Citations

Introduction and Purpose IRAK4 kinase activity is essential for signaling downstream of toll-like receptors (TLR) and the interleukin-1 receptor (IL-1R) family in a variety of myeloid and lymphoid cell types. Dysregulated signaling in these pathways is frequently observed in NHL, particularly in ABC-subtype of Diffuse Large B-Cell Lymphoma (DLBCL) and Waldenström macroglobulinemia (WM). A phase 1 trial in patients with NHL is being conducted to determine safety, pharmacokinetics, and preliminary efficacy of CA-4948 as monotherapy. Patients and Methods At the 18-Jul-2019 data cut-off date, 22 patients have been treated with single-agent CA-4948. Five dose-escalation cohorts from 50 mg QD to 200 mg BID have been tested and cleared; a cohort of patients treated at 400 mg BID dose is currently being evaluated. Patients were diagnosed with relapsed or refractory NHL, including DLBCL (n=13), FL (n=5), HGBL with MYC and BCL2 and/or BCL6 rearrangement (n=1), WM (n=1), LPL (n=1) and MCL (n=1), had a performance status of 0 or 1 (ECOG) at baseline, and were treated in 21-day cycles until progression of disease or unacceptable toxicity, lost to follow-up or death. 5 patients had prior autologous bone marrow transplants. Results CA-4948 has been generally well tolerated. Grade 3/4 treatment-related adverse events included amylase/lipase increased, diarrhea, neutrophil count decreased, rash, rhabdomyolysis. Pharmacokinetics has shown favorable characteristics with dose-proportional increases in exposure. Five patients have been on treatment through the end of Cycle 4, including one patient in Cycle 10 on study for over 7 months. Five patients experienced overall tumor burden decreases of ≥20% from baseline, including at least 2 of 4 patients treated at 200 mg BID. Downstream pharmacodynamic markers of IRAK4 activity are being evaluated. Molecular characteristics including cell-of-origin will be presented. Conclusion CA-4948 demonstrates preliminary clinical activity. Enrollment is on-going and the MTD has not been reached. These encouraging results warrant further clinical testing in patients with advanced hematological malignancies. Clinical trial: NCT03328078. Disclosures Younes: Roche: Consultancy, Honoraria, Research Funding; Takeda: Honoraria; Genentech: Research Funding; Pharmacyclics: Research Funding; Janssen: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Curis: Honoraria, Research Funding; Biopath: Consultancy; Xynomics: Consultancy; Celgene: Consultancy, Honoraria; HCM: Consultancy; BMS: Research Funding; AstraZeneca: Research Funding; Syndax: Research Funding; Abbvie: Honoraria; Epizyme: Consultancy, Honoraria. Nowakowski:Selvita: Membership on an entity's Board of Directors or advisory committees; NanoString: Research Funding; MorphoSys: Consultancy, Research Funding; Genentech, Inc.: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Curis: Research Funding; Bayer: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Tun:Mundi-pharma: Research Funding; DTRM Biopharma: Research Funding; BMS: Research Funding; Celgene: Research Funding; Curis: Research Funding; TG Therapeutics: Research Funding. Lunning:Janssen Scientific Affairs, LLC: Consultancy, Research Funding; Curis: Research Funding; Juno Therapeutics: Consultancy, Research Funding; MiRagen: Research Funding; TG Therapeutics: Consultancy, Research Funding; Spectrum: Consultancy; VANIUM: Consultancy; Verastem: Consultancy; DAVA: Consultancy; Bayer: Consultancy; AbbVie: Consultancy; Kite: Consultancy; Gilead Sciences, Inc.: Consultancy; Seattle Genetics: Consultancy; Portola: Consultancy; OncLive: Consultancy; Novartis: Consultancy. Isufi:Celgene: Consultancy; Novartis: Consultancy; Astra Zeneca: Consultancy. Martell:Curis, Inc.: Employment. Patel:AstraZeneca: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Genentech: Consultancy, Speakers Bureau; Pharmacyclics/Janssen: Consultancy, Speakers Bureau; Sunesis: Consultancy.

Introduction Waldenstrom macroglobulinemia (WM) is a rare, incurable, indolent non-Hodgkin lymphoma that is preceded by an IgM monoclonal gammopathy of undetermined significance (IgM MGUS). In recent years, better understanding of the pathobiology of WM and IgM MGUS has strengthened the hypothesis that they may represent different stages of the same disease. Studying the relationship between these two conditions is the essential first step to understanding the mechanisms driving the malignant transformation from IgM MGUS to WM. Recently long non-coding RNAs (lncRNAs) have garnered significant recognition for their roles in the regulation of gene expression and cellular function. lncRNA can regulate gene expression of neighboring protein-coding genes through multiple mechanisms such as by recruiting chromatin modifiers and increasing accessibility of genes to transcription proteins, or by directly binding to enhancers or promoters. Here we present the first analysis of the lncRNA expression profile in patients with WM compared to IgM MGUS. Methods Twenty-one patients with untreated WM (n=14) and IgM MGUS (n=7) seen at Mayo Clinic were included in this analysis. Malignant cells were isolated from bone marrow samples using CD19 and CD38 positive selection. Total RNA was extracted and sequencing was performed using the Illumina HiSeq4000 NGS platform. Differentially expressed lncRNAs in WM compared to IgM MGUS were defined as log2 fold change (FC) > 1.0 (upregulated) or < -1.0 (downregulated) and a false discovery rate (FDR) < 0.05. The nearest gene to each lncRNA was also identified and their gene expression was detected. Using the Ingenuity Pathway Analysis software and taking into account the transcriptional expression and known function of these genes, a correlation between cell function and disease analysis was performed. Results A total of 119 lncRNAs were differently expressed between WM and IgM MGUS (17 transcripts were upregulated in WM, while 102 were downregulated in WM). Sixteen unique genes were identified as the nearest gene to 17 upregulated lncRNAs, while 18 genes were identified as the nearest genes to the top 18 downregulated lncRNAs in WM compared to IgM MGUS. Several of the upregulated lncRNA in WM were in proximity to known oncogenes. The well-known oncogenic lncRNA PVT1 was found to be upregulated in WM compared to IgM MGUS (log2 FC 1.35, FRD 0.04). PVT1 is overexpressed in several malignancies and associated with inhibition of apoptosis and increased cell proliferation. PVT1 is in close proximity to MYC and co-expression of PVT1-MYC has been described in multiple cancers. PVT1 also potentiate MYC amplification by increasing MYC protein stability, therefore promoting malignant cell growth. The lncRNA TCB1D27, also upregulated in WM compared to IgM MGUS, is located in close proximity to the oncogene TNFRSF13B (TACI), which was found to be overexpressed in WM patients (log2 FC 1.61, FDR <0.001). TACI is a receptor for BLyS/BAFF, which modulates the development of normal B-cells and plays a role in various B-cell malignancies. In fact, BLyS/BAFF level is known to be increased in WM and to promote survival and proliferation of WM B cells. The upregulated lncRNA RP11-25K21.1 in WM is located in close proximity to the oncogene FCGR2B (CD32B), which was also upregulated in WM compared to IgM MGUS (log2 FC 1.59, FDR 0.001). Overexpression of CD32B was previously shown to be associated with inferior outcomes in DLBCL and FL patients, presumably secondary to an increased internalization and clearance of rituximab due to increased CD32B expression on malignant cells. Several other upregulated lncRNAs in WM compared to IgM MGUS are also in proximity of other oncogenes such as PCED1B, POLD3, CLLU1, and SMAD7. Finally, we considered the expression of the nearest genes and their reported cell function and association with diseases. Several genes that are known to have a role in the cell proliferation and/or neoplasm development were noted to be upregulated in WM (figure 1). Conclusion We present the first report of lncRNAs expression in WM and IgM MGUS in addition to a concurrent analysis of the gene expression of the nearest protein-coding genes. Several known oncogenes are in proximity of overexpressed lncRNAs in WM compared to IgM MGUS that could indicate potential implications in the pathobiology of these diseases and the mechanism driving the malignant transformation to WM. Disclosures Paludo: Celgene: Research Funding; Celgene: Research Funding; Verily Life Sciences: Research Funding; Verily Life Sciences: Research Funding. Dasari:The Binding Site: Patents & Royalties: US Patent Rights on Mass Spectroscopy Licensing agreement with The Binding Site, Research Funding. Kapoor:Celgene: Honoraria; Cellectar: Consultancy; Janssen: Research Funding; Sanofi: Consultancy, Research Funding; Amgen: Research Funding; Takeda: Honoraria, Research Funding; Glaxo Smith Kline: Research Funding. Ailawadhi:Amgen: Consultancy, Research Funding; Pharmacyclics: Research Funding; Takeda: Consultancy; Janssen: Consultancy, Research Funding; Cellectar: Research Funding; Celgene: Consultancy. Gertz:Amyloidosis Foundation: Research Funding; i3Health: Other: Development of educational programs and materials; Medscape: Consultancy, Speakers Bureau; Ionis/Akcea: Consultancy; Celgene: Consultancy; Appellis: Consultancy; Amgen: Consultancy; Teva: Speakers Bureau; Alnylam: Consultancy; Prothena Biosciences Inc: Consultancy; Janssen: Consultancy; Spectrum: Consultancy, Research Funding; Annexon: Consultancy; Physicians Education Resource: Consultancy; Abbvie: Other: personal fees for Data Safety Monitoring board; Research to Practice: Consultancy; Johnson and Johnson: Speakers Bureau; DAVA oncology: Speakers Bureau; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Proclara: Membership on an entity's Board of Directors or advisory committees; Springer Publishing: Patents & Royalties; International Waldenstrom Foundation: Research Funding. Novak:Celgene Coorperation: Research Funding. Ansell:Affimed: Research Funding; Regeneron: Research Funding; Mayo Clinic Rochester: Employment; Seattle Genetics: Research Funding; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Affimed: Research Funding; LAM Therapeutics: Research Funding; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding; Affimed: Research Funding; Affimed: Research Funding; Mayo Clinic Rochester: Employment; Bristol-Myers Squibb: Research Funding; Mayo Clinic Rochester: Employment; Seattle Genetics: Research Funding; Trillium: Research Funding; Mayo Clinic Rochester: Employment; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Trillium: Research Funding; Regeneron: Research Funding; Seattle Genetics: Research Funding; Mayo Clinic Rochester: Employment; Trillium: Research Funding; Trillium: Research Funding; Mayo Clinic Rochester: Employment; Regeneron: Research Funding; Regeneron: Research Funding; LAM Therapeutics: Research Funding; Mayo Clinic Rochester: Employment; Seattle Genetics: Research Funding; LAM Therapeutics: Research Funding; Seattle Genetics: Research Funding; Mayo Clinic Rochester: Employment; LAM Therapeutics: Research Funding; LAM Therapeutics: Research Funding; Trillium: Research Funding; Affimed: Research Funding; Trillium: Research Funding; Regeneron: Research Funding; Affimed: Research Funding; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; LAM Therapeutics: Research Funding; Trillium: Research Funding; LAM Therapeutics: Research Funding; Regeneron: Research Funding; LAM Therapeutics: Research Funding; Trillium: Research Funding; Mayo Clinic Rochester: Employment; Regeneron: Research Funding; Bristol-Myers Squibb: Research Funding; Affimed: Research Funding; Seattle Genetics: Research Funding; Affimed: Research Funding; Regeneron: Research Funding; Seattle Genetics: Research Funding; Bristol-Myers Squibb: Research Funding; LAM Therapeutics: Research Funding; Regeneron: Research Funding; Seattle Genetics: Research Funding; Trillium: Research Funding.

Abstract Introduction: Primary central nervous system lymphoma (PCNSL) is a rare intracranial lymphoma that accounts for less than 1% of all non-Hodgkins lymphomas and 3% of all brain tumors. Histopathologically, approximately 90% of PCNSL cases are categorized as a diffuse large B-Cell lymphoma (DLBCL). DLBCL malignancies are subdivided by Cell of Origin (COO), with the vast majority of PCNSL categorized as non-germinal center B cell (non-GCB) by immunohistochemistry. Gene expression profiling (GEP), however, has shown that immunohistochemically defined non-GCB resolves into two distinct subtypes, namely activated B-cell (ABC) and unclassified (UNC) subtypes. Using the Lymph2Cx molecular COO subtyping assay, we have found that 91% of PCNSL are ABC (unpublished data). Unlike systemic-DLBCL, PCNSL is largely confined to and rarely metastasizes outside of the immune privileged central nervous system. Despite this, PCNSL is one of the most aggressive forms of DLBCL. Given the immune privileged milieu in which PCNSL arises, we hypothesized that this milieu elicits a transcriptional profile that contributes to the enhanced aggressive nature of PCNSL compared to systemic-DLBCL. To investigate this hypothesis, this study assessed the gene expression differences between ABC-PCNSL and ABC-systemic-DLBCL, in order to identify novel players in the pathogenesis of ABC-PCNSL. Methods: A total of 35 HIV negative samples, with proven ABC-subtype COO as per the GEP Lymph2Cx assay, were employed; including 10 ABC systemic-DLBCL and 25 primary ABC PCNSL cases with no concurrent or prior history of systemic DLBCL. Samples were reviewed by a hematopathologist to confirm diagnoses and determine tumor content. Samples with <60% tumor content were macro-dissected before nucleic acid extraction, which was performed using the Qiagen AllPrep DNA/RNA FFPE Kit. Extracted DNA and RNA were quantified using the Qubit HS-kit and NanoDrop respectively. Digital gene expression technology was used to perform the PanCancer Pathways panel (NanoString, Seattle, WA). Differential gene expression analysis was performed using the NanoString specific statistical method NanoStringDiff. Identified gene sets were analyzed using the online Gene Set Enrichment Analysis (GSEA) Molecular Signatures Database (MSigDB). Results: Of the 739 cancer related genes targeted by the PanCancer panel, 256 were found to be significantly differentially expressed in the ABC-PCNSL cohort compared to the ABC-DLBCL cohort (p<0.05). Fifty six genes were upregulated and 200 were downregulated. With a 4.9 fold change, the most significantly overexpressed gene was FGF1 (p=4.7E-11). FGF1 encodes a primary ligand for the fibroblast growth factor receptors (FGFR) -1, -2, -3 and -4; of which, FGFR2 (p=1.0E-7) and FGFR3 (p=0.003) were also significantly overexpressed. Moreover, MSigDB identified the FGF signaling pathway as enriched in the upregulated gene set (5 genes, p=7.4E-9, FDR=6.6E-7). FGFRs are a family of receptors that activate known mitogenic signaling pathways including MAPK signaling, which MSigDB identified as the most enriched pathway in the upregulated gene set (14 genes, p=1.65E-19, FDR=2.2E-16). MSigDB analysis of the 200 down regulated genes revealed that 5 of the top 20 enriched signaling pathways were immune related and included Signaling by interleukins (26 genes, p=2.9E-38, FDR=3.2E-36), Immune cytokine signaling (31 genes, p=1.1 E-34, FDR=1.1E-32), chemokine signaling (28 genes, p=1.5E-34, FDR=1.4E-32), T-cell receptor signaling (24 genes, p=2.4E-34, FDR=1.9E-32) and Toll-like receptor signaling (23 genes, p=4.1E-33, FDR=3.0E-31). Conclusions: We show, for the first time, that ABC-PCNSL and ABC-systemic-DLBCL possess significantly different transcriptional profiles despite identical, molecularly determined, COO status. A principle difference between these DLBCL malignancies is their anatomical location related immune privilege status which is reflected as reduced immune related signaling in the CNS-DLBCL cohort and may have important mitogenic signaling implications. Indeed, the results suggest that the enhanced aggressive nature of PCNSL compared to systemic-DLBCL is mediated, at least in part, by enhanced FGF signaling; a pathway with known roles in cell survival and proliferation. Disclosures Rimsza: NanoString: Other: Inventor on the patent for the Lymph2Cx assay.

Abstract Background: Synthetic lethality (SL) is characterized by the chemical inhibition of multiple aberrant genes to differentially kill malignant cells. We investigated small-molecule combinations for SL through in vitro and in vivo screening and optimization studies (as in the granted patents in USA and China) and demonstrated the synergistic potential of best-in-class combinations of targeted agents, drug repositioning, immune modulation and low-dose combinations. We hypothesize that BTK and mTOR inhibition coupled with an IMID will target multiple key signaling pathways, improve differential apoptosis and target acquired drug resistance. DTRM-555, an optimized mechanism-based combination, consists of the clinically differentiated BTK inhibitor DTRMWXHS-12 (or DTRM-12), everolimus (EV) and pomalidomide (POM). In xenograft tumor models, DTRM-555 administered orally has demonstrated superior efficacy over monotherapy at very low dose combinations of the three agents (1/18 of DTRM-12, 1/6 of EV, and 1/6 of POM). DTRM-12 monotherapy has been safe and well tolerated in simultaneous phase Ia trials (US and China) with preliminary efficacy across 50 mg through 400 mg once daily (QD). Here we report the US clinical results of the oral combination therapies DTRM-505 (DTRM-12 plus EV) and DTRM-555 (DTRM-12 plus EV plus POM) for the first time (NCT02900716). Methods: The safety and anti-tumor activity of the oral doublet therapy DTRM-505 and the oral triplet therapy DTRM-555 are evaluated using a "3+3" study design. Enrollment was conducted concurrently with a phase Ia study of DTRM-12 monotherapy; with DTRM-505 opened for accrual when monotherapy DTRM-12 cleared the 200-mg dose level. Eligible patients are at least 18 years old, having ECOG performance status less than 2 with relapsed/refractory chronic lymphocytic leukemia (CLL), diffuse large B cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL) or classical Hodgkin lymphoma (cHL). Study treatment is administered daily for 21 consecutive days over a 28-day cycle. The dose-limiting toxicity (DLT) period was defined during the first cycle of therapy, and treatment was continued until disease progression or unacceptable toxicity. Patients underwent tumor evaluations every 2 months and response was recorded using revised response criteria (IWCLL and Cheson 2014). Results: Between 9/2016 and 7/2018, 19 patients have been treated with DTRM-12 monotherapy in the USA (6 pts, 50-300 mg) and China (13 pts, 50-400 mg). Patients have tolerated up to 23+ cycles of DTRM-12 monotherapy. Seven patients, including DLBCL, CLL, MCL, FL and cHL, have been treated with oral doublet therapy DTRM-505 for 2 to 12 cycles. Three patients (2 DLBCL, 1 FL) have been treated with oral triplet therapy DTRM-555, including one patient transitioned from the doublet DTRM-505 under an exploratory arm. No patient has discontinued due to an adverse event (AE) and no DLT has occurred. Recurring AEs are mostly grade 1 or 2 and responses have been seen with DTRM-505 and DTRM-555 across diverse lymphoma histologies (See Tables). All patients evaluable for response demonstrated partial response to DTRM-505 and DTRM-555, with 2/7 (doublet) and 3/3 (triplet) patients remaining on therapy. Conclusion: The maximum tolerated dose has not been reached for DTRM-12 monotherapy and for the current fixed dose doublet and triplet combinations. Toxicities have been mild and repeated cycles of study treatment have been well tolerated without delays of subsequent treatment cycles. Enrollment continues for refractory lymphoma patients to demonstrate the safety and efficacy for the first-in-class oral triplet therapy DTRM-555. Disclosures Huntington: Janssen: Consultancy; Bayer: Consultancy; Celgene: Consultancy. Schuster:Merck: Consultancy, Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; OncLive: Honoraria; Dava Oncology: Consultancy, Honoraria; Physician's Education Source, LLC: Honoraria; Nordic Nanovector: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis Pharmaceuticals Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees. He:Zhejiang DTRM Biopharma Co. Ltd.: Other: Founder and CEO; Zhejiang DTRM Biopharma LLC: Other: Founder and CEO. Shen:Zhejiang DTRM Biopharma LLC: Other: Clinical Operations Director. Kennard:AbbVie, Gilead, Verastem: Consultancy. Dwivedy Nasta:Incyte: Research Funding; Takeda/Millenium: Research Funding; Debiopharm: Research Funding; Pharmacyclics: Research Funding; Rafael/WF: Research Funding; Aileron: Research Funding; Roche: Research Funding; Merck: Other: DSMC; Celgene: Membership on an entity's Board of Directors or advisory committees. Landsburg:Takeda: Consultancy; Curis: Consultancy, Research Funding. Porter:Novartis: Other: Advisory board, Patents & Royalties, Research Funding; Genentech: Other: Spouse employment; Kite Pharma: Other: Advisory board. Svoboda:Bristol-Myers Squibb: Consultancy, Research Funding; TG Therapeutics: Research Funding; Kyowa: Consultancy; Regeneron: Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; KITE: Consultancy. Song:Peking University Cancer Hospital (Beijing Cancer Hospital): Employment. Zhu:Beijing Cancer Hospital: Employment. Brander:Pharmacyclics, an AbbVie Company: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; TG Therapeutics: Consultancy, Honoraria, Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; Novartis: Consultancy, Other: DSMB; Genentech: Consultancy, Honoraria, Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; Teva: Consultancy, Honoraria; Acerta: Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; DTRM: Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; BeiGene: Other: Institutional research funding for non investigator initiated clinical trial, Research Funding. Ding:Merck: Research Funding. Mato:Pharmacyclics, an AbbVie Company: Consultancy, Research Funding; AstraZeneca: Consultancy; Regeneron: Research Funding; Celgene: Consultancy; Acerta: Research Funding; TG Therapeutics: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Portola: Research Funding; Johnson & Johnson: Consultancy; Prime Oncology: Honoraria; Medscape: Honoraria.

Abstract Objectives: Primary central nervous system lymphoma (PCNSL) is a rare aggressive B-cell lymphoma, particularly in HIV-negative individuals, that represents a clinical challenge due to its location and lack of comprehensive molecular and biologic description. Histopathologic features are that of diffuse large B-cell lymphoma with expression of pan-B-cell markers as well as cell of origin (COO) germinal center B cell (GCB) and post-germinal center B cell (non-GCB) markers. Previous studies using immunohistochemistry (IHC) suggest that the majority of PCNSL cases are non-GCB. However, gene expression profiling has revealed non-GCB to be comprised of two distinct subtypes, namely activated B-cell (ABC) and unclassified (UNC) subtypes that are indistinguishable by IHC. To date COO testing using the highly accurate Lymph2Cx gene expression profiling assay has not been reported in PCNSL. Methods: IRB approval was obtained and HIV negative patients diagnosed with PCNSL, who had given informed consent and for whom archived tumor tissue was available for testing were identified. COO testing was performed using the Lymph2Cx NanoString assay on RNA extracted from formalin-fixed, paraffin embed tissues using our established laboratory protocols. Clinical data including patient demographics, lines of treatment and survival outcomes were collected and correlated with each other and Lymph2Cx COO results. Results: Thirty-two HIV-negative patients diagnosed between January 2005 and June 2015 were included. Median age was 61 years (30-82) and 53% were male. Radiographic information was available for 18/32 patients. Eleven (61%) had a single brain lesion at diagnosis, while 7 (39%) had >1 brain lesion. Lines of systemic therapy were 1 (91%) and 2 (9%). All patients received methotrexate-based induction therapy (44% received methotrexate, rituximab and temozolomide, 16% received single-agent methotrexate, 31% received methotrexate and rituximab, and 9% received the modified Bonn regimen; methotrexate and cytarabine-based induction). A total of 10 patients (31%) received high-dose chemotherapy and autologous stem cell transplant (ASCT) for consolidation. Of the 10 patients that underwent consolidation therapy, 9 underwent ASCT after first line induction, and 1 underwent ASCT after second line therapy. None of the patients received whole-brain radiation therapy. At a median follow-up of 29 months (range of 2-107) median event-free survival (EFS) was 16.3 months (95% CI, 8.8-45.7), and median overall survival (OS) was 41.2 months (95% CI, 28.5-NE). COO testing using the Lymph2Cx assay revealed that 91% (29/32) were ABC, 9% (3/32) were GCB, and none were UNC. Histopathology reports described COO using the Hans algorithm in 11 of the 32 cases. Of the 3 determined to be GCB on Lymph2Cx, 1 was denoted GCB by the Hans algorithm and 2 were not stained to determine COO. Of the 29 determined to be ABC by Lymph2Cx, 9 were denoted non-GCB and 1 was denoted GCB by the Hans algorithm, and 19 were not stained to determine COO. Conclusions: This series of HIV-negative patients with PCNSL showed median survival consistent with previous studies. In this first series using the Lymph2Cx assay, we confirmed that over 90% of PCNSLs are of ABC subtype, which concurs with previous reports that PCNSL tumors are predominately non-GCB by the Hans algorithm. These findings provide biological rationale forthat pharmacologic interventions targeting B-cell receptor signaling to be explored in clinical trials in the majority of patients with PCNSL. Figure. Figure. Disclosures Rimsza: NanoString: Other: Inventor on the patent for the Lymph2Cx assay.

Abstract Background: Lymphoma survivors are at risk for long term and late effects which may negatively impact quality of life (QOL). Few studies have assessed the impact of change in health behaviors (physical activity (PA), alcohol and smoking) on QOL, specifically in lymphoma survivors. Methods: Patients were prospectively enrolled <9 months of diagnosis into the Lymphoma SPORE Molecular Epidemiology Resource cohort. At baseline and 3-year follow-up (FU3), patients self-reported QOL, smoking, alcohol use and PA. At FU3, survivors reported change in health behaviors since diagnosis. The Godin Leisure Score Index (LSI) was calculated as a measure of PA (Pophali et al. ASH 2017); modeled by tertile. QOL was measured via FACT-G; the total and sub-scales [emotional (EWB), functional (FWB), physical (PWB), and social/family well-being (SFWB)] scores were transformed to a 0-100 scale. Patients who completed <80% of QOL questions were excluded. The association of QOL with health behaviors was evaluated using Kruskal-Wallis test (categorical) and Spearman's rank correlation (continuous). Results: At baseline, 2805 participants were evaluable for QOL of which 2025 were evaluable at FU3. The median age at diagnosis was 62 (IQR 52-69) years. Majority were males (N=1148, 56.8%), with advanced stage III-IV disease (N=941, 62%) and ECOG performance status <2 (N=1935, 96%). At baseline, smoking status was current (N=237), former (N=802), never (N=1310) or not available (NA, N= 456). Current smokers had a significantly lower median QOL scores compared to former and never smokers for EWB (75 vs 79 vs 79, p<0.01), FWB (71 vs 79 vs 79, p<0.01), PWB (86 vs 89 vs 89, p=0.02), SFWB (86 vs 90 vs 89, p=0.02) and total FACT-G (67 vs 82 vs 82, p<0.01). The median number of pack years smoked among current &former smokers was 15.6 (range 0.5-126). There was a significant negative correlation of pack years smoked with FWB (p=0.05), and total FACT-G (p=0.04). At FU3, current smokers had significantly lower median scores compared to former and never smokers for FWB (80 vs 86 vs 86, p=0.01), PWB (89 vs 93 vs 93, p<0.01) and total FACT-G (82 vs 86 vs 87, p<0.01). EWB (83 vs 88 vs 88, p=0.12) and SFWB (83 vs 86 vs 86, p=0.12) were also lower than never and former smokers but not statistically significant. Smoking status was decreased (N=30), increased (N=0) and unchanged (N=1439) at FU3. There was no association of change in smoking with change in QOL. At baseline, alcohol use status was current (N=1189), former (N=506), never (N=518) and NA (N=592). Current alcohol users had the highest FWB (79 vs 75 vs 75, p<0.01) vs former and never users. Former users vs current and never users had the lowest PWB (86 vs 89 vs 89, p<0.01), SFWB (88 vs 89 vs 92, p<0.01) and total FACT-G (80 vs 83 vs 82, p<0.01). EWB was similar in all 3 groups. Among current & former alcohol users, the average number of drinks/week was 3.4. There was no association of the number of drinks/week with QOL except positive correlation with PWB (p=0.01). At FU3, alcohol use was reported as increased (N=40), decreased (N=312) and no change (N=875). There was no association between change in alcohol use and change in QOL. At baseline, participants with PA in the high vs low LSI tertile had significantly better median scores for FWB (79 vs 75, p=0.01), SFWB (93 vs 89, p<0.01) and total FACT-G (83 vs 82, p<0.01). At FU3, participants in the high vs low LSI tertile had significantly better scores on all subscales and total FACT-G with a significant positive correlation between the continuous LSI and QOL (FACT-G total and subscales). PA was reported as increased (N=107), decreased (N=394) and no change (N=495). There was a significant association of increase in PA with change in PWB (p<0.01), EWB (p=0.01), FWB (p<0.01) and total FACT-G (p<0.01) from baseline to FU3, but not with change in SFWB (p=0.06). In a sensitivity analysis, QOL was modeled for health behaviors in the subset of patients with QOL assessed prior to treatment; results were consistent with the QOL in all patients. Conclusions: Health behaviors in lymphoma survivors are significantly associated with QOL: better QOL is associated with not smoking, more PA, and moderate alcohol use. Current alcohol consumption, as opposed to former alcohol use, may be related to overall health status. An increase in PA after lymphoma diagnosis is associated with an increase in the QOL. Thus, modification of health behaviors has the potential to impact QOL in lymphoma survivors. Figure. Figure. Disclosures Cerhan: Celgene: Research Funding; Nanostring: Research Funding; Jannsen: Other: Scientific Advisory Board.

Abstract Background: In Phase II trials, carfilzomib (Cfz) was associated with dyspnea (34%), hypertension (14%), renal insufficiency (24%), and peripheral edema (24%) with cardiac events reported in 7% of patients (pts). In order to better understand these toxicities, we prospectively instituted detailed cardiac evaluation in 62 Cfz treated multiple myeloma (MM) pts. Methods: Pts received Cfz between 8/11-5/14. Parameters recorded included Cfz dose, concurrent chemotherapy, hydration, blood pressure, day 1 and 2 creatinine, troponin and NT-proBNP, baseline and cycle 4 echocardiograms with EF, strain and compliance. Notable cardiac events were examined for attribution. Results: Median age was 65 years, with 60% male. 20 pts had no prior therapies, 42 were relapsed; mean 4 prior therapies (range 1-10). 20 received induction chemotherapy (Cfz, dex, thalidomide, cyclophosphamide). At relapse, Cfz was given alone in 21 pts, with added cyclophosphamide in 10, and with an IMiD in 10. Cfz dose was 20mg/m2 days 1,2 and ranged from 27-45mg/m2in subsequent treatment days. Dex was given at 20-40mg weekly in 77% pts. Hydration (250-500ml) was delivered in 89% of patients pre and 63% post treatment. Baseline hypertension (>140mmHg) was present in 20% of pts and rose ≥10mmHg in 26% on day 2, but dropped ≥10mmHg in 36%. On day 8, more pts (32%) had hypertension pre-treatment. Baseline creatinine was elevated in 25% pts. 7 of 55 (13%) pts had a creatinine rise (≥0.3 mg/dL) on day 2, 5 of whom had elevation at baseline. Thus, with normal baseline creatinine and pre-treatment hydration 2/45 (4%) pts had a creatinine rise. Troponin levels on day 1 were normal in all 16 tested patients. 2/25 pts had an elevated troponin on day 2, one with associated MI on day 4. In these 2 pts, symptomatic pre-existing ischemic heart disease and severe cardiac amyloid were confounding factors. Mean baseline NT-proBNP (n=22) was elevated at 565 pg/mL (range <50-3666; normal <77) with normal baseline values in only 41%. On day 2 (n=25), the mean was significantly higher at 1580 pg/mL. Between day 1 and 2, 72% of pts had a rise ≥50 pg/mL; mean change 1387 (range 0 to +6187). On day 2, 52% had a NT-proBNP ≥500 pg/mL, while 36% were ≥1000 pg/mL. 30 pts had baseline and post-C4 treatment echocardiograms, all with normal pre-treatment EFs. Three pts (10%) developed impaired systolic function (EF<50%), however, 2 had plausible concurrent alternative etiologies (VTE/PE, hospitalized multilobar pneumonia) while one patient (during C2) had an asymptomatic unexplained decline in EF (56 to 42%) detected pre-op while hospitalized for hip fracture. Thus, 1/30 (3%) had an EF change in absence of concurrent acute illness. A fourth patient had normal echo at C4 but was hospitalized at C10 with severe sepsis and a diminished EF was documented. All 4 pts with low EF were pre-treated (≥2 therapies plus SCT). Changes in cardiac strain often precede an EF fall. Only 14/25 pts had normal baseline cardiac strain (≥ -18%). Post treatment strain measurement significantly improved in 4 pts and worsened in 4 pts, the latter accompanied by EF decline within the normal range in 2 pts (68/60%, 65/58%). 28 pts had E/e’ ratio (LVEDP) reviewed as a marker of ventricular compliance. 46% had abnormal ratios (≥ 15), prior to Cfz treatment. 20% of patients experienced worsening parameters post treatment, however, an equal number of pts demonstrated improvement. There was no consistent correlation with change in EF. Conclusions: MM pts frequently have baseline elevated cardiac peptides (59%) and abnormal cardiac strain (15% of newly diagnosed and 36% at relapse). A frequent, and sometimes dramatic, rise in the NT-proBNP occurs immediately following Cfz based chemotherapy. Acute structural cardiac events were however uncommon (3%) in the absence of confounding illness. Overall 5/62 (8%) patients had serious cardiac events during treatment with Cfz (4 EF decline, 1 MI). These toxicities were considered probably attributable to Cfz in 3/62 (5%) patients. Prospective controlled studies with longer term follow up and bortezomib treated controls are necessary to accurately document the cardiovascular impact of Cfz and the role of proteasome inhibition. Disclosures Off Label Use: bortezomib was used in combination therapy to treat relapsed low grade lymphomas and Waldenstrom's macroglobulinemia. Fonseca:Medtronic, Otsuka, Celgene, Genzyme, BMS, Lilly, Onyx, Binding Site, Millennium, AMGEN: Consultancy, patent for the prognostication of MM based on genetic categorization of the disease. He also has sponsored research from Cylene and Onyx Other, Research Funding. Bergsagel:Novartis: Research Funding; Constellation Pharmaceutical: Research Funding; OncoEthix: Research Funding; MundiPharma: Research Funding. Reeder:Millennium, Celgene, Novartis: Research Funding. Mikhael:Onyx: Research Funding; Celgene: Research Funding; Sanofi: Research Funding; Novartis: Research Funding. Stewart:Celgene Novartis Array BioPharma BMS, research funding Millenium: Consultancy, Research Funding.

Abstract Introduction Non-Hodgkin lymphoma responds to single agents such as cyclophosphamide, combination therapy such as CVP and immunotherapy with monoclonal antibodies such as rituximab. There is no consensus on the optimal treatment for relapsed low grade or mantle cell lymphoma. Based on the success and tolerability of combining alkylating agents with proteasome inhibitors in multiple myeloma, a phase II clinical trial of rituximab, cyclophosphamide, bortezomib, and dexamethasone (R-CyBor-D) was designed to explore the efficacy and safety of this combination in relapsed low grade and mantle cell lymphoma (MCL). Methods This trial enrolled relapsed patients at Mayo Clinic from October 2008 to March 2014. Eligibility required age≥18; biopsy proven follicular grades 1 or 2 lymphoma (FL), MCL, small lymphocytic lymphoma/chronic lymphocytic leukemia, marginal zone B-cell lymphoma, or Waldenström’s macroglobulinemia (WM); life expectancy >3 months; ECOG PS 0, 1 or 2; measurable disease; Hb ≥8g/dl, ANC ≥1200/uL, platelet ≥75,000/uL, creatinine ≤1.5xULN, total bilirubin ≤1.5xULN, alkaline phosphatase ≤3xULN, AST ≤3xULN; and willingness to sign informed consent. Women of child bearing potential had pregnancy testing and all patients followed recommendations for contraception. Treatment included rituximab 375 mg/m2 IV on day 1 and oral cyclophosphamide 300 mg/m2, IV bortezomib 1.3 mg/m2, and oral dexamethasone 40 mg on days 1, 8, 15, and 22 in a 28-day cycle. Treatment was continued two cycles beyond best response or a maximum of 12 cycles. Allopurinol 300 mg on days 0-14 for the first cycle was strongly recommended. Results 21 patients were enrolled prior to study closure due to slow accrual. Bortezomib was initially given on days 1, 4, 8, and 11 in the first 16 patients, but was subsequently modified to days 1, 8, 15, and 22 due to significant peripheral neuropathy (PN). Median age was 69 years (range 51-80) and 13 (62%) were male. 62% had stage IV disease and 17 (81%) had 2 or more prior treatments with 3 (14%) having prior autologous stem cell transplantation. Histologies included FL-I (n=6), FL-II (n=2), MCL (n=8), and WM (n=5). Patients completed a median of 4 cycles of treatment (range 1-12), discontinuing due to 9 (43%) completion per protocol, 4 (19%) progression, 5 (24%) adverse events, 1 (5%) patient refusal, and 2 (10%) other reasons. Median follow-up is 32.8 months (0.9-54.8). CR or PR as best response was observed in 13 (62%, 95% CI 38-82%; 4 CR [19%], 9 PR [43%]) patients. By histology, CR or PR was observed in 7 (88%) FL patients (4 CR, 3 PR); 2 (25%) MCL patients (both PR), and 4 (80%) WM patients (all PR). CR or PR was observed in 10/16 (62%; 4 CR, 6 PR) before and 3/5 (60%; all PR) after the change in bortezomib schedule. Among 13 patients with CR or PR, median duration of response was 25.9 months (95% CI 8.0-not reached). Median PFS and OS were 11.6 months (95% CI 3.8-not reached) and 54.8 months (95% CI 24.6-54.8), respectively. At least one Gr≥3 adverse event at least possible related was observed in 14 (67%) patients, the most common being leucopenia (7, 33%), neutropenia (7, 33%), thrombocytopenia (6, 29%), anemia (5, 24%), PN (5, 24%), and fatigue (3, 14%). Peripheral sensory neuropathy at least possibly related was Gr1, Gr2, and Gr3 in 5 (24%) patients each, with a lower rate observed for patients after the change in bortezomib schedule (before 13/16 [81%] Gr≥1, after 2/5 [40%] Gr≥1). Among 14 patients who completed a baseline and at least one post-baseline FACT/GOG-NTX additional concerns questionnaire, 10 (71%) reported clinically meaningful (≥3-point) worsening in patient-reported neurotoxicity (8/11 [73%] before and 2/3 [67%] after the change in bortezomib schedule). Conclusions Our results suggest R-CyBor-D is a safe and effective combination in patients with relapsed low grade and mantle cell lymphomas. High response rates were seen in FL and WM. The majority of significant AE’s were hematologic. However, sensory neuropathy was common with twice weekly dosing of bortezomib and lessened with weekly dosing. Determination of optimal treatment regimens in this population remains an unmet need. Additional clinical trials including larger patient numbers are necessary to confirm these observations. This trial was sponsored by Millennium Disclosures Off Label Use: bortezomib was used in combination therapy to treat relapsed low grade lymphomas and Waldenstrom's macroglobulinemia. Bergsagel:Novartis: Research Funding; Constellation Pharmaceutical: Research Funding; OncoEthix: Research Funding; MundiPharma: Research Funding. Tiedemann:Janssen: Honoraria. Reeder:Millennium, Celgene, Novartis: Research Funding.