Shipp, Margaret Ann

Abstract B-cell receptor (BCR) signaling pathway components represent promising treatment targets in multiple B-cell tumors including diffuse large B-cell lymphoma (DLBCL). BCR signaling activates proximal pathway components such as the spleen tyrosine kinase (SYK) and downstream effectors including PI3K/AKT and NF-κB. In recent studies, we characterized distinct SYK/PI3K/AKT-dependent viability pathways in BCR DLBCL cell lines and primary tumors with high- or low-baseline NF-κB activity and defined additional SYK/PI3K/AKT-dependent processes essential for BCR DLBCLs with low- or high-baseline NF-κB (Chen et al Cancer Cell 2013; 23:826-838). For example, SYK/PI3K/AKT-dependent cholesterol biosynthesis was identified as a feed-forward mechanism of preserving the integrity of BCRs in lipid rafts in all BCR-dependent DLBCLs. In the current study, we sought to identify biomarkers of intact BCR signaling in DLBCLs with low or high baseline NF-κB. We found highly significant transcriptional upregulation of CXCR4 in all BCR-dependent DLBCLs treated with a chemical SYK inhibitor (R406). These results were of particular interest because BCR signaling inhibits stromal cell-derived factor (SDF)-1α chemotaxis and promotes intermobilization of the SDF-1α receptor, CXCR4. To expand on our findings, we analyzed CXCR4 transcript abundance in a large panel of cell lines including BCR-dependent/ low NF-κB (GC type) and BCR-dependent/ high NF-κB (ABC type) and BCR-independent/ OxPhos DLBCLs. CXCR4 transcript abundance was significantly and selectively upregulated in all BCR-dependent DLBCL lines assessed by qRT-PCR following chemical SYK inhibition. Consistent with the qRT-PCR results, SYK blockade also selectively upregulated cell surface CXCR4 expression in all BCR-dependent DLBCLs. Similar results were obtained following SYK knockdown with multiple independent shRNAs; CXCR4 transcript abundance was significantly and selectively upregulated in all BCR-dependent/ low NF-κB (GCB) DLBCLs and BCR-dependent/ high NF-κB (ABC) DLBCLs but was not altered in BCR-independent/ OxPhos tumors. Following SYK blockade, we also observed significant CXCR4 induction (by qRT-PCR) in multiple primary BCR-dependent DLBCLs (NF-κB low and NF-κB high) and unchanged CXCR4 levels in primary BCR-independent tumors. These data confirm that the observations regarding SYK blockade and CXCR4 induction in BCR-dependent DLBCL cell lines translated to primary tumors. Our recent studies indicate that all BCR-dependent DLBCLs exhibit SYK/PI3K/AKT signaling and modulation of FOXO1 regardless of baseline NF-κB levels. Given the recent identification of CXCR4 as a FOXO1 target, we asked whether modulation of CXCR4 in DLBCLs was via a PI3K/AKT pathway. In BCR-dependent DLBCLs with low or high baseline NF-κB, chemical PI3K inhibition (LY294002) phenocopied chemical SYK blockade (R406) with highly significant transcriptional upregulation of CXCR4. Moreover, in BCR-dependent DLBCL cell lines, enforced expression of a constitutively active form of AKT (myrAKT) abrogated CXCR4 upregulation resulting from SYK blockade. These data indicate that in BCR-dependent DLBCLs, CXCR4 is modulated by a SYK/PI3K/AKT-dependent pathway. To assess the functional significance of CXCR4 upregulation in BCR-dependent DLBCLs, we performed a transwell chemotaxis assay and evaluated migration toward a SDF-1α gradient. Following chemical SYK inhibition, all BCR-dependent DLBCLs exhibited significantly increased migration toward the CXCR4 ligand, SDF-1α, whereas the BCR-independent/ OxPhos DLBCLs were unaffected. The enhanced SDF-1α dependent migration was abrogated when the chemotaxis assay was performed in the presence of the specific CXCR4 inhibitor, AMD3100, confirming the specificity of the observed effect. Therefore, in BCR-dependent DLBCLs with low or high baseline NF-kB, SYK/PI3K inhibition is associated with significant and functionally relevant upregulation of CXCR4. For these reasons, CXCR4 may serve as a robust biomarker to assess the integrity of the BCR pathway and evaluate the efficacy of BCR inhibition in DLBCL. Disclosures: Off Label Use: R406 is not get approved, but is being evaluated in DLBCL and CLL.

Abstract Introduction: Genetic alterations at 9p24.1 resulting in overexpression of programmed death-1 (PD-1) ligands are near-universal in cHL (Roemer et al, J Clin Oncol 2016); cHL may thus be uniquely sensitive to PD-1 blockade. Nivolumab (nivo), an anti-PD-1 monoclonal antibody, was associated with an objective response rate (ORR) of 69% in relapsed/refractory (R/R) cHL after auto-HCT and irrespective of prior brentuximab vedotin (BV) in the phase 2 CheckMate 205 study (Armand et al, J Clin Oncol 2018; NCT02181738). Whether some patient (pts) can derive very long clinical benefit, whether depth of response predicts long-term outcome, whether treatment (Tx) can be interrupted in complete remission (CR), and whether the safety profile of nivo in R/R cHL changes with prolonged Tx all remain unclear. We therefore present an updated analysis of CheckMate 205, focusing on long-term efficacy and safety. Methods: This international, single-arm, multi-cohort study enrolled pts aged ≥18 y with R/R cHL after auto-HCT. Pts were BV naïve (Cohort A), had prior BV failure after auto-HCT (Cohort B), or had received BV before and/or after auto-HCT (Cohort C). Pts received nivo 3 mg/kg every 2 wk until disease progression (PD)/unacceptable toxicity. Pts in Cohort C discontinued nivo after 1 y in CR and could resume if they relapsed within 2 y of the last dose. Primary endpoint was ORR per independent radiology review committee (IRC); additional endpoints included duration of response (DOR) per IRC, progression-free survival (PFS) per IRC, overall survival (OS), and safety. Time to next Tx (TTNT: time from first dose to next systemic Tx or death) was an exploratory post-hoc analysis. Responses were assessed using International Working Group 2007 criteria. Results: In total, 243 pts were enrolled to Cohorts A (n=63), B (n=80), and C (n=100). Baseline characteristics have been previously described (Armand et al, J Clin Oncol 2018). At data cut-off, minimum follow-up was 31 mo and 49 pts (20%) were still on Tx; the most common reason for discontinuation was PD (35%). Median duration of Tx was 14 mo. ORR per IRC was 71% (65%, 71%, 75% in Cohorts A, B, C, respectively) with a best overall response (BOR) of CR in 21% (32%, 14%, 20% in Cohorts A, B, C, respectively). Among 51 pts who achieved CR, 20 had CR as the first response and 31 improved from partial remission (PR), mostly (n=28/31) within 1 year of first PR. Median time to response was 2 mo, and to CR was 4 mo. Within the first 6, 12, and 18 mo, 68%, 71%, and 71% of pts, respectively, achieved a response. Median DOR was 18 mo overall, and was 32 and 13 mo in pts with a BOR of CR and PR, respectively. Among responders, 64%, 44%, 31%, and 21% of pts had a DOR of at least 6, 12, 18, and 24 mo, respectively. Overall, 11 pts in Cohort C discontinued with persistent investigator-assessed CR; 2 reinitiated nivo due to PD. Median (95% CI) PFS per IRC among all pts was 15 (11-19) mo (Figure A), and was 17, 12 and 15 mo in Cohorts A, B, and C, respectively. Median OS was not reached in any cohort; 24-mo OS rates were 90%, 86%, and 86% in Cohorts A, B, and C, respectively, and were similar among pts in CR, PR, or with stable disease (SD; Figure B). Median TTNT was 29, 27, and 20 mo in Cohorts A, B, and C, respectively. The most common Tx-related adverse events (AEs) of any grade (G) were fatigue (24%), diarrhea (16%), and rash (12%), each <1% G3-4. Tx-related infections were reported in 15% of pts, 2% G3-4. Tx-related infusion related reactions were reported in 34 pts (14%), <1% G3-4. The most commonly reported immune-mediated AE category was rash, which was G3-4 in 4 pts (2%). In total, 26 pts (11%) experienced an AE of any cause leading to discontinuation. There were no Tx-related deaths. Conclusions: With the longest phase 2-3 study follow-up of a checkpoint inhibitor in R/R cHL to date, nivo was associated with frequent and durable responses regardless of BV Tx history. More than 1 in 5 responders remained in response ≥2 years later. With extended follow-up, additional pts achieved CR in all cohorts. Pts with CR had longer PFS than pts with PR or SD. However, pts with both PR and SD had prolonged OS, unlike pts with PD, which may suggest that clinical benefit duration is not well predicted by conventional response criteria. Nivo continued to be well tolerated, with no new safety signals. Characteristics of long-term responders will be presented. Study support: BMS. Medical writing: A Gill, Caudex, funded by BMS Figure. Figure. Disclosures Armand: Infinity: Consultancy; Affimed: Consultancy, Research Funding; Pfizer: Consultancy; Otsuka: Research Funding; Adaptive: Research Funding; Merck: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Roche: Research Funding; Tensha: Research Funding. Younes:Celgene: Honoraria; Genentech: Research Funding; Janssen: Honoraria, Research Funding; Bayer: Honoraria; Novartis: Research Funding; J&J: Research Funding; Astra Zeneca: Research Funding; BMS: Honoraria, Research Funding; Merck: Honoraria; Abbvie: Honoraria; Takeda: Honoraria; Seattle Genetics: Honoraria; Roche: Honoraria, Research Funding; Sanofi: Honoraria; Incyte: Honoraria; Curis: Research Funding; Pharmacyclics: Research Funding. Zinzani:PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Honoraria, Speakers Bureau; Celltrion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; SERVIER: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees. Collins:ADC Therapeutics: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Speakers Bureau; Celleron: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Speakers Bureau; Celgene Corporation: Research Funding; BMS: Consultancy, Honoraria, Research Funding; MSD: Consultancy, Honoraria; Amgen: Research Funding. Ramchandren:Merck: Research Funding; Bristol-Myers Squibb: Consultancy; Seattle Genetics: Consultancy, Research Funding; Pharmacyclics LLC an AbbVie Company: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Cohen:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BioInvent: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Takeda: Research Funding; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Infinity Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees. De Boer:Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; MSD: Membership on an entity's Board of Directors or advisory committees; EISA: Membership on an entity's Board of Directors or advisory committees. Kuruvilla:Lundbeck: Honoraria; Gilead: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Princess Margaret Cancer Foundation: Research Funding; Leukemia and Lymphoma Society Canada: Research Funding; Abbvie: Consultancy; Merck: Consultancy, Honoraria; Karyopharm: Honoraria; Roche: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria; Amgen: Honoraria; Celgene: Honoraria. Trněný:F. Hoffman-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory board, Research Funding; Sandoz: Honoraria; Gilead: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Abbvie: Honoraria, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Incyte: Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Morphosys: Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Advisory board. Shipp:Merck: Research Funding; Bayer: Research Funding; AstraZeneca: Honoraria; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Sacchi:Bristol-Myers Squibb: Employment, Equity Ownership. Sumbul:Bristol-Myers Squibb: Employment. Ansell:Trillium: Research Funding; Pfizer: Research Funding; Regeneron: Research Funding; Celldex: Research Funding; Seattle Genetics: Research Funding; Affimed: Research Funding; Merck & Co: Research Funding; LAM Therapeutics: Research Funding; Bristol-Myers Squibb: Research Funding; Takeda: Research Funding.

Abstract Diffuse Large B Cell Lymphoma (DLBCL) is the most common form of B-cell Non-Hodgkin Lymphoma (NHL), representing a third of all new cases. DLBCL is further sub-divided into various molecular sub-types based on gene expression and co-occurring genetic alterations. Gene expression based- subtypes include the germinal center B-cell (GCB) and the activated B-cell type (ABC) subtypes, with the ABC sub-type having a poorer prognosis than the GCB sub-type. Interestingly, 30-40% of all DLBCL patients harbor mutations in key epigenetic regulators, EZH2, KMT2D, CREBBP, EP300, and mutations in histone proteins themselves. Through an unbiased cell-based phenotypic screen, we discovered that inhibition of lysine demethylases, specifically KDM4C and KDM4A, represents a vulnerability across 15 different DLBCL cell lines including germinal center B-cell (GCB) and activated B-cell (ABC) type lines, with a GI50 value between 75nM to ~200nM, while sparing leukemia lines. Consistently, treatment of xenograft-based animal models of DLBCL with a low dose of KDM4A/KDM4C inhibitor delivered intra-peritoneally three times a week, results in a drastic reduction of tumor burden. Both KDM4A and KDM4C catalyze the removal of histone H3 K9 di- and tri-methylation (H3K9me2/3) and H3K36 di- and tri-methylation (H3K36me2/3). H3K9me2/3 is associated with promoter and enhancer repression, while H3K36me2/3 is present in gene bodies during transcription but also functions as a chromatin repressor Consistently, we have identified key enhancers, including those associated with IKZF1, that are "decommissioned" after inhibition of KDM4A/KDM4C. Repressed enhancer activity, through loss of H3K27 acetylation and H3K4me1, and gain of H3K9me2/3, results in a rapid transcriptional downregulation of IKZF1 and its partners including IKZF3. Given the role of IKZF1 in the transcriptional regulation of key B Cell Receptor (BCR) signaling components, we show that KDM4A/KDM4C inhibition leads to a downregulation of SYK, a proximal BCR-signaling component, which likely precedes DLBCL cell apoptosis. In addition, we observed an activation of extra-lineage transcription factors such as CEBPA and CEBPB, which are normally repressed by IKZF1 in the lymphoid lineage. A concomitant downregulation of the B-cell gene expression program and an upregulation of the myeloid (CD14+ monocytic) gene expression program is also observed, implying a "trans-differentiation" of DLBCL cells into the monocyte lineage. This lineage-switch correlates with an increased population of CD14+ expressing cells. Finally, using DLBCL patient data sets, we can show that over-expression of either KDM4A or KDM4C is associated with poor prognosis in DLBCL patients. In summary, we have discovered that KDM4A/KDM4C inhibition results in an increase of repressive histone modifications at several intra-genic "enhancers" of genes that are responsible for the survival and proliferation of DLBCL cells. The elucidation of this unique epigenetic mechanism provides a strong rationale for the development of novel targeted therapies against both multiple subtypes of DLBCL. Figure. Figure. Disclosures Shipp: Bayer: Research Funding; AstraZeneca: Honoraria; Merck: Research Funding; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Abstract Introduction: The phase 2 CheckMate 205 study (NCT02181738) of nivolumab (nivo) has demonstrated high objective response rates (ORRs), durable efficacy, prolonged overall survival (OS), and an acceptable safety profile in patients (pts) with relapsed/refractory classical Hodgkin lymphoma (R/R cHL) after failure of autologous hematopoietic cell transplantation (auto-HCT) irrespective of prior brentuximab vedotin (BV) treatment (Armand et al, J Clin Oncol 2018). Atypical response patterns have been observed with checkpoint inhibitors, and clinical benefits may be experienced by pts who are treated beyond progression (TBP) as defined by conventional criteria (Cheson et al, Blood 2016; Younes et al, Ann Oncol 2017). Stable reductions in tumor burden without symptoms of active disease were seen in pts TBP in CheckMate 205, suggesting that pts might continue to derive clinical benefits from nivo beyond disease progression. As TBP was an option for some pts in CheckMate 205, we report here updated outcomes of those pts. Methods: This single-arm, multicenter study enrolled pts (age ≥18 y) with R/R cHL after failure of auto-HCT into 3 cohorts (A: BV naïve; B: BV after auto-HCT; C: BV before and/or after auto-HCT). Nivo was administered at 3 mg/kg IV every 2 wk until disease progression or unacceptable toxicity (or after 1 year in complete response [CR] for cohort C). Response was assessed by 2007 International Working Group (IWG) criteria. A protocol amendment allowed pts with stable performance status and perceived clinical benefit to be TBP per investigator assessment. Tumor burden after initial progression was assessed; exploratory analyses included OS and time to next therapy (TTNT). Pts TBP were further categorized as PD-1 resistant (failure to achieve CR/partial response [PR] during initial treatment with nivo or CR/PR with subsequent progressive disease [PD] ≤90 d of response) and non-resistant pts (CR/PR followed by PD >90 d from response). Results: At data cutoff, 130 pts had PD, among whom 80 (62%) were TBP, and 50 (38%) were not (non-TBP). Demographics of pts TBP and non-TBP were similar to the overall study population, although more pts TBP had ECOG performance status of 0 at baseline (59% vs 36%) and stage IV disease at diagnosis (30% vs 22%), but fewer had B symptoms at baseline (23% vs 30%). In pts TBP vs non-TBP, the cause of initial progression was new lesions in 50 (63%) vs 23 (46%), increased total tumor burden in 17 (21%) vs 11 (22%), and non-target lesion progression in 19 (24%) vs 4 (8%) (pts could have multiple reasons for progression). ORR prior to progression was similar between TBP (54%) and non-TBP (64%) pts. At data cutoff, the median (range) doses of nivo given beyond progression was 11 (1-64) and median TBP duration was 5 (95% CI: 3, 7) mo. Nine (11%) pts TBP remained on treatment compared with 2 (4%) non-TBP. The most common reason for discontinuation was further disease progression in 55 (69%) and 28 (56%) pts TBP and non-TBP, respectively. The majority of pts TBP (37/67 evaluable pts) had stable or reduced target lesion tumor burden and most had sustained further reduction compared with the burden presented at the time of disease progression (Figure). There was no discernible difference in the response to TBP between PD-1 resistant vs non-resistant pts. Median OS for pts TBP was not reached; 1- and 2-yr OS (95% CI) was 94% (85, 97) and 87% (77, 93), respectively. Median TTNT was 20 (95% CI: 14, 24) mo for all pts TBP. Treatment-related adverse events (TRAEs) occurred in 50% of pts after progression vs 68% prior to progression. The most common TRAEs reported after progression were fatigue (8%) and increased lipase (6%). Treatment-related serious AEs after progression were reported in 2 (3%) pts: aspartate aminotransferase increase (n=1) and hypercalcemia (n=1). No deaths occurred in pts TBP. Conclusions: Among pts treated beyond investigator-assessed progression, most commonly due to development of new lesions, continued reductions in tumor burden were observed in a majority with further nivo treatment irrespective of prior PD-1 resistance status. Nivo continued to be well tolerated during TBP with no new safety signals. Pts who have stable performance status despite progression according to conventional criteria may derive continued clinical benefit from TBP. Future work will focus on identifying subsets of pts TBP who may benefit the most from continued nivo treatment. Study support: BMS. Disclosures Cohen: Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BioInvent: Consultancy; Bristol-Myers Squibb: Research Funding; Infinity Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees. Kuruvilla:Leukemia and Lymphoma Society Canada: Research Funding; BMS: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Princess Margaret Cancer Foundation: Research Funding; Seattle Genetics: Consultancy, Honoraria; Lundbeck: Honoraria; Gilead: Consultancy, Honoraria; Celgene: Honoraria; Amgen: Honoraria; Karyopharm: Honoraria; Roche: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy; Merck: Consultancy, Honoraria. Ansell:Celldex: Research Funding; Takeda: Research Funding; Pfizer: Research Funding; LAM Therapeutics: Research Funding; Merck & Co: Research Funding; Affimed: Research Funding; Trillium: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; Bristol-Myers Squibb: Research Funding. Younes:Abbvie: Honoraria; J&J: Research Funding; Roche: Honoraria, Research Funding; Merck: Honoraria; Curis: Research Funding; Janssen: Honoraria, Research Funding; Novartis: Research Funding; Pharmacyclics: Research Funding; Takeda: Honoraria; BMS: Honoraria, Research Funding; Seattle Genetics: Honoraria; Sanofi: Honoraria; Bayer: Honoraria; Celgene: Honoraria; Astra Zeneca: Research Funding; Incyte: Honoraria; Genentech: Research Funding. Trněný:Incyte: Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; F. Hoffman-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory board, Research Funding; Gilead: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Morphosys: Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Sandoz: Honoraria; Abbvie: Honoraria, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Advisory board. Ramchandren:Bristol-Myers Squibb: Consultancy; Merck: Research Funding; Seattle Genetics: Consultancy, Research Funding; Pharmacyclics LLC an AbbVie Company: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Collins:BMS: Consultancy, Honoraria, Research Funding; MSD: Consultancy, Honoraria; Celgene Corporation: Research Funding; Amgen: Research Funding; Takeda: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria; ADC Therapeutics: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Speakers Bureau; Celleron: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Speakers Bureau. Zinzani:Astra Zeneca: Speakers Bureau; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; MSD: Honoraria, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees; SERVIER: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celltrion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees. De Boer:EISA: Membership on an entity's Board of Directors or advisory committees; MSD: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding. Shipp:Merck: Research Funding; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Honoraria; Bayer: Research Funding. Sacchi:Bristol-Myers Squibb: Employment, Equity Ownership. Sy:Bristol-Myers Squibb: Employment. Armand:Otsuka: Research Funding; Affimed: Consultancy, Research Funding; Infinity: Consultancy; Pfizer: Consultancy; Merck: Consultancy, Research Funding; Adaptive: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Roche: Research Funding; Tensha: Research Funding.

Abstract Abstract 259 Despite recent progress, our understanding of the genomic basis of diffuse large B cell lymphoma (DLBCL) is incomplete. We have performed massively parallel whole exome sequencing with deep coverage of 57 primary tumor samples from patients with DLBCL and compared them to matched normal tissue to gain insight into the genetic defects leading to DLBCL. We define genes that are significantly enriched for somatic mutations, and thus, may be drivers of the disease. In addition to identifying genes that are well established to be functionally relevant in DLBCL, such as MyD88, CARD11, EZH2, and BCL2, we also discovered new genes that are significantly mutated that have not been described to play a role in DLBCL previously, such as MLL2, 3 and4 genes and PCLO. One of the challenges for the understanding of DLBCL biology is to determine the relative contribution of different genes with somatic mutations to the pathogenesis of the disease in an individual patient. Identification of functionally relevant mutated genes that only occur in a small number of patients based on prevalence alone may require thousands of patient samples. We therefore devise several strategies to discover genes with a high likelihood of functionally relevant mutations independent of their prevalence. Genes that do not co-occur with other mutated genes in the same patients, i.e. are mutually exclusive, are more likely to represent strong drivers, and to occur early in the development of DLBCL. We determined that TP53, BCL2, PIM1, and CD79B fall into this group. We apply pathway-focused analysis to identify mutated genes with low prevalence that are highly likely to have a functional impact. For instance, we identified G13D mutations in KRAS in two patients, and mutations in BRAF, NOTCH1, SOCS1, and PTEN in other patients that were previously described in other malignancies. These mutated genes are identified as part of significantly enriched gene sets, including the B cell receptor signaling/NFkB pathway, JAK/STAT, and antigen processing gene sets. In addition to these pathways that are important for physiological B cell activation, we find that many histone methyltransferases are enriched as a geneset in addition to MLL2. We identified a number of hotspots that are subject to somatic mutation. Our data imply that many of these hotspots may be targets of activation-induced cytidine deaminase (AID), which is usually involved in somatic hypermutation, suggesting a possible mechanism of how somatic mutation in DLBCL is mediated. In summary, our data define novel genetic defects in DLBCL by whole exome sequencing of 57 patients. Our data suggest that driver mutations may not be randomly distributed across the genome, but may occur in a directed fashion. We identified new genes not previously implicated in DLBCL, and have developed strategies to prioritize mutations that are most likely to be drivers of the disease. Disclosures: No relevant conflicts of interest to declare.

Abstract Introduction: Nivolumab (nivo) is a fully human IgG4 monoclonal antibody (mAb) targeting programmed death receptor-1 (PD-1). Nivo has demonstrated clinical activity and an acceptable safety profile in a phase 1b study (NCT01592370; CheckMate 039) in patients (pts) with relapsed/refractory hematologic malignancies. In pts diagnosed with Hodgkin lymphoma (HL), after a median 86 weeks of follow-up, 7/20 responders maintained a response for >1.5 years (Ansell S et al. Blood 2015;126:583), and after a median follow-up of 67 weeks, clinical activity (investigator-assessed objective response rate) was demonstrated in follicular lymphoma (FL; 40%), diffuse large B-cell lymphoma (DLBCL; 36%), mycosis fungoides (15%), and peripheral T-cell lymphoma (PTCL; 40%) (Lesokhin AM et al. J Clin Oncol 2016;34:2698). CheckMate 039 also included a cohort of pts who had received nivo in combination with ipilimumab (ipi), a fully human mAb targeting cytotoxic T-lymphocyte antigen 4 (CTLA-4). Combination of CTLA-4 and PD-1 blockade has shown superior efficacy compared with nivo or ipi alone in preclinical studies and solid tumor malignancies (Wolchok JD et al. N Engl J Med 2013;369:122; Larkin JM et al. N Engl J Med 2015;373:22; Antonia SJ et al. Lancet Oncol 2016;17:883). The aim of this cohort study was to evaluate the safety and efficacy of combined immune checkpoint blockade (nivo+ipi) in pts with the following hematologic malignancies: HL, B-cell non-Hodgkin lymphoma (B-NHL; FL and DLBCL), T-cell NHL (T-NHL; cutaneous T-cell lymphoma [CTCL] and PTCL]), and multiple myeloma (MM). Methods: Nivo+ipi were given at 3 mg/kg IV and 1 mg/kg IV, respectively, every 3 weeks for 4 doses, followed by nivo monotherapy (3 mg/kg) every 2 weeks for up to 2 years. Pts with any of the above histologies, relapsed or refractory disease after ≥2 prior lines of therapy, and adequate organ function were included in the study. Prior systemic therapy may have included chemotherapy and autologous hematopoietic stem cell transplantation (auto-HSCT). Prior anti-PD-1 therapy and allogeneic (allo)-HSCT were not permitted. The primary endpoint was safety. Secondary endpoints included investigator-assessed objective response rate (ORR), best overall response, duration of response (DOR), and progression-free survival (PFS). Results: In total, 65 pts were treated with nivo+ipi (31 HL, 15 B-NHL, 11 T-NHL, 7 MM, and 1 with primary mediastinal B-cell lymphoma [PMBL] who was included in the overall safety cohort only). Median (range) number of prior systemic therapies was 4 (2, 10; HL), 3, (1, 16; B-NHL), 4 (1, 11; T-NHL), and 5 (2, 20; MM). Among patients with HL, only 13% (4/31) had prior auto-HSCT. 2 pts with HL and 1 with T-NHL proceeded to allo-HSCT after stopping study therapy. Across all cohorts, median follow-up was 11.4 months. 5 pts (8%) discontinued due to a drug-related adverse event (AE). The most common drug-related AEs of any grade were fatigue (17 pts [26%]), pyrexia (15 [23%]), and diarrhea (12 [18%]). 19 pts (29%) had a drug-related AE of grade ≥3. 31 pts (48%) had a serious AE. 24 pts (37%) died: HL 2 pts, B-NHL 11, T-NHL 6, MM 4, PMBL 1. Among those pts, 22 (34%) were from disease progression (HL 2 pts, B-NHL 10, T-NHL 5, MM 4, PMBL 1); no deaths were due to an AE. Clinical outcome data are presented (Table). Conclusions: These are the first reported data of combination checkpoint blockade therapy in hematologic malignancies. Overall, the combination of nivo+ipi in these heavily pretreated patients demonstrated a safety and efficacy profile similar to that previously reported for nivo monotherapy in HL, NHL, and MM. Additional follow-up may further clarify the role of ipi in this cohort of patients. In this predominantly transplant-naïve group of patients with HL, the efficacy of nivo+ipi was similar to that seen in patients with relapsed/refractory HL treated with nivo alone. Funding: Bristol-Myers Squibb (BMS). Medical writing: S Addison, Caudex, funded by BMS Disclosures Ansell: BMS, Seattle Genetics, Merck, Celldex and Affimed: Research Funding. Gutierrez:Bayer Health Care Pharmaceuticals, Inc.: Other: Traveling and Lodging- Food and Beverage; E.R. Squibb & Sons, LLC (Bristol Myers Squibb): Consultancy, Other: Travel and Lodging; Incyte Corporation: Consultancy; Pfizer Inc: Consultancy; Merck Sharp & Dohme Corporation: Consultancy, Other: Travel and Lodging; Pharmacyclics LLC, An AbbVie Company: Other: Food and Beverage. Shipp:Cell Signaling: Honoraria; Bristol-Myers Squibb: Consultancy, Research Funding; Bayer: Research Funding; Merck, Gilead, Takeda: Other: Scientific Advisory Board. Moskowitz:Seattle Genetics: Research Funding; Seattle Genetics, Merck: Consultancy. Borello:Bristol-Myers Squibb: Research Funding, Speakers Bureau. Popa-Mckiver:Bristol-Myers Squibb: Employment, Equity Ownership. Farsaci:Bristol-Myers Squibb: Employment. Zhu:Bristol-Myers Squibb: Employment. Armand:Sequenta Inc: Research Funding; Pfizer: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Infinity Pharmaceuticals: Consultancy; Roche: Research Funding; Merck: Consultancy, Research Funding.

Abstract Classical Hodgkin lymphomas (cHLs) include infrequent malignant Hodgkin Reed-Sternberg (HRS) cells within an extensive but ineffective inflammatory/immune cell infiltrate. HRS cells exhibit frequent copy number alterations (CNAs) of 9p24.1/CD274 (PD-L1)/PDCD1LG2(PD-L2), ranging from low-level polysomy to relative copy gain and high-level amplification, all associated with increased expression of programmed death receptor-1 (PD-1) ligands on the tumor cell. PD-1 ligands engage the PD-1 receptor on T cells, inhibiting T cell activation and anti-tumor immune responses. cHL patients (pts) with the highest-level 9p24.1 alterations, PD-L1/PD-L2 amplification, have inferior progression-free survival (PFS) after standard primary chemotherapy (Roemer et al. J Clin Oncol 2016). Given the demonstrated responsiveness of cHL to PD-1 blockade, we examined the prevalence and type of 9p24.1 genetic alterations, PD-L1 expression, and association of these alterations with clinical outcome in pts receiving nivolumab (nivo; anti-PD-1) for relapsed/refractory (R/R) cHL. CheckMate205 is a multicenter, multicohort, phase 2 trial of nivo in R/R cHL. This analysis focused on 2 cohorts: pts with recurrent cHL following autologous stem cell transplantation (ASCT) and subsequent brentuximab vedotin (BV) (cohort B), and pts with R/R cHL following ASCT and BV given pre- or post-ASCT (cohort C). Pts received nivo 3 mg/kg every 2 weeks. Best overall response (BOR) and PFS were assessed by an independent radiological review committee (IRRC). In pts with available tumor biopsies, 9p24.1 genetic alterations were evaluated via fluorescence in situ hybridization (FISH) assay; probes encompassed CD274 (PD-L1, red) or PDCD1LG2 (PD-L2, green)and included a centromeric control (aqua).Dual immunohistochemical staining of PD-L1/PAX5 was performed to delineate PD-L1 expression in PAX5dim+ HRS cells and PAX5- cells in the tumor microenvironment. A modified PD-L1 H-score (range 0-300) was calculated by multiplying the percentage of PAX5+ (malignant) or PAX5- (non-malignant) cells with positive staining (0-100%) and the average intensity of positive staining (1-3+; ≥50 RS cells counted). All p-values are nominal. 96 pts had evaluable baseline tumor biopsy specimens; all 96 had detectable 9p24.1 alterations: polysomy in 10/96 (10%), copy gain in 56/96 (58%), amplification in 28/96 (29%), and presumptive rearrangement (split-apart FISH signal) in 2/96 (2%) (Figure). There was a significant association between PD-L1 protein expression (H-score) and the level of 9p24.1 alterations in HRS cells (p=0.002) (Figure). We next evaluated the association between BOR and defined 9p24.1 alterations and PD-L1 H-scores. The level of 9p24.1 CNAs was significantly associated with BOR (p=0.01); no pts with progressive disease (PD) had genomic amplification and no pts with complete response (CR) had polysomy. Similarly, there was significant association between PD-L1 H-score in HRS cells and BOR (p=0.02); all pts with PD had PD-L1 H-scores in quartiles (Q) 1/2, whereas most pts with CR had PD-L1 H-scores in Q4. We also assessed the association of PFS with 9p24.1 status and PD-L1 H-scores. The level of 9p24.1 alterations was associated with PFS; pts with 9p24.1 amplification had the most favorable PFS with nivo. HRS cell PD-L1 H-score (by quartiles) was also significantly associated with PFS (p=0.048), as pts with PD-L1 H-scores in Q1/Q2 had significantly shorter PFS than those with scores in Q3/Q4 (p=0.01). In contrast, there was no association between PD-L1 expression on non-malignant cells in the tumor microenvironment and PFS (p=0.43). In conclusion, all evaluable pts in this study had genetic alterations of 9p24.1/PD-L1/PD-L2 and copy number-dependent increased expression of PD-L1 in HRS cells. Although high-level alterations of 9p24.1 and increased PD-L1 expression were previously linked with inferior response to standard primary chemotherapy, we now associate these parameters with more favorable outcomes to targeted PD-1 blockade. These analyses also highlight the importance of quantifying and delineating PD-L1 expression in HRS cells and non-malignant cells in the tumor microenvironment in cHL biopsy evaluation. While further research is needed to guide possible use in clinical practice, these data advance understanding of 9p24.1 alterations and PD-L1 expression as prognostic biomarkers in cHL. Disclosures Engert: Takeda, BMS: Consultancy, Honoraria, Research Funding. Zinzani:Abbvie: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; MorphoSys: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Celegene: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees. Timmerman:Bristol-Myers Squibb, Kite Pharma, Valor Biopharmaceuticals, Janssen: Research Funding; Seattle Genetics, Genmab, Celgene: Consultancy, Honoraria. Ansell:BMS, Seattle Genetics, Merck, Celldex and Affimed: Research Funding. Armand:Bristol-Myers Squibb: Consultancy, Research Funding; Pfizer: Research Funding; Sequenta Inc: Research Funding; Roche: Research Funding; Merck: Consultancy, Research Funding; Infinity Pharmaceuticals: Consultancy. Kuruvilla:BMS: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Amgen: Honoraria; Celgene: Consultancy, Honoraria; Merck: Honoraria; Roche Canada: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Lundbeck: Honoraria. Cohen:Bristol-Myers Squibb: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium/Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Infinity: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Collins:Takeda: Consultancy, Honoraria, Speakers Bureau. Trneny:Roche, Celgene, Takeda, Janssen, Gilead, Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche, Celgene: Research Funding. Farsaci:Bristol-Myers Squibb: Employment. Kato:Bristol-Myers Squibb: Employment. Sumbul:Bristol-Myers Squibb: Employment. Rodig:Bristol-Myers Squibb: Honoraria, Research Funding; Perkin Elmer: Membership on an entity's Board of Directors or advisory committees. Shipp:Bayer: Research Funding; Merck, Gilead, Takeda: Other: Scientific Advisory Board; Cell Signaling: Honoraria; Bristol-Myers Squibb: Consultancy, Research Funding.

Abstract Introduction: The programmed death-1 (PD-1) immune checkpoint pathway regulates T-cell-mediated antitumor immune responses in solid tumors and hematologic malignancies. Nivolumab (Bristol-Myers Squibb, Ono Pharmaceutical) is a fully human IgG4 PD-1-blocking monoclonal antibody with demonstrated efficacy in a range of tumors. Results from an independent cohort of 23 pts with R/R cHL in a phase 1 study (CA209-039) showed that nivolumab was well tolerated and yielded an overall response rate (ORR) of 87% (Ansell et al, N Engl J Med, 2015). This raises important questions including the necessary duration of treatment, the relevance of the depth of response (complete response [CR] vs partial response [PR]), the duration of response, and the feasibility of retreatment. Here, we present the clinical course and post-treatment outcomes from extended follow-up of these pts to shed some light on these questions. Methods: Pts with R/R cHL received nivolumab 3 mg/kg at weeks (wks) 1 and 4, and then every 2 wks for up to 2 years (yrs). Therapy was stopped earlier in pts with intolerance to treatment or progressive disease (PD) without evidence of clinical benefit. Pts who discontinued treatment due to toxicity were followed for up to 120 days after discontinuation; other pts were followed for 1 yr after discontinuation. Responding pts discontinued after confirmed CR or 16 wks after unconfirmed CR, or continued treatment for up to 2 yrs if they had PR or stable disease (SD). Pts who discontinued treatment with ongoing CR, PR, or SD could be retreated for confirmed PD occurring <1 yr after nivolumab discontinuation. Responses were evaluated using the Revised Response Criteria for Malignant Lymphoma (Cheson et al, J Clin Oncol, 2007). The primary endpoint was safety, and the key secondary endpoint was antitumor activity. Results: A total of 23 pts with R/R cHL were treated. The median follow-up observation time is now 86 wks (range: 32-107 wks). Of 20 responders (14 PR, 6 CR), 10 have had durable responses per protocol assessment; their treatment durations and response characteristics are shown in Table 1. Responses were maintained in 2 pts (#5 and #6) after discontinuing nivolumab for >40 wks and in 1 pt (#7) after stopping due to toxicity. Eight pts with durable responses have received nivolumab for >1 yr, including 7 pts who have been in response for >1.5 yrs. One pt (#2) with an initial CR experienced a relapse 43 wks after treatment was discontinued, and achieved a second response (CR) after retreatment with nivolumab. Of the 10 remaining responders, 4 eventually progressed (time to progression [TTP] range: 21.4-92 wks), 1 discontinued treatment due to toxicity with no PD within the 120-day follow-up period, and 5 discontinued nivolumab to undergo stem cell transplant (SCT; 4 allogeneic, 1 autologous) after achieving remission. Time to CR for all responders ranged from 3-88 wks after starting nivolumab, including 2 pts with initial PRs that converted to CRs with continued treatment. All 5 pts who proceeded to SCT had responded to nivolumab within 16 wks of starting treatment (4 PR, 1 CR). Three pts had a best overall response of SD (1 discontinued due to toxicity without documented PD within the 120-day follow-up period; 2 subsequently discontinued for PD [TTP: 15 and 15.3 wks, respectively]). Overall, 3 pts discontinued nivolumab due to adverse events (AEs; Grade 2 peripheral neuropathy, Grade 3 myelodysplastic syndrome, Grade 3 pancreatitis). Grade 1 or 2 immune-related AEs (IR-AEs) occurred in 4 of 10 pts and resolved without treatment in 2 pts. The incidence of IR-AEs did not increase with time on treatment. Conclusions: In pts with R/R cHL, nivolumab was well tolerated and produced a high ORR. Responses occurred within 16 wks of nivolumab initiation in 15 of 20 pts. Early responses to nivolumab allowed 5 pts to proceed to SCT and lasted ≥1 yr in 7 of 10 pts who did not pursue SCT. One pt achieved CR again after retreatment with nivolumab when relapse occurred within 1 yr of discontinuing treatment following an initial CR. Table 1. Treatment and Response Parameters for Pts with Durable Ongoing Responses Pt # Best Response Duration of Response, wks Time to First Response, wks Time on Treatment, wks 1 PR 90.7 3.6 96+ 2 CR 82.1 7.1 91+ 3 PR 73.1 7.6 82.4+ 4 PR 71.4 14.9 88+ 5 CR 71.1 3.1 24.9 6 CR 65.1 7.1 22.9 7 PR 55.9 15.3 70.9 8 CR 48.3 39 87 9 CR 45.3 55 82.9 10 PR 41.7 38.7 82.1+ +Still on treatment Disclosures Ansell: Bristol-Myers Squibb: Research Funding; Celldex: Research Funding. Armand:BMS: Research Funding; Infinity: Consultancy, Research Funding; Sequenta, Inc.: Research Funding; Merck: Consultancy, Research Funding. Timmerman:Valor Biotherapeutics: Research Funding; Janssen: Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding. Shipp:BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy; Merck: Membership on an entity's Board of Directors or advisory committees. Bradley Garelik:Bristol-Myers Squibb: Employment. Zhu:Bristol-Myers Squibb: Employment. Lesokhin:Efranat: Consultancy; Genentech: Research Funding; Aduro: Consultancy; Janssen: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding.

Abstract Abstract 1534 + equal contributions Diffuse large B-cell lymphoma (DLBCL) is a clinically and biologically heterogeneous disease with a high proliferation rate and infrequent somatic mutations of TP53 and genes encoding cell cycle pathway components. Despite recent advances in the molecular understanding of DLBCL pathogenesis, clinical models such as the International Prognostic Index (IPI) are still used to identify high-risk patients. By integrating high-resolution high-density SNP array data with transcriptional profiles and performing pathway analysis in 180 primary DLBCLs, we identified a comprehensive set of copy number alterations (CNAs) that decreased p53 activity and perturbed cell cycle regulation. Primary DLBCLs with single copy loss of 17p13.1 (TP53/RPL26/KDM6B) often had CNAs of an additional p53 modifier – 9p21.3 (CDKN2A/ARF), 19q13.42 (BCL2L12), 12q15 (MDM2) or 1q23.3 (MDM4/RFWD2). CNAs of the respective p53 modifiers, CDKN2A (ARF, 9p21.3), MDM2 (12q15) and MDM4/RFWD2 (1q23.3), occurred in largely separate groups of tumors. DLBCLs with CNAs of p53 pathway members frequently exhibited concurrent alterations of additional cell cycle components such as CCND3 (6p21.32), CDK6 (7q22.1), CDK2/CDK4 (12q15) and/or RB1 (13q14.2) or RBL2 (16q12.2). When the primary DLBCLs were clustered in the space of CNAs that perturb p53 pathway and cell cycle components, 66% of tumors had multiple alterations (“complex” pattern) whereas the remaining 34% of tumors lacked these lesions (“clean” signature). Tumors with “complex” alterations of p53 pathway and cell cycle components also had more total CNAs and more frequent TP53 mutations, highlighting the association between p53 deficiency, cell cycle deregulation and increased genomic instability in DLBCL. The patterns of “complex” vs. “clean” CNAs of p53 pathway and cell cycle components and the association between the “complex” signature and total CNAs were confirmed in an independent series of primary DLBCLs. To further characterize DLBCLs with “complex” vs. “clean” CNA patterns, we performed gene set enrichment analyses with publicly available series of p53 target genes and a RB-deficiency gene set which included multiple E2F targets. The p53 target transcripts were significantly less abundant in “complex” DLBCLs, directly linking their genetic signature of p53 deficiency with decreased p53 activity. Furthermore, the RB-deficiency gene set was significantly enriched in “complex” DLBCLs suggesting that these tumors had increased E2F-mediated cell cycle progression. Consistent with these observations, DLBCLs with “complex” CNA patterns also had significantly higher proliferation indices as determined by Ki67 immunostaining. We next assessed the prognostic significance of the “complex” CNA pattern in the subset of patients who were treated with R-CHOP (rituxan, cyclophosphamide, adriamycin, oncovin, prednisone) and had long-term follow-up. R-CHOP treated patients with “complex” CNA patterns had a 5-year overall survival of only 62%; in contrast, those with “clean” CNA signatures had an 100% overall survival (p =.001). The association between CN complexity and outcome was independent of transcriptionally defined categories and additive to the clinical IPI risk model. Taken together, these data provide a structural basis for deregulated cell cycle, increased cellular proliferation and unfavorable outcome in DLBCL and suggest targeted treatment strategies. Disclosures: No relevant conflicts of interest to declare.

Abstract Introduction Programmed cell death-1 (PD-1) is an immune checkpoint receptor that inhibits T cell activation upon interaction with its ligands PD-L1 or PD-L2. Increased PD-L1 expression has been reported in various lymphoid malignancies, and may allow these tumors to circumvent host anti-tumor immunity. Nivolumab, a fully human IgG4 monoclonal PD-1 receptor blocking antibody, potentiates T cell activity, and has clinical efficacy in various solid tumors. We hypothesized that nivolumab might also have clinically important anti-tumor activity in patients with lymphoid malignancies. Methods This open-label study enrolled patients with relapsed or refractory lymphoid malignancies including B-cell non-Hodgkin lymphoma (B-NHL), T-cell NHL (T-NHL), multiple myeloma (MM), and classical Hodgkin lymphoma (cHL). Patients were treated using a dose escalation design (1 mg/kg and 3 mg/kg) of nivolumab administered every two weeks for up to two years. Responses were assessed using standard criteria. The primary endpoint was safety; key secondary endpoints included anti-tumor activity and expression of immunomodulatory proteins in tumor biopsies. The preliminary results for the cHL patients will be reported separately. Results Twenty-nine patients with B-NHL, 2 patients with primary mediastinal B-cell lymphoma; 23 patients with T-NHL; 27 patients with MM; and 1 with chronic myelogenous leukemia were enrolled. Patients were heavily pretreated with 67%, 69%, and 78% of MM, B-NHL, and T-NHL patients, respectively, having received ≥ 3 prior treatment regimens. Previous autologous stem cell transplantation was reported for 56% of MM, 14% of B-NHL, and 9% of T-NHL patients. Prior brentuximab treatment was reported in 7% of B-NHL and 26% of T-NHL patients. When this pre-planned interim analysis was performed, six patients had been treated at the 1 mg/kg dose with 2 dose-limiting toxicities (DLTs) occurring in the same patient: grade 3 pneumonia and pneumonitis. At the 3mg/kg dose, seven patients were treated with one patient experiencing two DLTs: grade 3 eosinophilia and diplopia. Additional patients were enrolled in the cohort expansion at 3 mg/kg. Drug-related adverse events (AEs) occurred in 72%, 65%, and 52% of B-NHL, T-NHL, and MM patients, respectively. Serious AEs in B-NHL patients were pneumonitis (7%), acute respiratory distress syndrome, dermatitis, diplopia, enteritis, eosinophilia, mucosal inflammation, pyrexia and vomiting, each occurring in 3%. In the T-NHL patients, serious AEs were pneumonitis, rash, and sepsis, each occurring in 4%, and in MM patients, serious AEs were pneumonitis, myositis, and increased creatine phosphokinase, each occurring in 4%. The incidence and severity of drug related AEs were similar across tumor types. Efficacy results are shown for each tumor type in the table. The overall response rate (ORR) and complete response (CR) rate in patients with B-NHL were 28% and 7%, respectively, including an ORR of 36% in patients with diffuse large B-cell lymphoma (DLBCL), and 40% in patients with follicular lymphoma (FL). In patients with T-NHL, ORR was 17% (no CR), including an ORR of 40% in the 5 patients with peripheral T cell lymphoma. No objective responses were observed in MM. Analysis of PD-L1 expression and correlation to clinical outcome is being performed and will be presented. Conclusions Nivolumab administered at a dose of 3 mg/kg every two weeks was tolerable and the safety profile was similar to that of the agent in solid tumors. Objective responses were observed in DLBCL, FL, mycosis fungoides (MF), and peripheral T cell lymphoma (PTCL). Durable stable disease was observed in relapsed MM. The results of this phase 1 study have led to phase 2 studies in DLBCL and FL, which are ongoing. Table: Efficacy Results Tumor N Complete Response n (%) Partial Response n (%) Stable Disease (SD) n (%) Progression Free Survival Rate at 24 Weeks (%) Diffuse Large B Cell Lymphoma (DLBCL) 11 1 (9) 3 (27) 3 (27) (24) Follicular Lymphoma (FL) 10 1 (10) 3 (30) 6 (60) (68) Other B Cell Lymphoma 8 0 0 5 (63) (38) Primary Mediastinal B Cell Lymphoma 2 0 0 2 (100) (0) Mycosis Fungoides (MF) 13 0 2 (15) 9 (69) (39) Peripheral T Cell Lymphoma (PTCL) 5 0 2 (40) 0 (30) Other T Cell Lymphoma 5 0 0 1 (20) (0) Multiple Myeloma (MM) 27 0 0 18 (67) (15) Chronic Myelogenous Leukemia 1 0 0 1 (100) (100) Disclosures Lesokhin: Bristol-Myers Squibb: Consultancy, Research Funding. Ansell:Bristol-Myers Sqibb: Research Funding. Armand:Merck: Consultancy. Cohen:Celgene: Member, Independent Response Adjudication Committee Other; Onyx: Advisory Board, Advisory Board Other; Bristol-Myers Squibb: Advisory Board, Advisory Board Other, Research Funding; Janssen: Advisory Board, Advisory Board Other. Lebovic:Genentech, Allos, Celgene, Onyx, Millennium: Consultancy, Research Funding, Speakers Bureau. Rodig:Bristol-Myers Squibb: Research Funding. Zhu:Bristol-Myers Squibb: Employment. Grosso:Bristol-Myers Squibb: Employment, Equity Ownership. Kim:Bristol-Myers Squibb: Employment. Shipp:Merck: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Sanofi: Research Funding; Janssen R&D: Membership on an entity's Board of Directors or advisory committees. Borrello:Bristol-Myers Squibb: Research Funding. Timmerman:Bristol-Myers Squibb: Research Funding.