ALBERT

Description: The chaperone protein SmgGDS promotes cell-cycle progression and tumorigenesis in human breast and nonsmall cell lung cancer. Splice variants of SmgGDS, named SmgGDS-607 and SmgGDS-558, facilitate the activation of oncogenic members of the Ras and Rho families of small GTPases through membrane trafficking via regulation of the prenylation pathway. SmgGDS-607 interacts with newly synthesized preprenylated small GTPases, while SmgGDS-558 interacts with prenylated small GTPases. We determined that cancer cells have a high ratio of SmgGDS-607:SmgGDS-558 (607:558 ratio), and this elevated ratio is associated with reduced survival of breast cancer patients. These discoveries suggest that targeting SmgGDS splicing to lower the 607:558 ratio may be an effective strategy to inhibit the malignant phenotype generated by small GTPases. Here we report the development of a splice-switching oligonucleotide, named SSO Ex5, that lowers the 607:558 ratio by altering exon 5 inclusion in SmgGDS pre-mRNA (messenger RNA). Our results indicate that SSO Ex5 suppresses the prenylation of multiple small GTPases in the Ras, Rho, and Rab families and inhibits ERK activity, resulting in endoplasmic reticulum (ER) stress, the unfolded protein response, and ultimately apoptotic cell death in breast and lung cancer cell lines. Furthermore, intraperitoneal (i.p.) delivery of SSO Ex5 in MMTV-PyMT mice redirects SmgGDS splicing in the mammary gland and slows tumorigenesis in this aggressive model of breast cancer. Taken together, our results suggest that the high 607:558 ratio is required for optimal small GTPase prenylation, and validate this innovative approach of targeting SmgGDS splicing to diminish malignancy in breast and lung cancer.

Description: Background: Outcomes of patients with AML have remained poor despite the availability of cytotoxic chemotherapy, hypomethylating agents (HMAs) and targeted therapies. HMAs, such as azacitidine, in combination with Bcl-2 inhibitors like venetoclax have demonstrated response rates of 67% in newly diagnosed AML and 21% in relapsed/refractory (RR) AML (DiNardo et al. Blood 2019 and Am J Hematol 2018). While the combination of azacitidine and venetoclax is efficacious in AML, preclinical studies indicate potential mechanisms of drug resistance including overexpression of MCL-1, an anti-apoptotic protein (Konopleva et al. Cancer Cell. 2006). Pevonedistat is a first in class inhibitor of Nedd8 activating enzyme that has demonstrated activity against AML (Swords RT et al. Blood. 2010). Pevonedistat induces NOXA, a pro-apoptotic protein leading to neutralization of MCL-1 inducing apoptosis (Wang et al. Biochem Biophys Res Commun. 2017). Preclinical studies evaluating the combination of pevonedistat and venetoclax against AML cell lines have demonstrated synergistic effect (Knoor KL et al. Cell Death Differ. 2015). Hence, we hypothesize that the addition of pevonedistat to the combination of azacitidine and venetoclax would enhance the therapeutic efficacy by overcoming resistance to apoptosis. Study design and methods: This is an investigator-initiated phase Ib study evaluating the safety of pevonedistat, azacitidine and venetoclax. Patients aged 18 years or above with morphologically documented AML (de novo, secondary or therapy-related), ECOG performance status 0-2 and adequate organ function are eligible for the study. Major exclusion criteria are patients with isolated extramedullary relapse, hematopoietic cell transplantation (HCT) within 100 days of enrollment, active acute GVHD, veno-occlusive disease, acute promyelocytic leukemia, liver cirrhosis and severe liver impairment. While the dose escalation phase is available only for patients with RR-AML, the dose expansion phase can also include newly diagnosed AML patients who are ineligible for intensive induction. The study is planned to be conducted at Medical College of Wisconsin, Mayo Clinic and University of Pennsylvania. The primary endpoint is to determine the recommended phase 2 dose (RP2D) and toxicity profile of pevonedistat, azacitidine and venetoclax. The secondary endpoints include determination of response rates, duration of response, survival and pharmacokinetics. Exploratory endpoints include correlation of response rates with AML genomic profile, correlation of pretreatment levels of BCL2, BCLXL, MCL1, BAX or BAK with response, determination of changes in NOXA (PMAIP1) mRNA and protein expression pre-and post-pevonedistat treatment, evaluation of BH3 mimetic profiling on bone marrow samples by flow cytometry and assessing the sensitivity of leukemia and leukemic stem/progenitor cells to pevonedistat ex vivo. The study will follow 3+3 design with dose escalation (Arms A and B), de-escalation in case of dose limiting toxicity (DLT) (arms Z and Y) and dose expansion phase (figure 1). Patients will be entered sequentially to each dose level, starting with dose level 0. The DLT observation period for dose-escalation will be 1 cycle. The maximal tolerated dose (MTD) will be defined as the highest dose level at which none of the first 3 treated subjects, or no more than 1 of the first 6 treated subjects experiences a DLT. A minimum of 9 and a maximum of 24 patients will be needed for the dose escalation phase and 6 patients for the dose expansion phase. Response rate, duration of response and exploratory endpoints will be analyzed using descriptive statistics. Kaplan-Meier method will be used to determine survival. Disclosures Guru Murthy: Cardinal Health Inc.: Honoraria. Michaelis:Incyte: Consultancy, Research Funding; Pfizer: Equity Ownership, Research Funding; Novartis: Consultancy; Macrogeneics: Research Funding; Millenium: Research Funding; BMS: Research Funding; Celgene: Consultancy, Research Funding; JAZZ: Other: Data Safety Monitoring Board, uncompensated, Research Funding; TG Therapeutics: Consultancy, Research Funding; Janssen: Research Funding; ASTEX: Research Funding; Bioline: Research Funding. Abedin:Jazz Pharmaceuticals: Honoraria; Agios: Honoraria; Helsinn Healthcare: Research Funding; Pfizer Inc: Research Funding; Actinium Pharmaceuticals: Research Funding. Runaas:Agios: Honoraria; Blueprint Medicine: Honoraria. Atallah:Jazz: Consultancy; Novartis: Consultancy; Takeda: Consultancy, Research Funding; Pfizer: Consultancy; Jazz: Consultancy; Helsinn: Consultancy; Helsinn: Consultancy.

Description: Background Allogeneic hematopoietic cell transplantation (AHCT) is a high risk treatment option for patients (pts) with myeloid malignancies. Advanced age and obesity can impact outcomes after AHCT. Previous registry studies of all age groups found that obesity does not affect AHCT outcomes. However, obesity can hasten age-related decline in physical function and exacerbate comorbid conditions in older pts. In this study we evaluated outcomes of both non-obese and obese elderly pts undergoing AHCT for myeloid malignancies. Methods We performed a retrospective, single-center analysis of all pts age≥60 who underwent unrelated or related AHCT for myeloid malignancies (acute myeloid leukemia [AML], myelodysplastic syndrome [MDS], or myeloproliferative neoplasms [MPN]) between 2010 and 2015. Descriptive statistics were used to measure baseline characteristics. A hematopoietic cell transplant co-morbidity index (HCT-CI) score was calculated for all pts. Acute graft-versus-host disease (aGVHD) was defined as occurring in

Description: Background Classical Hodgkin Lymphoma (cHL) is a highly curable disease; however, 10% of patients (pts) with limited stage and 20%-30% with advanced stage disease still fail first line-treatment. Autologous hemopoietic cell transplantation (auto-HCT) is the standard of care in pts who fail to achieve remission with first-line therapy, or who relapse after induction chemotherapy. However, approximately 50% of cHL pts will ultimately relapse post auto-HCT. These pts historically have had poor outcomes, with median survival in the 1.5 year range. In recent years, highly active new therapies such as brentuximab vedotin (BV), checkpoints inhibitors (i.e. nivolumab and pembrolizumab), and increased accessibility to allogeneic HCT (including utilization of haploidentical donors) have become more widely available. We hypothesized that, in recent years, survival has improved in cHL patients who relapse after auto-HCT since the introduction of these novel therapies into more widespread clinical practice. Methods We conducted a multi-center retrospective study from 3 academic institutions in the U.S. (Medical College of Wisconsin, Ohio State University, and Washington University in St. Louis) to evaluate survival of cHL pts after the failure of an auto-HCT. We reviewed 341 pts who received auto-HCT from 2006-2015. Among them, 126 (37%) pts relapsed post auto-HCT and were evaluated in more detail. For the purpose of analysis, pts were divided into 2 cohorts based on timing of auto-HCT; 2006-2010 (Cohort 1, n=57) and 2011-2015 (Cohort 2, n=69) to compare outcomes. Results The median age at auto-HCT, time from diagnosis to transplant, time from transplant to relapse were similar in Cohort 1 & 2 (see Table 1). The proportion of pts who achieved complete remission (CR) at the time of auto-HCT were 22.8% in Cohort 1 and 40.6% in Cohort 2. Whereas, 68.4% of pts in Cohort 1 and 52.2% of pts in Cohort 2 had partial remission (PR) at the time of auto-HCT. The median number of lines of therapy after relapse from auto-HCT were 2 each in Cohort 1 (range, 0-13) and Cohort 2 (range, 0-7), respectively (p= 0.74). Twenty-five (45%) pts in Cohort 1 and 49 (73%) pts in Cohort 2 received BV as a salvage therapy post auto-HCT (p= 0.002). Similarly, 3 (5.5%) pts in Cohort 1 versus (vs.) 21 (32%) pts in Cohort 2 received check point inhibitors as salvage therapy post auto-HCT relapse (p=

Description: Background: Advanced Stage Hodgkin lymphoma (HL) is a curable malignancy with combination chemotherapy. While most patients are cured with frontline therapy, for those with refractory disease or early progression, historically, the outcomes have been poor. Novel therapies, PET/CT adapted treatment approaches, and improvement in transplantation have changed the management of both frontline and relapsed HL. However, it remains unknown if these developments have improved the clinical outcomes at population level over time. Methods: Using Surveillance Epidemiology and End Results database, we identified patients aged ≥ 18 years with advanced stage (Stage III or IV) pathologically confirmed classical HL as the first primary malignancy,diagnosed between the years 2000-2014, treated with chemotherapy and actively followed. Patients were stratified by date of diagnosis into 3 groups - 2000-2004, 2005-2009, 2010-2014 to assess the trends in overall survival (OS) over time. Race/ethnicity was stratified into non-hispanic whites and minorities (Non-hispanic blacks, Hispanics, other non-hispanic races). Kaplan-Meier method and log rank test were used to analyze the OS among subgroups. Cox proportional hazard regression method was used to determine the influence of period and demographic factors on OS.Cumulative incidence of death from cardiac cause was estimated using the Nelson-Aalen estimates. Statistical analyses were carried out with significant two sided p〈 0.05. Results: A total of 9042 patients with a median age of 41 years were included. There were more males (60.1%) and non-Hispanic whites (64.2%) and most patients had nodal disease (98%) (Table 1).The use of frontline radiation therapy decreased in each 5-year time period (21.3% 2000-2004 vs 15.5% 2005-2009 vs 10.7% 2010-2014, p60 -54%, p〈 0.001, Figure 2).While outcomes were poorest in the age〉60 cohort, similar improvements were seen in OS over the three time periods among this patient population (48.6%- 2000-2004 vs 54.3% 2005-2009 vs 56.8% 2010-2014, p=0.005). On multivariate analysis, diagnosis in the earlier period was associated with higher mortality (2000-2004-HR 1.36, 95% CI 1.21-1.53, p〈 0.001; 2005-2009 -HR 1.14, 95% CI 1.01-1.28, p=0.02, both compared to reference group 2010-2014). Similarly, minority races (HR 1.36, 95%CI 1.23-1.49, p

Description: Gastrointestinal (GI) tract involvement is the major cause of morbidity and mortality in acute graft-versus-host disease (GVHD), and pathological damage is largely attributable to inflammatory cytokine production. Recently, granulocyte-macrophage colony stimulating factor (GM-CSF) has been identified as a cytokine that mediates inflammation in the GI tract, but the transcriptional program that governs GM-CSF production and the mechanism by which GM-CSF links adaptive to innate immunity within this tissue site have not been defined. In the current study, we identified Bhlhe40 as a key transcriptional regulator that governs GM-CSF production by CD4+ T cells and mediates pathological damage in the GI tract during GVHD. In addition, we observed that GM-CSF was not regulated by either interleukin 6 (IL-6) or IL-23, which are both potent inducers of GVHD-induced colonic pathology, indicating that GM-CSF constitutes a nonredundant inflammatory pathway in the GI tract. Mechanistically, GM-CSF had no adverse effect on regulatory T-cell reconstitution, but linked adaptive to innate immunity by enhancing the activation of donor-derived dendritic cells in the colon and subsequent accumulation of these cells in the mLNs. In addition, GM-CSF promoted indirect alloantigen presentation, resulting in the accumulation of donor-derived T cells with a proinflammatory cytokine phenotype in the colon. Thus, Bhlhe40+ GM-CSF+ CD4+ T cells constitute a colitogenic T-cell population that promotes indirect alloantigen presentation and pathological damage within the GI tract, positioning GM-CSF as a key regulator of GVHD in the colon and a potential therapeutic target for amelioration of this disease.

Description: Background: Readmissions within 30 days after index hospitalization is a quality and cost-containment metric. Financial penalties to hospitals with high rates of risk-adjusted readmissions have been expanded beyond medical conditions like heart failure and pneumonia. Published data show significant heterogeneity in readmission rates and recent data from elderly Medicare beneficiaries reported a 17.8% readmission rate for targeted conditions. Allo-HCT is a widely used therapeutic strategy in the management of various hematologic disorders like acute myelogenous (AML) and lymphoblastic leukemia (ALL). However, allo-HCT readmission rates are poorly described, and limited to single center studies only. The association between institution HCT volume and 30-day readmission metric has not been examined. Methods: In this observational study, we used the 2012-2014 Nationwide Readmission Database (NRD) to identify hospitals with established allo-HCT programs. Patients ≥18 years of age, discharged from hospital following an allo-HCT (identified using ICD-9 procedure code of 41.02, 41.03, 41.05, 41.06, or 41.08) were included. Annual hospital case volume was calculated as the sum of all discharges with allo-HCT within the calendar year; low, medium, and high annual case volume groups were created based on (survey weighted) tertiles of patients (pts.) in the analytic data domain (Figure 1). Rates, causes, and costs of 30-day readmissions were compared between low-, medium-, and high-volume hospitals. The analysis was limited to urban teaching hospitals and pts. admitted during month of December were excluded. The primary outcome, was the unplanned 30-day re-admission following allo-HCT. Multiple logistic regression was used to model each 30-day readmission outcome including hospital case volume with other predictors (age, sex, disease type, stem cell source, co-morbidity index, primary insurance, length of stay, infection and acute graft-versus-host-disease (aGVHD) at index admission, discharge disposition and median income quartile). Results: A total of 17,214 (weighted) allo-HCTs were performed during the time period. Baseline characteristics of pts. in low (158 allo-HCTs/yr.) hospitals were comparable as shown in Table 1. The overall rates of readmissions were significantly higher in low volume centers (24.7.4%; SE, 1.5) compared to medium (21.4% (1.7) and high volume (9.5% (1.8), centers (p=0.03). The mean time to readmission in low vs. medium vs. high volume centers was, 11.6 [0.39] days vs. 12 [0.26] days vs. 11.5 [0.57] days respectively, (p

Description: Introduction: Heparin-induced thrombocytopenia (HIT) is a severe prothrombotic syndrome with a mortality rate of 10% (Lancet Haematol. 2018 May; 5(5):e220-e231). Case reports show that Intravenous Immunoglobulin G (IVIg) can rapidly and durably counteract HIT antibody-mediated platelet activation in the setting of severe persistent HIT (Chest. 2017 Sep;152(3):478-485 and others). While this data supports use of IVIg in severe HIT, it is well documented that "positive result bias" enhances the likelihood of publication of studies that demonstrate salutary effects of interventions. IVIg has a black box warning for thrombosis which lists a number of potential predisposing states for this complication including hypercoagulable conditions (such as HIT). Thus, one concern is that of new/worsening thrombosis in HIT patients treated with this drug, something that is not evaluable with the limited publications in this area. The Nationwide Inpatient Sample (NIS) is the largest publicly available patient discharge database in the US that includes ~7 million discharges per year representative of discharges from all hospital types in the country. The goal of this study was to evaluate thrombosis, bleeding and mortality outcomes associated with IVIg use in HIT using the NIS database. Methods: Hospital discharges with an ICD-9-CM code for HIT (289.84) in the NIS were used to compare outcomes in adult patients (≥18yrs) who did and did not receive IVIg treatment (ICD-9-CM code 99.14) from October 1, 2008 to December 31, 2014. Discharges with diagnoses suggestive of a history of thrombosis (ICD-9-CM codes V12.51, V12.52, V12.55), idiopathic thrombocytopenic purpura (287.31), or secondary thrombocytopenia (287.4) were excluded. Patient characteristics included age, sex, all patient refined diagnosis related groups (APR-DRG) severity index, and APR-DRG mortality index. Outcomes included arterial thrombosis, venous thrombosis, bleeding, mortality, and a composite of all outcomes. Variables were compared by IVIg treatment status using survey weighted Chi-squared tests for categorical variables and ANOVA for continuous variables. Survey weighted multiple logistic regression was used to model each binary outcome by IVIg treatment status while adjusting for age, gender, APR-DRG severity index and mortality index. A matched analysis was performed as a sensitivity analysis for the multiple logistic regression results. Controls were matched with IVIg cases by exact gender, APRDRG severity index, and mortality index. Five matching controls were selected for each case based on nearest age. Conditional logistic regression was used to analyze each outcome using the matched dataset. Results: HIT patients treated with IVIg and those without were no different in age and sex (Table 1). Consistent with the limited published experience of IVIg use in HIT, those who received IVIg had more severe disease with greater likelihood of dying as indicated by their APR-DRG severity and mortality indices (Table 1). Multiple logistic regression showed that the adjusted odds ratio (aOR) was lower for all outcomes except bleeding in the IVIg-treated group, although this did not reach statistical significance (Fig 1; aOR of 0.766, 0.922, 1.049, 0.685 and 0.703 for arterial thrombosis, venous thrombosis, bleeding, death and composite outcome, respectively). Similar results were obtained in conditional logistic regression of matched data (Fig 2). Conclusions: Use of IVIg was not associated with worse thrombotic outcomes or mortality in HIT. On the contrary, results suggest a possible protective effect on these outcomes, but results did not achieve statistical significance possibly due to small numbers of IVIg-treated patients. The aOR was higher (but not significantly so) for bleeding in IVIg-treated HIT patients, however, this finding is consistent with the possibility that IVIg was used more frequently in patients who had more severe disease (and had already hemorrhaged), as suggested by worse APR-DRG severity and mortality indices in IVIg-treated patients. A prospective randomized treatment study may be necessary to provide conclusive data on IVIg efficacy and risk in HIT. Disclosures Dhakal: Amgen: Honoraria; Celgene: Consultancy, Honoraria; Takeda: Honoraria. Aster:BloodCenter of Wisconsin: Patents & Royalties. Padmanabhan:Janssen Pharmaceuticals: Consultancy; GE Healthcare: Other: Material support for Clinical Quality Improvement Initiative; Retham Technologies LLC: Equity Ownership, Other: Retham seeks to develop HITDx(TM), a new assay for HIT diagnosis; BloodCenter of Wisconsin: Patents & Royalties: Patent/royalties for HIT diagnostic testing; Veralox Therapeutics: Other: Advisory Board; TerumoBCT: Consultancy.

Description: Background: Readmissions within 30 days after index hospitalization is a quality, and cost-containment metric. It is now a major issue for hospitals, physicians and policy makers. Financial penalties to hospitals with high rates of risk adjusted readmissions have been expanded beyond medical conditions like heart failure and pneumonia. Auto-HCT is a widely used therapeutic strategy in the management of various hematological disorders, particularly multiple myeloma (MM) and non-Hodgkin lymphoma (NHL) in the US. However, auto-HCT readmission rates are poorly described in the literature and often limited to single center studies. To better address the incidence and underlying predictors of 30-day readmission following auto-HCT, we performed an analysis of the Nationwide Readmission Database(NRD). Methods: NRD data was queried from 2012-2014 to identify patients 〉18 years of age discharged from the hospital after auto-HCT (identified as presence of any ICD-9 procedure codes 41.00, 41.01, 41.04, 41.07, or 41.09). Survey weighted domain analysis was conducted to study incidence of 30-day readmission by center volume. Annual hospital case volume was calculated as the sum of all discharges with auto-HCT within the calendar year; low, medium, and high annual case volume groups were created based on (survey weighted) tertiles of patients (pts.) in the analytic data domain (Figure 1). Rates, causes, and costs of 30-day readmissions were compared between low-, medium-, and high-volume hospitals. The analysis was limited to urban teaching hospitals, and pts. admitted during month of December were excluded. The primary outcome was the unplanned 30-day re-admission following auto-HCT. Multiple logistic regression was used to model each 30-day readmission outcome including hospital case volume with other predictors (age, sex, disease type, primary insurance, median income, discharge disposition, co-morbidity, length of stay (LOS) and infection at index hospitalization). Results: A total of 28,356 (weighted) auto-HCTs were performed during the time period and MM remains the most common indication (~60%). Baseline characteristics of pts. in low (187/yr.) hospitals were comparable as shown in Table 1. The overall rates of readmissions were significantly higher in low volume 15.7% (SE, 1.5) compared to medium 9.9% (1.5) and high volume 9.5% (1.8), p=0.002 centers. The mean time to readmission in low vs. medium vs. high volume centers was (8.3 [0.41] days vs. 10.7 [0.78] days vs. 8.9 [0.26] days; p