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8063 Background: Information on central nervous system (CNS) involvement with NA-ATLL is limited. In this study, we describe CNS involvement in ATLL patients at a tertiary hospital in New York City. Methods: We considered CNS involvement if one of the following criteria was met 1) cerebrospinal fluid (CSF) cytology or flow cytometry was positive 2) CNS imaging was positive for disease involvement or 3) Physical exam findings were compatible with neurologic involvement. Results: Of 94 NA-ATLL patients, 21 (22.3%) had CNS involvement by ATLL. CSF was involved in 13/21 and 5/21 patients at diagnosis and relapse respectively. At diagnosis, MRI showed CNS involvement in brain and spine in 5/21 (24%) and 3/ 21 (14%) cases respectively. At relapse, imaging revealed brain and spine involvement in 2 patients each. Neurological exam was abnormal in 7 (33%) and 3 (14%) cases at diagnosis and relapse respectively. Next generation exon targeted sequencing was performed in 9 cases. Table shows the mutations (mtn) and functional groups with frequencies. XPO1 E571K mutation was present in 2 patients with extensive CNS disease and refractory to conventional treatment with an overall survival (OS) of 2 months. To our knowledge, this is the first time that XPO1 E571K is reported in a T-Cell malignancy. We also describe here a second set of mutations with CNS involvement (KLF2 and PI3KCD) in 2 patients. Median OS was 8.5 months, Median RFS was 6.5 months in our series. In most cases, the lymphomatous phenotype appeared to have direct mass-like extension (5/21) with several cases of accompanying osteolytic spine or skull lesions, whereas cases with hematogenous involvement tends to spread to the CSF by traversing the brain blood barrier. Conclusions: In this report we describe patterns of CNS involvement in ATLL and the associated mtns. We also describe two unique cases of XPO1E571K mtn in a TCL. [Table: see text]

Background: Despite recent data on clonal hematopoiesis, it remains unclear if patients with Myelodysplastic Syndromes (MDS) have a higher risk of cardiovascular disease (CVD) compared to the general population, as prior studies have not included a control group. Methods: Matched cohort study of MDS cases identified between 2004 and 2014 from Medicare claims linked to the SEER tumor registry, with controls from a 5% random sample of non-cancer Medicare beneficiaries. Patients with CVD prior to MDS diagnosis were excluded. Findings: A total of 9,047 MDS cases were 1:1 propensity-matched with non-cancer controls, based on age, gender, race and urban residence. The cumulative incidence of CVD was higher among MDS patients compared to controls (17% vs. 13%, p

Adult T-cell leukemia lymphoma (ATLL) is a rare T cell neoplasm that is endemic in Japanese, Caribbean, and Latin American populations. Most North American ATLL patients are of Caribbean descent and are characterized by high rates of chemo-refractory disease and worse prognosis compared with Japanese ATLL. To determine genomic differences between these 2 cohorts, we performed targeted exon sequencing on 30 North American ATLL patients and compared the results with the Japanese ATLL cases. Although the frequency of TP53 mutations was comparable, the mutation frequency in epigenetic and histone modifying genes (57%) was significantly higher, whereas the mutation frequency in JAK/STAT and T-cell receptor/NF-κB pathway genes was significantly lower. The most common type of epigenetic mutation is that affecting EP300 (20%). As a category, epigenetic mutations were associated with adverse prognosis. Dissimilarities with the Japanese cases were also revealed by RNA sequencing analysis of 9 primary patient samples. ATLL samples with a mutated EP300 gene have decreased total and acetyl p53 protein and a transcriptional signature reminiscent of p53-mutated cancers. Most importantly, decitabine has highly selective single-agent activity in the EP300-mutated ATLL samples, suggesting that decitabine treatment induces a synthetic lethal phenotype in EP300-mutated ATLL cells. In conclusion, we demonstrate that North American ATLL has a distinct genomic landscape that is characterized by frequent epigenetic mutations that are targetable preclinically with DNA methyltransferase inhibitors.

Eltrombopag (EP), a small molecule thrombopoietin receptor (TPO-R) agonist and potent intracellular iron chelator, has shown remarkable efficacy in stimulating sustained multilineage hematopoiesis in patients with bone marrow failure syndromes, suggesting an effect at the most immature hematopoietic stem and multipotent progenitor level. Although the functional and molecular effects of EP on megakaryopoiesis have been studied in the past, mechanistic insights into its effects on the earliest stages of hematopoiesis have been limited. Here, we investigated the effects of EP treatment on hematopoietic stem cell (HSC) function using purified primary HSCs in separation-of-function mouse models, including a TPO receptor-deficient strain, and stem cells isolated from patients undergoing TPO-R agonist treatment. Our mechanistic studies showed a stimulatory effect on stem cell self-renewal independently of TPO-R. Human and mouse HSCs responded to acute EP treatment with metabolic and gene expression alterations consistent with a reduction of intracellular labile iron pools that are essential for stem cell maintenance. Iron preloading prevented the stem cell-stimulatory effects of EP. Moreover, comparative analysis of stem cells in the bone marrow of patients receiving EP showed a marked increase in the number of functional stem cells compared to patients undergoing therapy with romiplostim, another TPO-R agonist lacking an iron-chelating ability. Taken altogether, our study demonstrates that EP stimulates hematopoiesis at the stem cell level through iron chelation-mediated molecular reprograming and indicates that labile iron pool-regulated pathways can modulate hematopoietic stem cell function.

Background ATLL is an aggressive T cell malignancy with dismal prognosis which occurs mainly in Caribbean immigrants in the US. AlloSCT is an effective treatment option in eligible patients (pts). We sought to identify barriers to alloSCT for these pts in a tertiary center with one of the largest ATLL populations in the US. Methods Pts with ATLL treated at Montefiore Medical Center were identified from 2003 to 2018. Comprehensive review of charts and donor registry searches were conducted. Results We identified 88 pts, mean age 56 yrs, 7 (8%) with chronic/smoldering subtypes. Of pts with acute (49, 60.5%) or lymphomatous (32, 39.5%) types, 48 (59.5%) were not considered for alloSCT due to early death (52%, n=25), lost to follow up (19%, n=10), uninsured (13%, n=7), declined HSCT (9%, n=5) and frailty (2%, n=1). Of 33 (40.7%) pts evaluated for alloSCT, 28 (34.6%) underwent HLA typing. A 10/10 matched related donor (MRD) was identified in 7 (25%). Registry search for matched unrelated donors (MUD) in the remainder 21 showed 10/10 (9.5%, n=2), 9/10 (19%, n=4), 8/10 (9.5%, n=2) and none (62%, n=13). Haploidentical donors were identified for 6 of 13 (46%) pts with no MUD. No donor options were available for 7 (25%) HLA-typed pts. AlloSCT was performed in 10/21 (47.6%) pts. Reasons for not undergoing alloSCT were progressive disease (50%, n=9), and patient declination (11%, n=2). AlloHSCT was associated with better median relapse-free (RFS) (26 vs. 11 mo, p=0.04) and overall survival (OS) (47 vs. 10 mo, p=0.03). Early transplant-related mortality (TRM) rate was 40%. Pts transplanted in complete remission (CR) and with MRD/MUD had better outcomes. Conclusion This is the first study demonstrating the barriers for alloHSCT for ATLL in the US. Only 12.3% pts proceed to alloSCT in ATLL. Early mortality, lost to follow up, uninsured status, lack of available suitable donors, including haploidentical, are significant problems. In pts who have successful induction, alloSCT can achieve long term remissions. Hence, better upfront treatments to achieve CR, early alloSCT, and consolidation/maintenance strategies in those who do not proceed to alloSCT are urgently needed to improve outcomes in ATLL.

The main objective of this chapter is to investigate the effect of economic crisis in Greece on companies’ corporate social responsibility (CSR) budgets. We have content-analyzed the CSR reports of twelve companies operating in Greece during the period 2008–2014 in order to identify the companies’ CSR activity patterns. In most of the companies examined, CSR activities reached their peak in 2009 and started declining since then, probably due to the adverse economic circumstances. Furthermore, the companies have reprioritized their CSR interests, doubling their society-related activities and reducing nearly by half those addressing the company personnel. Even though the study examines a limited number of companies, it makes an important contribution to the CSR literature in Greece, where CSR is a rather new concept both in terms of research and practice. Contrary to the majority of studies focusing on the effects of short recession periods on CSR, we focus on a long recession period and show how companies adapt to pressures during a period of adverse economic conditions and the way they learn to redeploy their resources allocated to social causes.

This chapter investigates the effect of employees’ perceptions of corporate social responsibility (CSR) activities of their organization on work-related attitudes. Extant research on CSR and consumer perceptions neglects the core assumption of stakeholder theory that a firm’s long-term value is grounded on the knowledge, abilities, and loyalty of its employees, as well as on its relationships with customers, local community, and other stakeholders. Our field survey is focused on employees of Greek port logistics management services. Building on the argument that employees’ perceptions of CSR activities may be significantly related to workplace attitudes, behaviors, and performance, this chapter examines two CSR aspects (social and environmental) and several work-related attitudes (job performance, employee satisfaction, organizational commitment, OCBO, and OCBI). Our findings highlight that different CSR aspects exert selective direct effects on specific employees’ attitudes, while the managerial implications on firms’ accountability and transparency are also discussed. Even though the study is based on a case study of a port logistics management services organization in Greece, the organizational phenomena under investigation provide interesting evidence that can be applied to other national and organizational contexts.

The tumor suppressor p53 is often inactivated via its interaction with endogenous inhibitors mouse double minute 4 homolog (MDM4 or MDMX) or mouse double minute 2 homolog (MDM2), which are frequently overexpressed in patients with acute myeloid leukemia (AML) and other cancers. Pharmacological disruption of both of these inter-actions has long been sought after as an attractive strategy to fully restore p53-dependent tumor suppressor activity in cancers with wild-type p53. Selective targeting of this pathway has thus far been limited to MDM2-only small-molecule inhibitors, which lack affinity for MDMX. We demonstrate that dual MDMX/MDM2 inhibition with a stapled a-helical peptide (ALRN-6924), which has recently entered phase I clinical testing, produces marked antileukemic effects. ALRN-6924 robustly activates p53-dependent transcription at the single-cell and single-molecule levels and exhibits biochemical and molecular biological on-target activity in leukemia cells in vitro and in vivo. Dual MDMX/MDM2 inhibition by ALRN-6924 inhibits cellular proliferation by inducing cell cycle arrest and apoptosis in cell lines and primary AML patient cells, including leukemic stem cell-enriched populations, and disrupts functional clonogenic and serial replating capacity. Furthermore, ALRN-6924 markedly improves survival in AML xenograft models. Our study provides mechanistic insight to support further testing of ALRN-6924 as a therapeutic approach in AML and other cancers with wild-type p53.

Background: MDS has been largely excluded from epidemiological studies that demonstrate an increased risk of CVD in older adults with cancer. Nevertheless, somatic mutations leading to clonally restricted hematopoiesis are associated with increased risk of CVD and CVD constitutes the most common non-disease-related cause of death among patients with MDS. Using the SEER Medicare tumor registry, we previously demonstrated that MDS was independently associated with increased risk of CVD and cardiovascular mortality in older adults, thus constituting an important but underestimated cardiovascular hazard. In this study, we sought to determine the influence of MDS-specific factors on the risk of CVD among MDS patients. Methods: We used the SEER Medicare database to identify individuals 66 years or older with an incident diagnosis of MDS between 2004 and 2014. Incident CVD was defined as new myocardial infraction and/or ischemic stroke occurring after diagnosis of MDS. Events were identified with ICD9 and HCPCS codes in Medicare claims from the date of MDS diagnosis to death or study end. Subjects with CVD prior to MDS diagnosis were excluded. Comorbidity burden was estimated with the Charlson comorbidity index (CCI), calculated using claims from the year before MDS diagnosis. MDS was classified into low, intermediate and high risk using ICD-O morphology codes. Subjects requiring 2 or more blood product transfusions within 60 days from MDS diagnosis were considered transfusion dependent. Cumulative incidence functions were used to assess the risk of new events. Cox proportional hazards models, extended for time dependent covariates and coefficients, were used to evaluate clinical variables associated with CVD. Results: The cohort included 13,972 subjects with MDS, most were male (55.2%), non-hispanic white (82.1%), and from metropolitan areas (82.5%). Median age at MDS diagnosis was 82 years (IQR, 78 - 87). MDS was of low, intermediate and high risk in 18.1%, 68.8% and 13.1% respectively. The median CCI score was 0 (IQR, 0 - 2). Red blood cells (RBC) and platelet transfusion dependence occurred in 29% and 6.1% of subjects. The 10-year cumulative incidence of CVD was 47%, 54% and 65% in subjects with low, intermediate and high-risk MDS, respectively (p Conclusion: In a large cohort of elderly Medicare beneficiaries with incident diagnosis of MDS, the cumulative incidence of CVD was greater in subjects with higher-risk MDS as determined by bone marrow morphology and in those who were RBC transfusion dependent. Both MDS risk and RBC transfusion dependence were independent risk factors for CVD in multivariate analysis accounting for demographic factors and comorbidity burden. These factors have been previously associated with increased mortality and risk of leukemia transformation in MDS but their role in risk of CVD has not been previously reported. CVD is an important cause of mortality among older adults with MDS and these results can help identify high risk patients for whom strict cardiovascular screening and preventive strategies could impact mortality. Though we used validated methods, study limitations include relying on administrative claims, absence of genetic information and unmeasured confounding factors. Prospective studies and further preclinical research is needed to clarify the mechanisms of CVD in patients with MDS. Figure 1 Disclosures Verma: Janssen: Research Funding; Stelexis: Equity Ownership, Honoraria; Acceleron: Honoraria; Celgene: Honoraria; BMS: Research Funding.

Prior studies have evaluated incidence and survival trends for B-Acute Lymphoblastic Leukemia (B-ALL) in children and adults. However, there have been no recent studies evaluating the difference in survival between different race and ethnicities in the era of tyrosine kinase inhibitors and novel combination therapy. We wanted to determine 5-year observed survival for adult patients with B-ALL diagnosed in recent years and assess for any difference in survival by race-ethnicity. Methods: We used Surveillance Epidemiology End Results (SEER) 18 registry to identify B-ALL patients using ICD-O-3 codes 9811-9818 and 9836. SEER 18 covers ~28% of US population. The year of diagnosis was limited to 2010-2016 in order to capture a patient population most likely treated with modern therapies. We limited our study to adults aged 20 years (yrs) or more, which were then divided into the following age groups: 20-29, 30-39, 40-49, 50-59, 60-69,70-79,80+ yrs of age. Gender, race-ethnicity, median family income and observed overall survival (OS) were obtained from SEER. For multivariate survival analysis, Cox proportional hazard model was used to adjust for clinically important and other relevant variables (age, gender, race-ethnicity, median income). We included median family income, a county level characteristic in our analysis as a surrogate for access to care. We divided these counties into quintiles based on median family income and included that variable in the multivariate model. We did not adjust for genetic risk or patient insurance status, as the information provided in SEER was inadequate and would likely lead to misclassification bias. SEER Stat 8.3.5 and SAS student edition were used for analysis. Results: 4244 cases of B-ALL were identified with an age adjusted incidence rate of 0.92 per 100,000. B-ALL occurred at all ages, but incidence was higher in young adults ( Age adjusted incidence was the highest among Hispanics (1.61{1.53-1.71}), followed by Non-Hispanic Whites (NHW)(0.77{0.73-0.8}, Non-Hispanic Asian Pacific Islander (NHAPI)(0.7{0.63-0.78}) and Non-Hispanic Blacks (NHB)(0.54{0.47-0.61}); this difference was statistically significant (p-value About 52% of population died during the study period from any cause. We limited our survival analysis to patients without second malignancy to avoid the confounding effect of another cancer associated mortality. We evaluated OS differences between race-ethnicity in a multivariate model that adjusted for age, sex and income. We found that when compared to NHW, Hispanics (Hazard Ratio (HR) 1.3{1.16-1.46}; p Conclusion: Our study showed a significant survival disparity in adult B-ALL by race and ethnicity in the modern era. This can partly be attributed to differences in access to care as shown in our study. Interestingly, Hispanic and NHB have a significantly worse overall survival compared to NHW and NHAPI even after accounting for income differences, as a surrogate for access to care. This could be due to other unaccounted measure of health disparity, availability of allogeneic transplantation and/or difference in disease biology. Further studies are needed to evaluate such differences, identify barriers to care in minority populations and characterize potential differences in the genetic make-up of B-ALL in the various ethnic/racial groups. Disclosures Sica: Physician's Education Resources (PER): Honoraria. Verma:Stelexis: Equity Ownership, Honoraria; Acceleron: Honoraria; Celgene: Honoraria; BMS: Research Funding; Janssen: Research Funding.

Adult T cell leukemia / lymphoma is a rare neoplasm with dismal cure rates and poor response to chemotherapy. The genetic basis of refractoriness against conventional agents is not known. We follow one of the largest cohorts of ATLL in the US and recently showed that North American ATLL (NA-ATLL) has a distinct mutational profile from Japanese ATLL (J-ATLL) with a higher incidence of epigenetic mutations (Shah et al, Blood, 2018; 132(14):1507-1518). Here, we analyze the mutational landscape of ATLL clones at diagnosis and at relapse in a pilot study of 7 NA-ATLL patients using deep targeted sequencing of 236 recurrently mutated genes. Our goal was to examine clonal evolution patterns that may result as a consequence of the selective pressure of chemotherapy by determining changes in mutational profiles as well as clonal abundance on patients with aggressive ATLL [acute and lymphomatous] (Table 1). All patients were treated with EPOCH (Etoposide, Prednisone, Vincristine, Cyclophosphamide and Doxorubicin) chemotherapy after initial diagnosis except one patient who received interferon therapy. Distinct patterns of clonal evolution were observed in patients with primary refractory disease when compared to those who relapsed after an initial remission. Group 1 has 3 cases (Pts 1 to 3), all of which experienced early relapse and showed mutation patterns suggestive of clonal replacement by a new emerging clone at relapse. Group 2 has 3 patients (Pts 4-6) that are characterized by worsening of primary refractory disease. Mutation patterns in the before-and-after sample pairs suggest linear progression from a previously existing clone during therapy. The clonal evolution status was not resolved in our third group (Pt#7) indicating that mutations outside the 236 genes evaluated might have been present. Frequent epigenetic mutations were found in both diagnostic and refractory/relapsed samples. Surprisingly, 4 epigenetic mutations (KMT2D, EP300, SPEN, SETBP1) identified in 4 cases were confirmed or suspected of germline origin. This suggests that ancestral genomic differences between the Caribbean and Japanese populations could contribute to the mutational and clinical disparities between NA- and J-ATLL. Multiple mutations with similar variant allele frequencies (VAF) at the time of relapse were identified, suggesting simultaneous acquisition of several mutations during clonal evolution. Clonal replacement by an emerging clone (Group 1) such as GATA3 (Pt#3) or KMT2D (Pt#1) (either germline or founding mutation) was observed in patients who achieved an initial response. On the other hand, in primary refractory disease (Group 2), relapse was driven by dominant TBL1XR1 mutations in 2 out of the 3 cases either alone (Pt#6) or in combination with mutated SMARCB1 (Pt#5). The protein encoded by TBL1XR1 is a negative regulator of the nuclear receptor corepressor (NCoR) /histone deacetylase 3 (HDAC3) complex. Therefore, TBL1XR1 inactivation is expected to result in hyper-activity of NCoR/HDAC3, an epigenetic abnormality targetable by HDAC inhibitors. SMARCB1 is also an epigenetic regulator associated with several malignancies and has been targeted with alisertib. A subclonal expansion of EP300 (a histone acetyltransferase) appears to drive relapse in the other case of this group (Pt#4). Therefore, our primary refractory cases show that epigenetic mutations seem to be of utmost importance not only at diagnosis as we have previously shown, but as the driving force behind chemotherapy refractoriness and subsequent relapse. Conclusion: To our knowledge, this is the first mutation-based clonal evolution study aimed to examine dynamic changes induced by chemotherapy among NA-ATLL patients. Early relapse appears to be driven by the emergence of new mutant clones. On the other hand, primary refractory disease appears to have epigenetic drivers that convey chemotherapy refractoriness and evolve from linear progression of a previously existing clone. Serial mutational testing can provide critical information on clonal architecture and identify actionable molecular vulnerabilities in a cohort without effective therapeutic options and a dismal prognosis. Disclosures Sica: Physician's Education Resource (PER): Honoraria. Shah:Physicians' Education Resource: Honoraria. Steidl:Aileron Therapeutics: Consultancy, Research Funding; Stelexis Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Other: Scientific Co-Founder; Pieries Pharmaceuticals: Consultancy; BayerHealthcare: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; GlaxoSmithKline: Research Funding; Celgene: Consultancy. Verma:Stelexis: Equity Ownership, Honoraria; Acceleron: Honoraria; Celgene: Honoraria; BMS: Research Funding; Janssen: Research Funding.

Introduction: Multiple Myeloma (MM) is a disease of the elderly; with approximately two-thirds of cases diagnosed at ages older than 65 years. However, this population has been underrepresented in clinical trials. Hence, there are no evidence-based guidelines to select the most appropriate treatment that would balance effectiveness against risk for side effects in the real world. Currently, guidelines advise that doublet regimens should be considered for frail, elderly patients; but more detailed recommendations are lacking. This study aims to describe treatment patterns in older patients with MM and compare treatment response and side effects between doublet and triplet regimens. Methods: Patients diagnosed with MM at 70 years or older and treated at Montefiore Medical Center between 2000 and 2017 were identified using Clinical Looking Glass, an institutional software tool. Recipients of autologous stem cell transplant were excluded. We collected demographic data and calculated comorbidity burden based on the age-adjusted Charlson Comorbidity Index (CCI). Laboratory parameters included cell blood counts, renal function, serum-protein electrophoresis and free kappa/lambda ratio pre and post first-line treatment. Treatment was categorized into doublet [bortezomib/dexamethasone (VD) and lenalidomide/dexamethasone (RD)] or triplet regimens [lenalidomide/bortezomib/dexamethasone (RVD) and cyclophosphamide/bortezomib/dexamethasone (CyborD)]. Disease response was reported as VGPR, PR, SD or PD using pre-established criteria. Side effects included cytopenias, diarrhea, thrombosis and peripheral neuropathy. Clinical and laboratory data were obtained by manual chart review. Event-free survival was defined as time to treatment change, death or disease progression. Data were analyzed by treatment group using Stata 14.1 Results: A total of 97 patients were included, of whom 46 (47.4%) were males, 47 (48.5%) were Non-Hispanic Black and 23 (23.7%) were Hispanic. Median age at diagnosis was 77 years (range: 70-90). Median baseline hemoglobin was 9.4 (8.5-10.5) and 14 (16.1%) had grade 3/4 anemia. Baseline thrombocytopenia and neutropenia of any grade were less common (18.4% and 17.7%, respectively) and 11 patients (20%) had GFR ≤30. Treatment regimens included VD (51, 52.6%), CyborD (18, 18.6%), RD (15, 15.5%) and RVD (13, 13.4%). Overall, doublets were more commonly used than triplets (66, 68% vs 31, 32%). Baseline characteristics were similar among treatment regimen groups. There was no difference in treatment selection among patients with baseline anemia or baseline neutropenia; however, doublets were preferred for those with underlying thrombocytopenia compared to triplets (93.8% vs 6.2%, p Conclusions: We show a real-world experience of an inner city, elderly MM cohort, ineligible for autologous transplantation. A doublet combination and specifically the VD regimen was the treatment of choice in the majority of cases. In this cohort, triplet regimens did not show better response rates and led to treatment change more often than doublets. Among patients requiring treatment, approximately a third switched from doublet to triplet or viceversa which suggest that current evaluation of patient frailty at diagnosis is suboptimal. Despite similar frequency of side effects among groups, there was a trend towards longer event-free survival in patients receiving doublets. Larger retrospective studies are needed to confirm these results. Disclosures Verma: Janssen: Research Funding; BMS: Research Funding; Stelexis: Equity Ownership, Honoraria; Acceleron: Honoraria; Celgene: Honoraria.

e19070 Background: Peripheral T-cell lymphomas (PTCL) are a rare heterogenous group of lymphomas and modern studies on incidence patterns of PTCL are lacking. Methods: Using the National Program of Cancer registries (NPCR) database, which covers 99% of the US population, we aim to evaluate the incidence of PTCL according to age, race-ethnicity, and gender; and examine trends over time. We identified PTCL using ICD-O-3 codes and evaluated incidence trends from 2001 to 2015. Results: A total of 78722 PTCL cases were identified, the most common were Mycoses fungoides/Sezary syndrome (MF-SS), PTCL Not Otherwise Specified (NOS), and ALK+ Anaplastic Large Cell Lymphoma (ALK+ ALCL). The age-adjusted incidence rate was 2.1 per 100,000. Incidence of PTCL increased with age (6.7/100,000 in 80+years). PTCL was more common in males than females (incidence rate ratio [IRR] of 0.6, p

High prevalence and allele burden-independent prognostic importance of p53 mutations in an inner-city MDS/AML cohort

Background: MDS originates from somatic mutations leading to clonally restricted hematopoiesis causing cytopenias and cellular dysplasia. Clonal expansion of these mutations in the absence of MDS criteria is known as clonal hematopoiesis of indeterminate potential (CHIP) and is considered a MDS precursor. CHIP is associated with increased risk of CVD, especially early onset myocardial infarction (MI) (Jaiswal S et al, NEJM, 2017). CVD events increase with clone size and a potential causal relationship involves accelerated atherosclerosis from an altered cell-mediated inflammatory response in the atherosclerotic plaque. It is suggested that MDS patients carry an increased risk of CVD mortality (Brunner AM et al, Bld Advances, 2017); it is unclear however if the increased risk of CVD persists even after developing MDS or is limited to CHIP. The influence of demographic factors & comorbidities on CVD among MDS patients is also unknown. The SEER Medicare tumor registry was queried to help answer these questions. Methods: Individuals 65 years or older from the SEER Medicare database with incident diagnosis of MDS between Jan. 1, 2004 and Dec. 31, 2014 (n=13,193) were identified. Demographic data and Charlson comorbidity index (CCI) 1 year prior to MDS diagnosis were analyzed. A control set of 5% randomly sampled non-cancer Medicare beneficiaries was paired to cases by propensity score matching (PSM) accounting for age, gender, race and urban/rural residence. The MDS diagnosis date served as the pseudodiagnosis date for non-cancer paired subjects. New onset MI or ischemic strokes (CVA) were identified with ICD9 and HCPCS codes in Medicare claims from date of diagnosis to death or study end. Incident cases were those with claims occurring after, and absent 1 year before, the MDS diagnosis date. Cumulative incidence functions were used to assess the risk of new events. Cox proportional hazards models, extended for time dependent covariates and coefficients, were used to evaluate clinical variables associated with new onset CVD and death. Results: MDS patients were predominantly male (55.2%) and non-hispanic whites (82.1%) from metropolitan areas (82.5%). Median age at diagnosis was 82 years (66 - 112) and median CCI score was 0 (0 - 13). The 5-year cumulative incidence of MI was 12.5% for MDS patients vs. 7% for controls (p Conclusion: Cumulative incidence of MI was higher in Medicare beneficiaries with MDS compared to non-cancer controls. The association of MI and MDS was even stronger in patients with a lower CCI score, particularly in patients with score ≤ 1. Thus, a diagnosis of MDS confers an independent risk for early MI in relatively healthy patients with little or no prior cardiovascular comorbidities. Furthermore, survival after a new CVD event was significantly reduced in subjects with MDS compared to controls. Evaluation and modification of cardiovascular risk factors is essential in patients with MDS and should be instituted early as it directly impacts their survival. Although we used validated methods, study limitations include relying on administrative claims from Medicare beneficiaries, absence of genetic or lifestyle information and unmeasured confounding factors not accounted for by PSM. While the risk of CVA was not impacted by a diagnosis of MDS, thrombocytopenia, anemia and transfusion dependence likely influenced the risk of these ischemic events and will be further explored as cofactors. Disclosures Janakiram: Seatle Genetics: Membership on an entity's Board of Directors or advisory committees.

INTRODUCTION: There is a lack of data on early mortality in aggressive lymphomas, particularly HIV-related lymphomas. Patients who present with advanced disease and poor performance status are at a higher risk of adverse outcomes and are not offered clinical trial enrollment. Factors that may contribute to early mortality have not been delineated. In this retrospective analysis, we sought to identify causes and predictors of early mortality, occurring within 180 days of index diagnosis, in patients with HIV-positive and negative DLBCL, at an academic medical center. METHODS: We reviewed an electronic database to identify patients with a diagnosis of HIV-related DLBCL, treated at our center between January 1, 2005 and December 31, 2017. We further identified patients with non-HIV positive DLBCL diagnosed from January 1, 2015 to December 31, 2017. Data on patient demographics, clinical outcomes and treatment was collected. We defined early mortality as those patients who died within 180 days of diagnosis. RESULTS: HIV-NEGATIVE DLBCL: There were 103 HIV-negative patients with DLBCL, with a mean age of 65 years. N=17 (16.5%) patients expired within 180 days of diagnosis. In univariate analysis, factors predicting increased risk of mortality included poor ECOG performance status (PS) 3-4, presence of B-symptoms and higher international prognostic index (IPI) scores (Table 1). In multivariate analysis, poor PS (HR 4.86, p HIV-POSITIVE DLBCL: We identified 82 patients with HIV-positive DLBCL and divided patients into Cohort A (N=25) patients who expired within 180 days and Cohort B (N=57), patients who were alive beyond 180 days. 9 patients died within the first 30 days, 20 patients within 90 days and 25 patients within 180 days of index diagnosis. Both groups predominantly consisted of African-Americans with advanced stage DLBCL with a mean age of 53 and 48 years respectively (p=0.02). In univariate analysis, more patients in Cohort A had Stage 3-4 DLBCL (100% vs. 86%), poorer ECOG PS of 3-4 (52% vs. 7%), higher IPI scores (56% vs. 11%), lower CD4 counts (median of 70 cells/uL vs. 140 cells/uL) and higher LDH (544 U/L vs. 270 U/L). In multivariate analysis, we found that poor ECOG PS (HR 2.4, p We wanted to examine whether the time period of diagnosis affected mortality from HIV-related DLBCL in patients. Group 1 patients were diagnosed from January 2005 to December 2010 (N=20) and Group 2 from January 2011 to December 2017 (N=29). We found that in Group 1, 50% of patients died from progressive disease and 15% of patients died from an acute event. Meanwhile, in Group 2, 38% of patients died from progressive disease, and 52% died from an acute event. Sepsis was the most common acute event in both groups. CONCLUSION: Preventing early mortality in aggressive lymphomas is crucial to improving overall survival. For patients with non-HIV related DLBCL, we found poor ECOG PS and presence of B-symptoms to be predictors of early mortality. In patients with HIV-positive DLBCL, poor ECOG PS, higher LDH and older age were contributing factors. The leading cause of death in both HIV-positive and HIV-negative patients (2011- 2017) was sepsis followed by progressive disease at 180 days after diagnosis. Although sepsis is a major factor contributing to early mortality and morbidity, it is preventable with prophylaxis against opportunistic infections. In order to decrease sepsis related mortality, we propose early initiation of antimicrobial therapy in patients at high risk based on independent clinical variables identified in this study. A prospective study preventing sepsis in high risk patients is warranted to decrease early mortality in patients with aggressive lymphoma. Disclosures Janakiram: Seattle Genetics: Membership on an entity's Board of Directors or advisory committees.

Introduction: As people with HIV live longer, the epidemiology of plasma cell disorders (PCD) including MGUS, smoldering myeloma and Multiple myeloma (MM) becomes relevant and remains unknown. Moreover, patients with HIV have a higher incidence of monoclonal proteins which may not be related to an underlying lymphoproliferative disorder[1, 2] . There are mostly anecdotal reports and very few studies in HIV myeloma[3]. A retrospective study of 10 patients with HIV+ve symptomatic MM reported possible therapeutic benefit of ART and reported better overall survival of HIV+ve MM on ART as compared to HIV -ve MM. There is a paucity of data in PCD in this population whose incidence can be expected to increase globally. We conducted a single-institution retrospective study to look at the incidence of PCD. Methodology:We reviewed an electronic database of patients with HIV related PCD treated at Montefiore Medical Center between 2001 and 2018. All patients with a new diagnosis of PCD between January 1 2001 to July 15 2018 were identified. Data on patient demographics, HIV status, clinical outcomes (including mortality) and therapy was collected. Results: Between 2001 and 2018, 14438 patients were identified with HIV and 1986 patients had a monoclonal band in SPEP (13.8%). Based on our previous study, patients who had a definitive monoclonal band or suspected MM underwent a BM biopsy. 34 patients were diagnosed with PCD --MGUS 16 (47.05%), Smoldering MM 1 (2.94%), MM 16 (47.05%) and Primary plasma cell leukemia (PCL) 1 (2.94%). The majority of the patients were AA consistent with demographics of the Bronx. Interestingly HCV co-infection was identified in 50% (n=17) of patients and HBV co-infection was present in 15% (n=5) patients. The median CD4 count was 381 (12-1080), median viral load 237 (0-501534) and 53% patients were on ART at the time of diagnosis. The median time from HIV diagnosis was 13.9 (-2.8 to 29) years. In patients with MGUS the predominant heavy chain involvement was IgG, the median protein on SPEP was 1.1 g (0.7-1.9 g) and percentage of BM involvement was 5% (2-10%). In patients with MM IgG was the predominant heavy chain involved. On presentation, ISS Stage was Stage I in 2 patients (15.4%), 4 (30.7%) had at least Stage 2, 7 patients (53.9%) had stage 3. On presentation, 10 (58.8%) patients presented with anemia, 10 (58.8%) presented with renal impairment (Cr>=1.3), 16 (94.1%) presented with bone lesions, 6 (37.5%) presented with hypercalcemia. 5 patients (34.6%) had extramedullary presentation including 1 patient (2.9%) with PCL, 2 (5.8%) with anaplastic plasmacytoma. All patients were treated with an imid or bortezomib based regimen and there were no unusual side effects in these patients. 5 patients (29.4%) underwent autologous stem cell transplant with successful outcomes. Discussion: The prevalence of a positive SPEP is 13.8% in patients with HIV and the prevalence of plasma cell dyscrasias (PCD) in our population is 0.02%. A previous study from this cohort[2] showed that approximately 6.4% of patients with a positive SPEP developed hematological malignancy and all patients with a faint monoclonal band had lymphoma (70.5%) and those with a definite monoclonal band had myeloma (29.5%). Even though prevalence is less than the general population rate of 3%, as patients with HIV live longer this number may increase. In our study there was a high rate of co-infection with HCV in patients who had a PCD and this needs further investigation to determine causality. PCD developed at a median of 13.9 years after HIV diagnosis. The ISS staging distribution in patients presenting with myeloma is consistent with non HIV myeloma. People with HIV tolerate standard imid or proteasome inhibitor based triple drug therapy and have successful outcomes with autologous transplantation. This is the largest cohort and report describing PCD in HIV population. References:Jou, E., et al., Viral co-infections and paraproteins in HIV: effect on development of hematological malignancies. Ann Hematol, 2016. 95(4): p. 575-80.Jou, E., et al., Retrospective study of the prevalence and progression of monoclonal gammopathy in HIV positive versus HIV negative patients. Hematol Oncol, 2017. 35(1): p. 64-68.Li, G., et al., A retrospective analysis of ten symptomatic multiple myeloma patients with HIV infection: A potential therapeutic effect of HAART in multiple myeloma. Leukemia Research, 2014. 38(9): p. 1079-1084. Disclosures Janakiram: Seattle Genetics: Membership on an entity's Board of Directors or advisory committees.

Introduction: The critical role of cyclin-dependent kinases in cell division and gene transcription has made them targets for anti-cancer therapies. Positive transcription elongation factor b (PTEFb)/cyclin-dependent kinase 9 (CDK9) plays a key role in transcription of short-lived anti-apoptotic survival proteins and oncogenes such as MYC and MCL-1. BAY 1251152 (BAY) is a potent and highly selective second generation PTEFb/CDK9 inhibitor. We report here the results of a phase I study to determine the safety, tolerability, pharmacokinetics (PK), maximum tolerated dose and preliminary anti-tumor activity of BAY in patients with AML. Methods: Patients with confirmed AML who are refractory to or have exhausted all available therapies were eligible. A minimum of 3 and a maximum of 9 patients were to be enrolled per dose level in a sequential dose escalation design. BAY was administered intravenously over 30 minutes once weekly for 21-day cycles. PK was assessed at cycle-1, day 1/D8/D15. Dose-limiting toxicities (DLTs) for hematologic events were defined as prolonged grade (G) 4 neutropenia and/or G3 thrombocytopenia and/or any G5 event. DLTs for non-hematological toxicity were any G3-G5 event not clearly resulting from underlying malignancy, among others. Responses were evaluated using Cheson (2003) criteria. Adverse events (AEs) were assessed using CTCAE v4.03. Results: A total of 30 patients were enrolled, 9 of whom failed screening. Twenty one patients received treatment with BAY in 4 dose cohorts: 5, 10, 20, and 30 mg. The median age was 66 (range 20-79), with 62% being male. The median number of prior lines of therapy was 3 (range 1 - 6). Four patients were treated per dose cohorts 1-3 without occurrence of DLTs. Nine patients were treated in cohort 4 (30 mg) and were evaluable for safety, with 7 evaluable for response. Nine patients (43%) discontinued treatment due to clinical progression, 19% due to withdrawal by subject, 19% due to lack of efficacy, 14% due to an AE associated with disease progression. A MTD was not defined. PK assessment indicated that the mean elimination half-life was 3-9 hours with no accumulation over multiple doses. The mean AUC of the 30 mg cohort was within the expected therapeutic exposure range based on preclinical studies. Interestingly, pharmacodynamic assessment of MYC, MCL-1 and PCNA mRNA in whole blood indicated that BAY treatment led to significant, but short-lived, reductions; highest degree of down-regulation was achieved 0.5-4 hours post-dose for MYC, 1-3 hours post-dose for MCL-1, and 1-4 hours post-dose for PCNA. However, no objective responses were observed, with only modest reductions in bone marrow blasts in some patients. In the 30 mg cohort, the longest treatment duration was 63 days. Single patients in each of cohorts 1-3 exceeded this duration but only minimally. Overall treatment-emergent G3/G4 AEs recorded in >10% of patients included anemia (G3 26.7%/G4 6.7%), lung infection (G3 23.3%), neutrophil count decreased (G4 20%), febrile neutropenia (G3 13.3%), and leukocytosis (G3 10%). Clinical laboratory assessments in cohort 4 indicated that 7 of 9 patients (78%) had G4 neutrophil count decreased and G3 anemia, and 5 of 9 (56%) had platelet count decreased. G5 events included 2 each for sepsis and cardiac arrest, and 1 patient with leukocytosis; none of the G5 events were considered related to the study treatment. Conclusions: Treatment of AML patients with BAY did not result in objective responses despite achieving drug levels in the expected therapeutic range and evidence of target engagement. Given the good tolerability and on-target activity, BAY 1251152 might be a good candidate for future combination therapies. Disclosures Ottmann: Celgene: Consultancy, Research Funding; Amgen: Consultancy; Pfizer: Consultancy; Incyte: Consultancy, Research Funding; Takeda: Consultancy; Fusion Pharma: Consultancy, Research Funding; Novartis: Consultancy. Scholz:Bayer: Employment. Ince:Bayer: Employment. Valencia:Bayer: Employment. Souza:Bayer: Employment.

Background: Multiple Myeloma (MM) represents 1.8% of all new cancers in the United States and is the second most common hematologic malignancy in the US with 30,000 new cases/year. The highest incidence is amongst African Americans (AA) (SEER, 2018). Increased use of autologous stem cell transplant (AHSCT) as well as introduction of proteasome inhibitors (PIs) and immunomodulatory agents (iMiDs) have led to an improvement in overall survival (OS) from 35.6% between 1998-2001 to 50.7% in 2008-2014 (Child et al. 2003; Pulte et al. 2014). Despite these improvements, outcomes in MM are heterogeneous and are influenced by sociodemographic factors like race and ethnicity, disease biology (laboratory markers, cytogenetics) and access to transplantation (Al-Hamadani, Hashmi, and Go 2014; Ailawadhi et al. 2016). Several large population-based studies report that Hispanics have low stem cell utilization rates, limited access to novel therapeutics and clinical trials as well (Ailawadhi et al. 2018; Costa et al. 2015; Schriber et al. 2017; Pulte et al. 2014). Hence, outcomes for Hispanics and AA lag behind non-Hispanic Whites as well (Pulte et al. 2014). We wanted to evaluate outcomes of MM patients at Montefiore Medical Center where AA and Hispanics have access to novel agents and therapeutics, and most of whom hail from a poor socio-economic status. Methods: We obtained a cohort of patients diagnosed with MM between 1/1/2000-12/31/2017 from the Montefiore Medical Center Cancer Registry database via Clinical Looking Glass software. Socio-demographic characteristics including self-reported ethnicity, date of diagnosis, histology, laboratory parameters (hemoglobin (Hgb), creatinine (Cr), albumin (Alb), serum lactate dehydrogenase (LDH)) within 30 days of diagnosis were obtained. Ethnicity and race variables were condensed to Hispanics, Non-Hispanic Whites (NHW) and Non-Hispanic African Americans (NHAA). Charlson comorbidity score and its age-adjusted version were calculated. Primary payor (Medicaid, Medicare, private insurance or self-pay) was identified for each patient. Descriptive statistical analysis was performed using STATA 15.1 statistical software. OS was estimated using the Kaplan-Meier method and HR and corresponding 95% confidence intervals (CI) were estimated using the cox proportional hazard model. All the variables in the Cox proportional hazard ratio model fulfill the proportional hazard assumption. Results: We identified 1630 patients during the study period; 1502 patients were available for analysis (Table 1) The mean age of diagnosis was 66 years, and NWH were diagnosed at older age when compared to Hispanics or NHAA (71 vs 64 vs 66, p=0.001) respectively. Hispanics had a higher proportion of Medicaid affiliation. The baseline mean Hb (p=0.02), Cr (p=0.02) and LDH (p=0.09) were different; however this difference is unlikely to be clinically relevant (Table 1). Median survival for the cohort was 63 months (95% CI: 59-69). Hispanics had better mean OS (118 months, (95% CI 96-128) as compared to NHW (49 months, 95% CI 40-68)) and NHAA (60 months, 95% CI 53-66) and others (32 months, 95% CI 21-46) (Figure 1). After controlling for age at diagnosis, gender, socioeconomic status, modified Charlson age score, race had a statistically significant impact on the outcome, with NHW (HR-2.01) and NHAA (HR 1.77) having poorer survival when compared to Hispanics (P Conclusion The study cohort is significantly different to prior reports, with a higher rate of NHAA and Hispanics. Hispanics had a higher percentage of Medicaid as primary payor. Contrary to prior reports, we show that with access to novel agents and transplantation, MM in Hispanics has a better OS than AA and NHW. We also show that NHAA (41%) despite being diagnosed at a younger age than NHW continue to have poorer outcomes than Hispanics. Further characterization including risk stratification and cytogenetics is underway to identify factors leading to better and worse outcome in Hispanics and AA respectively. Disclosures Janakiram: Seattle Genetics: Membership on an entity's Board of Directors or advisory committees.

Introduction Adult T-cell leukemia/lymphoma (ATLL) is a rare, aggressive T cell neoplasm associated with a retrovirus human T cell lymphotropic virus (HTLV-1) and carries a dismal prognosis. Within the United States, New York, and Florida see the majority of cases due to the concentration of Caribbean immigrants (Zell, Assal et al. 2016, Malpica, Pimentel et al. 2018). SEER data does not include states like New York and Florida where most cases are seen and therefore a true estimate of the disease burden in this country is not known (Chihara, Ito et al. 2012, Adams, Newcomb et al. 2016). Aim We aim to study the epidemiology and clinical outcomes of ATLL in the United States particularly in the state of New York. Methods Data for New York was obtained from the New York State Cancer Registry (NYSCR). Data were also retrieved from 18 Surveillance, Epidemiology, and End Results (SEER) registries in the United States. Patients with ATLL (HTLV-1 positive) (includes all variants) were categorized using the International Classification of Diseases for Oncology, Third Edition codes ICD-O-3 as 9827/3. Race/ethnicity was categorized as non-Hispanic white, non-Hispanic black, all Hispanic and other/unknown in the NYSCR whereas it was categorized as non-Hispanic white, non-Hispanic black, all Hispanic, non-Hispanic American Indian/Alaska Native, non-Hispanic Asian or Pacific Islander, and non-Hispanic unknown race in SEER. ATLL patients ≥ 15 years of age were identified from 1995 to 2014 in SEER and all ages were included in NYSCR. Survival was estimated from SEER follow-up data with Kaplan Meier survival analysis. For NYSCR mean and median survival time (month) for deceased patients - cases diagnosed through death certificate only were removed. NYSCR does not conduct active patient follow-up and assumes patients are still alive if we didn't find a deathmatch through vital record or National Death Index linkages. Results Five hundred and eleven patients with ATLL were identified in SEER. These patients had a median survival of 8 months (m) which was worse than all other subtypes of peripheral T cell lymphoma. (Figure 1) Four hundred and twenty-nine patients with ATLL were identified in NYSCR and these patients had a median survival of 4.5 m. (Figure 2) Over the years from 2000 until 2014 the number of cases diagnosed within SEER registry coverage areas has not changed. In New York state however there has been a doubling in the number of cases diagnosed from 1995 to 2014. (Figure 3A, B) The non-Hispanic black population was diagnosed at a median age of 52.5 in SEER and 54 in NYSCR while the non-Hispanic whites were diagnosed at a median age of 71 in SEER and 64.5 in NYSCR. The Hispanic patients were diagnosed at a median age of 58.5 in NYSCR and 52.5 in SEER. (Figure 4A, B) There was no gender predominance with 50% males in both registries. ATLL patients in SEER were 47.2% non-Hispanic white, 31.7% non-Hispanic black, 9.8% Hispanic and 11.4% other/unknown. There were 5.5% Japanese patients (n=28) diagnosed in SEER. NYSCR had 22.4% non-Hispanic white, 59.4% non-Hispanic black, 15.9% Hispanic and 2.3% other/unknown. (Figure 5A, B) Within SEER registries most cases occurred in New Jersey, California, Connecticut and Georgia. (Figure 6) New York state had a significantly higher number of cases than these states. Seventy four percent cases diagnosed within New York state are diagnosed in New York city and only 26% of cases are diagnosed in upstate New York. Based on reported country of birth within New York state, only 27% of the ATLL cases diagnosed are born in the US whereas 49% are born in the Caribbean (most likely to be from Jamaica, Dominican Republic and Haiti). (Figure 7A, B, C) For SEER and NYSCR the age-adjusted cancer incidence rate by race year and other factors will be presented at the meeting. Conclusions ATLL has a worse prognosis than all other PTCL subtypes. New York State has a high endemicity for ATLL with a rising number of cases. The higher percentage of non-Hispanic black patients in New York compared to the rest of the country is consistent with the diverse racial demographics in this state. Survival varied significantly by race/ethnicity and disparities were evident especially for non-Hispanic blacks who were diagnosed at a younger median age and had a shorter survival. Further research into this aggressive disease is needed to improve outcomes for these patients. Disclosures No relevant conflicts of interest to declare.

Introduction: Human T-cell lymphotropic virus (HTLV) is a retrovirus that has been associated with adult-T cell leukemia/lymphoma (ATLL) and other inflammatory conditions. Pulmonary involvement has not been widely associated to HTLV infection; however, high rates of imaging abnormalities in patients with and without ATLL have been reported. Okada reported 30%, 69% and 94% of abnormalities in HTLV1 carriers, ATLL and patients that transformed into ATLL. Whether these abnormalities follow a pattern related to each condition individually has not been defined. Hence, we undertook a retrospective study in ATLL and HTLV infected patients to determine the lung abnormalities which could be due to ATLL involvement rather than HTLV infection. Objectives: To compare the CT pulmonary findings among patients with HTLV infection with and without ATLL diagnosed at Montefiore Medical Center between 2004 and 2017. Methods: Patients diagnosed with HTLV infection by ICD9 were identified using the software Clinical Looking Glass and those with an available chest CT scan were selected. Data regarding demographics, smoking history, prior pulmonary conditions, HTLV and ATLL-associated characteristics was collected by chart review. CT chest was reviewed by an expert radiologist who was unaware of the patient diagnosis (ATLL versus non-ATLL) and findings were compared among groups. The staging CT scan was used to determine baseline pulmonary findings in patients with ATLL and the first CT chest around HTLV diagnosis was used for HTLV patients. Results: A total of 97 patients (72 with ATLL and 25 with HTLV alone) were identified. Mean age at HTLV diagnosis was 58.4 years (range: 33-88), 54.6% were females, 72.2% were Black Non-Hispanics while 27.8% were Hispanic. 88.3% were from Caribbean origin. Smoking history was similar between ATLL and non-ATLL groups (12% vs 8%, p=0.07) with no cases of prior active TB infection. Abnormal CT chest findings were present in 92.8%, 94.4% and 88% for the total cohort, ATLL and non-ATLL patients. Among patients with ATLL, 52.1% had acute and 43.7% had lymphomatous types; while only 1.4% and 2.8% had smoldering and chronic type. The most common CT chest findings were lymphadenopathy (50, 69.4%); followed by 3-10 mm nodules (32, 44.4%), ground-glass opacity, pleural effusion (31, 43.1% each), centrilobular nodules (28, 39.4%), thickening of interlobular septum (23, 31.9%) and bronchiectasis (18, 25%). Compared to the acute subtype, patients with lymphomatous subtype had higher rates of lymphadenopathy (83.9% vs 64.9, p=0.07) and lower rates of bronchiectasis (16.1% vs 35.1%, p=0.07). Among patients with non-ATLL, HTLV infection was diagnosed at an older age (63.8 vs. 56.6 years, p=0.03); HTLV-associated comorbidities were found in 16 cases (64%). Of these, myelopathy was the most frequent (10, 40%), followed by strongyloides (4, 16%). After HTLV diagnosis, CT chest was indicated in 28% patients for otherwise unexplained respiratory symptoms and to evaluate lung nodules or other chest X-ray abnormalities in 24% of cases. Bronchiectasis was the most common finding (12, 48%) followed by pleural thickening (11, 44%), ground-glass opacity and thickening of interlobular septum (10, 40%, each). Persistent abnormalities on follow-up imaging were present in 86.7% of the cases. Among patients with HTLV infection, those with ATLL were more likely to have nodules and lymphadenopathy (41.7% vs 20%, p=0.05 and 69.4% vs 24%, p Conclusions: Pulmonary findings are highly prevalent in CT chest of patients with HTLV infection with and without ATLL. Bronchiectasis and pleural thickening was more frequently encountered in non-ATLL patients while lymphadenopathy and nodules were common finding in patients with ATLL. Pulmonary involvement in lymphoma is usually characterized by nodules and lymphadenopathy but patients with ATLL had a higher incidence of findings including ground glass opacities, bronchiectasis and interlobular septal thickening possibly due to their underlying HTLV infection. Based on this data, nodules and lymphadenopathy should be classified as ATLL involvement of the lung while other findings described here could be due to HTLV infection. These findings are important in staging and response criteria for ATLL. Disclosures Janakiram: Seatle Genetics: Membership on an entity's Board of Directors or advisory committees.

Trastuzumab is considered effective against human epidermal growth factor receptor (HER)-2–positive breast cancer as assessed by immunohistochemistry (IHC) and fluorescence or chromogenic in situ hybridization (FISH/CISH) on biopsy material. Trastuzumab is now approved in both the adjuvant and metastatic settings for this patient population. Because HER-2 extracellular domain (ECD) levels have been correlated with disease progression in the metastatic setting, we considered trastuzumab salvage therapy plus a taxane in heavily pretreated trastuzumab-naive relapsed breast cancer patients with high serum levels of HER-2 ECD (≥15 ng/ml). All patients had previously failed at least two lines of anthracycline- and taxane-based regimens and were HER-2 negative by IHC and FISH/CISH prior to a centralized reanalysis, and were serum positive for HER-2 ECD (≥15 ng/ml) at baseline. Regular serum accounts of HER-2 ECD were recorded and compared with response and survival outcomes. Twenty-two patients were finally eligible for salvage therapy. Minor responses were observed in five (23%) and stable disease (SD) was observed in 11 patients, leading to a clinical benefit rate of 73% (16 of 22 patients). The median time to progression and overall survival time were 5 (6.5 months in minor responders and SD) and 12 months, respectively; 11 and eight patients remained progression free for >6 and >12 months, respectively. Eleven and seven patients were alive at 12 and 15 months, respectively, after treatment start. Furthermore, in total, 13 (59.1%) patients obtained a biochemical response. In our study, patients with conventionally HER-2–negative disease but with expression of HER-2 ECD above the normal limit (≥15 ng/ml) displayed a rapid response, both biochemically and clinically, to the trastuzumab–taxane combination. This is the first study assessing anti-HER-2–based treatment in HER-2–negative advanced breast cancer according to HER-2 ECD positivity; if our results are confirmed, additional patients with “hidden” HER-2–positive breast cancer might benefit from anti-HER-2 treatment.

Tyrosine kinase inhibitors (TKIs) have become the first-line treatment of choice for chronic myelogenous leukemia (CML) after imatinib was shown to offer improved and durable responses.[1,2] Second...

// Monica Zell 1, * , Amer Assal 2, * , Olga Derman 2 , Noah Kornblum 2 , Ramakrishna Battini 2 , Yanhua Wang 3 , Deepa M. Narasimhulu 1 , Ioannis Mantzaris 2 , Aditi Shastri 2 , Amit Verma 2 , Hilda Ye 4 , Ira Braunschweig 2 , Murali Janakiram 2 1 Albert Einstein College of Medicine, Bronx, NY, USA 2 Department of Oncology, Montefiore Medical Center/ Albert Einstein College of Medicine, Bronx, NY, USA 3 Department of Pathology, Montefiore Medical Center/ Albert Einstein College of Medicine, Bronx, NY, USA 4 Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY, USA * These authors have contributed equally to this work Correspondence to: Murali Janakiram, email: mjanakir06@gmail.com Keywords: human T-cell lymphotropic virus type-1 (HTLV-1), adult T-cell leukemia/lymphoma (ATLL), non-Hodgkin lymphoma, T-cell lymphoma, allogeneic stem cell transplantation Received: January 27, 2016 Accepted: May 09, 2016 Published: June 22, 2016 ABSTRACT Adult T-cell leukemia/lymphoma (ATLL) is a rare and aggressive disease caused by human T-cell lymphotropic virus type 1 that predominantly affects Japanese and Caribbean populations. Most studies have focused on Japanese cohorts. We conducted a retrospective analysis of 53 cases of ATLL who presented to our institution between 2003-2014. ATLL in the Caribbean population presents more often as the acute and lymphomatous subtypes, is associated with complex cytogenetics, and has a high rate of CNS involvement. The overall response rate to first-line therapies with anthracycline-based regimens was poor (32%), with a median survival of only 6.9 months. A complete or partial response to first-line regimens was associated with better survival. There was no difference in survival between patients who received chemotherapy alone versus chemotherapy with antiviral agents. Allogeneic transplantation was performed in five patients, two of whom achieved complete remission despite residual or refractory disease. Recipients of allogeneic transplantation had significantly improved overall survival compared to non-transplanted patients. This is the first analysis to describe ATLL pathological features, cytogenetics, and response to standard therapy and transplantation in the Caribbean cohort.

828 Background: Pts with mCRC who progress on all standard therapies have a poor prognosis and limited therapy options. Phase 1 trials represent a valuable treatment option. Herein we report the characteristics and outcomes of mCRC patients treated at our institution. Methods: We reviewed records of pts with mCRC enrolled on phase I trials at our institution from January 1999 to December 2016. Treatment-related response, toxicity, and deaths were recorded. Prognostic factors for overall survival (OS) were calculated using univariate (UVA) and multivariable Cox PH analysis (MVA). Results: We observed 187 enrollments with 152 unique patients accrued on 37 phase I trials. Median age was 59 years (range 29-83) and median number of prior therapies was 3 (range 0-8). 144 patients were evaluable for response. The clinical benefit rate (SD+response, CBR) was 33.2% and the ORR was 4.3%. Grade 3/4 non-hematological and hematological AE were seen in 25.5% and 17.3% of patients, respectively. Treatment-related mortality was 0.5%. Median PFS was 1.7 mos and OS was 8.2 mos. In UVA, the following variables predicted a shorter OS: age (p = 0.049); PS > 1 (p < 0.01); sites of metastases > 2 (p = 0.04); LDH > ULN (p < 0.001); albumin < 3.5 (p < 0.001); direct bilirubin > ULN (p = 0.02); WBC > 5.2 (p = 0.001); anemia (p = 0.046). In MVA, age > 60 (HR 1.63, p < 0.004), albumin < 3.5 (HR 3.69, p < 0.001), direct bilirubin > ULN (HR1.69, p < 0.01), and WBC > 5.2 (HR 1.97, p < 0.001) were negative prognostic factors for OS, adjusted for race and sex. A risk score based on MVA revealed that patients with a score of 0-1 had an improved OS (12.5mos) compared to a score of 2 (9.1mos, p-value < 0.005) and 3 (3.2 mos, p-value < 0.001). Conclusions: Patients with mCRC enrolled on phase 1 trials had a CBR of 33.2% and median OS of 8.2 mos, which exceeds third line therapies including regorafenib and trifluridine/tipiracil. Negative prognostic factors for OS were: age > 60, albumin < 3.5, direct bilirubin > ULN, and WBC > 5.2. A risk score based on these parameters showed that patients with a higher score had a significantly shorter OS, which may be useful in selecting patients for phase 1 trials.

Functionally critical decreases in levels or activity of the ETS family transcription factor PU.1 are present in approximately 2/3 of patients with acute myeloid leukemia (AML), across different AML subtypes (Sive, Leukemia 2016) including at the stem cell level (Steidl, Nat Genet 2006; Will, Nat Med 2015). Thus, targeting PU.1 could be an appealing option for treatment. As complete loss of PU.1 leads to stem cell failure (Iwasaki, Blood 2005), we hypothesized that PU.1 inhibition could eradicate leukemic cells harboring already low levels of PU.1, with modest effects on normal cells. We initially tested this hypothesis using 3 different shRNAs, and found that PU.1 inhibition led to a significant decrease in proliferation and clonogenicity, and increased apoptosis of mouse and human leukemic cell lines with low PU.1 levels, as well as the majority of primary human AML cells tested. We demonstrated that these effects were indeed due to decreased PU.1 levels by retroviral add-back experiments. The direct pharmacologic targeting of transcription factors has proven challenging in the past. Besides the core ETS binding motif (GGAA) in the DNA major groove, PU.1 binding to chromatin depends on additional minor groove contacts enriched for AT nucleotides upstream of the ETS motif, which determine selectivity for PU.1. Using an integrated screening strategy utilizing biosensor surface plasmon resonance, DNA footprinting, and cell-based dual-color PU.1 reporter assays, we developed novel small molecules of the heterocyclic diamidine family acting as first-in-class PU.1 inhibitors. Targeted occupancy by our compounds in the minor groove induces perturbations in DNA conformation that are transmitted to the PU.1 site in the major groove and thus inhibits PU.1 binding via an allosteric mechanism. Consistent with this, the inhibitory effects were selective for PU.1 versus other ETS transcription factors. Treatment with 3 different compounds led to cell growth inhibitory effect with respect to PU.1 level and preferentially affects PU.1low AML cells. Similarly to what we observed with shRNAs, treatment with our novel inhibitors led to decreased proliferation and colony forming capacity, increased apoptosis, and disrupted serial replating capacity of PU.1low AML cells and a majority of primary AML cell samples. Targeted ChIP and expression analysis showed that the compounds disrupt PU.1-promoter interaction and lead to downregulation of canonical PU.1 transcriptional targets in AML cells, confirming on-target activity in AML cells. Genome-wide analysis showed highly significant enrichment of known transcriptional targets of PU.1, and selectivity over genes regulated by other ETS family members. Comparison with published transcriptomic and PU.1 ChIP-seq data sets, as well as ARACNe analysis of the PU.1 regulon in primary AML cells, demonstrated that the inhibitors antagonize PU.1-regulated pathways at a genome-wide level. ChIP-seq performed in PU.1low AML cells confirmed a genome-wide decrease of PU.1 peaks after treatment and provides novel insight into the molecular mechanisms mediating the anti-leukemic effects of pharmacological PU.1 inhibition. To test the effects of PU.1 inhibition on normal hematopoiesis, we treated normal hematopoietic stem/progenitors cells (HSPC) in colony forming assays and saw decreased production of mature granulo-monocytic cells, consistent with PU.1's known role in this lineage. However, this effect was reversible upon drug removal, and serial replating capacity was not affected suggesting no significant effects on more immature HSPC. Congenic transplantation assays of treated normal bone marrow cells led to no change in myeloid and T-cells and only a modest decrease in B-cell numbers. Lastly, in vivo treatment with PU.1 inhibitors in mouse and human AML (xeno)transplantation models significantly decreased tumor burden and increased survival. To conclude, our study provides proof-of-principle for PU.1 inhibition as a novel therapeutic strategy in AML. Furthermore, we present the development of first-in-class PU.1 inhibitors acting via an allosteric minor groove-mediated mechanism. Our work shows that the specific pharmacological targeting of the DNA interaction of transcription factors such as PU.1 is feasible in principle, and may open the way for targeting of other transcription factors through minor groove-directed approaches. Disclosures Will: Novartis Pharmaceuticals: Consultancy, Research Funding. Steidl: Celgene: Consultancy; Aileron Therapeutics: Consultancy, Research Funding; Novartis: Research Funding; GlaxoSmithKline: Research Funding; Bayer Healthcare: Consultancy.

While the TP53 tumor suppressor gene is mutated in more than 50% of human tumors, in Acute Myeloid Leukemia (AML) TP53 mutations are rare, occurring in less than 10% of cases. Yet, functional inactivation of wild-type p53 due to non-mutational abnormalities occurs frequently in AML and other hematological malignancies. A major mechanism of p53 inactivation results from the overexpression of its endogenous inhibitors MDMX (also known as MDM4, HDMX, and HDM4) and MDM2 which are frequently overexpressed in various p53 wild-type human cancers, including AML. Strikingly, MDMX has been reported to be overexpressed in over 92% of AML cases, while MDM2 overexpression is less frequent. Pharmacological disruption of both these interactions has long been sought after as an attractive strategy to fully restore p53-dependent tumor suppressor activity in AML and other cancers with wild-type p53. Nonetheless, selective targeting of this pathway has thus far been limited to MDM2-only small molecule inhibitors which lack affinity for MDMX. ALRN-6924 is an optimized alpha helical p53 stapled peptide and first-in-class dual MDMX/MDM2 inhibitor which has recently entered phase I/II clinical testing (NCT02264613, NCT02909972) in solid tumors and lymphomas with, thus far, excellent tolerability and objective responses as single agent1. The goal of our study was to evaluate the molecular, cellular, and biochemical mechanisms of action of ALRN-6924 in AML. We used biochemical affinity studies as well as single molecule FISH and live single cell imaging to assess MDMX/MDM2 binding as well as p21 transactivation by p53 in response to ALRN-6924. Effects on cellular proliferation, apoptosis, DNA repair, cell cycle, clonogenic capacity, and serial replating were determined using AML cell lines and primary human AML patients' cells, including in leukemic stem (CD34+ CD38-) and progenitor (CD34+CD38+) cells. Genome-wide molecular effects were determined by RNA seq. P53 activity in a patient undergoing treatment with ALRN-6924 was measured by intracellular staining of p53 and its target gene p21 in CD34+ cells by flow cytometry. Furthermore, we evaluated ALRN-6924 activity in a xeno-transplantation model of human AML in NSG mice. We found that MDMX is significantly overexpressed in highly fractionated leukemic stem (Lin-CD34+CD38-CD90-) and progenitor (Lin-CD34+CD38+CD123+CD45+) cells in AML patients compared to identically sorted, age-matched healthy controls (p Our study provides insight into the molecular, cell biological, and in vivo effects of pharmacological dual MDMX/MDM2 inhibition in AML, which may have important implications for other MDMX/MDM2-related cancers. Our findings provide proof-of-concept for ALRN-6924 as a novel therapeutic in p53-wildtype AML, and provide a rationale for its further preclinical and clinical development in AML and other cancers. Furthermore, the success of targeting p53 raises the intriguing prospect that the same development path is possible for other helix-in-groove targets, and may thus pave the way for a new class of targeted therapeutics. 1 ASCO 2017 annual meeting: J Clin Oncol 35, 2017 (suppl; abstr 2505) Disclosures Guerlavais: Aileron: Employment. Annis: Aileron Therapeutics: Employment. Will: Novartis Pharmaceuticals: Consultancy, Research Funding. Aivado: Aileron: Employment. Steidl: Novartis: Research Funding; Celgene: Consultancy; Bayer Healthcare: Consultancy; GlaxoSmithKline: Research Funding; Aileron Therapeutics: Consultancy, Research Funding.

e18557 Background: Chronic hepatitis C virus (HCV) infection has been associated with hematologic malignancies such as B-cell non-Hodgkin lymphoma. In contrast, there is very little known about the relationship between HCV and myeloid malignancies such as myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). To determine the effect of HCV on MDS/AML clinical outcomes we conducted a retrospective analysis in a large inner city cohort of patients (pts) Methods: 478 pts with MDS and MDS-transformed AML were identified between 1997 and 2016; 13 pts were HCV-positive (HCV+/MDS) and 465 were HCV-negative (HCV-/MDS). Demographics, hematologic parameters, cytogenetics, IPSS-R scores and molecular profiles were compared for both groups (grp). Survival (surv) analysis was done using the Kaplan-Meier method Results: HCV+/MDS had significantly worse surv than HCV-/MDS pts on univariate analysis (UA) (median surv 16 vs 52 months, HR 2.8, 95% CI 1.4-5.5, p < 0.01). Difference remained strongly significant after exclusion of HIV-coinfected pts (HR 2.7, p = 0.02) and pts w/ AML on presentation (HR 3.1, p < 0.01). Cytopenias were worse in HCV+/MDS (mean Hgb level 8.2 vs 9.4 g/dl, p = 0.04; mean plt count 64 vs 139 103/µL, p = 0.03). Average IPSS-R score was higher in HCV+/MDS pts (5.5 vs 3.8, p = 0.02). IDH1 mutation was more prevalent in HCV+/MDS (25% vs 2%, p < 0.01). Differences in age between HCV+/MDS and HCV-/MDS were non-significant (mean 64 vs 69 respectively, p = 0.2). Male-to-female ratio was higher in HCV+/MDS but difference was non-significant (2.3 vs 0.9, p = 0.2). Interestingly, high HCV viral load and cirrhosis did not correlate with poor surv in the HCV+/MDS grp, suggesting deleterious effect occurs even in early stages of HCV infection. Conclusions: Our analysis suggests that chronic HCV infection strongly correlates with worse surv in UA and is associated with lower blood counts and higher IPSS-R scores at the time of diagnosis of MDS. We observed a high rate of MDS refractory to standard therapies and speculate that HCV may affect biology of the disease. Larger studies are warranted to determine the effect of HCV on surv in this population and to provide a rationale for trials of anti-HCV drugs concomitantly with MDS Tx.

Even though alterations in platelet counts are presumed to be detrimental, their impact on the survival of patients has not been studied in large cohorts. The prevalence of thrombocytopenia and thrombocytosis was examined in a large inner city outpatient population of 36,262 individuals aged ≥65 years old. A significant association with shorter overall survival was found for both thrombocytopenia (HR=1.45; 95% CI: 1.36–1.56) and thrombocytosis (HR=1.75; 95% CI: 1.56–1.97) when compared to the survival of patients with normal platelet counts. This effect persisted across all ethnic groups. However, African-Americans (non-Hispanic Blacks) with either thrombocytopenia or thrombocytosis were at significantly lower risk compared to non-Hispanic Caucasians (HR=0.82; 95% CI: 0.69–0.96 and HR=0.70; 95% CI: 0.53–0.94, respectively). Furthermore, Hispanics with thrombocytosis were found to have a lower mortality risk compared to non-Hispanic Caucasians with thrombocytosis (HR=0.60; 95% CI: 0.44–0.81). A value of

Introduction Adult T-cell leukemia/lymphoma (ATL) is a rare, aggressive disease caused by human T cell lymphotropic virus type 1 (HTLV1) that predominantly affects Japanese and Caribbean populations. (Goncalves, Proietti et al. 2010) Most studies have focused on Japanese cohorts. A recent whole genome/exome sequencing of 81 Japanese ATL cases identified alterations that overlap with the HTLV1 Tax interactome and are highly enriched for T cell receptor-NF-kB signaling, and T cell trafficking (Kataoka, Nagata et al. 2015). We recently showed that ATL in Caribbean patients has a poor prognosis and may have distinctive clinical features when compared to the Japanese cohort (Zell, Assal et al. 2016). In order to determine whether there are genomic differences between the two cohorts, we sequenced 15 ATL samples from the Caribbean cohort. Methods In this prospective study we perform comprehensive Next Generation Sequencing to assess the mutational spectrum of ATL in Caribbean patients. Samples were analyzed by complete genetic profiling with the Genoptix Nexcourse complete assay that contains 173 cancer related genes. Patient genomic DNA was utilized to identify relevant single nucleotide variants, insertion/deletions, copy number variations, and translocation fusion genomic alterations in a panel of up to 173 reportable genes at an average mean sequencing depth of 500X coverage. Results In the 15 patients, a total of 49 genes were found to be mutated ranging from 3 to 7 mutated genes in each patient. The percent of mutated genes amongst the total analyzed ranged from 1.7-4% for each patient and the percent of mutated genes known to be pathogenic ranged from 0-2.3% for each patient. There were 18 known pathogenic mutations in a total of 70 genetic mutations identified in this cohort (25.7%). The mean number of mutations in the acute and lymphomatous subtype was approximately 0.9%. Genes most commonly mutated in out cohort were TP53 (26.7%), FAT1 (26.7%), NOTCH1 (20%) and APC (20%). Novel mutations not reported by the Japanese cohort but present in our cohort are - NRAS, KRAS, EZH2, RICTOR, XPO1, VHL (known to be pathogenic), FAT1, APC, DDX3X, KIT, NOTCH2, MYC, TSC1, PLCG2, FGFR2, FGFR4, PDGFRA, EGFR, KEAP1, MCL1, ALK, BCL6, RIPK1, IGF1R, DDR2, KDR, AKT1, ERBB2, NKX2-1, BRCA2, PBRM1, CD79A, STAG2, PTCH1, KMT2A, HIST1HE, SPEN, ASXL1 (not known to be pathogenic). Mutations common to both the Japanese and our Caribbean cohort are - CARD11, TNFAIP3, TRAF3 (TCR signaling/NFkB pathway), NOTCH1 (signaling pathway), GATA3, CEBPA, TBL1XR1 (transcriptional regulation), EP300 (epigenetic regulation), TP53, POT1 (Telomere regulation and DNA repair). Serial analysis of a patient revealed increase in the size of the pathogenic clone with XPO1 mutation. XPO1 has been involved in nuclear transport of p53 and the increase in its clone size occurred with relapse after cytotoxic chemotherapy. The overall survival (OS) was shorter for TP53 mutated patients (99.3 days) versus non TP53 mutated patients (307.8 days). Discussion We report on mutational profiling in the largest cohort of Caribbean ATL and an additional 8 patients will be included in the analysis to be presented at ASH. A significant number of genes found to be mutated affected known pathways in the pathogenesis of ATL. There are known genes which are common between the Japanese and Caribbean cohorts but there are some notable differences. Previously we showed that the Caribbean cohort has a poorer OS than the Japanese cohort. TP53 mutations are more frequent and associated with decreased OS in this cohort. Genes involved in Wnt pathway - FAT1, APC, NOTCH1 were more frequently mutated in our cohort. FAT1 mutations have not been described in ATL. However, they have been implicated in oncogenesis in solid tumors, chronic lymphocytic leukemia and T-cell acute lymphoblastic leukemia. FAT1 acts as a tumor suppressor gene and encodes a cadherin-like protein, which potently suppresses cancer cell growth. Inactivation of FAT1 via mutation therefore promotes Wnt signaling and tumorigenesis and affects patient survival (Morris, Kaufman et al. 2013). In in-vitro models of ATL, Wnt pathway dysregulation has been shown to promote ATL tumorigenesis (Bellon, Ko et al. 2013, Ma, Yasunaga et al. 2013). Based on this study the driver mutations of the Caribbean cohort appear to be the Wnt signaling pathway which is different from the TCR- NF-kB signaling pathway seen in the Japanese cohort. Figure Figure. Disclosures Hall: Genoptix, a Novartis Company: Employment.

Myelodysplastic syndrome (MDS) & Acute Myeloid Leukemia (AML) arise from a population of aberrant hematopoietic stem cells (HSCs) that have been altered by multiple genetic & epigenetic alterations. A preliminary genomewide transcriptomic and epigenomic analysis of stem and progenitor cells from MDS and AML patients revealed STAT3 upregulation with corresponding loss of promoter methylation in diseased samples (Will et al, Blood, 2012). We now demonstrate that STAT3 is overexpressed in highly purified FACS sorted disease initiating populations in MDS/AML. STAT3 expression was determined to be significantly higher in phenotypic LT-HSC (CD34+/CD38-/CD90+/Lin -ve), ST-HSC (CD34+/CD38-/CD90-/Lin -ve) and GMP (CD34+/CD38+/CD123+/CD45Ra+/Lin -ve) from 10 diseased and 6 control sorted samples. Transcriptomic data from another cohort of CD34+ cells from 183 MDS patients found significantly increased expression of STAT3 in MDS samples when compared to healthy controls and importantly, found that increased STAT3 expression was predictive of significantly adverse prognosis (P value < 0.01, median survival of 2.6 years compared to 5.8 years for group with lower STAT3). Clinical correlations revealed that MDS patients with higher STAT3 expression in stem/progenitor cells were significantly more anemic (Mean Hgb 9.4gm/dl vs 10.2gm/dl, P=0.002) and had higher blast counts (Mean Blast Count 7.1% vs 5.3%, P=0.02), further demonstrating STAT3 to be an adverse prognostic marker in MDS. To functionally determine the role of STAT3 in MDS/AML pathogenesis, we used AZD9150, a Gen 2.5 Antisense Oligonucleotide (ASO) specific inhibitor of STAT3 (Hong et al, SciTM, 2015). This ASO has recently demonstrated safety and single-agent antitumor activity in patients with refractory lymphoma in a phase 1 dose-escalation study. We evaluated its efficacy in multiple leukemic cell lines and primary MDS/AML samples and used an inactive structural analogue oligonucleotide as control. AZD9150 treatment led to significantly decreased viability in numerous AML and MDS derived cell lines. (N=7, P < 0.01). Loss of viability was accompanied by dose dependent increase in apoptosis in leukemic cells. Specific inhibition of STAT3, but not STAT5, was seen in AZD9150 treated leukemic cells in luciferase reporter assays. AZD9150 treatment also led to decreased expression of important oncogenic downstream genes including not only STAT3 itself, but also IL8, IL6, CXCR2 and others. In vivo studies using a leukemia xenograft model in NSG mice demonstrated that treatment with AZD9150 at 50mg/kg/day led to significantly improved survival compared to control oligonucleotide (p-value: 0.004). It is generally challenging to show uptake of oligonucleotide-based therapeutics by primary cancer samples. Here, we treated healthy stem cells and AML primary patient samples with AZD 9150 and determined by intracellular flow cytometry that the ASO were readily taken up by primary patient- or cord blood-derived HSCs, myeloid progenitors and lymphocytes in a time and dose-dependent manner. We then treated a cohort of MDS and AML primary samples (N= 7) with AZD9150 or control and found qualitatively decreased leukemic colony growth, enhanced erythroid colony formation, and increased myeloid differentiation following STAT3 inhibition. In conclusion, we demonstrate that STAT3 is upregulated in highly purified stem and progenitor cells in MDS and AML and is an adverse prognostic marker. Importantly, a clinically applicable oligonucleotide inhibitor of STAT3 shows preclinical in vitro and in vivo efficacy in MDS and AML models, thereby providing a rationale for further development and clinical testing in MDS and AML. Supported by LLS Disclosures No relevant conflicts of interest to declare.

Introduction: Previous studies have suggested differences in presentation, prognostic factors and treatment outcomes between blacks and whites with acute myeloid leukemia (AML). Such differences, however, are not well described in Hispanics, who are otherwise known to have higher rates of B-ALL and APL compared to whites. This study aimed to examine the relationship of the hispanic ethnicity with non-APL AML baseline characteristics and treatment outcomes in comparison to non-Hispanic whites. Methods: All patients diagnosed with AML between the years 2000-2010 were identified within the Montefiore Medical System in the Bronx, NY. Descriptive statistics were used to compare differences in baseline patient and disease characteristics between white and hispanic subjects. Kaplan Meier survival function was utilized to compare the survival experience of patients, stratified by key prognostic factors. Cox PH multivariable models were constructed to look at ethnic differences in overall survival (OS), adjusted for clinically important and statistically significant prognostic variables. Results: 248 evaluable subjects with newly diagnosed AML were identified, among which 153 were whites (n=80) and Hispanics (n=73). Hispanics were significantly younger at presentation compared to whites [median age 59 (45-71) vs 70yrs (57-82), p Conclusion: In this multiethnic, multiracial, single-center, inner-city adult AML cohort, we report for the first time that even though AML in Hispanics presents at an earlier age, it is associated with worse OS. The higher frequency of deleterious p53 mutations in hispanic AML patients could explain their poorer outcomes. Ongoing mutational studies are testing larger cohorts of patients and will be reported at ASH. Disclosures No relevant conflicts of interest to declare.

Introduction: While the presence of HIV portends a poor prognosis in many malignancies, its clinical association with MDS and AML has not been well studied, and is known primarily from small case reports and case series. We evaluated the prevalence and clinical course of unexplained cytopenias and clinically proven MDS/AML in a large cohort of HIV-positive (HIV+) patients (pts) seen at a single center, and compared their clinical course to MDS/AML in non-HIV (HIV-) pts. Methods: Data from 15,120 HIV+ pts seen between 1/1/1997 to 6/1/2016 was analyzed for hematologic parameters, HIV status (CD4 count, HIV viral load), chronic disease status and nutrient deficiencies. Anemia was defined as hemoglobin Results: Out of 13,277 HIV+ pts that had evaluable blood counts, 1075 pts (8.1%) had cytopenias affecting more than one lineage. 912 pts had bilineage cytopenias and 163 pts had a pancytopenia. This was significantly higher than the frequency of bi/trilineage cytopenias in a non-HIV elderly population that was recently analyzed; 8.1% in HIV+ pts vs 0.9% in non-HIV pts, p 250 and HIV viral load We also identified 10 MDS and 9 AML pts in our HIV+ cohort. Mean CD4 count for these cases was 340 cells/mm3, with only 4 pts < 200 cells/mm3. Median time to MDS or AML diagnosis from date of HIV diagnosis was 15.6 and 13.7 yrs respectively. All pts were receiving anti-retroviral therapy at the time of MDS or AML diagnosis. Only 3 MDS pts and 1 AML patient had a history of prior exposure to chemotherapy. Clinical characteristics of the HIV+ MDS pts (n=10) were compared to HIV- MDS pts (n=135) from the same institution diagnosed between 1997-2011. HIV+ MDS pts presented at a younger age (59.5 vs 70.6 yrs, p = 0.001) and also had significantly higher risk (Int-2/High) disease by IPSS (87.5% vs 17.8%, p Conclusions: Anemia occurs in most HIV pts at some point in their course, however, bicytopenia and pancytopenia are generally thought to be uncommon, especially in pts with well-controlled disease. We demonstrated in our cohort an unexpectedly high prevalence of unexplained bi/trilieneage cytopenias, not associated with advanced HIV, chronic disease or nutrient deficiencies. This finding suggests the presence of an independent, HIV-specific, mechanism of hematopoietic suppression, acting either at the level of the stem cell, or the bone marrow milieu. We also report on the largest cohort of HIV+ MDS/AML cases in the literature and demonstrate that HIV+ pts who develop MDS and AML do so at a younger age, present with more advanced disease that is resistant to standard therapy, and have worse overall survival than a control cohort of HIV- pts. These data present evidence that suggests that MDS should be considered as a diagnosis early in HIV. Appropriate risk stratification and new therapeutic approaches are needed. Kaplan-Meier curve comparing overall survival in HIV infected and non-HIV infected MDS patients. Kaplan-Meier curve comparing overall survival in HIV infected and non-HIV infected MDS patients. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Background: SL-401 is a novel targeted therapy directed to the interleukin-3 receptor (CD123), a target overexpressed on acute myeloid leukemia (AML) blasts and AML cancer stem cells (CSCs), and a variety of additional hematologic malignancies. While conventional chemotherapy can induce remission in a majority of treatment-naive AML patients, relapse rates remain high. Outcomes are particularly poor when minimal residual disease (MRD), as determined by genetic and/or flow cytometric analyses, remains after therapy, with high rates of relapse and short disease-free survival. Conceivably, a therapy directed at lowering MRD burden may improve long-term outcomes. Given the association of MRD with CD123+ AML CSCs, SL-401 is being evaluated in patients with AML in first or second complete remission (CR1 or CR2, respectively) with high risk of relapse including persistent MRD. Preliminary results are reported here. Methods & Results: This multicenter, single-arm Phase 2 trial of AML patients in CR1 or CR2 with high risk of relapse includes a lead-in (stage 1) and expansion (stage 2). In stage 1, patients (MRD+ or MRD-) receive SL-401 as a daily IV infusion at 7, 9, or 12 ug/kg/day for days 1- 5 of a 28 day cycle in a 3x3 design. In stage 2, patients (MRD+ only) receive SL-401 at the dose determined in stage 1. Presence of MRD for eligibility requires either molecular (by cytogenetics, FISH, PCR, or next-generation sequencing of AML-associated mutations) or multiparameter flow cytometry (MFC) evidence of persistent abnormalities in the setting of morphologic CR. In stage 2, MRD assessment will include MFC of bone marrow aspirates conducted at a central laboratory for uniformity. Objectives include characterization of SL-401 safety with determination of the maximum tolerated or tested dose, and preliminary assessment of efficacy including changes in MRD burden and response duration. As of 7/27/16, stage 1 has been completed and stage 2 is open for enrollment. Nine patients (stage 1) received SL-401 (7 ug/kg, n=3; 9 ug/kg, n=3; 12ug/kg, n=3). The median age was 63 years (range: 51-78 years); 6 males and 3 females were treated; 8 patients were in CR1 and 1 patient was in CR2 at enrollment. The 12 ug/kg dose level was the highest tested dose with no DLTs; MTD was not reached. The most common treatment-related AEs, all grades, were thrombocytopenia (3/9; 33%) and hypoalbuminemia (3/9; 33%); the most common ≥ grade 3 treatment-related AE was thrombocytopenia (1/9; 11%); there was no DLT. Patients treated at all doses received 1+ to 5+ cycles (ongoing) of SL-401, including 3 MRD+ patients treated at 7 ug/kg (n=1) or 9 ug/kg (n=2) who received 1-5 cycles, and 1 MRD+ patient treated at 12 ug/kg who is receiving ongoing SL-401 for 4+ cycles. For all 3 patients treated at 12 ug/kg (MRD+, n=1; MRD-, n=2), 2 patients remain on SL-401 and have received 1+ and 4+ cycles (both ongoing); one other patient treated at 12 ug/kg discontinued the study because of infection unrelated to study drug. Notably, the one MRD+ patient treated at 12 ug/kg (ongoing at 4+ cycles) had marked MRD reduction as determined by MFC at the local institution; this patient is being considered for stem cell transplant (SCT). Conclusions: Stage 1 is complete without DLT or MTD, and stage 2 (expansion) is open to enroll AML patients in CR1 or CR2 who are MRD+ at the highest tested dose of 12 ug/kg. The safety profile has been similar to that observed in other SL-401 clinical studies, with no unexpected AEs. Targeting MRD with SL-401 has the potential to reduce this chemo-resistant cell population and offer improved long-term outcomes for AML patients in remission with high risk of relapse. Updated data will be presented. Clinical trial information: NCT02270463. Disclosures Lane: N-of-1: Consultancy; Stemline Therapeutics: Research Funding. Sweet:Pfizer: Speakers Bureau; Karyopharm: Honoraria, Research Funding; Incyte Corporation: Research Funding; Novartis: Consultancy, Speakers Bureau; Ariad: Consultancy, Speakers Bureau. Wang:Immunogen: Research Funding; Incyte: Speakers Bureau. Stein:Seattle Genetics: Research Funding; Amgen: Consultancy, Research Funding, Speakers Bureau; Stemline Therapeutics: Consultancy, Research Funding; Argios: Research Funding; Celgene: Research Funding. Carraway:Incyte: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding, Speakers Bureau; Baxalta: Speakers Bureau. Prebet:celgene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Chen:Stemline Therapeutics, Inc.: Employment, Equity Ownership. Lindsay:Stemline Therapeutics, Inc.: Employment, Equity Ownership. Shemesh:Stemline Therapeutics: Employment, Equity Ownership. Brooks:Stemline Therapeutics, Inc.: Employment, Equity Ownership, Patents & Royalties. Stone:Novartis: Consultancy; Juno Therapeutics: Consultancy; Celgene: 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; Agios: Consultancy; Amgen: Consultancy; Celator: Consultancy; Karyopharm: Consultancy; Jansen: Consultancy; Pfizer: Consultancy; ONO: Consultancy; Merck: Consultancy; Roche: Consultancy; Seattle Genetics: Consultancy; Sunesis Pharmaceuticals: Consultancy; Xenetic Biosciences: Consultancy. Jabbour:ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. Konopleva:Cellectis: Research Funding; Calithera: Research Funding.

Treatment of non-small cell lung cancer (NSCLC) with tyrosine kinase inhibitors (TKIs) of epidermal growth factor receptor (EGFR) and particularly erlotinib (Tarceva) has been a field of intense research. This retrospective study was conducted to assess the efficacy of erlotinib and its impact on survival.Patients with stage IIIB or IV, advanced or recurrent metastatic NSCLC were included in the study and were administered erlotinib 150 mg daily, at different lines of treatment.Thirty-six patients were included in the study: 29 (81%) male, 7 (19%) female. At the time of analysis, all patients had progressed and died. Median progression-free survival (PFS) was 4 months +/- 2.43 months (range 0-8 months), whereas median overall survival (OS) was 7 months +/- 2.65 months (range 3-15 months). Patients with ECOG performance status of 0 or 1 had better OS and significantly higher PFS rates. Overall response rate was 16.7%, while the disease control rate was 81%.Erlotinib is effective and well tolerated in pretreated patients with advanced NSCLC and a good performance status.

The marrow microenvironment contributes to the pathogenesis of ineffective hematopoiesis in Myelodysplastic Syndromes (MDS). Since mutations and cytogenetic alterations seen in the hematopoietic compartment are generally not present in marrow stromal cells, we hypothesized that epigenetic alterations may be responsible for altered stroma function in MDS. To elucidate the epigenome of MDS microenvironment, we used the HELP (HpaII tiny fragment Enrichment by Ligation-mediated PCR) assay to study cytosine methylation patterns of 50,000 CpGs loci covering 14,000 promoters in primary stromal cells. Global DNA methylation of 6 MDS marrow-derived stroma was analyzed by HELP assay and compared to 3 healthy controls. MDS stroma showed aberrant hypermethylation compared with controls (3626 hypermethylated vs 306 hypomethylated loci in untreated MDS stromal cells) that preferentially occurred outside of CpG islands (Test of Proportions, P value After demonstrating aberrant hypermethylation in MDS stroma, we next examined the functional role of these alterations by treatment with DNMT inhibitors. 5-Aza treatment of MDS stroma enhanced hematopoietic activity and erythroid differentiation from co-cultured healthy CD34+ cells. Significantly increased erythroid differentiation was seen in CD34+ cells cocultured with aza pretreated MDS stroma as shown by their glycophorin A positivity. Conclusions: These results reveal widespread aberrant epigenetic changes in the MDS marrow microenvironmentthat affect many important pathways. A recent report had shown that activation of beta-catenin in the bone marrow niche can trigger MDS/AML in vivo. Our results demonstrate that epigenetic silencing of WNT antagonists can potentially lead to activation of the WNT pathway in MDS stroma. Finally, we demonstrate that DNA methyl transferase inhibitors alter the epigenomic profiles of stromal cells and it raises the possibility that epigenetic modulation of the stroma by these drugs contributing to their therapeutic efficacy. Disclosures No relevant conflicts of interest to declare.

Introduction- MDS and AML are hematologic malignancies that are characterized by malignant cell expansion and suppression of normal hematopoietic activity. An inflammatory cytokine milieu in the marrow has been implicated in suppression of normal hematopoietic activity in MDS and AML. Since cytopenias are a major source of morbidity, these incurable diseases need agents that can target the malignant clones while also relieving the repression of healthy hematopoietic stem cells (HSCs) in the marrow. Angiopoietin -1 (Ang-1) is a cytokine that is implicated in vascular development and angiogenesis and has also been shown to regulate stem cell quiescence. Methods and Results- We determined Angiopoietin-1 levels in a large cohort of MDS CD34+ stem cells (n=183) and found its expression to be significantly elevated when compared to marrow CD34+ cells from healthy controls (n=17) (P Value To test the functional role of Angiopoietin-1 signaling in MDS/AML, we designed specific siRNAs against Tie-2 and determined that receptor knockdown led to decreased leukemic cell proliferation in multiple cell lines. Next, we tested the efficacy of ARRY-614, a novel inhibitor of Tie-2 that also inhibits p38 MAPK. ARRY-614 is being presently tested in clinical trials in MDS and has led to hematologic responses in preliminary analyses. Treatment of leukemic cells with ARRY-614 led to dose dependant decrease in proliferation. Immunoblotting showed that ARRY-614 inhibited p38 MAPK effectively in leukemic cells and also blocked downstream activation of effector kinases MapKapK2 and EIF4E in these cells upon inhibitory cytokine stimulation. Functionally, ARRY-614 treatment was able to inhibit TNF-alpha mediated inhibitory affects on normal hematopoietic stem cells in colony assays in vitro. Finally treatment of primary MDS samples with the dual inhibitor led to stimulation of erythroid and myeloid colonies. Conclusion- These data demonstrate elevated levels of Angiopoietin-1 and its receptor Tie-2 in MDS and show that these are prognostic for worse overall survival. A dual inhibitor of Tie-2 and p38 MAPK is able to inhibit leukemic cell growth and reverse inhibitory effects of cytokines on healthy hematopoiesis. Disclosures Humphries: Array Biopharma: Employment. Winski:Array Biopharma: Employment. Verma:Array Biopharma: Grants Other, Research Funding.

Myelodysplastic syndromes (MDS) are hematologic malignancies characterized by hematopoietic stem cell dysfunction that leads to ineffective hematopoiesis and cytopenias. Even though a third of MDS cases transform to leukemia, most of the mortality in MDS is due to low blood counts that occur because of failure of hematopoiesis. Development of effective treatments for MDS have been impeded by a limited understanding of the molecular pathways that suppress hematopoietic stem cells. We previously demonstrated that the myelosuppressive cytokine TGF-β mediated SMAD2 activation can inhibit stem and progenitor cells in MDS. We demonstrated that SMAD7, a negative regulator of TGF-β receptor-I kinase, is markedly reduced in MDS, and can lead to ineffective hematopoiesis by overactivation of Smad2/3 mediated TGF-β signaling. To determine the cause of SMAD7 reduction in MDS, we analyzed the 3′UTR of the gene and found a highly conserved binding site for microRNA-21. Strikingly, we observed significantly elevated levels of miR-21 in MDS marrow samples when compared with age matched controls. miR-21 was shown to directly bind to the 3′UTR of SMAD7 and reduce its expression in hematopoietic cells. Next, we tested the role of miR-21 in regulating TGF-β signaling in a TGF-β overexpressing transgenic mouse model that develops progressive anemia and dysplasia and thus serves as a model of human bone marrow failure. Treatment with a chemically modified miR-21 inhibitor led to significant increases in hematocrit and an increase in SMAD7 expression in vivo. Inhibition of miR-21 also led to increase in erythroid colony formation from primary MDS bone marrow progenitors, demonstrating its ability in stimulating hematopoiesis in vitro. Even though miR-21 was found to be elevated in MDS, the mechanisms of its elevation in MDS as well as in other cancers are not well elucidated. The miR-21 gene locus has been shown to contain upstream STAT3 binding sites. Furthermore, STAT3 has also been shown to directly lead to miR-21 upregulation in myeloma and other immune cells. Genomic profiling of highly purified hematopoietic stem cells in MDS by us demonstrated that STAT3 is selectively upregulated in these cells. STAT3 overexpression was validated in an expanded set of 183 MDS CD34+ cells as well. These results suggest that a STAT3-miR-21 pathway leads to enhancement of TGF-β signaling, thus leading to ineffective hematopoiesis in MDS. Citation Format: Tushar D. Bhagat, Li Zhou, Lubomir Sokol, Ioannis Mantzaris, Sanchari Bhattacharyya, Shanisha A.K. Gordon, Yiting Yu, Krishna Gundabolu, Sangeeta Nischal, Rahul Polineni, Carolina Schinke, Grigorios Chrysofakis, Amittha Wickrema, Andrea Pellagatti, Jacqueline Boultwood, Ulrich Steidl, Gang Liu, Alan F. List, Markus Bitzer, Amit Verma. MicroRNA mediated regulation of TGF-β signaling leads to stem cell alterations in myelodysplastic syndromes. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5224. doi:10.1158/1538-7445.AM2014-5224

Abstract 3813 Myelodysplastic syndromes (MDS) are characterized by ineffective hematopoiesis that leads to peripheral cytopenias. TGF-b is a hematopoietic inhibitory cytokine that has been indirectly linked to the pathogenesis of some subsets of MDS. We have shown that smad2, a component of the TGF- signaling pathway, is constitutively activated and upregulated in MDS progenitors (Blood, 112(8):3434; 2008). Since there is conflicting data about upregulation of TGF- b levels in MDS, we next sought to determine the molecular basis of TGF- b pathway activation in this disease. We observed that smad-7, a negative regulator of TGF- b receptor-I kinase, is markedly down regulated in MDS and leads overactivation of the receptor and subsequent smad2 phosphorylation / activation in this disease (Cancer Res, 71(3):955–63). In the present study we wanted to determine the cause of smad7 reduction in MDS. Since microRNA dysregulation has been reported in many malignancies, we explored the 3'UTR of the smad7 gene for putative microRNA binding sites and observed predicted mir-21 and mir-15/16 binding sites that were conserved across species. mir-21 was found to be elevated in a microarray screen in MDS (British J. Haem. 153(1):24–32) and was subsequently found by us to be significantly elevated by qPCR in MDS marrow samples when compared with age matched controls (TTest, N=11 in each group, P Value= 0.02). Luciferase reporters containing wild type and mutant 3' UTR of the smad7 gene were then used to determine whether mir21 was able to directly bind to the predicted sequence in the gene. Enforced expression of mir-21 was able to inhibit the wild type smad7 reporter expression and a mutation of 4 complementary residues in the 3'UTR led to abrogation of this effect, thus demonstrating direct effects of mir-21 on smad7 gene. To test the role of mir-21 in regulating TGF-b signaling in vivo, we used chemically modified, locked nucleic acid (LNA) inhibitors of mir-21. These were used in a TGF-overexpressing transgenic mouse model that develops progressive anemia and dysplasia and thus serves as a model of human bone marrow failure. Treatment with the mir-21 inhibitor led to significant increases in RBC counts when compared to placebo (P value Disclosures: List: Celgene: Consultancy.

15085 Background: Bevacizumab (BEV), a recombinant humanized monoclonal antibody against VEGF, is approved for intravenous administration in combination with standard chemotherapy (CT) regimens for...