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Background: The chronic lymphocytic leukemia (CLL) tumor microenvironment (TME) is laden with hyporesponsive T-cells that permit disease persistence. Yet, redundant TME immunosuppressive mechanisms and epigenetic maintenance of T-cell exhaustion limit the efficacy of T-cell targeted therapies in CLL. Bromodomain and extra-terminal (BET) proteins regulate key pathways contributing to CLL pathogenesis and TME interactions, including T-cell function and differentiation. We hypothesize that blocking BET protein function can reverse T-cell exhaustion to yield durable tumor elimination in CLL. Methods: WT C57BL/6 mice were engrafted with Eμ-TCL1 spleen-derived lymphocytes, then treated daily with the novel pan-BET inhibitor, OPN-51107 (OPN5; 20mg/kg PO) for up to 4 weeks. Splenic gene expression was evaluated with the NanoString PanCancer iO360 panel. T-cell differentiation status, immune inhibitory receptor (IR) expression, proliferation (72 h ex vivo α-CD3/α-CD28 stimulation), and cytokine production (6 h ex vivo PMA/ionomycin stimulation) was measured via flow cytometry. CLL patient and healthy donor PBMCs were used for validation studies and to assess T-cell transcription factor (TF) expression via flow cytometry. Evaluation of BRD4 occupancy at select T-cell TFs via ChIP qPCR is ongoing. Results: OPN5 significantly increased cytotoxic cell signatures and reduced exhaustion-associated cell signatures in leukemic mice through inhibition of T-cell exhaustion signaling, as well as activation of Th1, natural killer cell, and IL-7 signaling pathways. Correspondingly, T-cells from OPN5-treated mice demonstrated greater ex vivo proliferative capacity and effector response to stimuli. A greater proportion of CD8+ T-cells from OPN5-treated mice were classified as naïve, and OPN5 significantly reduced KLRG1 expression on antigen-experienced CD8+ T-cells. Importantly, OPN5 curtailed IR co-expression (PD-1, PD-L1, VISTA, CD244, CD160, and LAG3) on splenic T-cells. These findings were confirmed with primary CLL cells ex vivo. OPN5 also impaired expression of terminal differentiation-associated TFs in CLL patient-derived T-cells, enriching for a TCF1+ progenitor T-cell population. While BTK inhibitors are known to similarly improve T-cell function in CLL, ibrutinib treatment was inadequate to revert CLL T-cell terminal differentiation. Future ATAC-sequencing analysis will inform how BET inhibition alleviates exhaustion-associated chromatin organization in CLL T-cells. Conclusion: BET inhibition dismantles immunosuppressive mechanisms in the CLL TME, alleviating CLL-induced T-cell dysfunction and terminal differentiation. These findings suggest that BET inhibition may be a useful component of combination strategies for the treatment of CLL to yield lasting anti-cancer immune memory and prevent relapsed/refractory disease. Citation Format: Audrey L. Smith, Alexandria P. Eiken, Sydney A. Skupa, Christopher R. D'Angelo, Avyakta Kallam, Matthew A. Lunning, Gregory Bociek, Julie M. Vose, Ben Powell, Gideon Bollag, Dalia El-Gamal. BET inhibition alleviates T-cell dysfunction in chronic lymphocytic leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6396.

Background: We used the Therapy Preference Scale, a 30-item questionnaire, to determine cancer treatment preferences of adults with cancer. Methods: We used Wilcoxon’s rank sum test and Fisher’s exact test to compare the preferences of younger (

Non-Hodgkin lymphoma (NHL) is one of the most prevalent cancers in the Western world with an increasing incidence in US (Zelenetz, et al 2010) This group of lymphomas encompasses a heterogeneous group of diseases with a wide range of histology, pathogenesis and clinical course ranging from indolent to aggressive diseases. The most common indolent subtype of B-cell lineage is follicular lymphoma (FL), and that of the T-cell lineage is cutaneous T-cell lymphoma (CTCL), whereas aggressive subtypes include diffuse large B-cell lymphoma (DLBCL) and peripheral T-cell lymphoma (PTCL), representing approximately 80% of all NHL diagnoses in adults (Swerdlow et al 2016). There is often patient-to-patient variability in clinical course, with a significant proportion of patients relapsing or refractory to first line therapies. While many treatment difficulties exist in NHL, relapsed/refractory disease represents a major challenge and is currently under intense investigation, especially in the rituximab era for B-cell lineage lymphomas. The use of the monoclonal antibody rituximab, as a single agent or in combination with cytotoxic chemotherapy, is currently the standard of care in the first line setting for B-cell NHLs and has significantly improved the prognosis of affected patients. However, rituximab resistance has been reported in multiple NHL subtypes, including relapsed FL or low-grade NHL, and is associated with poor prognosis (Davis, et al 2000, Hagberg and Gisselbrecht 2006, Martin, et al 2008). Patients with PTCL generally have a poor prognosis with current standard-of-care therapy, and no progress in their outcome has been achieved in the past two decades (Xu and Liu 2014). The prognosis of relapsed PTCL is very poor and novel effective treatments are urgently needed. Autologous haematopoietic stem cell transplantation has been associated with extended survival in relapsed/refractory NHL, however the Collaborative Trial in Relapsed Aggressive Lymphoma (CORAL) demonstrated that, in the post-rituximab era, patients with DLBCL, the most common type of NHL in the US, derive less benefit from autologous transplant, with a dismal progression-free survival (PFS) of 20% at 3 years (Gisselbrecht, et al 2010). As patients relapse after autologous transplant, progress through multiple lines of treatment, the subsequent responses achieved are incrementally shorter, with eventual exhaustion of meaningful options. This clearly highlights the need for additional safe, effective and targeted agents for this high-risk population. Several novel classes of drugs, such as next generation monoclonal antibodies, antibody–drug or radioactive isotope conjugates and specific small-molecule inhibitors of oncogenic pathways, are emerging as therapeutic options in NHL. However, despite the recent array of drug approvals, long-term remission remains elusive for a significant proportion of NHL patients, particularly those with relapsed/refractory disease (Crump, et al 2017). In this context, we studied the safety and efficacy of single agent dasatinib in patients with relapsed/refractory NHL. Dasatinib, originally developed as a pan-Src kinase inhibitor, is a potent and broad-spectrum multi-kinase inhibitor with proven safety and efficacy in chronic myeloid leukaemia (CML) and Philadelphia chromosome positive acute lymphoblastic leukaemia (Ph+ ALL) (Cortes, et al 2016, Lilly, et al 2010). Dasatinib has selective 100-fold higher affinity for ABL1 than imatinib mesylate (Shah, et al 2004), and targets several tyrosine kinase families that are implicated in cell survival in NHLs (Brave, et al 2008, Sprangers, et al 2006). The half-life of the drug is approximately 5 h, shown to be well tolerated in CML patients (Talpaz et al. 2004), and achieves sustained inhibition of Lyn kinase, which is critical for B-cell survival. Given that Lyn could be inhibited by dasatinib at tolerable doses, we initiated this phase 1/2 trial in patients with relapsed NHLs.

Introduction : Chronic Lymphocytic Leukemia (CLL) is characterized by the clonal expansion of mature CD19+/CD5+ lymphocytes in the peripheral blood and secondary lymphoid organs. The accumulation of B-CLL cells yields profound immune defects in the CLL tumor microenvironment (TME), promoting evasion of immune surveillance that contributes to tumor persistence and thus relapsed/refractory disease. The bromodomain and extra-terminal domain (BET) family of proteins are epigenetic readers that bind acetylated histone residues to regulate transcription of numerous genes involved in critical CLL protumor pathways. Of the BET family proteins, BRD4 is overexpressed in CLL and highly enriched at super-enhancers of genes that regulate CLL-TME interactions such as B cell receptor pathway components, chemokine/cytokine receptors, and immune checkpoint molecules. Pan BET inhibitors (BET-i), such as PLX51107 (Plexxikon Inc.) significantly improve survival in aggressive CLL murine models. Here we demonstrate that blocking BRD4 function with PLX51107 (PLX5) can alleviate the inherent immune defects observed in CLL, hence reducing B-CLL induced T cell dysfunction and allowing for robust B-CLL cell elimination. This therapeutic strategy may be vital in overcoming frequent drug resistance and/or bolstering the anti-tumor effect of current CLL therapies. Methods : Primary leukemic B cells were isolated from the peripheral blood of CLL patients and co-cultured with healthy donor T cells to evaluate the effect of PLX5 (0.1-0.5μM) on CLL-induced T cell immunosuppression ex vivo via an array of flow cytometry assays. T cell proliferation was assessed using CFSE after 96 h co-culture with α-CD3/α-CD28 stimulation. Effector cytokine production was evaluated after 48 h co-culture in the presence of PMA/ionomycin (final 6 h) and brefeldin A (final 5 h). Immune inhibitory molecule surface expression was measured following 48 h co-culture with α-CD3/α-CD28 stimulation. To further validate our ex vivo findings, the E μ-TCL1 adoptive transfer model was used. Once disease onset was confirmed in recipient WT B6 mice (>10% CD45+/CD19+/CD5+ peripheral blood lymphocytes), mice were randomized to receive either PLX5 (20 mg/kg) or vehicle (VEH) equivalent daily by oral gavage for 4 weeks. Following treatment, mouse spleens were processed to evaluate exhaustion marker expression, T cell proliferation (CellTrace™ Violet, 72 h a-CD3/α-CD28 stimulation ex-vivo), and T-cell effector function (ex-vivo mitogenic stimulation, 6 h). Results : T cell proliferation indices were reduced following ex vivo co-culture with primary B-CLL cells (mean ± SEM for T cells vs. co-culture, 2.0 ± 0.13 vs. 1.57 ± 0.05; P Conclusion : Epigenetic-targeted therapies such as BET-i have the potential to alleviate CLL-induced T cell dysfunction while eliminating B-CLL cells and preventing tumor expansion. Future profiling studies are pending to further illuminate how BET proteins regulate immune function in CLL. Figure 1 Figure 1. Disclosures Lunning: AstraZeneca: Consultancy; Legend: Consultancy; Acrotech: Consultancy; ADC Therapeutics: Consultancy; Kyowa Kirin: Consultancy; Myeloid Therapeutics: Consultancy; Beigene: Consultancy; Celgene, a Bristol Myers Squibb Co.: Consultancy; Verastem: Consultancy; Janssen: Consultancy; Daiichi-Sankyo: Consultancy; Morphosys: Consultancy; TG Therapeutics: Consultancy; Novartis: Consultancy; Karyopharm: Consultancy; AbbVie: Consultancy; Spectrum: Consultancy; Kite, a Gilead Company: Consultancy. Vose: Kite, a Gilead Company: Honoraria, Research Funding. Powell: Plexxikon Inc.: Current Employment.

Background: Acute Lymphoblastic Leukemia (ALL) outcomes have significantly improved over time with multi-agent chemotherapy, and the addition of asparaginase (ASP) has demonstrated the ability to prolong overall survival. ASP has multiple toxicities, and it remains a challenge to manage them safely, particularly coagulopathy and thrombosis (30-40% based on historical studies). The best prophylactic anticoagulation strategy in patients with acute leukemias, particularly ALL with asparaginase use, remains unclear due to severe coexisting thrombocytopenia and coagulopathy. Though the current guidelines recommend using Antithrombin (AT) replacement or low molecular weight heparin (LMWH) for thrombosis prophylaxis, the evidence is weak with concerns of thrombosis (Blood (2020) 136 (3): 328-338) with the use of fibrinogen concentrates(cryoprecipitate) and limited efficacy data with AT replacement and unfractionated heparin (UFH) for thrombosis prophylaxis. Due to potential "resistance" to LMWH and UFH from acquired AT deficiency with ASP use, our institution in 2017 has adopted the use of the direct Xa inhibitor, Apixaban for thrombosis prophyalxis. We report the safety and effectiveness of Apixaban for thrombosis prophylaxis with ASP. Methods: In this retrospective study, we reviewed the data on 20 patients treated with ASP between 2017-2020. Thrombosis prophylaxis was instituted with Apixaban 2.5 mg PO Q 12 hourly for three weeks along with cryoprecipitate as needed for bleeding or fibrinogen levels Results: Among the 20 patients treated during this period, 18 (90%) had ALL, and 2(10%) had NK/T cell lymphoma. Of the patients with ALL, 67% had high risk and 33% with standard-risk ALL. The median age of this cohort was 29.5 years (range: 19-63 years), 80% were males, 70% white, 30% were Latino or Hispanic, median body mass index-BMI of 30.2 kg/m 2(19.4-40.7 kg/m 2) and 65% were non-smokers. The median baseline AT activity was 107% (79-221%), 95% used concurrent corticosteroids (65%- Prednisone, and 30% used Dexamethasone). The most common induction treatment was CALGB 10403 (55%). Of the total, 95% received pegylated ASP, and only one patient received Erwinia ASP due to prior history of anaphylaxis. The major toxicities attributed to ASP included 5% grade II and 15% grade III-IV aspartate aminotransferase (AST) or alanine aminotransferase (ALT) elevation, 20% had bilirubin elevation, 10% developed grade III-IV acute pancreatitis, and 5% developed severe hypertriglyceridemia needing aphaeresis. Two patients (10%) developed thrombosis [catheter associated deep venous thrombosis (DVT) and one patient with lower extremity proximal DVT] within 4 weeks of use of ASP, with one of the two patients (5%) developing (lower extremity proximal DVT) while on being off anticoagulation due to bleeding. Major bleeding or CRNMB developed in 5% (spontaneous splenic rupture from ALL leading to hemorrhagic shock). The median number of cryoprecipitate units used per patient during weeks 1,2,3, and 4 was 5(0-35), 5(0-40), 5(0-15), 7.5(0-15), respectively; No patients received fresh frozen plasma or AT concentrates. Conclusions: With the use of Apixaban prophylaxis, the incidence of thrombosis was 10% within four weeks from ASP and 5% while on anticoagulation. The incidence of major bleeding or CRNMB was 5%. Hypofibrinogenemia, acquired AT deficiency due to ASP, was seen between days 7-21 after using ASP (figure 1 & 2) and recovered subsequently. This study demonstrates initial evidence of the safety and efficacy of Apixaban for thrombosis prophylaxis and cryoprecipitate infusions in patients treated with ASP. Figure 1 Figure 1. Disclosures Gundabolu: Samus Therapeutics: Research Funding; Pfizer: Research Funding; BioMarin Pharmaceuticals: Consultancy; Bristol-Myers Squibb Company: Consultancy; Blueprint Medicines: Consultancy. Bhatt: Jazz: Research Funding; Incyte: Consultancy, Research Funding; Pfizer: Research Funding; Tolero Pharmaceuticals, Inc: Research Funding; National Marrow Donor Program: Research Funding; Abbvie: Consultancy, Research Funding; Genentech: Consultancy; Abbvie: Consultancy, Research Funding; Partnership for health analytic research, LLC: Consultancy; Servier Pharmaceuticals LLC: Consultancy; Rigel: Consultancy. Vose: Kite, a Gilead Company: Honoraria, Research Funding. Lunning: Myeloid Therapeutics: Consultancy; Janssen: Consultancy; Kyowa Kirin: Consultancy; AstraZeneca: Consultancy; ADC Therapeutics: Consultancy; Novartis: Consultancy; Celgene, a Bristol Myers Squibb Co.: Consultancy; AbbVie: Consultancy; TG Therapeutics: Consultancy; Daiichi-Sankyo: Consultancy; Legend: Consultancy; Kite, a Gilead Company: Consultancy; Verastem: Consultancy; Acrotech: Consultancy; Karyopharm: Consultancy; Spectrum: Consultancy; Beigene: Consultancy; Morphosys: Consultancy. Baljevic: BMS/Celgene: Consultancy; Oncopeptides: Other: Advisory Board; Janssen Research: Other: Advisory Board; Karyopharm: Other: Advisory Board; BMS/Celgene: Other: Advisory Board; Amgen: Research Funding; Exelixis: Research Funding. Ganti: Merck: Research Funding; Apexigen: Research Funding; Nektar: Research Funding; Top Alliance Biosceinces: Research Funding; Lovance: Research Funding; Novartis: Research Funding; WindMil Therapeitucs: Research Funding; Takeda: Research Funding; Flagship Biosciences: Consultancy; AstraZeneca: Consultancy, Other: Advisory Board; Mirati Therapeutics: Consultancy, Other: Advisory Board; G1 Therapeutics: Consultancy, Other: Advisory Board; Blueprint Medicines: Consultancy, Other: Advisory Board; Cardinal Health: Consultancy, Other: Advisory Board; Roche: Consultancy, Other: Advisory Board; YMabS Therapeutics: Other: DSMC Chair.

PURPOSE/OBJECTIVE(S) The role of radiotherapy following high dose chemotherapy and autologous stem cell transplantation (ASCT) for relapsed or refractory Hodgkin lymphoma (HL) has not been addressed in a prospective randomized trial. While the benefit of consolidative radiotherapy has been demonstrated in other clinical settings for HL, concern of late radiotherapy associated toxicity and uncertain treatment efficacy remain as deterrents in the peritransplant setting. MATERIALS/METHODS We retrospectively reviewed patients with relapsed or refractory HL who underwent high dose chemotherapy and an ASCT from 2000-2019 at our institution. The association of clinicopathologic factors with the delivery of consolidative radiotherapy was assessed by Chi squared analysis. Kaplan Meier and a cox regression analysis were used to estimate factors independently associated with progression-free survival (PFS) and overall survival (OS). RESULTS From 2000-2019, 179 consecutive patients underwent salvage chemotherapy (most commonly ICE: ifofsamide, carboplatin, and etoposide) followed by high dose chemotherapy (most commonly BEAM: BCNU, Etoposide, Ara-C and Melphalan) and an autologous stem cell transplant for relapsed (63.4%) or refractory (36.6%) HL with a median follow up of 59.4 months. Post-transplant consolidative radiotherapy was delivered to a median dose of 3600 cGy in 20 fractions to 72 patients (40.2%). Consolidative radiotherapy was associated with younger age (median age 32 vs. 42 years, P < 0.001), stage I-II disease at the time of salvage chemotherapy (76.4% vs 52.3%, P = 0.001), and no prior radiotherapy (76.4% vs 45.8%, P < 0.001). On univariate analysis, consolidative radiotherapy was associated with an improved two-year PFS (84.1% vs 64.1%, P = 0.005) and OS rates (95.7% vs 80.8%, P = 0.017). In the Cox regression analysis, consolidative radiotherapy was significantly associated with improved PFS (HR: 0.492, 95% CI: 0.288-0.84, P = 0.009) along with ECOG performance status < 2 (HR: 0.188, 95% CI: 0.045-0.79, P = 0.022), achieving a complete response to salvage chemotherapy (HR: 0.463, 95% CI: 0.233-0.92, P = 0.028), and stage I-II disease (HR: 0.546, 95% CI: 0.325-0.918, P = 0.022). Similarly, consolidative radiotherapy was associated with significantly improved OS (HR: 0.398, 95% CI: 0.205-0.771, P = 0.006) along with ECOG performance status < 2 (HR: 0.073, 95% CI: 0.016-0.333, P = 0.001). Following transplantation, grade ≥2 pneumonitis was identified in 10 patients (5.6%) of which only 7 patients underwent consolidative radiotherapy which was delivered to mediastinal (50.0%), supraclavicular (10.0%), or abdominal (10.0%) fields. No patient deaths were associated with pneumonitis. CONCLUSION Our findings suggest that consolidative radiotherapy in the salvage management of HL is associated with improved PFS and OS with low rates of treatment associated complications. Further investigation in the role of consolidative radiotherapy in this setting is warranted.

Background Follicular lymphoma (FL) is the second most common type of non-Hodgkin lymphoma (NHL) and most common of the clinically indolent NHLs. Although often considered an incurable disease, overall survival has increased significantly with refinement in diagnostic techniques and the addition of rituximab. The course of FL is quite variable and presence of symptoms, organ dysfunction, cytopenias, aggressiveness of tumor are all taken into consideration when deciding individual treatment. In this study, we evaluated a large patient cohort with FL treated over a 35 year period for progression free survival (PFS), overall survival (OS) based on FLIPI score, tumor grade, and treatment regimen and also looked at causes of late failures. Methods We evaluated 1037 patients (pts) from the Nebraska Lymphoma Study Group that were diagnosed with FL between the years of 1983-2020. Descriptive statistics were stratified according to age, histological subtype, treatment regimen, FLIPI category, presence and type of secondary malignancy. PFS was calculated from the time of diagnosis to progression or death and OS was the time from diagnosis to death from any cause. PFS and OS were plotted as Kaplan-Meier curves with statistically significant p Results The median age at diagnosis and treatment was 61 years (yrs, range 17-91). A total of 9.1% were characterized as FLIPI high risk, 37.8% intermediate risk, and 33.6% low risk, 19.5% unavailable. Among the histological grade, 23.1% had FL- grade 1, 30.2% FL-2, 27.3% FL-3A, 2.5 % FL-3B and 16.9 % Composite Lymphoma. Anthracycline + rituximab was given in 24.5% of pts, whereas 43.8% of pts received an anthracycline based regimen without rituximab, 9.8% received rituximab without an anthracycline and 10.6% received neither of these agents. 6.75% (70 pts) were later found to have secondary malignancies of which 11 pts had myelodysplastic syndrome, 10 pts had acute leukemia and 9 pts had lung cancer. With a median follow up of 9.2 yrs and a maximum of 36 yrs, 29.7% (308 pts) had not relapsed. The median PFS across all groups was 4.6 yrs (Fig 1) and OS was 12.1 yrs. Median OS was significantly longer in patients that received rituximab at 16.1 yrs as compared to patients that did not receive rituximab at 9.89 yrs (Fig 2). PFS was 8.6 yrs, 3.6 yrs and 2.1 yrs and OS was 15.1 yrs, 11.7 yrs and 4.9 yrs in FLIPI low, intermediate and high risk groups respectively (p= When pts with FL-3A and FL-3B were grouped together and stratified according to treatment regimen, the group that received anthracycline and rituximab combination has highest PFS and OS at 13.3 yrs and 18.8 yrs (p Among the pts that relapsed/died after 10 years (n=190), the cause of death was relapsed lymphoma in 13.7%, unknown in 55.8%, secondary malignancies in 4.2%, treatment related in 2.6% and not related to disease in 23.7%. A total of 278 pts survived > 10 yrs, and of these pts, 119 (30%) had not relapsed at the last follow up. Conclusion The addition of rituximab to standard anthracycline based chemotherapy has resulted in significant improvements in the PFS and OS rates of FL. These results also support the prognostic value of the FLIPI in patients treated in the rituximab era. Late relapses after 10 yrs from disease can occur, but 11.5% of patients had not relapsed with long term follow up. Secondary malignancies are also an important consideration in the long term survivors. Disclosures Lunning: Acrotech: Consultancy; TG Therapeutics: Research Funding; Novartis: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Curis: Research Funding; Beigene: Consultancy, Honoraria; Aeratech: Consultancy, Honoraria; Bristol Meyers Squibb: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; Legend: Consultancy; Verastem: Consultancy, Honoraria; ADC Therapeutics: Consultancy. Armitage:Trovagene/Cardiff Oncology: Membership on an entity's Board of Directors or advisory committees; Samus Therapeutics: Consultancy; Ascentage: Consultancy. Vose:Bristol-Myers Squibb: Research Funding; Karyopharm Therapeutics: Consultancy, Honoraria; Seattle Genetics: Research Funding; Allogene: Honoraria; AstraZeneca: Consultancy, Honoraria, Research Funding; Kite, a Gilead Company: Honoraria, Research Funding; Wugen: Honoraria; Novartis: Research Funding; Celgene: Honoraria; Incyte: Research Funding; Roche/Genetech: Consultancy, Honoraria, Other; Verastem: Consultancy, Honoraria; Miltenyi Biotec: Honoraria; Loxo: Consultancy, Honoraria, Research Funding; Janssen: Honoraria; Epizyme: Honoraria, Research Funding; AbbVie: Consultancy, Honoraria.

The optimal management of hematologic malignancy-associated venous thromboembolism (VTE) in patients with moderate-to-severe thrombocytopenia is unclear. This is a retrospective study of 128 adult patients with hematologic malignancies who were diagnosed with VTE. The outcome of patients with significant thrombocytopenia (≤50,000/µL) was compared with those without. Forty-seven patients (36.7%) had a platelet count ≤50,000/µL during a period of time of perceived need for new or continued anticoagulation. The median nadir platelet count in those with significant thrombocytopenia was 10,000/µL (range 2,000-45,000/µL) versus 165,000/µL (50,000-429,000/µL) in those without (P < 0.001). The median duration of significant thrombocytopenia in the first group was 10 days (1-35 days). Therapy during the period of significant thrombocytopenia included prophylactic-dose low-molecular-weight heparin (LMWH) (47%), therapeutic-dose LMWH or heparin (30%), warfarin (2%), inferior vena cava filter (2%), and observation (17%). Patients without thrombocytopenia were managed with the standard of care therapy. At a median follow-up of more than 2 years, the risk of clinically significant bleeding (11% vs 6%, P = 0.22) including major bleeding (6% vs 2%) and clot progression or recurrence (21% vs 22%, P = 1.00) were similar in patients with or without significant thrombocytopenia. In a multivariate analysis, the risk of recurrence/progression (hazard ratio, HR 0.59, 95% CI 0.21-1.66, P = 0.31) and hemorrhage rate (HR 0.29, 95% CI 0.05-1.56, P = 0.15) did not differ based on the presence of significant thrombocytopenia. Within the limits of this retrospective study, cautious use of prophylactic-dose LMWH may be safe in thrombocytopenic patients with hematologic malignancy-associated VTE. Am. J. Hematol. 91:E468-E472, 2016. © 2016 Wiley Periodicals, Inc.

Introduction Chimeric Antigen Receptor (CAR) T-cell therapy has been approved for the treatment of relapsed or refractory diffuse large B-cell lymphoma (DLBCL). Long-term follow-up of the ZUMA-1 trial demonstrated that 39% of patients who received axicaptogene ciloleucel were progression free at two-years. Objectives CAR-T cell therapy, as a treatment option, has likely been hindered by logistical barriers, including patients' insurance approval/single case agreement (SCA) process and the distance to the CAR-T treatment center from their home. Methods Patient (Pt) information was retrospectively reviewed from our commercial CAR-T cell therapy experience between 1/2018 and 7/2019. Standard patient demographics and disease characteristics were collected. Progression free survival (PFS) and overall survival (OS) time points started with the treating physician's documentation of intent to CAR-T (iCAR-T). Pts were further assessed based on public (Medicare/Medicaid) or private insurance and distance from CAR-T center to home (> or ≤ than 120 miles). Statistical analysis was then completed on the data. Fischer's Exact tests and Mann-Whitney tests were used to compare the patients, while log-rank tests were used to compare Kaplan-Meier Curves. Results A total of 25 pts were reviewed. Four pts had intended to be apheresed for CAR-T but did not reach the apheresis time point. In the entire cohort, the median PFS and OS have not been reached. The median follow-up was 5.5 months (range: 1.5 to 15 months) for those infused with CAR-T. Pts with public insurance (N=7) received CAR-T infusion more quickly (p = 0.0080) than those with private insurance (N=14). However, this did not influence PFS (p = 0.2856) or OS (p = 0.5073) with balanced disease and demographic characteristics other than age 120 miles; N=10 or ≤ 120 miles; N=11) from a patient's home to the CAR-T center did not affect PFS (p = 0.8914) or OS (p = 0.9078). Neither analysis for PFS or OS was significantly altered with the addition of the iCAR-T population. Conclusion In this experience, pts with public insurance appear to proceed from agreement to CAR-T with subsequent CAR-T infusion (Brain to Vein) more quickly, but the time to apheresis does not appear to affect outcome. Also, the distance from the CAR-T cell center does not appear to be a predictor for worse outcomes. Both logistical barriers occurring pre-apheresis warrant further assessment in a larger multicenter experience.

Autologous stem cell transplantation (ASCT) is standard of care for patients with Hodgkin lymphoma (HL) who have relapsed/refractory disease after frontline chemotherapy. Achievement of complete remission (CR) with pre-ASCT salvage chemotherapy predicts favorable outcomes post-ASCT. This phase 1/2 study evaluated the combination of brentuximab vedotin (BV) plus bendamustine as a first salvage regimen in relapsed/refractory HL. A total of 55 patients (28 primary refractory and 27 relapsed) were enrolled. Patients received BV (1.8 mg/kg) on day 1 and bendamustine (90 mg/m 2 ) on days 1 and 2 of a 21-day cycle for up to 6 cycles. Patients could undergo ASCT any time after cycle 2. Following ASCT or completion of combination therapy if not proceeding to ASCT, patients could receive BV monotherapy for up to 16 cycles of total therapy. After a median of 2 cycles of combination therapy (range, 1-6), the objective response rate among 53 efficacy-evaluable patients was 92.5%, with 39 patients (73.6%) achieving CR. Forty patients underwent ASCT. Thirty-one patients (25 of whom underwent ASCT) received BV monotherapy (median, 10 cycles; range, 1-14). After a median of 20.9 months of follow-up, the estimated 2-year progression-free survival was 69.8% and 62.6% for patients who received ASCT and all patients, respectively. Thirty-one patients (56.4%) experienced infusion-related reactions (IRRs), with a majority occurring during cycle 2 of combination therapy. A protocol amendment requiring premedication reduced IRR severity. BV plus bendamustine as first salvage therapy in relapsed/refractory HL is highly active with a manageable toxicity profile. This trial was registered at www.clinicaltrials.gov as #NCT01874054.

Introduction Hematopoietic cell transplantation-specific comorbidity index (HCT-CI) is a validated scoring system that assesses the risks of patients (pts) undergoing allogenic stem cell transplant. [Sorror et al. 2005] There has been emerging evidence of its value in risk discussion for pts undergoing autologous stem cell transplantation (ASCT). In a recent large (N=1730) retrospective study in pts with multiple myeloma (MM) or lymphoma, a high-risk HCT-CI was associated with higher rates of orotracheal intubation (OTI), 100-day non-relapsed mortality (NRM), and 1-year mortality. [Berro et al. 2017] Not well studied was disposition of a pt at the time of discharge post-transplant as it relates to HCT-CI risk. This could be an additional useful variable in pts/caregiver discussions pre-ASCT. Herein, we report a retrospective single institution review of our experience as it relates to HCT-CI to post-ASCT outcomes including level of care requirements at time of discharge. Methods We performed a retrospective review of pts with MM or lymphoma who received consolidative ASCT between May 2013 and March 2018. Pt demographic were collected. Pts HCT-CI were collected per defined variables by Sorror et al. Each pt was divided into three cohorts: low risk (HCT-CI score of 0), intermediate risk (HCT-CI score of 1-2), and high risk (HCT-CI ≥ 3). Discharge location was categorized into five dispositions: home with caregiver, home with supplemental care, skilled nursing facility, acute rehab facility, and died during transplant. Results Four hundred sixty-one charts were reviewed. Males were 62.0% of the population with a median age of 58.5. Disease populations were balanced with MM/lymphoma at 48.4%/51.6% respectively. MM pts received melphalan (140 or 200 mm/m2) and lymphomas received BEAM based conditioning. We found no statistical correlation of high-risk HCT-CI patients requiring higher rates of OTI during ASCT (p=0.1066) nor requiring a higher level of care post-ASCT transplant (p=0.2998). Furthermore we were unable to statistically correlate high-risk HCT-CI score with an increased rates of 100-day NRM (p=0.0681) or 1-year mortality (p=0.0656). We further investigated the breakdown of HCT-CI scoring of high-risk pts (n=177). The dominant comorbid conditions that appeared to be driving points towards a high-risk designation was cardiopulmonary (70.5%) and psychiatric (34.5%). Conclusion In our single center experience the categorization of high-risk HCT-CI prior to ASCT did not portend a higher risk with regards to OTI, 100-day NRM, or 1-year NRM when compared to pts categorized as low and intermediate risk in ASCT. A high risk HCT-CI score did not predict for a statistically significant increase in need for higher level of care post ASCT beyond caregiver support.

Essential thrombocythemia is well-known to transform to other myeloid disorders, such as leukemia; however, the risk for development of lymphoma is not as well studied. This case report discusses a 76-year-old man with a history of prefibrotic post-essential thrombocythemia myelofibrosis on ruxolitinib, who developed anemia, thrombocytopenia, and leukocytosis with peripheral blasts. Results of a bone marrow biopsy and PET and CT scans revealed stage IV leukemic diffuse large B-cell lymphoma. Several days after cessation of ruxolitinib, the patient developed fevers, hypotension, and low-grade disseminated intravascular coagulation, and subsequently developed spontaneous tumor lysis syndrome, which resulted in death. This case is unique in several aspects: it highlights the rare possibility of lymphomatous transformation of myeloproliferative disorders, an unusual presentation of lymphoma masquerading as leukemia, and the possibility of ruxolitinib withdrawal syndrome. Additionally, this case serves as a reminder that the use of novel therapies should be adopted after a thorough assessment of long-term risks, including those associated with abrupt withdrawal.

The use of radiation (RT) in primary mediastinal large B-cell lymphoma (PMBCL) may predispose young patients to the risk of cardiopulmonary toxicities and secondary malignancies. We used Surveillance, Epidemiology and End Results (SEER) 18 database to compare the overall survival (OS) differences among adult patients treated with and without RT after rituximab approval in the US. Multivariate analyses were performed using Cox proportional hazards regression to compare OS based on the use of RT while adjusting for age, year of diagnosis, race, stage and gender. PMBCL patients (n = 258), who received RT (48%), were similar in terms of age, gender, race, and stage at diagnosis to patients who did not receive RT. The five year OS was similar between patients treated with versus without RT (82.5% vs. 78.6%, P = 0.47). In a multivariate analysis, the use of RT did not influence OS in the rituximab era (HR 0.83; 95% CI 0.43-1.59; P = 0.56). Rituximab may reduce the benefit of RT in select patients such as those who achieve a metabolic complete remission at the end of chemotherapy.

Classical Hodgkin lymphoma treatment is evolving rapidly with high response rates from antibody-drug conjugates targeting CD30 and immune checkpoint antibodies. However, most patients do not achieve a complete response, therefore development of novel therapies is warranted to improve patient outcomes. In this phase II study, patients with relapsed or refractory Hodgkin lymphoma were treated with entinostat, an isoform selective histone deacetylase inhibitor. Forty-nine patients were enrolled: 33 patients on Schedule A (10 or 15 mg oral entinostat once every other week); 16 patients on Schedule B (15 mg oral entinostat once weekly in 3 of 4 weeks). Patients received a median of 3 prior treatments (range 1-10), with 80% of the patients receiving a prior stem cell transplant and 8% of patients receiving prior brentuximab vedotin. In the intention-to-treat analysis, the overall response rate was 12% while the disease control rate (complete response, partial response, and stable disease beyond 6 months) was 24%. Seven patients did not complete the first cycle due to progression of disease. Tumor reduction was observed in 24 of 38 (58%) evaluable patients. Median progression-free survival and overall survival was 5.5 and 25.1 months, respectively. The most frequent grade 3 or 4 adverse events were thrombocytopenia (63%), anemia (47%), neutropenia (41%), leukopenia (10%), hypokalemia (8%), and hypophosphatemia (6%). Twenty-five (51%) patients required dose reductions or delays. Pericarditis/pericardial effusion occurred in one patient after 12 cycles of therapy. Future studies are warranted to identify predictive biomarkers for treatment response and to develop mechanism-based combination strategies. (clinicaltrials.gov identifier: 00866333).

Background: This large population-based study determined the epidemiology and outcomes of secondary acute myeloid leukemia (sAML) developing in Hodgkin lymphoma survivors. Methods: We utilized the Surveillance Epidemiology and End Results (SEER) 9 database to identify 104 cases of sAML. Results: Patients with sAML (median age: 47 years; 82%

The optimal management of hematologic malignancy-associated venous thromboembolism (VTE) in patients with moderate-to-severe thrombocytopenia is unclear. This is a retrospective study of 128 adult patients with hematologic malignancies who were diagnosed with VTE. The outcome of patients with significant thrombocytopenia (≤50,000/µL) was compared with those without. Forty-seven patients (36.7%) had a platelet count ≤50,000/µL during a period of time of perceived need for new or continued anticoagulation. The median nadir platelet count in those with significant thrombocytopenia was 10,000/µL (range 2,000-45,000/µL) versus 165,000/µL (50,000-429,000/µL) in those without (P 0.001). The median duration of significant thrombocytopenia in the first group was 10 days (1-35 days). Therapy during the period of significant thrombocytopenia included prophylactic-dose low-molecular-weight heparin (LMWH) (47%), therapeutic-dose LMWH or heparin (30%), warfarin (2%), inferior vena cava filter (2%), and observation (17%). Patients without thrombocytopenia were managed with the standard of care therapy. At a median follow-up of more than 2 years, the risk of clinically significant bleeding (11% vs 6%, P = 0.22) including major bleeding (6% vs 2%) and clot progression or recurrence (21% vs 22%, P = 1.00) were similar in patients with or without significant thrombocytopenia. In a multivariate analysis, the risk of recurrence/progression (hazard ratio, HR 0.59, 95% CI 0.21-1.66, P = 0.31) and hemorrhage rate (HR 0.29, 95% CI 0.05-1.56, P = 0.15) did not differ based on the presence of significant thrombocytopenia. Within the limits of this retrospective study, cautious use of prophylactic-dose LMWH may be safe in thrombocytopenic patients with hematologic malignancy-associated VTE. Am. J. Hematol. 91:E468-E472, 2016. © 2016 Wiley Periodicals, Inc.

Diffuse large B-cell lymphoma (DLBCL) includes two prognostically important subtypes, the germinal center B-cell (GCB) and the non-GCB types. The aim of this study was to evaluate immunohistochemical approaches for predicting the survival of patients with DLBCL following autologous hematopoietic stem cell transplantation (AHSCT). We identified 62 patients with DLBCL who either had an initial complete remission (17 patients) or received salvage chemotherapy for relapsed or refractory disease (45 patients), followed by AHSCT. Tissue microarrays were immunostained with monoclonal antibodies against GCET1, CD10, BCL6, MUM1, FOXP1 and LMO2. Using the Hans algorithm, we classified 50% of the cases as GCB type, whereas the Choi algorithm classified 58% as GCB type and LMO2 was positive in 69%. However, no significant differences were found in the 5-year overall or event-free survivals using any of these approaches. In conclusion, cell of origin fails to predict survival of DLBCL patients treated with AHSCT.

Primary central nervous system (CNS) lymphoma, most frequently a diffuse large B-cell lymphoma, is a rare aggressive lymphoma confined to the CNS, thus requiring differentiation from other brain malignancies such as glioblastoma. Although stereotactic biopsy can confirm the diagnosis, this is invasive, not always feasible and can be inconclusive after steroid use. Hence, cranial magnetic resonance imaging (MRI) with contrast and cerebrospinal fluid analysis are frequently used to make a prompt diagnosis. We report a case of a woman with two brain masses who presented unique diagnostic challenge.

Introduction: Umbralisib (UMB) is a next generation, once daily, PI3Kδ/CK1ε inhibitor, active in patients with relapsed or refractory (rel/ref) hematologic malignancies that, in long-term follow-up, has demonstrated a uniquely differentiated safety profile from prior PI3Kδ inhibitors (Davids, 2018). Ublituximab (UTX) is a novel glycoengineered mAb targeting a unique epitope on the CD20 antigen. Bendamustine (Benda) is an active chemotherapy agent in pts with lymphoma. The combination of UMB + UTX (U2) is tolerable and active in patients with rel/ref hematologic malignancies and registration directed trials for patients with CLL & NHL are ongoing. This Phase 1 trial evaluates the safety and efficacy of U2 + Benda in patients with advanced diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). Methods: Eligible patients had rel/ref DLBCL or FL with an ECOG PS ≤ 2 w/o limit to number of prior therapies. ANC of ≥ 750 and Platelets ≥ 50,000 were required; no growth factor support was permitted in Cycle 1 (cohort escalation group only). Patients refractory to prior PI3Kδ, Benda, or anti-CD20's were eligible. UTX was dosed on Days 1, 8, 15 of Cycle 1, Day 1 of Cycle 2-6, followed by Cycle 9 & 12. UMB was started at 800 mg QD with a -1 dose reduction cohort at 600 mg if not tolerated in ≥ 2/6 patients. Benda was dosed at 90 mg/m2 on Days 1 & 2 of Cycles 1-6 only. Primary endpoints included safety and efficacy (Cheson 2007). Results: Thirty-nine patients were evaluable for safety: 26 DLBCL and 13 FL. Med age 67 yo (range 31-81); 23 M/16 F; median prior treatment regimens = 2 (range 1-6); 22 pts (56%) were refractory to prior treatment and 6 patients had progressed post-transplant; ECOG PS 0/1/2 (12/25/2). Initially 2/4 patients at 800 mg UMB experienced AE's in Cycle 1 that led to treatment interruption (rash, neutropenia) thus the 600 mg dose of TGR-1202 was explored. No additional Cycle 1 treatment delays were reported at the 600 mg dose level, which was later expanded and the 800 mg UMB dose was evaluated with the use of growth factor support in cycle 1 permitted. The most common AE's regardless of causality included diarrhea (54%; G3/4 15%), nausea (49%; G3/4 5%), vomiting (38%; G3/4 0%), neutropenia (33%; G3/4 33%) and pyrexia (31%; G3/4 0%). Thirty-eight patients (25 DLBCL/13 FL) were evaluable for efficacy (1 DLBCL patient came off study for G4 neutropenia prior to first assessment). ORR in the respective groups is shown in Table 1. The median time to response was 8 weeks. The median DOR was 9.6 months (95% CI: 2.5-NR) for patients with DLBCL, and was not reached (95% CI: 8.0-NR) for patients with FL, at a median duration of follow-up for responders of 11.5 months (range 2.9 - 30+ mos). Conclusions: The combination of U2 + bendamustine has exhibited manageable toxicity with significant activity in advanced DLBCL and FL patients, including an encouraging CR rate in advanced patients. Based upon the early activity of the triplet, a registration directed study is underway for patients with rel/ref DLBCL (UNITY-NHL). Disclosures Lunning: Gilead: Consultancy; Astra-Zeneca: Consultancy; Genentech: Consultancy; Spectrum: Consultancy; TG Therapeutics: Consultancy; Bayer: Consultancy; Celgene: Consultancy; AbbVie: Consultancy; Genzyme: Consultancy; Kite: Consultancy; Juno: Consultancy; Genentech: Consultancy; Portola: Consultancy; Janssen: Consultancy; Seattle Genetics: Consultancy; Verastem: Consultancy. Siddiqi:Juno Therapeutics: Other: Steering committee. Flowers:Abbvie: Research Funding; TG Therapeutics: Research Funding; Gilead: Research Funding; Eastern Cooperative Oncology Group: Research Funding; National Cancer Institute: Research Funding; Genentech/Roche: Research Funding; Genentech/Roche: Consultancy; Pharmacyclics: Research Funding; V Foundation: Research Funding; Abbvie: Consultancy, Research Funding; Bayer: Consultancy; Karyopharm: Consultancy; Burroughs Wellcome Fund: Research Funding; Celgene: Research Funding; BeiGene: Research Funding; Gilead: Consultancy; Millennium/Takeda: Research Funding; OptumRx: Consultancy; Pharmacyclics/ Janssen: Consultancy; Spectrum: Consultancy; Janssen Pharmaceutical: Research Funding; Denovo Biopharma: Consultancy; Acerta: Research Funding. Cohen:Millennium: 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; 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; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Infinity Pharmaceuticals: 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; Infinity Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Janssen: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: 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; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioInvent: Consultancy; Takeda: Research Funding; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BioInvent: Consultancy. Blumel:TG Therapeutics, Inc.: Consultancy. Cutter:TG Therapeutics, Inc.: Consultancy. Pauli:TG Therapeutics, Inc.: Consultancy. Sportelli:TG Therapeutics: Employment, Equity Ownership. Miskin:TG Therapeutics: Employment, Equity Ownership. Weiss:TG Therapeutics: Employment, Equity Ownership. Vose:Kite Pharma: Research Funding; Legend Pharmaceuticals: Honoraria; Roche: Honoraria; Incyte Corp.: Research Funding; Bristol Myers Squibb: Research Funding; Novartis: Honoraria, Research Funding; Abbvie: Honoraria; Seattle Genetics, Inc.: Research Funding; Merck Sharp & Dohme Corp.: Research Funding; Acerta Pharma: Research Funding; Epizyme: Honoraria; Celgene: Research Funding.

Introduction: Treatment for relapsed or refractory (rel/ref) diffuse large B-cell lymphoma (DLBCL) remains an unmet medical need despite the recent approval of chimeric antigen receptor T-cell (CAR-T) therapeutic constructs. Many patients will be "too sick to CAR-T" or may have logistical/financial challenges that will not allow this treatment. As a result, non-chemotherapy agents with activity in rel/ref DLBCL require further development to help fill this need. Umbralisib (UMB) is dual PI3K delta/CK-1ε inhibitor that has single agent activity in rel/ref DLBCL with an ORR of 31% [Burris et al. 2018]. Ibrutinib (IBR) is a Bruton Tyrosine kinase (BTK) inhibitor with activity seen in the activated B-cell (ABC) subtype of DLBCL with an ORR of 37% in this subtype [Wilson et al. 2015]. Pre-clinical data (not shown) demonstrated synergistic activity of UMB-IBR against cell lines of both germinal center B-cell (GCB) and non-GCB subtypes of DLBCL. We report results of phase IIa study of the combination of UMB-IBR in rel/ref DLBCL. Methods: Eligible patients (pts) had relapsed or refractory DLBCL, ANC ≥1000 cells/mm3, platelets ≥100 K/mm3, and adequate organ function. The Hans algorithm defined cell of origin. UMB was dosed at 800 mg daily in AM and IBR 560 mg daily in PM. Treatment stratification was performed on a 1:1:1 design to Cohort A (UMB), B (IBR), or C (UMB+IBR) by consent to optional biopsies, which included optional pre-treatment and day 8 biopsies to assess pre-specified correlative flow cytometric analysis of the B-cell receptor (BCR) pathway. In cohorts A/B the combination was initiated at day 8. A cycle was 28 days. Pts received UMB-IBR for up to 1-year of therapy in the absence of progression disease (PD) or excess toxicity. The primary endpoint was monitoring for cumulative toxicity events (CTEs) occurring during cycles 1-4. A CTE was defined as grade (G) 4 neutropenia or thrombocytopenia, G3 neutropenia or thrombocytopenia last longer than 7 days, G3 non-hematologic toxicity, or any G adverse event which led to a drug hold > 7 days. Consecutive stopping rules for CTEs and efficacy were employed. Secondary endpoints included overall response rate (ORR), complete response (CR) rate, partial response (PR) rate, progression-free survival (PFS), time to response (TTR), and duration of response (DOR). Results: Thirteen pts with rel/ref DLBCL were enrolled. Median age was 71 years (range 27-81) and 9 were male. Median number of prior therapies was 2 [range 1-7] with 8% having undergone prior autologous transplantation. Sixty-two percent were refractory to last therapy. DLBCL subtypes were GCB in 7 and non-GCB in 6 pts. The first 3 pts were enrolled to Cohort C regardless of optional biopsy consent. Cohorts A (n=1) and B (n=1) included pts that consented to optional biopsies. Cohort C (n=11) included the first 3 pts enrolled into the study and those thereafter that did not consent to optional biopsies. Two CTEs were seen: G3 rash and G3 Clostridium difficile (C. diff) diarrhea. No CTEs occurred during cycle 1. Notable serious or recurrent adverse events (SAEs or AEs) of interest occurring across all cycles regardless of attribution included elevated AST/ALT 0% G 3-4 (all G 31%), nausea 15% G 3-4 (all G 54%), and diarrhea 15% G 3-4 (all G 31%). The ORR of the UBR-IBR regimen was 23% with 2 PRs (both GCB) and 1 CR (non-GCB). The pt in CR remains on treatment at 7 months and recovered from a CTE during cycle 4 (C. diff). The median PFS was 3 months [95 % CI 0.85, 3.8]. No patient was taken off study for toxicity and there were no dose reductions necessary. Conclusion: In this phase IIa study of rel/ref DLBCL, the non-chemotherapy regimen of UMB-IBR was well tolerated with only 2 CTEs and limited AEs. The evaluation of CTEs was limited by the rapid PD in many pts seen prior to 4 cycles of therapy. The ORR of the UMB-IBR was modest (23%) and of limited durability in this difficult to treat patient population. Based on limited activity and difficulty in obtaining biopsies for correlative analyses, this study was terminated prematurely. Disclosures Lunning: Portola: Consultancy; Spectrum: Consultancy; Genzyme: Consultancy; Genentech: Consultancy; Juno: Consultancy; Bayer: Consultancy; Seattle Genetics: Consultancy; Celgene: Consultancy; Astra-Zeneca: Consultancy; Genentech: Consultancy; Kite: Consultancy; AbbVie: Consultancy; Janssen: Consultancy; Gilead: Consultancy; TG Therapeutics: Consultancy; Verastem: Consultancy. Blumel:TG Therapeutics, Inc.: Consultancy. Vose:Epizyme: Honoraria; Seattle Genetics, Inc.: Research Funding; Merck Sharp & Dohme Corp.: Research Funding; Roche: Honoraria; Acerta Pharma: Research Funding; Abbvie: Honoraria; Kite Pharma: Research Funding; Legend Pharmaceuticals: Honoraria; Incyte Corp.: Research Funding; Bristol Myers Squibb: Research Funding; Novartis: Honoraria, Research Funding; Celgene: Research Funding.

Background: Standard therapeutic regimens for older HL patients (pts) may confer significantly increased toxicity and inferior survival compared with younger pts. Reported complete remission (CR) rates for older pts are 45-76% with 2-year (yr) progression-free survival (PFS) rates of 50-71% (eg, Evens et al. Blood 2012). With a goal of improving outcomes for older cHL pts, this multicenter phase 2 study tested Bv given sequentially before and after standard AVD chemotherapy. Methods: Older pts (aged ≥60 yrs) with stage IIB-IV, untreated cHL were eligible. Pts received 2 'lead-in' doses of single-agent Bv 1.8 mg/kg (q 3 weeks) followed by 6 cycles of standard AVD. Supportive antibiotics were encouraged & granulocyte growth factor was allowed. Responding pts proceeded to consolidation (Cx) therapy with 4 Bv cycles. Study design was a Simon 2-stage; the primary endpoint was CR rate after AVD (ie, prior to Bv Cx) using revised Cheson with FDG-PET; pts must have received 2 cycles of AVD to be evaluable for response. The study was considered promising if >70% of evaluable pts demonstrated CR. Univariate & multivariate analyses (MVA) were performed using Cox proportional hazard regression for associations between lab and clinical factors (including co-morbidities assessed by the Cumulative Illness Rating Scale (CIRS)) with survival. Results: 48 pts enrolled to the study (8/2012-8/2016) with 41 being evaluable for response. Characteristics for all pts included: median age 69 yrs (60-88); 30M:18F; median ECOG PS of 1 (21% PS=2); 82% stage III/IV disease (bone marrow involved 23%); and IPS 3-7 in 60%. No pts had loss of activities of daily living (ADL) at baseline, while 12% had loss of instrumental ADLs. Median CIRS co-morbidity score at baseline was 6 (0-20). 6 pts received 1 pt were neutropenia (60%); infection (15%), febrile neutropenia (8%); transaminitis (6%); renal insufficiency (6%); urinary infection (6%); pneumonia (6%); hyponatremia (6%); fatigue (6%); febrile neutropenia (6%); diarrhea (4%); pancreatitis (4%), & peripheral neuropathy (PN) (4%). 33% of all pts experienced grade 2 PN (6% motor/27% sensory); the majority were reversible. Treatment related mortality on study was 2% (n=1 pancreatitis). Reasons for study discontinuation were: completed treatment (52%); toxicity/AEs (33%); withdrew consent/refused additional treatment (9%); & progressive disease or death (6%). Finally, for pt prognostication, increasing age (continuous) (P=0.005), female (P=0.05) & increased CIRS (continuous) (P=0.006) were associated with inferior PFS on univariate analysis; on MVA, only increasing age remained significant (HR 1.19 per yr >60, 95%CI 1.02-1.37, P=0.02). Conclusions: Bv-AVD incorporating Bv sequentially before and after chemotherapy represents among the best-reported outcomes to date for untreated older cHL pts. Efforts to maintain these robust remission and survival rates, but with less toxicity, should be a focus of ongoing investigation. This should include response-adapted design and integration of other novel agents (eg, checkpoint inhibitors), especially for pts with advanced ages and/or multiple co-morbidities. Disclosures Evens: Novartis: Consultancy; Affimed: Consultancy; Merck: Consultancy; Kite Pharma: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Millennium: Consultancy; AbbVie: Consultancy; Pharmacyclics: Consultancy; Seattle Genetics: Consultancy; • Spectrum Pharmaceuticals: Consultancy. Advani: Spectrum: Consultancy; Gilead: Consultancy; Agensys: Research Funding; Bayer Healthcare Pharmaceuticals: Research Funding; Merck: Research Funding; Celgene: Research Funding; Seattle Genetics: Research Funding; Kura: Research Funding; Regeneron: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Nanostring: Consultancy; FortySeven: Research Funding; Janssen: Research Funding; Cell Medica: Research Funding; Millennium: Research Funding; Pharmacyclics: Consultancy; Sutro: Consultancy; Juno Therapeutics: Consultancy; Pharmacyclics: Research Funding; Infinity: Research Funding; Genentech: Research Funding. Fanale: ONYX: Research Funding; CELGENE: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; TAKEDA: Honoraria, Research Funding; AMGEN: Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; SEATTLE GENETICS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GENENTECH: Research Funding; MERCK: Membership on an entity's Board of Directors or advisory committees, Research Funding; MOLECULAR TEMPLATES: Research Funding; ADC THERAPEUTICS: Research Funding. Winter: Merck: Research Funding; Glaxo-Smith-Kline: Research Funding. Gordon: Janssen: Other: Data Monitoring Committee. Hamlin: Celgene: Consultancy, Honoraria; Portola: Consultancy, Honoraria, Other: research support; Incyte: Other: research support; Gilead: Consultancy, Honoraria; Novartis: Other: research support; Seattle Geneitcs: Other: research support.

Phase 1 testing of SGN-30, a chimeric monoclonal antibody for the treatment of CD30+ malignancies, was conducted in a multicenter study. To explore the safety profile and establish the maximum tolerated dose (MTD), 24 patients with refractory or relapsed Hodgkin lymphoma or CD30+ non-Hodgkin lymphoma received 6 weekly doses of intravenous SGN-30 at 4 dose levels (2, 4, 8, or 12 mg/kg). Serum concentrations of SGN-30 rose rapidly and were dose dependent. Adverse events were mild, with nausea, fatigue, and fever attributed to study treatment. One episode of hypersensitivity rash was reported. The MTD was not reached. Serious adverse events included herpes zoster (n = 2), influenza, and pneumonia. One patient with cutaneous anaplastic large cell lymphoma (8 mg/kg) achieved a complete response. Six patients, of whom 4 had Hodgkin lymphoma, achieved stable disease with durations ranging from 6 to 16 months. The pharmacokinetic profile of SGN-30 showed a biphasic disposition, and estimated half-lives ranging between 1 to 3 weeks. The 6 weekly infusions of SGN-30 resulted in approximately 2- to 3-fold accumulation in serum exposures consistently across the dose range. These results demonstrate that weekly administration of SGN-30 is safe and has modest clinical activity in patients with CD30+ tumors. This trial is registered at as no. [NCT00051597][1]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00051597&atom=%2Fbloodjournal%2F111%2F4%2F1848.atom

Although results of autologous stem cell transplantation (SCT) for recurrent follicular non-Hodgkin lymphoma (NHL) have been previously reported, the long-term results and evaluation of prognostic factors in a large patient population receiving this therapy are difficult to find in the literature. To address these issues, we evaluated 248 patients with recurrent follicular NHL treated with high-dose chemotherapy and autologous SCT between 7/87 and 6/03. According to the World Health Organization (WHO) classification system, 64 patients (26%) had follicular NHL grade 1 (FL 1), 98 (40%) had FL 2, and 86 (35%) had FL 3. At the time of transplantation, 88 of the patients (35%) had a Follicular Lymphoma International Prognostic Index (FLIPI) score of low risk, 87 (35%) had an intermediate-risk FLIPI score, 37 (15%) had a high-risk FLIPI score, and 36 (15%) had at least 1 missing value, preventing calculation of the FLIPI score. The 5-year overall survival (OS) for all patients was 63%, and the 5-year progression-free survival (PFS) was 44%. In a multivariate analysis, a histological grade of FL 3, a high-risk FLIPI score at the time of transplantation, and having received 3 or more previous chemotherapy regimens were significant factors for predicting a worse OS. In addition, the use of a transplantation regimen including a monoclonal antibody decreased the relative risk of progressive lymphoma. These data suggest that transplantation earlier in the course of the disease for patients with follicular lymphoma with use of a monoclonal antibody–based regimen may lead to improved outcomes.

The use of radiation (RT) in primary mediastinal large B-cell lymphoma (PMBCL) may predispose young patients to the risk of cardiopulmonary toxicities and secondary malignancies. We used Surveillance, Epidemiology and End Results (SEER) 18 database to compare the overall survival (OS) differences among adult patients treated with and without RT after rituximab approval in the US. Multivariate analyses were performed using Cox proportional hazards regression to compare OS based on the use of RT while adjusting for age, year of diagnosis, race, stage and gender. PMBCL patients (n = 258), who received RT (48%), were similar in terms of age, gender, race, and stage at diagnosis to patients who did not receive RT. The five year OS was similar between patients treated with versus without RT (82.5% vs. 78.6%, P = 0.47). In a multivariate analysis, the use of RT did not influence OS in the rituximab era (HR 0.83; 95% CI 0.43-1.59; P = 0.56). Rituximab may reduce the benefit of RT in select patients such as those who achieve a metabolic complete remission at the end of chemotherapy.

Summary. The cell surface proteins CD20 and CD52 differ significantly in their structures and are expressed on the majority of B cells. Both circulating CD20 (cCD20) and circulating CD52 (cCD52) have been recently documented in patients with chronic lymphocytic leukaemia. A retrospective study to establish whether cCD20 and/or cCD52 were detectable in patients with lymphoma, and the clinical associations of these soluble antigens if detected, was conducted. cCD20 and cCD52 levels were analysed in a cohort of 65 patients with non-Hodgkin's lymphoma (NHL) and 37 with Hodgkin's disease (HD). Patients with NHL had elevated pretherapy levels of cCD20 and cCD52 compared with normal individuals. Patients with HD had significantly lower than normal pretherapy levels of both cCD20 and cCD52. cCD20 levels were marginally elevated post-therapy in NHL patients while in patients with HD, cCD20 levels remained significantly lower than normal after therapy. Serum cCD52 levels became significantly lower than normal post-therapy in NHL patients, and remained significantly lower than normal in HD patients. No predictive effects were found for pretherapy or post-therapy levels of cCD52 on survival for either cohort of patients. Post-therapy cCD20 levels independently highly correlated with survival in patients with NHL. Prospective evaluation will be required to establish if cCD20 and cCD52 may be used as biomarkers in the diagnosis, prognostic categorization, and monitoring of the clinical course in patients with lymphoma. The clinical significance of circulating antigen in patients receiving monoclonal antibody therapy directed against CD20 and/or CD52 warrants study.

PURPOSE: To evaluate the results of high-dose chemotherapy and transplantation of highly purified "mobilized" peripheral blood CD34+Thy-1+ hematopoietic stem cells (HSCs) in patients with recurrent indolent non-Hodgkin's lymphoma (NHL) or mantle cell lymphoma (MCL). PATIENTS AND METHODS: Twenty-six patients with recurrent indolent NHL or MCL were mobilized witheither granulocyte colony-stimulating factor (G-CSF) alone or cyclophosphamide plus G-CSF. Apheresis was performed, and the product was purified using the Isolex immunomagnetic positive CD34+ cell selection device initially and subsequent high-speed flow-cytometric cell sorting for the final purification of CD34+Thy-1+ HSCs. The patients received high-dose chemotherapy with BEAC (carmustine, etoposide, cytarabine, and cyclophosphamide) followed by transplantation with the purified HSCs in 2 dose cohorts (cohort 1: > or=5 x 10(5) viable and pure HSC/kg; cohort 2: > or=3 x 10(5) HSC/kg). RESULTS: We attempted to mobilize 26 patients with G-CSF alone. Six patients did not collect adequate cells with G-CSF alone; subsequent mobilization with cyclophosphamide plus G-CSF was attempted, but adequate CD34+Thy-1+ HSCs could not be collected on these 6 patients. Twenty patients underwent transplantation with the BEAC transplantation regimen followed by purified HSCs. Patients in cohort 1 engrafted at a median of day 12 to an absolute neutrophil count (ANC) >500/microL, a median of day 19 for platelet transfusion independence, and a median of day 20 for red blood cell transfusion independence. Patients in cohort 2 engrafted at a median of day 12 to an ANC >500/microL, a median of day 12 for platelet transfusion independence, and a median of day 12 for red blood cell transfusion independence. Fourteen of the 20 patients had significant infections reported at some point posttransplantation, including influenza, respiratory syncytial virus, pneumonitis, and Pneumocystis carinii pneumonia. With a median follow-up of 38 months, 8 of the 20 patients have had progressive lymphoma and 5 patients have died. The 3-year event-free survival is 55%, and overall survival is 78%. CONCLUSIONS: CD34+Thy-1+ HSCs can be collected successfully from most lymphoma patients mobilized with G-CSF alone. The engraftment and disease outcomes in the patients in this small pilot study using these cells do not appear to be different from the outcomes of similar patients cited in the literature. However, the short- and long-term risks of infection were a concern in this patient population. Biol Blood Marrow Transplant 2001;7(12):680-7.

Patients receiving high-dose preparation for stem cell transplantation are at risk for organ dysfunction (OD). Signs of early OD include hypoxia, mental status changes, and liver dysfunction. These early signs have not been correlated with potential cytokine mediators. We compared plasma concentrations of IL-6, TNF-α, and IL-10 in OD patients and controls. Cytokines were measured before preparation, 5 days before OD, day of OD, and 5 days after OD. TNF-α and IL-10 were not measurable prior to preparation. IL-10 was more likely to be measurable in OD patients than in controls 5 days prior to onset of OD (P = 0.039), on the day of OD (P = 0.023), and 5 days later (P < 0.0001). TNF-α was more likely to be measurable only on the day of OD (P = 0.0035). IL-6 was significantly elevated in OD patients at all time points. Patients who had measurable IL-6 on admission were 5.1 times more likely to develop OD (95% CI = 1.4–17.9; P = 0.011). Five days prior to OD for each 100 pg/ml increase in IL-6, patients were 2.75 times more likely to develop OD (95% CI = 1.3–5.8; P = 0.0087). The early elevation of IL-6 in patients who develop OD may help identify a high risk group where preventive therapies can be evaluated. Bone Marrow Transplantation (2001) 28, 889–893.

Introduction: Ublituximab (UTX) is a novel glycoengineered mAb targeting a unique epitope on the CD20 antigen. TGR-1202 is a next generation, once daily, PI3Kδ inhibitor, active in patients (pts) with rel/ref hematologic malignancies that has demonstrated a notably differentiated safety profile, including in long-term follow up (Burris, 2016). Bendamustine (Benda) is an active chemotherapy agent in pts with lymphoma. The combination of UTX + TGR-1202 has been previously explored in patients with rel/ref hematologic malignancies and is both well tolerated and highly active. This Phase 1 trial evaluates the safety and efficacy of UTX + TGR-1202 + Benda in pts with advanced diffuse large B-cell lymphoma (DLBCL) and Follicular Lymphoma (FL). Methods: Eligible pts had rel/ref DLBCL or FL with an ECOG PS ≤ 2 w/o limit to number of prior therapies. ANC of ≥ 750 and Platelets ≥ 50,000 were required; no growth factor support was permitted in Cycle 1 (safety evaluation period). Pts refractory to prior PI3Kδ, Benda, or anti-CD20's were eligible. The study was designed to evaluate the safety and efficacy of the triplet combination. UTX was dosed on Days 1, 8 & 15 of Cycle 1, Day 1 of Cycle 2-6, followed by Cycle 9 & 12. TGR-1202 was started at 800 mg QD with a -1 dose reduction cohort at 600 mg if not tolerated in ≥ 2/6 pts. Benda was dosed at 90 mg/m2on Days 1 & 2 of Cycles 1-6 only. Efficacy was evaluated per Cheson 2007. Results: Thirteen pts were evaluable for safety: 9 diffuse large B-cell (DLBCL) and 4 follicular (FL). Med age 65 yo (range 51-81); 7 M/6 F; median prior treatment regimens = 3 (range 1-6); 8 pts (62%) were refractory to prior treatment; 10 pts (77%) were rituximab refractory; ECOG PS 0/1 (1/12). Two of four pts at 800 mg TGR-1202 experienced AE's in Cycle 1 (rash, neutropenia) that led to treatment interruption thus the 600 mg dose of TGR-1202 was explored. No additional Cycle 1 treatment delays were reported at the 600 mg dose level, which was later expanded (n=9). The most common AE's regardless of causality included diarrhea (46%), nausea (38%), decreased appetite and neutropenia (31% each). Grade 3/4 AE's (all causality) reported in > 10% of pts were neutropenia (31%), followed by anemia and hypokalemia (15% each). Two pts had dose reductions (both benda and TGR-1202 reduced). Eight pts (6 DLBCL/2 FL) were evaluable for efficacy (4 too early, 1 withdrew due to non-related AE): ORR was 100% (8/8) with all pts achieving a response at the first efficacy assessment (8 weeks), and 50% (4/8) achieving a complete response (CR), of which 3 were DLBCL and 1 FL. Median follow-up time on study is 3 mos for all pts (range 1 - 9+ mos). No pts have progressed on study to date. Conclusions: The combination of UTX, TGR-1202, and bendamustine has exhibited manageable toxicity with significant activity (100% ORR) including a 50% CR rate in pts with advanced DLBCL and FL. Enrollment continues at the 600 mg TGR-1202 dose level and the use of growth factor prophylaxis is now being explored at the TGR-1202 800 mg dose in consideration of the advanced patient population. Safety and efficacy data for all pts will be updated at the meeting. Based upon the early activity of the triplet, future registration directed studies are under consideration. Disclosures Lunning: Bristol-Myer-Squibb: Consultancy; AbbVie: Consultancy; Pharmacyclics: Consultancy; Juno: Consultancy; TG Therapeutics: Consultancy; Gilead: Consultancy; Genentech: Consultancy; Spectrum: Consultancy; Celgene: Consultancy. Blumel:TG Therapeutics, Inc.: Consultancy. Sportelli:TG Therapeutics, Inc.: Employment, Equity Ownership. Miskin:TG Therapeutics, Inc: Employment, Equity Ownership. Weiss:TG Therapeutics, Inc.: Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

Background: Peg-asparaginasecan cause dysregulationof pro-coagulant and anti-coagulant proteins, resulting in a significant risk of venous thromboembolism(VTE) in ALL, particularly in adults undergoing induction chemotherapy. In late 2014, we adopted a policy at our institution to use prophylactic dose ofenoxaparin 40 mg daily for up to 3 weeks following the administration of peg-asparaginase. Patients are also to undergo monitoring of complete blood count, and coagulation parameters including fibrinogen and anti-thrombin. Enoxaparin may be held if patients develop severe thrombocytopenia (platelet count Methods: This is a single-center study of17 consecutive adult patients (>18 years old) treated for ALL with peg-asparaginasecontaining induction regimen before and after the establishment of institutional policy to useenoxaparinprophylaxis. Patients were identified from hospital research database. The diagnoses were verified. Medical records were reviewed for the occurrence of any clinically relevant bleeding and VTE within 3 months of receiving peg-asparaginase. Levels of coagulation parameters, whenever available, were collected at baseline and at weekly intervals for up to 4 weeks after receiving peg-asparaginase. The risk of bleeding and VTE among patients receivingenoxaparinwas compared to those who did not receiveenoxaparin. Fisher exact test was used for testing the association of categorical variable, and binomial exact test was used for computing confidence intervals. T-test or nonparametric test was used for comparing the continuous variables depending on whether or not the data were normally distributed. Results: The patient population consisted of 59% females. Mean age was 35 years. Histology consisted of Pre-B ALL in 76%, pre-T ALL in 18% and mixed lineage leukemia in 6%. 88% percent received pediatric-type chemoregimenand intramuscular peg-asparaginase; the most common doses of peg-asparaginaseincluded 2000 mg/m2 (41%) and 2500 mg/m2 (35%). Duration ofenoxaparin prophylaxis was 21 days in 66.7% and 7 days in 33.3%. Average changes in coagulation parameters at baseline and at weekly intervals following the use of peg-asparaginase therapy are highlighted in figures 1 and 2. The drop inantithrombin and fibrinogen levels was the highest during the first two weeks after the administration of peg-asparaginase. 41% of patients required cryoprecipitate (median 15 units, range 5-35 units over 4 weeks). No patients, including theenoxaparin group, had any clinically relevant bleeding event. The risk of VTE was 18% (95% confidence 4-43%); 2 out of 3 VTE events were cerebral venous thrombosis. No VTE occurred in theenoxaparin prophylaxis group (n=9), whereas 37% of patients (3 out of 8 patients), who did not receiveenoxaparin, developed VTE.Enoxaparin prophylaxis was associated with a trend towards a lower risk of VTE, however, the difference was not statistically significant (p=0.08). Conclusion: Within the limits of this study, in adult ALL patients receiving peg-asparaginase, the use of daily prophylactic dose ofenoxaparinmay not be associated with an increased risk of clinically relevant bleeding, and may have a potential to lower the risk of VTE. Patients receivingenoxaparin, however, should be carefully monitored for the need of platelet transfusion and cryoprecipitate supplementation. The difference in the risk of VTE was not statistically significant, which may be, in part, due to a small sample size.Antithrombindepletion may also contribute to a reduction in the efficacy ofenoxaparin. Larger prospective studies should be performed to validate the preliminary findings. Figure 1 Changes in prothrombin time and partial thromboplastin time Figure 1. Changes in prothrombin time and partial thromboplastin time Figure 2 Changes in antithrombin and fibrinogen levels Figure 2. Changes in antithrombin and fibrinogen levels Disclosures Armitage: Spectrum Pharmaceuticals: Consultancy; Roche: Consultancy; Conatus - IDMC: Consultancy; GlaxoSmithKline IDMC: Consultancy; ZiopharmOncology: Consultancy; Tesaro bio Inc: Membership on an entity's Board of Directors or advisory committees. Lunning:Genentech: Consultancy; AbbVie: Consultancy; Bristol-Myer-Squibb: Consultancy; Juno: Consultancy; Spectrum: Consultancy; Pharmacyclics: Consultancy; Celgene: Consultancy; Gilead: Consultancy; TG Therapeutics: Consultancy.

BACKGROUND. The objective of this study was to correlate the failure pattern of localized prostate carcinoma after radiotherapy (RT) with pretreatment (preTx) PSA and post-RT nadir PSA, using systematic biopsies and serum PSA in the assessment of outcome. METHODS. From January 1990 to February 1994, 207 patients treated with external beam RT were followed prospectively with systematic transrectal ultrasound-guided biopsies and measurements of serum PSA levels. Three hundred forty-three biopsies were performed, with 4-7 samples taken per session. The distribution of T classification was as follows: 19 patients had T1b, 15 had T1c, 34 had T2a, 79 had T2b/c, 53 had T3, and 7 had T4. Median follow-up was 36 months (range, 12-70 months). Failures were categorized as biochemical (chemF) (PSA > 2.0 ng/mL and >1 ng/ mL over nadir), local (LF) (positive biopsy and PSA > 2), and distant (DF). The Cox proportional hazards model was used for multivariate analysis (MVA). RESULTS. Overall, failures were seen in 68 of 207 patients: 20 LF, 24 DF, 7 LF + DF, and 17 chemF. In univariate analysis, failures correlated significantly with preTx PSA, post-RT nadir PSA, T classification, and Gleason's score (GS). The total failure rate was 12% for T1b, T1c, and T2a; 39% for T2b and T2c; and 60% for T3 and T4 (P 50 ng/ml. (P 2 ng/mL (P < 0.0001). In MVA, nadir PSA (P < 0.0001) and T classification (P < 0.0005) were independent predictors for any failure. LF occurred in 13% of patients (27 of 207). For these 27 patients, the categorization of T classification was: T1b/T1c/T2a, 7%; T2b/T2c, 16%; and T3/T4, 15% (P = not significant). In MVA, only nadir PSA (P = 0.0004) predicted for LF. DF occurred in 15% of patients (31 of 207). In MVA, nadir PSA (P < 0.0001) and T classification (P < 0.0001) predicted for DF, with pretreatment PSA of borderline significance (P < 0.05). To assess preTx predictors of outcome, post-RT nadir PSA was removed from the model. PreTx PSA then became the dominant variable to predict any failure (P < 0.0001), LF (P = 0.05), chemF (P = 0.0001), and DF (P < 0.003), while T classification also predicted for any failure (P = 0.03), chemF (P = 0.05), and DF (P < 0.0001). CONCLUSIONS Systematic prostate biopsies, performed as part of the rigorous followup of prostate carcinoma after RT, define the pattems of failure and confirm the prognostic value of preTx PSA, post-RT nadir PSA, and T classification. Prior to treatment, preTx PSA is the overwhelming independent predictor of failure, but it is surpassed by post-RT nadir PSA when this is added to the model.

Earlier, we reported that CTLA4 expression is inversely correlated with CD38 expression in chronic lymphocytic leukemia (CLL) cells. However, the specific role of CTLA4 in CLL pathogenesis remains unknown. Therefore, to elucidate the possible role of CTLA4 in CLL pathogenesis, CTLA4 was down-regulated in primary CLL cells. We then evaluated proliferation/survival in these cells using MTT, (3)H-thymidine uptake and Annexin-V apoptosis assays. We also measured expression levels of downstream molecules involved in B-cell proliferation/survival signaling including STAT1, NFATC2, c-Fos, c-Myc, and Bcl-2 using microarray, PCR, western blotting analyses, and a stromal cell culture system. CLL cells with CTLA4 down-regulation demonstrated a significant increase in proliferation and survival along with an increased expression of STAT1, STAT1 phosphorylation, NFATC2, c-Fos phosphorylation, c-Myc, Ki-67 and Bcl-2 molecules. In addition, compared to controls, the CTLA4-downregulated CLL cells showed a decreased frequency of apoptosis, which also correlated with increased expression of Bcl-2. Interestingly, CLL cells from lymph node and CLL cells co-cultured on stroma expressed lower levels of CTLA4 and higher levels of c-Fos, c-Myc, and Bcl-2 compared to CLL control cells. These results indicate that microenvironment-controlled-CTLA4 expression mediates proliferation/survival of CLL cells by regulating the expression/activation of STAT1, NFATC2, c-Fos, c-Myc, and/or Bcl-2.

Background: Patients (pts) with relapsed or refractory (R/R) non-Hodgkin's lymphoma (NHL), including DLBCL, MCL, and FL, have poor outcomes and few therapy options. Activation of the phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway plays an important role in NHL pathogenesis. The relative expression of aberrant PI3K isoforms can change over the course of disease: for example in MCL, PI3Kd (frequently overexpressed in B-cell malignancies) is more common initially, while PI3Kα plays a more significant role in disease progression and has been identified as an escape mechanism to selective PI3Kd inhibition (Iyengar et al. 2013). Therefore, an agent that targets multiple PI3K isoforms might elicit more durable responses, particularly in later stages of disease. The oral pan-class I PI3K inhibitor buparlisib (BKM120) showed activity in DLBCL cells in vitro (decreased phosphorylation of downstream PI3K signaling effectors, reduced cell proliferation and survival (Zang et al. 2014)) and has shown clinical activity in solid tumors. This study evaluated the safety and efficacy of buparlisib in pts with R/R NHL. Methods: In this multicenter, parallel-arm, open-label, global Phase II study (NCT01693614), pts with DLBCL, MCL, or FL received buparlisib (100 mg QD) continuously until progression, intolerance, or withdrawal of consent. Key inclusion criteria were R/R disease following ≥1 prior therapy, ≥1 measurable lesion per local assessment using standard criteria (Cheson et al. 2007), and Eastern Cooperative Oncology Group (ECOG) performance status ≤2. Pts with DLBCL were eligible if they had received or were ineligible for autologous stem cell transplant (ASCT). The primary endpoint was overall response rate (ORR). Secondary endpoints were progression-free survival (PFS), duration of response, overall survival, safety, and tolerability. PI3K pathway activation status, an exploratory endpoint, was assessed by mutation analysis (PIK3CA, PTEN) and immunohistochemistry (PTEN loss) in archival tumor tissue samples. Results for the 6-month primary efficacy and safety analysis of buparlisib in pts with DLBCL and FL were previously presented (Younes et al. ASH 2014). Here, we report results for pts enrolled in the MCL cohort. Results: At this 6-month primary analysis (data cut-off, February 25, 2015), 22 pts with MCL were enrolled. The median age was 68.5 years (range 47-79 years). The median number of prior therapies was 2 (range 1-6), which included intensive combination chemoimmunotherapy regimens, radiotherapy, and/or ASCT. The median duration of exposure was 20.6 weeks (range 1.7-54.1 weeks). Overall, 17 (77.3%) pts discontinued study treatment for the following reasons: 9 (40.9%) adverse events (AEs); 5 (22.7%) disease progressions, 2 (9.1%) protocol deviations, and 1 (4.5%) physician decision. Four pts died during the study: 1 due general deterioration and 3 due to underlying disease (with 1 on-treatment death due to disease progression). The most common AEs regardless of causality were hyperglycemia (n=10 [45.5%]), and fatigue, anxiety, depression, and weight decrease (n=7 [31.8%] each). The most frequent grade 3/4 AEs were asthenia, confusional state, leukopenia, and febrile neutropenia (n=2 [9.1%] each). Abnormal laboratory values grade 3/4 included elevated levels of fasting glucose (18.2%), aspartate transaminase and alanine transaminase (4.5% each), and neutropenia (18.2%). ORR was 22.7% (95% CI, 7.8-45.4), with 1 (4.5%) complete response and 4 (18.2%) partial responses (Figure 1). Thirteen (59.1%) pts had stable disease. The disease control rate was 81.8% (95% CI, 59.7-94.8). With 7 PFS events, the median PFS was 11.3 months (95% CI, 3.8-not estimable).The estimated PFS rate at 6 months was 68.6% (95% CI, 39.8-85.7). Of the 11 pts with evaluable samples, none showed PI3K pathway activation at baseline. Conclusions: Buparlisib treatment was moderately well tolerated, had an acceptable safety profile, and elicited sustained reduction in tumor burden in pts with R/R MCL with a median PFS of 11.3 months. Despite the limited ORR (22.7%), the observed disease control with targeted inhibition of all 4 PI3K isoforms in this cohort of pts with MCL is encouraging, and warrants further exploration of buparlisib in pts with NHL. Updated results for the DLBCL and FL cohorts will be presented at this meeting. Disclosures Younes: Celgene: Honoraria; Sanofi-Aventis: Honoraria; Bayer: Honoraria; Bristol Meyer Squibb: Honoraria; Curis: Research Funding; Novartis: Research Funding; Incyte: Honoraria; Janssen: Honoraria; Takeda Millenium: Honoraria; Seattle Genetics: Honoraria, Research Funding; Johnson and Johnson: Research Funding. Salles:Roche: Consultancy, Honoraria, Research Funding; Janssen: Honoraria; Gilead: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Gerecitano:AbbVie: Consultancy, Other: Advisory Board; Genentech: Consultancy, Other: Advisory Board. Herbst:Novartis: Employment. Williams:Novartis: Employment. Mukherjee:Novartis: Employment. Tavorath:Novartis: Employment, Equity Ownership.

Introduction: The management of hematologic malignancy-associated VTEin patients with moderate to severe thrombocytopenia is unclear. Clinical trials of anticoagulants in VTE exclude such patients, hence do not inform the risk of bleeding or clot progression. Consensus-based guidelines recommend case-by-case consideration for either platelet transfusion to maintain platelet count >50,000/µL and therapeutic anticoagulation, or 50% dose reduction in LMWH (J Thromb Haemost. 2013 Jan;11(1):56-70.; Curr Oncol. 2015 Apr;22(2):144-55). At our institution, our approach is to use prophylactic dose LMWH for patients with platelet count ≤50,000/µL. Method: This is a single-center retrospective study of 128 adult patients with hematologic malignancies, who were diagnosed with VTE. Patients were identified from hospital research database. The diagnoses were verified after the review of medical records. The platelet count was assessed during the period of anticoagulation for VTE. The outcomes of patients with significant thrombocytopenia (≤50,000/µL) was compared with those without. Bleeding and clot recurrence was assessed until the last follow-up (median of >1 month). Fisher's Exact test was used to test the association between two categorical variables, and Analysis of Variance (ANOVA) was used to test the association between a continuous variable and a categorical variable. Results: Characteristics of the study population were as follows: 51% male, 47% non-Hodgkin lymphoma, 20% acute leukemia/myelodysplastic syndrome, 40% status-post hematopoietic stem cell transplant, 9% with creatinine >2 mg/dl, 36% with pulmonary embolism and 28% with catheter-related VTE. Forty six patients (36%) had a platelet count ≤50,000/µL during a period of time of perceived need for new or continued anticoagulation. The median nadir platelet count in those with significant thrombocytopenia was 9000/µL( range 2000-45,000/µL) versus 166,000/µL (range 50,000-389,000/µL) in those without (p50,000/µL) | p-value | | ------------------------------------------------------------------------------------------------- | --------------------------------------------------- | ------------------------------------------------------------------------- | ------- | | Bleeding after VTE treatment | | | 0.65 | | No | 38 (82.6%) | 75 (91.5%) | | | Minor (without significant clinical implications) | 1 (2.2%) | 1 (1.2%) | | | Clinically significant (causing drop in hemoglobin; requiring transfusion or other interventions) | 4 (8.7%) | 5 (6.1%) | | | Missing | 3 (6.5%) | 1 (1.2%) | | | Clot progression or recurrence at last follow-up | | | 0.81 | | No | 35 (76.1%) | 67 (81.7%) | | | Yes | 9 (19.6%) | 15 (18.3%) | | | Missing | 2 (4.3%) | | | Table 1. Outcome of patients with VTE Disclosures Vose: Allos Therapeutics/Spectrum: Research Funding; US Biotest, Inc: Research Funding; Janssen Biotech: Research Funding; Celgene: Research Funding; Genentech: Research Funding; Bristol-Myers Squibb: Research Funding; Incyte Corp: Research Funding; Acerta Pharma: Research Funding; GlaxoSmithKline: Research Funding. Armitage: Celgene: Consultancy; Ziopharm: Consultancy; Spectrum: Consultancy; Roche: Consultancy; GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees; Conatus: Consultancy, Membership on an entity's Board of Directors or advisory committees; Tesaro Bio, Inc: Membership on an entity's Board of Directors or advisory committees. Lunning: Spectrum: Consultancy; Genentech: Consultancy; BMS: Consultancy; Juno: Consultancy; Gilead: Consultancy; TG Therapeutics: Consultancy.