ALBERT

Description: Sickle cell disease (SCD) is a clinical syndrome that encompasses several different genotypes, the 3 most common being homozygosity for the bS allele (HbSS), compound heterozygosity of HbS and HbC (HbSC), and compound heterozygosity of HbS and HbSb thalassemia (HbSb+ or HbSb0 thalassemia). Generally, patients with HbSS and HbSb0 thalassemia genotypes have the most severe clinical manifestations, while patients with HbSC and HbSβ+-thalassemia are thought to be less severe. Within each of these genotypic groups, however, there are also substantial phenotypic differences. This heterogeneity makes it difficult to quantify the severity of the disease process and to guide therapeutics. As more intensive, high risk and costly treatments such as hematopoietic stem cell transplant and gene therapy are developing, the ability to assess patients at highest risk of early mortality becomes increasingly important. Integrating varied clinical, laboratory, and imaging markers for personalized risk prediction has been difficult, however, newer machine learning methods for outcome prediction take a more agnostic approach than traditional statistical methods and can detect complex, non-linear relationships in the data. In this study, we sought to apply machine learning methods to a well-characterized cohort of SCD patients followed at the National Institutes of Health in order to identify clinically meaningful subgroups of patients at highest risk of mortality. Between 2006 and 2017, 601 patients (age 35±13 years, 51% female) underwent echocardiogram, standard laboratory markers and hemoglobin electrophoresis resulting in 61 candidate variables. Among these patients, 488 had HbSS, 12 HbSb0 thalassemia, 80 HbSC, 20 HbSb+ thalassemia. All-cause mortality was ascertained by proxy interview, through medical records, and through the CDC National Death Index. Average follow-up time was 5 years and 130 patients were deceased. A random survival forest (RSF) algorithm followed by nested model selection and AIC Cox regression analysis identified 13 predictors of mortality (estimated right ventricular systolic pressure, peak tricuspid regurgitant (TR) velocity, mitral E velocity, septal and posterior wall thickness, IVC diameter, right atrial area, BUN, alkaline phosphatase, N-terminal-pro brain natriuretic peptide (BNP), creatinine, potassium and bicarbonate). This model performed better than individual clinical and laboratory variables with a C-statistic of 0.822 (genotype 0.524, eGFR 0.624, NT-proBNP 0.686, TR velocity 0.703). K-means clustering grouped all patients into 3 main clusters with significant survival differences. Survival at 8 years for the entire group was 70%; for individual clusters, survival was 43% for cluster 1, 72% for cluster 2, and 88% for cluster 3 (Figure 1A). Since TR velocity is recognized as one of the most specific independent predictors of mortality, we compared our results with this parameter. There was a better stratification of mortality risk using the 7 strongest parameters from RSF compared with TR velocity alone (Figure 1B), particularly for longer term outcomes. In this cohort of 601 patients with SCD, machine learning methods were used to show the heterogeneity of this disorder and the ability to detect phenotypic clusters with different mortality profiles. Although there are many individual predictors of mortality, few methods other than assessment by an expert clinician can integrate all known variables in deeply phenotyped patients. RSF and cluster analysis was used in this cohort to analyze a large amount of data in order to identify seven variables that could stratify patients into groups with significantly different outcomes. The specificity of this approach was high (c-statistic 0.822) and better than that of individual markers of end-organ involvement. Disclosures No relevant conflicts of interest to declare.

Description: Abstract 3240 The role of pulmonary hypertension as a common and attributable cause of mortality in patients with sickle cell disease remains controversial. To assess this question and explore risk factors for death in patients with sickle cell disease we evaluated 632 patients in the Walk-PHASST pulmonary hypertension screening cohort, recruited from nine different study sites in the United States and one site in the United Kingdom. Methods: Patient characteristics and their associations with mortality were analyzed with Cox proportional hazards regression analysis. Based on data from three right heart catheterization screenings studies that have recently been published, we defined the presence of pulmonary hypertension for this analysis by a Doppler-echocardiographic measurement of the tricuspid regurgitant jet velocity (TRV) ≥ 3.0 m/s, which has a 67–75% positive predictive value for a mean pulmonary artery pressure ≥ 25 mm Hg by right heart catheterization. This therefore represents a very conservative threshold for a large population screening study. Among subjects with a measurable TRV (n=572), 64 (11.2%) had measurements of ≥ 3.0 m/sec. Among those with measurable NT-proBNP (n=582), 140 (24.1%) had measurements ≥160 pg/mL, a value associated with both pulmonary hypertension and mortality. A total of 39 (7.4%) had both high TRV (≥3.0 m/sec) and high NT-proBNP (≥160 pg/mL). Results: Over a median follow-up time of 29 months, we observed 22 deaths. 50% (N=11) of these patients had a TRV≥ 3.0 m/sec. At 24 months the cumulative survival was 83% for patients with TRV ≥ 3.0 m/sec and 98% for patients with TRV 〈 3.0 m/sec (p

Description: Introduction The advent of new therapies for the treatment of multiple myeloma (MM) has resulted in improved clinical outcomes and patient (pt) survival. However, the best combination of agents from different drug classes and subsequent therapeutic strategies for pts with newly diagnosed MM (NDMM), while investigated, has not yet been established. The goal of the Connect(R) MM registry is to provide insight into the disease and explore the management and outcomes of pts with NDMM who are treated at community and academic sites in the United States. This analysis aims to describe the combinations used in NDMM outside the interventional clinical trial setting and the activity and outcome response to different regimens by class of therapeutic agents in clinical practice. Methods Connect MM is an ongoing prospective, longitudinal, observational registry of NDMM pts. This multicenter US pt registry was initiated in 2009. Pts who were newly diagnosed with symptomatic MM within 2 months of enrollment were eligible to participate. Data were collected at baseline and every 3 months. Pts who had response data 12 months after enrollment, met CRAB criteria, and received treatment were eligible for this analysis. Treated pts were stratified according to SCT status. Data on baseline demographic and clinical characteristics, and initial therapies (proteasome inhibitors [PI], IMiD(R) immunomodulating agents, alkylating agents [AA], corticosteroids, and combinations) were collected. The overall response rate (ORR), as assessed by the site investigator, was defined as the best response during the course of initial therapy and is presented as cumulative ORR over 3, 6, and 12 months. Results As of the data cutoff (April 15, 2013), 1494 pts were enrolled in the registry; 1312 pts met CRAB criteria and received treatment. Of these, 439 received SCT or were anticipated to receive (had undergone a stem cell harvest) SCT and 873 would not receive SCT (non-SCT). Mean (SD) age for SCT and non-SCT pts was 58.9 years (8.7) and 69.8 years (10.7), respectively. Majority of pts in both groups were male (62.0% vs 56.5%) and Caucasian (85.4% vs 81.4%). Among SCT pts, ISS stages were: I/II (55.1%), III (25.3%), and unknown (19.6%) and ECOG performance status (PS) was 0/1 (63.1.%), 2/3 (7.1%), and unknown (29.8%). Among non-SCT pts, ISS stages were: I/II (42.0.%), III (32.2%), and unknown (25.8%) and ECOG PS was 0/1 (56.6%), 2/3/4 (14.7%), and unknown (28.8%). ORR to initial therapy and 1-year survival for the 5 most commonly used regimens are presented in the Table. A triplet regimen is 2 times more likely to be selected for SCT pts than for non-SCT pts, suggesting investigator bias in selecting more aggressive therapy for younger pts. For the 5 most commonly used regimens, 1-year survival was 97.9% for SCT pts and 83.3% for non-SCT pts. Conclusion Outside an interventional clinical trial setting, the most commonly used initial treatment regimens for NDMM were IMiD + PI + steroid for SCT pts and PI + steroid for non-SCT pts. Response rates were higher among SCT pts regardless of regimen. The investigator-assessed response rates were similar across the various combinations including 2 vs 3 drug combinations in SCT pts. Disclosures: Abonour: Celgene: Honoraria, Research Funding; Millennium: Honoraria, Research Funding; Onyx: Honoraria, Research Funding. Off Label Use: This abstract will report on an observational study. There is no pre-specified use of drugs; treating physicians determined what drugs to use and some could be off-label. Shah:Millenium: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Array: Consultancy, Research Funding; Onyx: Consultancy, Research Funding. Durie:Celgene: Consultancy; Millennium: Consultancy; Onyx: Consultancy. Terebelo:Amgen: Honoraria; Millennium: Honoraria. Gasparetto:Celgene ( 2012): Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millennium (2012): Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Onyx: Membership on an entity's Board of Directors or advisory committees. Mehta:Celgene: Speakers Bureau; Millennium: Speakers Bureau. Narang:Celgene: Membership on an entity's Board of Directors or advisory committees. Toomey:Celgene: Consultancy. Sullivan:Celgene: Employment. Srinivasan:Celgene: Employment. Nagarwala:Celgene: Employment. Rifkin:Celgene: Consultancy, Honoraria; Millennium: Consultancy, Honoraria; Onyx: Consultancy, Honoraria.

Description: IKZF1 (Ikaros) encodes a kruppel-like zinc finger protein that is essential for normal hematopoiesis and acts as a tumor suppressor in acute lymphoblastic leukemia (ALL). The deletion and/or mutation of Ikaros is associated with the development of human T-cell and B-cell acute lymphoblastic leukemia (B-ALL) with poor outcome. In vivo, Ikaros binds DNA and regulates gene expression by chromatin remodeling. Since there is a paucity of known genes that are regulated by Ikaros, the molecular mechanisms through which Ikaros exerts its tumor suppressor function remain unknown. Here we describe studies that identify the targets and mechanisms of Ikaros-mediated epigenetic regulation in human B-ALL. We used chromatin immunoprecipitation coupled with next generation sequencing (ChIP-seq) to identify target genes that are bound by Ikaros in vivo in human B-ALL, and to define epigenetic patterns associated with Ikaros binding. ChIP-seq revealed a large set of Ikaros target genes that contain a characteristic Ikaros binding motif. The largest group of genes that are direct Ikaros targets included genes that are essential for cell cycle progression. These included CDC2, CDC7, CDK2 and CDK6 genes whose deregulation is associated with malignant transformation. The strong binding of ikaros to the promoters of cell cycle-promoting genes was confirmed by quantitative immunoprecipitation in primary leukemia cells. To establish whether Ikaros directly regulates transcription of the cell cycle-promoting genes, their expression was measured in B-ALL cells that were transduced with either a retroviral vector that contains Ikaros, or a control vector. Target gene expression was monitored by qRT-PCR. Ikaros strongly repressed transcription of the cell cycle-promoting genes, which resulted in cell cycle arrest. Global epigenetic profiling using ChIP-seq suggested that Ikaros represses cell cycle-promoting genes by inducing epigenetic changes that are consistent with repressive chromatin. High-resolution epigenetic profiling of the upstream regulatory elements of the cell cycle-promoting genes targeted by Ikaros showed that increased Ikaros expression results in the formation of heterochromatin, which is characterized by the presence of the H3K9me3 histone modification and associated transcriptional repression. Functional analysis revealed that phosphorylation of Ikaros by the oncogenic protein. Casein kinase II (CK2), impairs its function as a transcriptional repressor of the cell cycle-regulating genes. Inhibition of CK2 by specific inhibitors enhances Ikaros-mediated repression of the cell cycle-regulating genes resulting in cessation of cellular proliferation and cell cycle arrest in vitro and in vivo in a B-cell ALL preclinical model. This was associated with increased Ikaros binding and the formation of heterochromatin at upstream regulatory elements of the cell cycle-promoting genes. Our results provide evidence that Ikaros functions as a repressor of cell cycle-promoting genes in B-ALL by directly binding their promoters and inducing the formation of heterochromatin with characteristic H3K9me3 histone modifications Ikaros repressor function is negatively regulated by CK2 kinase in B-cell ALL. Inhibition of CK2 enhances Ikaros mediated-repression of cell cycle-promoting genes resulting in an anti-leukemia effect in a preclinical model of B-cell ALL. Presented data identified the mechanism of action of CK2 inhibitors and demonstrated their efficacy in B-cell ALL preclinical model. Results support the use of CK2 inhibitors in Phase I clinical trial. Supported by National Institutes of Health R01 HL095120 and a St. Baldrick’s Foundation Career Development Award (to S.D.). Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 2658 Introduction: Six minute walk distance (6MWD), is a measure of exercise capacity commonly used as an endpoint in pulmonary hypertension (PH) clinical trials. Many patients with sickle cell disease (SCD) have acute pain crises or chronic pain syndromes that impair their quality of life. While patients with SCD who are undergoing screening for PH are generally screened in steady state, i.e., when they have not had a recent pain crisis, the impact of chronic pain on exercise capacity in this group of patients has not been previously evaluated. Methods: walk-PHaSST was a multi-center screening study designed to identify subjects with SCD at increased risk for symptomatic PH, defined by a tricuspid regurgitant velocity (TRV) ≥ 2.7 m/sec and 6MWD between 150–500 meters, for enrollment in a double-blind placebo controlled trial of sildenafil. The primary endpoint was the change in 6MWD after 16 weeks of treatment. We examined the relationship between subjects' self-reported acute and chronic pain and baseline 6MWD in the screened SCD patients in walk-PHaSST. Results: For 90% of subjects, the information about pain was reported by the patient or parent/family member. Documentation of pain management and utilization of services was verified from medical records in 10% of subjects. Ninety four percent of all subjects reported having a history of acute sickle cell pain crises; 6% reported never having had an acute pain crisis. For the subjects who reported a history of acute pain crises, the ‘typical’ acute pain rating on a scale of 0 to 10 was ≥ 7 (maximum 10) for 77% of this subset of subjects. A total of 342 (50%) subjects reported not having had any pain crises in the preceding week. Of 720 subjects screened medical history and 6 MWD was available in 673 patients. Of these 633 (94%) subjects did not report having had a pain crisis requiring an emergency department visit or hospitalization in the preceding week. A total of 39% of subjects reported chronic sickle cell related pain; no rating was reported for chronic pain. 88% of patients reported using medications for pain control while 15% reported using non-drug therapy including physical therapy in 3%, alternative therapy in 2%, acupuncture in 2% and hypnosis in 〈 1% of patients. The mean 6MWD for the screened population was 439 meters (median 438 m, range 123–713 m). A total of 171/673 (26%) subjects had a 6MWD 〉500 meters, which was above the screening cut-off for enrollment in the main interventional trial. By univariate analysis, subjects reporting chronic pain had a significant lower odds ratio for walking 〉 500 meters (OR 0.637, 95% C.I 0.44–0.99); a similar observation was seen with those subjects with a history of acute pain crises (OR 0.47, 95% C.I 0.24–0.91). Multivariable logistic regression analysis revealed a significant inverse relationship between chronic pain but not acute pain and 6MWD after adjusting for age, TRV, gender, hematocrit and smoking history (See Table 1). The mean 6MWD decreased by 27 meters with self reported chronic pain after adjusting for TRV, age, gender, hematocrit and 6MWD. Conclusions: TRV is a known predictor of 6MWD. However, these data suggest that patient self reported sickle cell related chronic pain is also an independent predictor of 6MWD. This relationship raises interesting questions about the potentially confounding effects of pain on exercise capacity as assessed by the 6MW test. Further study is warranted to investigate an association between chronic pain and exercise capacity in SCD as well as exploration of appropriate endpoints for future clinical trials in patients with SCD and suspected symptomatic PH. Disclosures: Barst: Pfizer: Consultancy, Research Funding. Rosenzweig:Pfizer: Research Funding. Badesch:Pfizer: Honoraria, Research Funding. Hassell:Novartis: Research Funding.

Description: Background: Interferon-alpha (IFNα) is a pleiotrophic cytokine with direct anti-tumor and immunostimulatory effects. Currently IFNα is approved for the treatment of multiple hematologic malignancies, including non-Hodgkin lymphoma (NHL). However, its clinical utility has been hindered by dose-limiting toxicitiy due to systemic activation of the interferon receptor. To overcome this limitation, we engineered anti-tumor antibody-IFNα fusion proteins to selectively increase delivery of IFN to the tumor site and reduce systemic toxicity. We previously reported that IGN002, an anti-CD20-IFNα fusion protein, exhibits enhanced complement-dependent cytotoxicity (CDC) compared to rituximab, and inhibits proliferation and induces apoptosis of human B-cell NHL (Yamada et al, ASCO 2013). We now extend these previous findings and show that IGN002 possesses enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) effector function and superior in vivo anti-tumor activity against B-cell NHL, compared to rituximab. Methods: IGN002 was evaluated against a panel of human Burkitt and diffuse large B-cell lymphoma (DLBCL) cell lines. Proliferation was measured by [3 H]-thymidine incorporation, STAT1 activation by flow cytometry, ADCC by lactate dehydrogenase release using human PBMC effectors, and IFN bioactivity by encephalomyocarditis (EMC) viral protection assay. NHL xenografts were grown in SCID mice. Results: IGN002 more potently inhibited the growth of NHL cell lines expressing CD20 than rituximab or unfused IFNα. Intrinsic IFNα activity of IGN002 was reduced in viral protection and anti-proliferation assays using cells lacking CD20 expression. STAT1 activation by IGN002 was enhanced on cells expressing the target antigen, whereas a control antibody-IFNα fusion protein showed reduced STAT activation activity compared to unfused IFNα. Together, these results indicate that fusion of IFNα to the antibody results in reduced IFN effects on cells not bearing the tumor antigen target. IGN002 exhibited enhanced ADCC activity compared to rituximab against Daudi, Ramos, and Raji NHL cells in long-term (overnight incubation) assays, demonstrating both higher potency and higher maximal cytotoxicity. This result is possibly due to activation of the effector cell populations by the fused IFNα moiety, as IFN is known to activate both NK cells and monocytes. The in vivo anti-tumor efficacy of IGN002 was compared to rituximab and a control antibody-IFNα fusion protein against 10-day established Raji NHL xenografts. IGN002 was superior to both rituximab and the control fusion protein, achieving a longer median survival and higher long-term survival rate (p = 0.0015 and 〈 0.0001 vs. rituximab and control fusion protein, respectively). The in vivo anti-tumor efficacy of IGN002 was also compared to rituximab at three equimolar dose levels (5 mg/kg, 1 mg/kg, and 0.2 mg/kg antibody) against 10-day established Daudi NHL xenografts. IGN002 showed superior efficacy compared to rituximab at all doses (p 〈 0.001), achieving tumor eradication (100% long-term survival) in all mice treated at all three dose levels, whereas rituximab only delayed tumor progression. Conclusions: IGN002 demonstrated more robust direct anti-proliferative and antibody effector functions than rituximab against human NHL cells in vitro, and also showed the ability to eradicate established NHL xenografts in vivo. Against cells expressing the CD20 target antigen, IGN002 exhibited greater anti-proliferative potency than unfused IFNα. In contrast, the anti-proliferative and anti-viral potency of IGN002 was reduced against cells lacking CD20, compared to unfused IFNα. These findings support the hypothesis that tumor antigen-targeted IFN therapeutics may possess a broader therapeutic index than unfused IFNα, inhibiting tumor growth by multiple mechanisms while reducing systemic toxicity. These results support the further development of IGN002 for the treatment of B-cell NHL, and a first-in-human phase I clinical study will begin later this year in the United States. Disclosures Timmerman: Janssen: Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Valor Biotherapeutics: Research Funding. Steward:ImmunGene, Inc.: Employment. Minning:Valor Biotherapeutics, LLC: Consultancy. Sachdev:ImmunGene, Inc.: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Gresser:ImmunGene, Inc.: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Valor Biotherapeutics: Membership on an entity's Board of Directors or advisory committees. Khare:Valor Biotherapeutics: Membership on an entity's Board of Directors or advisory committees; ImmunGene, Inc.: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Morrison:ImmunGene, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Description: Abstract 4804 Introduction: Smoking is known to promote vascular inflammation, in-vitro platelet aggregation and expression of endothelial adhesion molecules, processes that contribute to vasculopathy. Inflammation, abnormal platelet activation with thrombus formation and endothelial cell activation also play a role in vaso-occlusion in sickle cell disease (SCD). These overlapping pathobiological mechanisms suggest the possibility of a relationship between smoking and SCD vaso-occlusive pain. While small single center studies have suggested a link between environmental smoke exposure and hospitalization rate for acute chest syndrome and SCD pain (West et al 2003, Cohen et al 2010) there is a paucity of data derived from large multicenter studies about the interplay between smoking and pain phenotype in SCD. Aims: To determine the relationship between patient self reported chronic pain and history of current or former cigarette smoking in the SCD subjects screened in the walk-PHaSST study. Methods: Walk-PHaSST was a multi-center, placebo-controlled, double-blind 16-week trial designed to evaluate the safety and efficacy of sildenafil in patients with tricuspid regurgitant velocity [TRV] ≥2.7m/s and decreased exercise capacity as assessed by the six-minute walk distance (6MWD). We analyzed the data from all subjects screened for the walk-PHaSST trial. In the screening trial, subjects were evaluated by medical history, physical examination, laboratory screening, echocardiography and 6MWD testing. Univariate and stepwise multivariable logistic regression was used for this analysis. P value of

Description: Sexual hormones are potent regulators of various immune functions. Although androgens are immunosuppressive, estrogens protect against septic challenges in animal model. In human sepsis studies post surgery, post trauma in adults have shown survival advantage for female sex with sepsis. Other reality is that in a developing country like India with a population of 1 billion, sex ratio has been gradually falling in the general population. In year 1901 females per 1000 males were 972 and in 2001 females per 1000 males are 933. Neglect of female child and unwillingness on the part of parents to spend money for treatment of girl child is one of the main reason for less number of girls getting treatment for cancer as compared to males. This study was done to find gender difference in incidence of severe sepsis in children with cancer in a single centre in Delhi, India. It was a retrospective analysis of children with and without cancer admitted to the Pediatric Intensive care Unit (PICU) at Sir Ganga Ram Hospital from January 2003 to January 2006, who met the following criteria: 1) severe sepsis by American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference criteria and 2) receipt of fluid boluses of 〉30 mL/kg or receipt of a dopamine infusion of 〉5 ug/kg/min. Data evaluated were demographic variables, oncologic diagnosis and time from diagnosis to PICU admission, Pediatric Risk of Mortality I (PRISM I) score, neutropenia, use of inotropes, use of mechanical ventilation, culture results, survival to PICU discharge, and 6-month survival. Total admissions in PICU were 1450 out of which 977 were males (M) and 473 females (F) with M:F =2:1.Total number of children admitted with sepsis in PICU were 517 out of which males were 342 and females 175 with M:F= 2:1. Total number of pediatric oncology admissions in hospital (PICU and Ward) were 420 out of which males were 294 and females 126 with M:F = 2.3:1. Total number of pediatric oncology patients admitted in PICU were 60 out of which 44 were males and 16 were females with M:F = 2.8:1. Total number of consecutive pediatric oncology patients admitted to PICU with severe sepsis were 20 out of which 18 were males and 2 females with M:F =9:1. Overall mortality was 40 % at PICU discharge and 50% at 6 months follow up. 6 /18 (33%) males died as compared to 2/2 (100%) deaths in females. Mean PRISM I score was 11.9 among survivors and 19.4 among non-survivors. Mean Prism score for females was 16 as compared to 14.8 in males. We looked at gender distribution of 35 consecutive pediatric oncology patients with febrile neutropenia in the hospital. 28 were males and 7 females (Ratio M:F = 4:1) We looked at 30 consecutive non-oncology patients admitted with severe sepsis in PICU which showed 25 males and 5 females with a ratio of M:F = 5:1.In conclusion, m ale children with cancer have increased incidence of severe sepsis. This small study may reflect a bias of parents not electing to admit female patients with severe sepsis in hospital but as compared to ratio in total admission in PICU and admissions of oncology patients in ward and PICU the ratio is markedly increased to 9:1 which may indicate gender difference due to genetic basis.

Description: Abstract 2081 Poster Board II-58 AZD6244 is an orally bioavailable small molecule inhibitor of the MEK kinase. MEK is downstream of the RAS/RAF pathway, which is activated by mutations occurring in RAS as well as mutations and/or overexpression of upstream receptor tyrosine kinases such as FLT3 and c-KIT in AML. In addition, elevated levels of phosphorylated-ERK (p-ERK), the only known substrate of MEK, have been demonstrated in 〉75% of patients(pts) with AML, and MEK inhibition of primary AML cells in vitro results in growth arrest. AZD6244 was well tolerated in phase I trials in advanced solid tumors and had a favorable pharmacokinetic profile; the recommended phase II dose was 100mg twice daily. We hypothesized that in AML, a MEK inhibitor would lead to inhibition of RAS-mediated signal transduction, with subsequent antiproliferative effects and inhibition of the leukemia clone. We report our experience with the first clinical trial utilizing a MEK inhibitor in advanced AML. Methods: 47 pts were enrolled on a Phase II multicenter study of AZD6244 in relapsed/refractory AML. Median age was 69 years (range, 26-83 yrs) with 57% males. ECOG performance status at baseline was 0, 1 and 2, respectively, in 12, 27 and 8 pts. 14 pts (30%) were previously untreated for AML and 〉60 yrs; 11 of these pts had received prior therapy for an antecedent hematologic disorder (AHD); 1 had therapy-related AML (t-AML) and only 2 pts (4%) had previously untreated de novo AML. 6 pts (13%) had AML in first relapse, 14 (30%) had AML beyond first relapse, and 13 (27%) had primary refractory disease. 4% had good risk cytogenetics, 28% intermediate risk, 49% poor risk, and 19% had other or unknown cytogenetics. Overall, 53% had AML that had evolved from an AHD and/or t-AML. Ten pts had a FLT3 ITD or TKD, 36 had no FLT3 mutation detected, and FLT3 mutational status was unknown in 1. Median number of prior therapies for AML and/or MDS was 2 (range, 0-6). AZD6244 was given at 100mg twice daily without interruption; cycles were repeated every 28 days. Dose modifications and/or delays occurred for grade 3&4 non-hematologic toxicities, or prolonged grade1&2 toxicities. Peripheral blood and/or marrow samples were obtained at baseline for mutational analysis (RAS/c-KIT/FLT3), and at serial time points to measure p-ERK. Results: Daily AZD6244 was tolerable. 42 pts are evaluable for efficacy and safety. Median number of cycles administered was 1 (range, 1-9). 19 pts (40%) received ≥2 cycles. 4 pts required dose reduction. The most common drug-related toxicities were grade 1&2 diarrhea, nausea, fatigue and vomiting, occurring in 43%, 36%, 31% and 24%, respectively. Grade 3&4 adverse events possibly related to AZD6244 included fatigue, nausea and dehydration, occurring in 7%, 5% and 5%, respectively. 4 pts had a minor response (defined as 〉50% decline in peripheral blood and/or marrow blasts lasting 4 weeks). 2 additional patients also had 〉50% decline in marrow blasts but did not have a follow up confirmatory biopsy. In 1 of these pts, the decline in blasts was associated with sustained improvement in platelets (〉100K/uL) lasting 4 months. 6 additional pts had evidence of disease stabilization, lasting a median of 34 days (range, 21-222+ days). Analysis of p-ERK by flow cytometry has just been intiated, and in the first 3 pts analyzed, baseline p-ERK levels were low, and none of these pts responded. In contrast, p-mTOR levels (downstream of the PI3 Kinase pathway) were significantly elevated in these same pts. Conclusions: Administration of the oral MEK inhibitor AZD6244 is feasible in AML. Modest evidence of antileukemic activity has been observed, consistent with the predicted cytostatic activity of this class of drugs. Analysis of the effect of AZD6244 on p-ERK and signaling intermediates of the PI3 Kinase pathway such as p-mTOR is ongoing. Given its modest toxicity profile, AZD6244 should be investigated further in combination with drugs that target other critical signaling pathways and/or dysregulated transcriptional pathways in AML. Sponsored by NCI grant NO1-CM-62201 Disclosures: No relevant conflicts of interest to declare.

Description: Background: MM treatment (Tx) advances have greatly improved clinical outcomes for patients (pts). A recent study demonstrated improved survival in MM through the past decade attributable to the impact of initial therapy with lenalidomide, bortezomib, and thalidomide. The greatest impact was observed in older pts (Kumar, et al. Leukemia, 2014). Connect MM, the first and largest prospective, observational, US-based, multicenter registry was designed to characterize pts, Tx patterns, and outcomes in newly diagnosed MM (NDMM). Methods: This ongoing registry was initiated in September 2009. Eligible pts with NDMM (diagnosis must have occurred within 2 mos of study entry) were enrolled at 234 US sites. Data were collected at baseline and each subsequent quarter using an electronic case report form. The initial enrollment includes all pts who had provided informed consent as of November 1, 2012 (N = 1493). The data cutoff for this analysis was Dec 10, 2013. A total of 1444 pts were treated and were included in overall survival (OS) analyses. Survival was examined for all treated pts adjusting for pt and Tx characteristics including age, autologous stem cell transplant (ASCT) status, gender, race, disease risk factors (International Myeloma Working Group [IMWG] high risk vs. non-high risk), and therapy received (triplet vs. non-triplet) among others. Triplet therapy was defined as any combination of 3 or more drugs during the first Tx regimen. OS was estimated using Kaplan-Meier methods and comparisons across groups were assessed used the log-rank test. Results: At the time of data cutoff, 1493 pts were enrolled with 1444 having received Tx. Of the treated pts 253 pts (18%) had IMWG high-risk disease and 108 pts (7%) had del(17p) at baseline. Median age was 67 y (range, 24-94 y), 57.2% were male, and 81.9% were white. Median follow-up was 29 mos (0-49.4 mos). The median OS for all treated pts was 44.4 mos. When assessed by age group, OS was significantly different (log-rank P 〈 .0001) with a median of 47.6 mos for pts aged 〈 65 y (n = 632), 45.0 mos for those aged 65 to 〈 75 y (n = 443), and 33.7 mos for those aged ≥ 75 y (n = 369). OS was significantly longer for pts with ASCT vs. no ASCT (P 〈 .0001), but not different by gender (P = .962) or race (Caucasian vs. African American vs. other; P = .250). Three-year OS probabilities by subgroup are listed in Table 1. When considering risk factors, IMWG risk was borderline significant (high vs. non-high; P = .106), and presence of del(17p) by cytogenetics and FISH was associated with significantly shortened OS (P = .005; Figure 1A). Interestingly, use of triplet therapy vs. non-triplet therapy was associated with significantly prolonged OS regardless of IMWG risk (non-high: P 〈 .0001; high: P = .003; Figure 1B). However, no improvement was noted for triplet vs. non-triplet therapy in pts with del(17p). By multivariate analysis, the significant (P 〈 .05) factors impacting OS were age (in 10-yr increments), International Staging System (ISS) disease stage, ECOG performance status, history of diabetes, anemia, renal function, and platelet count. Conclusions: This interim analysis based on initially treated pts demonstrated that age, ISS stage, and co-morbidities impact OS irrespective of IMWG cytogenetic risk. Triplet Tx was associated with significantly longer OS in pts regardless of IMWG risk status. This is the largest prospective pt cohort with high-risk disease including del(17p). Pts with high-risk disease did not have significantly lower OS vs. pts without high-risk features. Pts with del(17p) (p53 deletion) continue to have shorter OS approaching 3 y and increased survival with use of triplet therapy. Table 1. Kaplan-Meier Estimated 3-Y OS Probability Patients 3-y OS Probability (%) (95% CI) All (N = 1444) 62.6 (59.5-65.8) 〈 65 y (n = 632) 69.8 (65.2-74.3) 65 to 〈 75 y (n = 443) 65.0 (59.4-70.6) ≥ 75 y (n = 369) 47.2 (40.7-53.8) Gender Male (n = 831) 62.1 (57.9-66.3) Female (n = 613) 63.4 (58.7-68.2) Race Caucasian (n = 1191) 61.8 (58.3-65.3) African American (n = 183) 64.4 (55.4-73.5) Other (n = 27) 77.6 (57.3-98.0) ASCT Yes (n = 494) 77.1 (72.5-81.7) No (n = 950) 54.2 (50.0-58.3) Triplet therapy Yes (n = 778) 69.3 (65.3-73.3) No (n = 666) 54.8 (49.9-59.6) IMWG risk High (n = 253) 59.0 (51.6-66.4) Standard (n = 566) 66.3 (61.4-71.2) Low (n = 86) 75.7 (63.6-87.8) del(17p) Present (n = 108) 52.7 (41.8-63.6) Absent (n = 1336) 63.4 (60.1-66.7) Figure 1 Figure 1. Disclosures Shah: Celgene Corp: Consultancy, Research Funding. Abonour:Celgene Corp: Honoraria, Speakers Bureau. Durie:Celgene Corp: Export Board Committee Other, Membership on an entity's Board of Directors or advisory committees; IRC Onyx: Membership on an entity's Board of Directors or advisory committees; DMC Millennium: Membership on an entity's Board of Directors or advisory committees; IRC J&J: Membership on an entity's Board of Directors or advisory committees. Mehta:Celgene Corp: Consultancy, Speakers Bureau. Narang:Celgene Corp: Membership on an entity's Board of Directors or advisory committees. Terebelo:Celgene Corp: Membership on an entity's Board of Directors or advisory committees. Gasparetto:Celgene: Consultancy, Honoraria; Millenium: Honoraria. Thomas:Celgene Corp: Membership on an entity's Board of Directors or advisory committees. Toomey:Celgene Corp: Membership on an entity's Board of Directors or advisory committees. Hardin:Celgene Corp: Research Funding. Srinivasan:Celgene Corp: Employment, Equity Ownership. Ricafort:Celgene Corp: Employment. Nagarwala:Celgene Corp: Employment. Rifkin:Celgene Corp: Consultancy; Millenium: Consultancy; Onyx: Consultancy; Takeda: Consultancy; Amgen: Consultancy.