Background: With currently available therapies, relapsed/refractory aggressive non-Hodgkin lymphoma (NHL) after high-dose therapy or, in not transplant-eligible patients, after first-line chemotherapy represents an unequivocally unmet clinical need. Aim and Methods: Therefore, we aimed at evaluating a combination chemotherapy regimen based on pixantrone (Pix), a novel aza-anthracenadione recently approved by the European Medicines Agency in adult patients with multiply relapsed or refractory aggressive non-Hodgkin lymphoma (NHL). Etoposide and bendamustine were chosen as companion compounds due to available feasibility data in combination with Pix, as well as to their documented efficacy in salvage regimens in relapsed/refractory aggressive NHL and to a well-known feasibility profile when given alone or in combination. The monoclonal anti-CD20 antibody rituximab was added if tumor cells in the relapse biopsy specimen were CD20-positive. The adopted schedule consisted of Pixantrone 50 mg/m2 i.v. day 1+8, Etoposide 100 mg i.v. day 1, Bendamustine 90 mg i.v. day 1 with or without the addition of Rituximab 375 mg/m2 i.v. day 1 (PREBEN/PEBEN). If feasible, each cycle was given at 3-weekly intervals for a maximum of 6 cycles. All patients were assessed for chemosensitivity with PET/CT after cycle 1 or 2. G-CSF support was administered according to local guidelines. Results: A total of 8 evaluable patients with relapsed/refractory aggressive NHL were treated according to the PREBEN/PEBEN schedule. Abstract 5435. Table 1summarizes the clinico-pathological features of the patient cohort along with selected feasibility and efficacy parameters related to the PREBEN/PEBEN regimen (PET/CT status after 1 or 2 courses):Patient characteristicsPREBEN/PEBEN-related parametersPt #DxAgeSexCS at relapseN of prior Rx linesPrior TxN coursesTox grade 3-4Best responseDoR1DLBCL (ABC)70MIV3N6thrombocytopeniaCR*6 mo2DLBCL (ABC)49MIV3Y2-PD-3DLBCL (ABC)53MIV2N2neutropenic fevergoodPR4+ mo4DLBCL (ABC)64MIV2N2neutropenic fevergoodPR3+ mo5DLBCL (GCB)69FIV3N2-CR2+ mo6tFL62MIII3Y2neutropenic feverSD-7tCLL51FIV5Y2neutropenic feverPD-8PTCL-NOS57FIV2N6diarrhoeaCR4+ mo Baseline (pt#1) after 1 x PREBEN (pt#1) Figure 1 Figure 1. Figure 2 Figure 2. Conclusion: The PREBEN/PEBEN schedule is feasible (out-patient regimen) and in individual patients it elicits profound responses early in the course of therapy. A phase 1-2 study in relapsed/refractory DLBCL and PTCL is in preparation. Disclosures d'Amore: Amgen: Research Funding; Sanofi Aventis: Research Funding; CTI Life Sciences: Advisory board, Advisory board Other, Speakers Bureau; Mundipharma: Advisory board, Advisory board Other, Speakers Bureau; Takeda: Advisory board, Advisory board Other, Speakers Bureau; Kyowa Kirin Pharmaceuticals: Advisory board Other, Speakers Bureau; Roche: Research Funding.

7520 Background: We report results of a phase 2, open-label study of durvalumab (durva) in combination with R-CHOP or R2-CHOP (R-CHOP + lenalidomide) in previously untreated, high-risk diffuse large B-cell lymphoma (DLBCL). Methods: Subjects (≥18 y; ECOG 0–2) with previously untreated, high/high-intermediate risk DLBCL (IPI ≥3/NCCN-IPI ≥4) were stratified to durva + R-CHOP (Arm A, GCB DLBCL) or R2-CHOP for 6–8 cycles (Arm B, ABC DLBCL) based on cell of origin identified by gene expression followed by durva consolidation up to month 12 from start of induction. After FDA placed clinical holds on trials including combination therapy with checkpoint inhibitors and immunomodulatory agents, the study was revised to include both ABC and GCB in Arm A (durva + R-CHOP). The primary endpoint was complete response rate (CRR) at end of induction; secondary endpoints were rate of subjects continuing to consolidation, safety, and response in biological. Results: A total of 46 subjects were treated (safety; A/B, n=43/3); median age, 62/66 y; male, 61%/67%; ECOG 2, 19%/33%; Ann Arbor stage IV, 79%/33%; bulky disease: 49%/67%; double/triple-hit lymphoma, 30%/33%. As of Aug 2, 2018, 30/3 (A/B) had completed induction therapy, and 19 subjects (A) were ongoing. CRR (95% confidence interval) at end of induction was (A) 54% (37%-71%) and (B) 67% (9%-99%); 68%/67% (A/B) continued to consolidation therapy and were progression free at month 12. Safety profile was as expected for the components of the combination regimen with no new safety signal identified. Frequent treatment-emergent adverse events (TEAEs; ≥25%; A+B) included fatigue (61%), neutropenia (52%), peripheral sensory neuropathy (50%), nausea (46%), diarrhea (28%); constipation, decreased appetite, insomnia, pyrexia (24% each); and alopecia, dizziness, dyspnea, headache, stomatitis (22% each). Grade 3/4 TEAEs occurred in 84%/100% of subjects (A/B), and 3 subjects (2/1) died with no death related to study treatment. Follow-up for efficacy and safety is ongoing. Conclusions: Durva + R-CHOP combination therapy is safe and demonstrates encouraging response rates in subjects with high-risk DLBCL including double-hit lymphoma. Clinical trial information: NCT03003520.

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). Results: 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 Background: Survival of patients with high-risk diffuse large B-cell

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Introduction: Tumor microenvironment (TME) and limited immune surveillance impact lymphoma pathogenesis and survival. Immune checkpoint receptors, such as programmed cell death-1 (PD1), lymphocyte-activation gene-3 (LAG3) and T-cell immunoglobulin and mucin domain-3 (TIM3), mediate signals leading to T-cell exhaustion and immune escape. Here, we have characterized the immunological profiles of diffuse large B-cell lymphoma (DLBCL) and associated the findings with outcome. Methods: We utilized the NanoString nCounter platform with a 770-gene PanCancer Immune panel to profile gene expression from 81 RNA samples collected from high-risk DLBCL patients. Multiplex immunohistochemistry (mIHC) with digital image analysis was used to characterize the T-cell phenotypes (CD3, CD4, CD8, PD1, LAG3, and TIM3) in two DLCBL patient cohorts (n=52 and n=136). The findings from gene expression profiling and mIHC were correlated with clinical parameters and patient outcome (i.e. progression-free survival (PFS) and overall survival (OS)). Results: Gene expression profiling revealed a high degree of heterogeneity among DLCBL. Unsupervised hierarchical clustering identified gene clusters differentially expressed between the patients. The distinct clusters contained genes for cytolytic factors and immune checkpoint molecules (GZMB, PRF1, IFNG, TIM3, LAG3), T-cells (CD3, CD2, CD28), macrophages (CD68, CD163), B-cells (MS4A1, CD19, CD79A/B), and extracellular matrix (FN1, ITGA1/5/6, VEGFA). mIHC revealed that the proportion of CD3+ T-cells varied markedly between the patients (median 24.8%, range 0.5-65.1%). On average, 8.8% (0-34.3%) of the CD3+ T-cells were positive for TIM3, whereas 0.6% (0-5.4%) were positive for LAG3. High content of TIM3+ cells was associated with poor outcome (PFS: HR 1.06, 95%CI 1.02-1.10, P=0.003; OS: HR=1.12, 95%CI 1.04-1.20, P=0.003) in a cohort of 52 DLBCL patients independent of the international prognostic index (IPI). In addition, high proportion of TIM3+CD3+ cells associated with poor survival independently of IPI (PFS: HR 1.07, 95%CI 1.00-1.14, P=0.040; OS: HR 1.087, 95%CI 1.01-1.17, P=0.019). The prognostic impact of TIM3 on survival was validated in a separate mIHC cohort of 136 DLBCL patients (PFS: HR 1.07, 95%CI 1.02-1.14, P=0.014; OS: HR 1.10, 95%CI 1.03-1.16, P=0.002). Conclusions: Our data demonstrates that the molecular immunological profile of DLBCL is heterogenic and that the expression of T-cell exhaustion marker TIM3 correlates with poor prognosis in patients with DLBCL. A more detailed characterization of immune cell composition in the TME and its impact on survival is ongoing. Citation Format: Suvi-Katri Leivonen, Matias Autio, Oscar Bruck, Satu Mustjoki, Judit M. Joergensen, Marja-Liisa Karjalainen-Lindsberg, Klaus Beiske, Harald Holte, Sirpa Leppä. Clinical impact of T-cell exhaustion in patients with diffuse large B-cell lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 980.