 2014. Adverse events (AEs) were graded by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) 5.0.Results: From October 22 nd , 2018 to October 27 th , 2020, twenty-five patients with relapsed or refractory PMBCL were enrolled and treated. As of data cut-off on March 12 th , 2021, patients received a median of 28 (2-56) cycles of treatment. At a median follow-up of 56 (3.86-112.14) weeks, overall response rate (ORR) was 64% (16/25, 95% confidence interval [CI]: 42.52%, 82.03%), including 6 patients (24%) with a complete response and 10 patients (40%) with a partial response. Median progression-free survival and duration of response have not reached yet. Treatment-related adverse events (TRAEs) of any grade occurred in 84% (21/25) patients. The most common grade 3-4 TRAEs were leucopenia (5/25, 20%), neutropenia (4/25, 16%) and lymphopenia (4/25, 16%).Conclusions: Geptanolimab showed good anti-tumor activity with ORR of 64% and manageable safety profile in Chinese patients with relapsed or refractory PMBCL.