Citations

Abstract Small lymphocytic lymphoma (SLL) is an incurable indolent lymphoma, and there are relatively few prognostic biomarkers for this important NHL subtype. We evaluated the hypothesis that inherited variability in cytokine and immune-related genes was associated with overall survival in SLL. We genotyped 73 SNPs in 44 candidate genes in 140 SLL patients aged 20–70 years who participated in a population-based case-control study conducted from 1998–2000 through the Surveillance, Epidemiology, and End Results (SEER) cancer registries in Detroit, Seattle, Iowa, and Los Angeles. DNA was extracted from a venous blood sample or mouthwash buccal cell sample. All genotyping was conducted at the National Cancer Institute Core Genotyping Facility using the Taqman platform. Histology, stage, presence of B-symptoms, first course of therapy, date of last follow-up, and vital status were derived from linkage to registry databases at each study site in the spring of 2005. Cox proportional hazards analysis was used to estimate the hazard ratio (HR) and 95% confidence interval for the association between individual SNPs and overall survival, adjusted for age, demographic and clinical factors. Multiple simultaneous modeling strategies were used to identify the best summary multi-SNP risk score to predict survival. At last follow-up, there were 45 deaths in 140 patients (32%). The median follow-up of the 95 surviving patients was 58 months (range 24–75 months). In multivariate modeling, SNPs in IL13 (rs1800925; HRCC=2.36, 1.24–4.49), IL7R (rs1494555; HRGG =2.20, 0.84–5.76), and TNF-alpha (rs1800630; HRAC/AA=1.73, 0.95–3.17) were the strongest and most robust predictors of survival. Two or more deleterious genotypes from these three SNPs increased the risk of death (HR=2.2, 1.2–4.1) compared with one or fewer deleterious genotypes (p=0.009). Three groups (low, intermediate, and high risk) were defined by combining the SNP score and a clinical/demographic score. The 5-year Kaplan-Meier survival estimates for these groups were 85%, 65%, and 11%, respectively. Compared to patients with a low risk score, patients with intermediate (HR=2.5, 1.2–5.1) or high (HR=11, 4.3–27.7) risk scores had poorer overall survival (p=3.9 x 10−8). Our preliminary results suggest that SNPs in IL13, IL7R, and TNF-alpha alone and in combination predict overall survival in SLL, lending support to the hypothesis that host genetic background is a promising class of prognostic biomarkers in SLL.

Abstract The peripheral blood absolute lymphocyte count (ALC) on day 15 after autologous stem cell transplantation (ASCT) has been shown to be an independent predictor for overall survival (OS) for many malignancies including acute myelogenous leukemia (AML), breast cancer, multiple myeloma (MM), primary systemic amyloidosis, and Hodgkin’s and non-Hodgkin’s lymphoma (NHL). However, due to the retrospective nature of previous studies, the peripheral blood lymphocyte subpopulations that predict survival are unknown. To prospectively correlate peripheral blood lymphocyte subpopulations after ASCT and progression free survival, peripheral blood lymphocytes collected from patients before and on day 15 after ASCT were analyzed by four color flow cytometry for CD3, CD4, CD8, CD16, CD 19, and CD56. Patients were then dichotomized into two groups: patients achieving normal numbers of lymphocyte subset (i.e. CD4, CD8, CD19, CD16/56) count versus those who did not. Progression free survival was then analyzed by the Kaplan-Mier method. In our cohort of 14 patients, 9 were male and 5 were female. Nine patients were diagnosed with diffuse large cell B cell lymphoma, two with mantle cell, two with follicular, and one with peripheral T cell lymphoma. On presentation, one patient had stage I, four patients had stage II, four had stage III, and five patients had stage IV disease. The median age at ASCT was 53 years (range: 26–70). The preliminary data from this ongoing prospective study of 14 patients shows that on day 15 after ASCT, 4/14 (29%) of patients achieved a normal CD3 count (median 321, range: 69–2069 cells/ml) 3/14 (21%) achieved a normal CD4 count (median 206, range: 31–1091 cells/ml), 6/14 (43%) achieved a normal CD 8 count (median 88.5, range: 13–813 cells/ml) 1/14 (7%) achieved a normal CD19 count (median 2, range:0–227 cells/ml), and 8/14 (57%) achieved a normal CD16/56 count (median 85.5, range: 10–744 cells/ml). The median follow-up was 12 months (range: 3–45 months). On univariate analysis, patients achieving an absolute NK cell count of ≥ 80 cells/μ on day 15 had significantly improved progression free survival compared to those who did not (not reached vs 3 months, p<0.006, respectively). Similar analysis evaluating the absolute CD3, CD4, CD8, and CD 19 count was not significant (p=0.1, p=0.258, p= 0.06, and p=0.55, respectively). To our knowledge, this is the first report detailing the critical role of NK cell immune reconstitution after ASCT in progression free survival. Figure Figure

Abstract DLBCL is a curable subtype of non-Hodgkin lymphoma, although a significant number of patients do not achieve a remission or they relapse with conventional chemotherapy. While clinical variables (e.g., IPI), tumor (somatic) genetic alterations, and gene expression profiling have all been shown to predict outcome, there remains a need for additional prognostic biomarkers. One understudied class of biomarkers is host genetic background. We evaluated the hypothesis that germline variability in 73 SNPs from 44 candidate immune genes was associated with overall survival in DLBCL. We addressed this hypothesis in 365 DLBCL patients aged 20–70 years who participated in a population-based case-control study conducted from 1998–2000 (prior to the use of R-CHOP) through the Surveillance, Epidemiology, and End Results (SEER) cancer registries in Detroit, Seattle, Iowa, and Los Angeles. Germline DNA was extracted from a venous blood sample or mouthwash buccal cell sample, which was collected a median of 4.8 months after diagnosis in this population-based study. All genotyping was conducted at the National Cancer Institute Core Genotyping Facility using the Taqman platform, and was successful in over 95% of the DNA samples for the SNPs evaluated. Histology, stage, presence of B-symptoms, first course of therapy, date of last follow-up, and vital status were derived from linkage to registry databases at each study site in the spring of 2005. Cox proportional hazards analysis was used to evaluate the association between individual SNPs, adjusted for age, demographic and clinical factors. Parallel modeling strategies were used to identify the best summary multi-SNP risk score to predict survival. At a median follow-up of 56 months (range, 27-78 months) for surviving patients, there were 96 deaths in 365 patients (26%). In multivariate modeling, SNPs in IL1A (rs1800587; HRCT/TT=1.90, 1.26–2.87), IL6 (rs1800795; HRGG=1.48, 0.99–2.23), IL-10 (rs1800896; HRAG/GG=1.48, 0.91–2.38), and IFNGR2 (rs2070385; HRAG/GG=1.35, 0.86–2.11) were the strongest and most robust predictors of overall survival. A summary score of the number of deleterious genotypes from these four genes in combination with clinical and demographic variables was strongly associated with survival (p=9.3 x 10−12); Kaplan-Meier 5-year survival estimates for low, intermediate, and high risk patients were 89%, 68%, and 47% respectively. In conclusion, host genetic background as measured by germline polymorphisms in immune genes including IL1A, IL6, IL10, and IFNGR2 were associated with overall survival in DLBCL after accounting for clinical and demographic factors. These promising results require confirmation and need further evaluation in patients treated with R-CHOP in conjunction with tumor and other prognostic biomarkers.

Abstract BACKGROUND: Complement-mediated thrombotic microangiopathies (TMAs) are a subset of TMAs in which the thrombocytopenia, microangiopathic hemolytic anemia, and end organ damage are caused by mutations in genes encoding the alternative complement pathway. Numerous complement genes have been implicated in complement-mediated TMAs including complement factor H (CFH), CD46 (MCP), complement factor I (CFI), complement component 3 (C3), complement factor B (CFB), factor H related 5 (CFHR5), and thrombomodulin (THBD) among others. Genetic analysis typically yields a mutation in 60% of patients whose TMA is presumed to be mediated by complement dysregulation. However, the description of novel disease-associated variants may increase this proportion. METHODS: A retrospective study of patients with TMAs diagnosed between 2000 and 2014 was performed. TMA diagnosis was made based on thrombocytopenia and evidence of microangiopathic hemolytic anemia. Analysis was performed with Alamut¨ software with additional in silico prediction tools (SIFT, MutationTaster, and Polyphen) for classification of gene variants. Variants of unknown significance (VUS) and likely pathogenic variants were further assessed using several mutation databases, including HGMD, ClinVar, and Factor H database RESULTS: Of patients diagnosed with a TMA, genetic analysis was performed in only a 10% of patients. Of the 29 patients with genetic studies performed, mutations were identified in 18 patients (62%). The majority of the mutations had been described previously in the literature, but four novel variants were identified: three missense and one splice-site. The table below summarizes these variants as well as laboratory findings on presentation. These were two variants of CFH, one variant of CFHR5, and one variant of CFI. In silico modeling of these variants revealed two polymorphisms likely to be pathogenic, one polymorphism likely benign given the lack of predicted splicing changes, and one VUS. Table 1. Protein Mutation Classification Age Sex Hemoglobin (g/dL) Platelets (thousands) Creatinine (mg/dL) CFH c.245-10_245-9dup Likely benign 61 F 11.6 51 6.7 CFH c.476G>A, p.Ser159Asn Likely pathogenic 43 F 9.1 101 9.1 CFHR5 c.1412G>A p.Gly471Glu Likely pathogenic 30 F 9.8 129 4.9 CFI c.1190T>A p.Val397Glu Unknown significance 51 M 9.4 125 6.1 DISCUSSION: With therapy available to target the alternative complement pathway, genetic analysis to identify genetic variants capable of causing complement mediated TMAs is an essential part of the evaluation. This genetic data must be interpreted and correlated with functional analysis and clinical phenotype. The reporting of novel variants in clinical databases, with inclusion of relevant clinical findings, is necessary to accurately classify and verify variants as pathologic mutations or benign polymorphisms. The full understanding of this diverse disease requires a more complete understanding of its genetics. While complement pathway-directed therapies are available, their rational use requires thorough interpretation of laboratory data, including genetic analysis. Disclosures Murray: Mayo Clinic: Patents & Royalties: Patent Application Filed.

Abstract Abstract Our group recently reported a Phase III clinical trial (Porrata et al. Biology of Blood and Marrow Transplantation 2016; 22: 1017-1023) demonstrating that the infusion of the autograft-absolute lymphocyte count (A-ALC) and autograft natural killer cells (A-NKC) are survival prognostic factors in non-Hodgkin lymphoma (NHL) patients treated with autologous peripheral blood hematopoietic stem cell transplantation (APBHSCT). A limitation of our Phase III clinical trial was the short-term follow-up of just two years. Therefore, we evaluated longer follow-up and assessed the role of the infused A-ALC, infused A-NKC, and peripheral blood absolute natural killer cell count (ANKC) recovery on survival post-APBHSCT. Of the 122 patients that participated in the Phase III trial, 111 patients were able to complete APBHSCT and included in the current study. With a median follow-up of 57.2 months (range: 2.1-84.6 months), superior overall survival (OS) and progression-free survival (PFS) was observed in patients infused with an A-ALC ≥ 0.5 x 109 lymphocytes/kg [OS: HR = 0.429, 95%CI, 0.128-0.828, p < 0.01; and PFS: HR = 0.456, 95% CI, 0.177-0.863, p < 0.01] and an A-NKC ≥ 0.09 x 109 cells/kg [OS: HR = 1.58e-3, 95% CI, 1.046e-6-0.179, p < 0.003; and PFS: HR= 1.58e-3, 95% CI, 7.81e-7-0.064, p < 0.003]. Furthermore, patients that maintained an ANKC ≥ 250 cells/µl at 3 months, 6 months, 9 months and 12 months post-APBHSCT also experienced superior OS (Figure 1A) and PFS (Figure 1B)[OS and PFS times in months were evaluated from infusion date of stem cells]. In the multivariate analysis a sustained ANKC ≥ 250 cells/µl was an independent predictor for OS (HR = 0.013, 95% CI, 0.001-0.063, p < 0.0001) and PFS (HR = 0.014, 95% CI, 0.001-0.067, p < 0.0001). This study is an extension of our Phase III clinical trial showing that sustained innate immunity by measuring the ANKC correlated with superior clinical outcomes; thus providing a platform to develop innate immunity immunotherapeutic strategists directing to improve clinical outcomes post-APBHSCT in NHL patients. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Abstract Abstract 1517 Purpose: Decitabine, a deoxycytidine nucleoside derivative, is an inhibitor of DNA-methyltransferases indicated for treatment of myelodysplastic syndrome (MDS) including previously treated and untreated, de novo or secondary MDS of all French-American-British (FAB) subtypes, Intermediate-1, Intermediate-2, and High-Risk International Prognostic Scoring System (IPSS) groups. Laboratory evidence shows that pretreatment of AML cell lines can sensitize leukemia cells to chemotherapy as well as inhibit clonogenic potential. The purpose of this study is to evaluate the safety, pharmacokinetics, and efficacy of decitabine when used as priming before induction therapy in children with newly diagnosed AML. Exploratory analyses of genomic methylation and RNA expression patterns and minimal residual disease (MRD) are embedded correlative studies. Methods: This multicenter, randomized, two-arm, open-label study enrolls pediatric pts ages 1–16 with newly diagnosed AML to either Arm A: daunorubicin, cytarabine, etoposide (D-ADE) preceded by a 5-day course of decitabine (experimental arm) or Arm B: daunorubicin, cytarabine, etoposide (ADE; control arm). Following completion of induction on study, post-induction therapy is at the treating physician's discretion. To date, 20 pts, 10 in each arm (1–16 yrs, median 9.4 yrs in both arms) have been enrolled. Results: At the protocol-specified bone marrow sampling time 3 weeks post-induction, there were 2 CRs, 6 CRi (CR with incomplete hematopoietic recovery), 1 leukemia not in remission and 1 pt who discontinued due to an AE in Arm A. In Arm B, 6 CRs, 2CRi, 1 PR and 1 pt with marrow aplasia have been confirmed. Decitabine PK in all arm A pts (100%) were characterized by mean+SD Cmax, 297+109 ng/mL, AUC0-t, 216+73.7 ng*h/mL, CL, 136+93.9L/h, Vdss 93.1+70.7 L, t1/2 0.456+0.073 h, and median tmax0.925 h. All pts had at least one AE. Grade 3 and 4 non-hematologic AEs in Arm A that were not seen in Arm B were caecitis in 2 (20%), anorexia in 3 (30%), and hypophosphatemia in 2 (20%) of pts. All pts experienced neutropenia and thrombocytopenia as expected. One pt in Arm A had appendicitis and colon perforation on Day 6 that led to study discontinuation, later determined to have been leukemic infiltrate. Two pts have died to date (both in Arm A), one of necrotic bowel, Pseudomonas sepsis and multisystem organ failure 6 months after completing study induction therapy. One pt died 5 months following study treatment from multisystem organ failure after stem cell transplant. Epigenetic changes associated with decitabine pretreatment were analyzed and will be presented. Conclusions: Decitabine in combination with ADE chemotherapy is well tolerated in children with newly diagnosed AML. There were no AEs that had not been previously identified in adults with MDS or AML. No differences have been observed between treatment arms in hematologic toxicities based on the current sample size. To date, the decitabine-treated pts in this study may have more gastrointestinal toxicity and hypophosphatemia. Decitabine-treated pts achieved PK exposures that were similar to those observed in adults treated with decitabine. Preliminary responses by CR/CRi were similar between treatment arms; expected adverse events of neutropenia and thrombocytopenia were similar between both Arms. Molecular changes associated with decitabine pretreatment may be important in the sensitization of clonogenic AML cells. Total accrual of 40 subjects is planned. Disclosures: Off Label Use: AC220 in relapsed/refractory pediatric acute leukemia. Tarassoff:Eisai, Inc.: Employment. Jones:Eisai Inc: Employment.

Abstract Background: Retrospective analyses have demonstrated significantly improved survival for AYA ALL patients (pts) aged 16-21 years (yrs) when treated on pediatric versus adult U.S. NCI Cooperative group regimens where 2-yr event-free survivals (EFS) have been only 35-40%. The purpose of C10403, a large prospective US intergroup trial, was to evaluate the feasibility and effectiveness [with EFS as a primary endpoint), of treating AYA ALL pts (ages 16-39 yrs) using the standard arm of the successful Children's Oncology Group regimen (COG AALL0232) . Methods: Newly diagnosed AYA patients with B-precursor (B-ALL) or T-precursor (T-ALL) ALL were eligible to enroll on C10403. Burkitt type and Ph+ ALL were excluded. The regimen was identical to the Capizzi methotrexate arm of COG AALL0232 (Larsen E. JCO 2011; 29 suppl:3) and consisted of four intensive courses: remission induction, remission consolidation, interim maintenance, delayed intensification, and prolonged maintenance therapy. Pts with M2 marrow response (>5% but < 25% lymphoblasts) after remission induction received an extended remission induction course of therapy. Events were defined as induction failure (M3 [³25% blasts] day 29 of induction or M2 day 43 of extended induction), death, relapse, or second malignancy. Key correlative science studies in a subset of the total accrued population included assessment of Minimal Residual Disease (MRD) using quantitative real-time PCR of clonal IgH or TCR gene rearrangements as well as Low Density Microarray (LDA) assays designed to detect a previously validated gene expression profile (Harvey, R; ASH 2013, abstract 826) which can prospectively identify ALL pts with Ph-like (BCR-ABL1-like) ALL. Results: 318 pts were enrolled on C10403 from 11/2007 to 8/2012; 22 withdrew prior to therapy. Of 296 evaluable pts, the median age at diagnosis was 24 yrs (range: 17 to 39): 25% were 17-20 yrs, 53% were 21-29 yrs, and 22% were 30-39 yrs. The majority had B-ALL (76%) and were male ( 61%). Approximately 25% were non-Caucasian and 15% were Hispanic or Latino. 32% of pts were obese (BMI³30). There were 5 (2%) treatment-related deaths during protocol therapy: liver failure (n=2, both during induction), infection (1 in induction, 1 in consolidation), and ventricular arrhythmia (1 in induction). Overall, treatment toxicities were similar to those reported in the standard arm of COG AALL0232, with an increased thrombosis and early hyperbilirubinemia for C10403 pts, as reported previously (Advani A, ASH 2013, abstract 303). To date, 70 deaths have been reported and 87 pts remain on protocol therapy. With a median follow-up of 28 months for surviving pts, 105 events have been observed. The median EFS overall is 59.4 months (95% CI: 38.4 to NR) and the 2-yr EFS rate overall is 66% (95% CI: 60 – 72%) [Fig 1a] with similar 2-yr EFS rates for B and T- ALL pts (65%, and 68%). The 2-yr OS rate is 78% (95% CI: 72 – 83%)[Fig 1b], which is similar for B (78%, 95% CI: 72 – 84%) and T-ALL, (80%, 95% CI: 70 – 91%). These results allow rejection of the null hypothesis of this Phase II trial that the true median EFS is, at most, 32 months. In multivariable analysis of presenting clinical features, age > 20 years and initial WBC count ³ 30k/microliter were significantly associated with worse EFS and OS. Presence of MRD at day 28 following initiation of induction therapy and presence of a Ph-like gene expression signature were significantly associated with both worse EFS and OS. Notably, absence of detectable MRD noted in 22/58 [38%] evaluable pts at day 28 of induction was associated with 100% EFS (p=0.0006). The Ph-like like signature was detected in 28% of pts tested on C10403 and the 2 yr EFS for these patients was only 52%, compared to 81% for those without Ph-like disease (p = 0.04). Conclusions: This large prospective US adult intergroup trial (C10403) for pts 16-39 years old employing an intensive pediatric regimen demonstrates a significant improvement (compared to historical controls) in AYA EFS and OS and validates this approach for treatment of AYA with ALL by adult hematologists. The improved clinical outcomes and the predictive value of the correlative studies in this trial lay the foundation for the design of future trials, where incorporation of novel agents to eradicate MRD, and/or use of tyrosine kinase inhibitors to target the frequently detected Ph-like ALL in AYA pts may further improve survival for young adults with ALL. Figure 1a Figure 1a. Figure 1b Figure 1b. Disclosures Stock: Sigma-Tau: Membership on an entity's Board of Directors or advisory committees, Research Funding. Advani:Sigma Tau: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees. Liedtke:Onyx: Membership on an entity's Board of Directors or advisory committees. Larson:Novartis: Consultancy, Research Funding.

Abstract Background: Myelofibrosis (MF), polycythemia vera (PV), and essential thrombocythemia (ET), are chronic MPNs associated with a broad array of symptoms that may negatively impact patients’ quality of life (QoL). To enhance patient care, it is important to have a current and clear understanding of how MPNs affect the overall health and daily lives of patients. The MPN LANDMARK SURVEY was developed to examine patients’ perceptions of these MPNs related to disease burden, QoL, productivity, and activities of daily living (ADLs). Methods: Eligible patients diagnosed with an MPN were recruited to participate in an online survey conducted from May–July 2014in the US. Patients were asked about the overall burden of disease and impact of symptoms on their QoL, productivity, and ADLs. Descriptive analyses were conducted to assess these outcomes and examined by calculated (not reported) prognostic risk score (MF - DIPSS: Passamonti, Blood 2010; PV: Tefferi, Leuk 2013; ET - IPSET: Passamonti, Blood 2012) and symptom severity quartiles, which were determined using the MPN Symptom Assessment Form (MPN-SAF) total symptom scores. Results: 813 patients (MF=207; PV=380; ET=226) responded to the survey. A majority of patients were female (MF, 54%; PV, 62%; ET, 72%), approximately half were aged 60–74 years (MF, 55%; PV, 51%; ET, 46%), and most were covered by health insurance (>98%). Nearly half (48%) were diagnosed within the last 5 years and average time to diagnosis from first symptoms was >2 years. A high proportion of patients had intermediate to high prognostic risk scores (MF, 94%; PV, 87%; ET, 44%). The majority of patients reported feeling anxious or worried about their MPN (MF, 91%; PV, 78%; ET, 74%). Among all groups, fatigue was the most severe symptom reported (mean MPN-SAF score=6.0–6.4 on a scale of 0–10). A subset of patients in each group described their symptoms as very severe (severity score ≥7 on a scale of 0–10; MF: fatigue [59%], problems with sexual desire [49%], inactivity [46%]; PV: inactivity [48%], fatigue [49%], problems with sexual desire [49%]; and ET: problems with sexual desire [49%], fatigue [50%], headaches [40%]). The majority of patients reported that MPN-related symptoms reduced their QoL (MF, 81%; PV, 66%; ET, 57%); this was reported in all risk groups but more frequently by patients with a high risk score vs a low risk score in MF and ET (MF, 89% vs 69%; PV, 63% vs 65%; ET, 71% vs 59%). A more substantial QoL impact was reported by patients in high vs low symptom quartiles (MF, 95% vs 51%; PV, 94% vs 33%; ET, 93% vs 15%). Similarly, MPNs also had a marked negative impact on reduced work hours, sick days, voluntary job termination, receipt of medical disability, early retirement, and ADLs (Table 1). For example, among patients employed, approximately one fourth reported missing ≥1 day of work (MF, 29%; PV, 19%; ET, 23%) in the last 30 days before the survey. Even patients with low prognostic risk scores often reported missing ≥1 day of work (MF, 33%; PV, 23%; ET, 22%) or cancelling ≥1 day of planned activities (MF, 46%; PV, 35%; ET, 34%). Patients in the high vs low symptom quartiles were more likely to call in sick to work (MF, 48% vs 0%; PV, 52% vs 4%; ET, 38% vs 0%) or cancel ≥1 day of planned activities (MF, 77% vs 5%; PV, 56% vs 7%; ET, 67% vs 3%). Conclusion: The findings from this large, first-of-its-kind survey demonstrate a marked burden of disease across all 3 MPNs that is not limited to symptoms but extends to QoL, productivity, and ADLs. Although high prognostic risk scores have long been associated with a significant burden of disease, in this study, patients with a low risk score also reported significant burden. The symptom burden reported is consistent with previous studies, thus validating the present dataset. MPN treatment considerations should include reducing the symptom burden and improving QoL and productivity to enhance the overall health and lives of MPN patients. Disclosures Mesa: Incyte Corporation: Research Funding; CTI: Research Funding; Gilead: Research Funding; Genentech: Research Funding; Eli Lilly: Research Funding; Promedior: Research Funding; NS Pharma: Research Funding; Sanofi: Research Funding; Celgene: Research Funding. Miller:Incyte Corporation: Honoraria, Research Funding. Thyne:Incyte Corporation: Speakers Bureau. Mangan:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees; Alexion Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Goldberger:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees. Fazal:Incyte Corporation: Consultancy, Research Funding, Speakers Bureau; Gilead: Research Funding, Speakers Bureau. Ma:Incyte Corporation: Consultancy. Wilson:Incyte Corporation: Honoraria. Dubinski:Incyte Corporation: Employment, Equity Ownership. Boyle:ICF International: Employment, Equity Ownership. Mascarenhas:Incyte Corporation: Consultancy, Research Funding; Novartis Pharmaceuticals Corporation: Research Funding.

Abstract Background : Patients diagnosed with myeloproliferative neoplasms (MPNs), including myelofibrosis (MF), polycythemia vera (PV), and essential thrombocythemia (ET), experience disease burdens that can negatively affect their quality of life. Disconnects between patient and physician perceptions of disease burden or poor patient-physician communication may delay or prevent achievement of treatment goals. The MPN LANDMARK SURVEY is the first large US-based survey designed to evaluate disease burden and patient-physician communication in MPN disease settings. Methods : All eligible patients diagnosed with 1 of the 3 MPNs and physicians treating patients with MPNs that were recruited were surveyed in the US during May-July 2014.The surveys included ≤67 questions (depending on the type of MPN and respondent) and required approximately 20–25 minutes to complete. Descriptive analyses were conducted to identify gaps in perceptions of disease burden and patient-physician communication. Results : The MPN LANDMARK SURVEY was completed by 813 patients (MF=207; PV=380; ET=226) and 457 physicians. Approximately half of the patients were 60–74 years of age (MF, 55%; PV, 51%; ET, 46%), the majority were female (MF, 54%; PV, 62%; ET, 72%) and had a degree from a 4-year college or postgraduate institution (MF, 65%; PV, 65%; ET, 58%), and >98% had health insurance. The majority of physicians graduated from medical school 5–24 years before the survey (67%) and practiced in outpatient settings (single specialty groups, 42%; academic hospitals, 31%). Patient-physician communication gaps were identified in several important areas: (1) Prognostic assessment: most patients did not recall receiving a prognostic risk score, but most physicians reported classifying patients by prognostic risk (Table 1). (2) Symptom assessment: physicians were more likely than patients to report that physicians ask about patients' most important disease-related symptoms or about a full and comprehensive list of symptoms (Table 1). (3) Treatment goals: the most important treatment goals were different in MF (patients: delay disease progression; physicians: improve symptoms) and PV (patients: delay disease progression; physicians: prevent vascular/thrombotic events) settings (Table 2). Patients and physicians in the ET setting both reported that prevention of vascular/thrombotic events was the most important treatment goal. Patients and physicians in the MF and PV settings reported fatigue as the most pressing disease manifestation that patients would like to resolve (MF: patients, 47%; physicians, 65%; PV: patients, 33%; physicians, 31%), whereas patients and physicians differed in the ET setting (patients: fatigue, 33%; physicians: stroke, 29%). Most patients reported a desire to be ≥50% responsible for their treatment decisions (MF, 72%; PV, 71%; ET, 75%). Physicians reported that most patients sometimes or often did not wish to comply with their primary treatment recommendation (MF, 77%; PV, 84%; ET, 79%). (4) Treatment satisfaction: overall, more than one third of patients were “somewhat satisfied” or “dissatisfied” with their physician's communication about their condition and treatment (MF, 34%; PV, 43%; ET, 45%) and with their physician's overall management of their disease (MF, 36%; PV, 40%; ET, 42%). Among patients who changed their MPN doctor (MF, 47%; PV, 46%; ET, 56%), dissatisfaction with prior care received was the most frequently reported reason for the change (MF, 40%; PV, 37%; ET, 33%). Approximately one fifth to one fourth of patients included their doctor's office among the most helpful sources of information about their diagnosis (MF, 27%; PV, 22%; ET, 20%), and most patients included the internet among the most helpful sources (MF, 90%; PV, 87%; ET, 89%). Conclusion : Important disconnects exist between patients' and physicians' perceptions in MPN disease settings. In addition, the majority of physicians report classifying patients by prognostic risk, including PV and ET settings, which do not have widely accepted prognostic risk scores. Although physicians generally appreciate the burden that MPNs have on patients, patient management may be enhanced with improved elucidation of patient symptoms and clear communication regarding the goals and potential benefits of interventions. Disclosures Mesa: Incyte Corporation: Research Funding; CTI: Research Funding; Gilead: Research Funding; Genentech: Research Funding; Eli Lilly: Research Funding; Promedior: Research Funding; NS Pharma: Research Funding; Sanofi: Research Funding; Celgene: Research Funding. Miller:Incyte Corporation: Honoraria, Research Funding. Thyne:Incyte Corporation: Speakers Bureau. Mangan:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees; Alexion Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Goldberger:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees. Fazal:Incyte Corporation: Consultancy, Research Funding, Speakers Bureau; Gilead: Research Funding, Speakers Bureau. Ma:Incyte Corporation: Consultancy. Wilson:Incyte Corporation: Honoraria. Dubinski:Incyte Corporation: Employment, Equity Ownership. Boyle:ICF International: Employment, Equity Ownership. Mascarenhas:Novartis Pharmaceuticals: Research Funding; Incyte Corporation: Consultancy, Research Funding.

Abstract Introduction: Guadecitabine (SGI-110) is a novel next-generation HMA administered as a small volume subcutaneous (SC) injection which results in extended decitabine exposure. Phase 2 studies have been conducted in TN-AML patients who were not candidates for intensive chemotherapy using two different doses and schedules of guadecitabine. We report here a comparative efficacy and safety analysis of the 5-day and 10-day regimens. Methods: TN-AML patients who were not candidates for intensive chemotherapy based on age (≥ 65 y), poor performance status (PS 2), comorbidities, or poor risk cytogenetics were enrolled in 2 separate treatment cohorts in the Phase 2 study. In the first cohort, patients were randomized (1:1) to either 60 mg/m2/d or 90 mg/m2/d on Days 1-5 (5-day regimen). In the second cohort, patients were treated with 60 mg/m2/d on Days 1-5 and Days 8-12 (10-day regimen) for up to 4 cycles, followed by 60 mg/m2/d Days 1-5 in subsequent cycles. Cycles were scheduled every 28 days for both regimes with dose reductions/delays allowed based on response and tolerability. Patients remained on treatment as long as they continued to benefit with no unacceptable toxicity. The primary endpoint was the composite Complete Response (CRc): Complete Response (CR) + CR with incomplete platelet recovery (CRp) + CR with incomplete neutrophil recovery (CRi) using modified International Working Group (IWG) criteria (Cheson et al, 2003). Secondary endpoints included overall survival (OS), and safety. Results: There was no difference in efficacy or safety between 60 and 90 mg/m2/d on the 5-day regimen (Yee et al, European Hematology Association meeting 2014, S647), so data are reported here for the two doses combined on the 5-day cohort. There were 51 patients treated in the 5-day regimen cohort and 52 treated with the 10-day regimen. There was no statistically significant difference in patient characteristics between the 2 regimens; median age 77.9 vs. 77.3 years ; male 59% vs. 65%; PS 2 or higher 35% vs. 40%; median BM blasts 40.0% vs. 49.5%; poor risk cytogenetics 46% vs. 43% for the 5-day and 10-day cohorts, respectively. Follow up of the 10-day cohort patients was shorter as it started after completion of enrolment of the 5-day cohort. The median follow up was 25.7 and 12.4 months and median number of cycles was 5 (range 1-26) and 3 (range 1-13) for the 5-day and 10-day cohorts, respectively. There was no significant difference in the primary efficacy endpoint, CRc, between the 2 regimens (p=0.43). CRc was achieved in 29/51 patients (57%) on the 5-day regimen (19 CR, 3 CRp, and 7 CRi) and in 25/52 patients (48%) on the 10-day regimen (16 CR, 5 CRp, and 4 CRi). Median OS was 10.5 and 8.7 months for the 5-day and 10-day cohorts, respectively (p=0.89). The 30, 60, and 90-day all-cause mortality rates were not statistically significant between the two cohorts: 5.9%, 15.7%, and 21.6% on the 5-day regimen and 1.9%, 17.3%, and 28.8% on the 10-day regimen. The most common Grade ≥3 AEs regardless of relationship to guadecitabine were: febrile neutropenia 59% vs. 60%, thrombocytopenia 47% vs. 38%, neutropenia 39% vs. 33%, anemia 27% vs. 19%, pneumonia 24% vs. 27%; and sepsis 12% vs. 19%, for the 5-day and 10-day cohorts respectively, none of which was statistically significant. Fifteen patients remain on treatment (5 from the 5-day cohort and 10 from the 10-day cohort). Conclusions: Guadecitabine is clinically active with a good safety profile in TN-AML patients not candidates for intensive chemotherapy. Unlike in relapsed/refractory AML, where the 10-day regimen of guadecitabine showed a trend toward improved efficacy (Roboz et al, Annals of Oncology 25 Supplement 4, 2014), there was no significant difference in either efficacy or safety between the 5-day and 10-day regimens in newly diagnosed AML patients. Guadecitabine 60 mg/m2/d SC Days 1-5 is currently being investigated in an 800-patient multicenter randomized phase 3 study in TN-AML patients unfit to receive intensive chemotherapy (ASTRAL-1 Phase 3 clinical trial: ClinicalTrials.gov reference NCT02348489). Disclosures Kropf: Teva Pharmaceuticals: Consultancy. O'Connell:Celgene: Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees. Griffiths:Astex: Research Funding; Alexion Pharmaceuticals: Honoraria; Celgene: Honoraria. Rizzieri:Teva: Other: ad board, Speakers Bureau; Celgene: Other: ad board, Speakers Bureau. Stock:Gilead: Membership on an entity's Board of Directors or advisory committees. Savona:Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees. Rosenblat:Astex Pharmaceuticals, Inc.: Research Funding. Berdeja:Celgene: Research Funding; Onyx: Research Funding; BMS: Research Funding; Abbvie: Research Funding; Array: Research Funding; Curis: Research Funding; Acetylon: Research Funding; MEI: Research Funding; Janssen: Research Funding; Novartis: Research Funding; Takeda: Research Funding. Wilson:Astex Pharmaceuticals, Inc.: Employment. Lowder:Astex Pharmaceuticals, Inc.: Employment. Taverna:Astex Pharmaceuticals, Inc.: Employment. Hao:Astex Pharmaceuticals, Inc.: Employment. Azab:Astex Pharmaceuticals, Inc.: Employment. Issa:Janssen: Consultancy; Astex Pharmaceuticals, Inc.: Consultancy.