Citations

Abstract Abstract 5061 Background: Ruxolitinib was approved for commercial use for the therapy of intermediate- and high-risk myelofibrosis (MF) in the USA in November 2011. We sought to assess the initial clinical experience on the use of ruxolitinib outside of the clinical trial setting at our high volume MPN program. Methods: Twenty-eight patients with intermediate- or high-risk myelofibrosis (including PMF, post-PV and post-ET myelofibrosis) prescribed ruxolitinib at our center within the first seven months after FDA approval were included in this analysis. Baseline disease information, treatment history, dynamics of ruxolitinib dosing, impact on cytopenias, splenic response, and symptoms were assessed. Results: A total of 28 patients with post-ET MF (n=7), post-PV MF (n=6) and primary MF (n=15) began ruxolitinib between November, 2011 and May, 2012. Twenty-seven patients had been treated with previous therapies. The JAK2V617F mutation was present in 79% of patients. The mean number of weeks from diagnosis of MF to treatment with ruxolitinib was 218 (8–929). The average spleen size at the start of therapy was 11. 5cm (0–36) below the left costal margin. DIPSS Plus scores classified patients as Intermediate-1 (53%), Intermediate-2 (29%) and High risk (18%). Symptoms at the start of therapy included fatigue (78%), early satiety (25%), night-sweats (68%), abdominal pain (61%), pruritis (32%), weight-loss (57%), bone pain (21%), and fevers (11%). The average hemoglobin concentration, WBC count and platelet counts were 10. 9 g/dL (7. 6–13. 8), 13. 5 × 10(9)/L (3. 1–53. 8) and 295 × 10(9)/L (32–844) respectively. The median duration to follow-up was 72 days (4–144 days). The majority of patients began therapy at 20 mg BID (68%). Most patients seen in follow-up experienced reduction in splenic size (64%), 36% of which had complete resolution of palpable splenomegaly within a mean follow-up of 78 days (10–142). Significant improvements were noted in symptoms including fatigue (68%), early satiety (71%), night sweats (47%), abdominal pain (71%), pruritis (55%), weight loss (69%), bone pain (33%) and fevers (33%). Dosage reductions were required for four patients with anemia (n=3) and thrombocytopenia (n=1). Two patients required the addition of anagrelide/hydroxyurea for platelet counts >1, 000 × 10(9)/L. Excluding patients with preexisting thrombocytosis >600 × 10(9)/L, the percentage reduction of platelets from baseline by weeks 4, 9 and 15 were 34%, 13%, and 12% respectively. Eight patients required red blood cell transfusions for anemia, three of which who had begun therapy with hemoglobin concentrations under 9 g/dL. Excluding the 8 transfusion-dependent patients, the percentage reduction in hemoglobin concentration from baseline by weeks 4, 9, and 15 was 7%, 6%, and 14% respectively. Non-hematological toxicities requiring dosage adjustments included hyperkalemia (n=1) and fatigue/dizziness/headaches (n=1). Five patients underwent dose increases for lack splenic (n=3) and symptomatic (n=2) response. Six patients discontinued the drug for disease progression requiring stem cell transplant (n=2), lack of constitutional symptom improvement (n=1), diarrhea (n=1), thrombocytopenia (n=1) and anemia (n=2). Five patients had platelet counts below 100 × 10(9)/L (19–94 × 10(9)/L) and began therapy at reduced starting doses. All patients seen in follow-up reported significant improvements in symptoms and splenomegly was reduced >50% in two patients seen in follow-up within 4 weeks of initiating therapy. Two patients underwent dose increases after 5 months of therapy to enhance response. No bleeding events were reported. By week 15, no decrease was noted in platelet levels from baseline in the 3 patients seen in follow-up. Two patients required danzol (n=1) or platelet transfusions (n=1) for thrombocytopenia. Conclusion: Randomized controlled trials have proven ruxolitinib's efficacy in reducing constitutional symptoms, cytopenias and splenomegaly in myelofibrosis patients. This study represents a confirmation of the efficacy this drug provides in reducing splenomegaly and symptoms observed in clinical trials when utilized in a standard practice setting. Toxicities are minimal and have been generally well controlled with dose reductions, even in patients with baseline thrombocytopenia. In conclusion, ruoxlitinib appears to be an efficacious and well-tolerated therapy with limited adverse effects. Disclosures: Mesa: Incyte: Research Funding; Lilly: Research Funding; Sanofi: Research Funding; NS Pharma: Research Funding; YM Bioscience: Research Funding.

Abstract Abstract 414 Background: SGI-110 is a dinucleotide of decitabine (DAC) and deoxyguanosine formulated as a low volume and pharmaceutically stable SQ injection allowing more extended decitabine exposure than DAC IV infusion. The anticipated differentiated PK profile offers the potential of improved biological and clinical activity and safety over currently available HMAs. Methods: A randomized Phase 1–2 FIH Pharmacokinetics/Pharmacodynamics (PK/PD)-guided, dose-escalation study has been conducted in patients with relapsed/refractory intermediate or high-risk MDS or AML. The objective of the first stage (dose escalation) is to determine safety and tolerability and to establish the Maximum Tolerated Dose (MTD) and Biologically Effective Dose (BED). Patients were randomized to one of two SQ regimens (dailyx5 or once weeklyx3, 28-day courses). PD is evaluated by LINE-1 global DNA hypomethylation. The second stage (dose expansion) is to determine the clinical activity and safety in AML and MDS using the established BED and MTD. We report here the results of the dose escalation phase which has completed enrolment. Results: 78 patients (64 AML, 14 MDS) were enrolled in the dose escalation phase: 44 patients in the dailyx5 regimen and 34 in the weeklyx3 regimen. Median age was 69 years (range 29–86), 65% were male, and 82% had ECOG PS of 0–1. Median number of prior regimens was 3 (range 1–9), 59% of patients had prior HMA treatment (50% of AML patients, and 100% of MDS patients). Six patients are still ongoing treatment. The PK profile demonstrated efficient conversion of SGI-110 to decitabine as predicted from the SGI-110 rational design, resulting in longer decitabine exposure window (beyond 8 hrs) compared to DAC IV (3–4 hrs). At SGI-110 dose range of 60–125 mg/m2, observed mean decitabine AUCs (88–231 ng*hr/mL) reach or exceed the therapeutic range seen with 20 mg/m2 DAC IV (115 ng*hr/mL) while achieving only a small fraction of the Cmax (26–64 ng/mL vs 146 ng/mL for DAC IV). The effective half-life for decitabine after SQ SGI-110 injection appeared to be prolonged (up to 4-fold or ∼2.4 hrs) compared to DAC IV (0.58 hrs). Decitabine exposures (AUC) increased in a dose-proportional manner regardless of the regimen and no accumulation was observed. Dose-related LINE-1 hypomethylation was observed in patients treated with the daily regimen between 18 and 60 mg/m2; a plateau in maximum average hypomethylation (∼25%) was evident at higher daily doses (90-125 mg/m2) and therefore the BED for the dailyx5 schedule is established at 60 mg/m2. The 25% average hypomethylation of LINE-1 compares favorably with that observed historically after DAC IV at the dose of 20 mg/m2 dailyx5. The extent of LINE-1 hypomethylation after weeklyx3 SGI-110 was inferior as the maximum average hypomethylation plateaued at ∼8% from baseline. Starting at 36 mg/m2 daily and 60 mg/m2 weekly (44 AML, and 7 MDS patients), clinical responses were observed: 2CRs, 1CRp, and 1CRi in heavily pretreated AML patients; 1 mCR and 1 HI in MDS patients previously treated with azacitidine. All responses were in patients who achieved >10% LINE-1 hypomethylation. The most common Adverse Events (AEs), regardless of relationship to SGI-110, were diarrhea (21%), febrile neutropenia (17%), fatigue/injection site pain/nausea at 15% each. The most common drug-related AEs were injection site pain (15%), fatigue (8%), nausea (6%), and thrombocytopenia (5%). MTD was not reached with the weekly regimen up to 125 mg/m2 weeklyx3. With the daily regimen, 125 mg/m2dailyx5 resulted in 2 Dose-Limiting Toxicities (DLTs) of febrile neutropenia in 3 MDS patients (1 associated with bacteremia, and the other with sepsis and thrombocytopenia Grade 4) while none of the 9 patients with AML had DLT at that dose. Conclusions: SGI-110 is well tolerated at doses higher than BED which is established at 60 mg/m2 dailyx5 where average hypomethylation of ∼25% was achieved. MTD estimated to be 90 mg/m2 dailyx5 for MDS and 125 mg/m2dailyx5 for AML patients. SQ administration of SGI-110 achieved efficient conversion to decitabine resulting in an improved PK profile over DAC IV. Clinical responses were observed in this heavily pretreated population and they seem to correlate with the extent of LINE-1 hypomethylation. Study is currently enrolling patients in the dose-expansion Phase 2 stage. Disclosures: Kantarjian: Astex Pharmaceuticals: Research Funding. Roboz:Astex Pharmaceuticals: Research Funding. Rizzieri:Astex Pharmaceuticals: Research Funding. Stock:Astex Pharmaceuticals: Research Funding. O'Connell:Astex Pharmaceuticals: Research Funding. Griffiths:Astex Pharmaceuticals: Research Funding. Yee:Astex Pharmaceuticals: Research Funding. Tibes:Astex Pharmaceuticals: Research Funding. Garcia-Manero:Astex Pharmaceuticals: Research Funding. Ravandi:Astex Pharmaceuticals: Research Funding. Walsh:Astex Pharmaceuticals: Research Funding. Feldman:Astex Pharmaceuticals: Research Funding. Ritchie:Astex Pharmaceuticals: Research Funding. Rao:Astex Pharmaceuticals: Research Funding. Decastro:Astex Pharmaceuticals: Research Funding. Schimmer:Astex Pharmaceuticals: Research Funding. Mesa:Astex Pharmaceuticals: Research Funding. Syed:Astex Pharmaceuticals: Research Funding. Choy:Astex Pharmaceuticals: Employment. Oganesian:Astex Pharmaceuticals: Employment. Taverna:Astex Pharmaceuticals: Employment. Azab:Astex Pharmaceuticals: Employment. Chung:Astex Pharmaceuticals: Research Funding. Issa:Astex Pharmaceuticals: Honoraria, Research Funding.

Abstract Abstract 1954 Introduction: Vitamin D (VD) deficiency can cause osteomalacia, aching bone pain, muscle weakness, fatigue, increase risk of fracture and precipitate or exacerbate osteopenia/osteoporosis. Allogeneic hematopoietic stem cell transplant (HCT) patients are susceptible to low VD level secondary to poor oral intake, decreased exposure to sunlight and treatment related malabsorption. VD level has been correlated to cancer incidence and VD metabolites have been used in the treatment of myeloid leukemia. VD shows promising immunomodulatory properties and correction of low VD level may mitigate manifestations of graft versus host disease (GVHD). Reports have suggested that low VD level appears to increase the incidence of GVHD. We hypothesize that there is a relationship between low VD level and morbidity (specifically incidence of acute GVHD), mortality and relapse incidence after HCT. We therefore studied VD levels pre- and post-HCT to determine if VD level impacts these outcomes. Patients and Methods: 241 patients underwent myeloblative or non-myeloablative HCT between January 1, 2009 and January 31, 2011 at our institution. Baseline demographic data, disease characteristics, transplant variables and outcomes data were obtained from the transplant database. These data were supplemented by retrospective chart review for pre- and post-transplant VD level. Categories for VD level included normal (>30 ng/ml) or abnormal (<30 ng/ml). Results: 131 (54%) of patients who underwent myeloblative or non-myeloablative HCT had their VD level evaluated either pre-transplant, post-transplant or both. Pre-HCT 57 (56%) patients, 100 days post-HCT 55 (59%) patients and 365 days post-HCT 12 (32%) patients had a low VD level. 51 (38%) of patients had a reduced intensity HCT and 80 patients (62%) had an ablative conditioning regimen. 11 (8.4%) patients had acute GVHD. Comparison of VD level among those with acute GVHD did show a higher incidence of acute GVHD between those with a low or normal VD level (HR=3.14, 95% CI: 0.35–28.33) however this association was not statistically significant (p=0.3079). Survival analysis in those with a low VD level pre-HCT showed there was not a higher risk of mortality (HR=1.14, 95% CI: 0.18–7.38) after adjusting for post- VD level, and this association was not statistically significant (p=0.8921). Survival analysis in those with a low VD level post-HCT did show a higher risk of mortality (HR=2.59, 95% CI: 0.26–25) after adjusting for pre-HCT VD level, however, this association was not statistically significant (p=0.4155). The relationship between VD level and relapse at 1 year post-HCT was not able to be examined because the VD level for patients who relapsed was not available. Conclusions: Half of patients undergoing HCT had VD testing pre- or post- HCT. Just over half of the patients tested had a low VD level pre- and 100 days post-HCT. It is notable that 365 days post HCT the number of patients with low VD level had decreased. This could be attributable to less time in the hospital thus increasing sun exposure, increasing performance status allowing better ingestion and absorption of VD in the gastrointestinal tract or proper supplementation of a low level noted previously. There was no significant difference in incidence of acute GVHD by VD level though there was a trend for increased risk. Pre- and post-HCT VD level did not significantly impact mortality but there was a trend toward higher risk in those with a low VD level post-HCT. This is the first study, to our knowledge, to evaluate the impact of VD level on mortality post-HCT. Our study confirms that many patients have a low VD level pre-and post-HCT. These findings, especially the trend towards a higher mortality risk and higher incidence of acute GVHD in those who have a low VD level post-HCT, warrant further prospective investigation. VD supplementation may be a low cost, easy to implement addition to routine post HCT care that might reduce HCT associated mortality. Disclosures: Reeder: Celgene: Research Funding.

A 56-year-old truck driver with a history of tobacco use presented with acute onset digital ischaemia in the ulnar distribution of his dominant hand, associated with severe pain. Occupational exposures included extensive manual labour and prolonged vibratory stimuli. Workup with Doppler and angiography confirmed the diagnosis of hypothenar hammer syndrome (HHS). After the failure of medical management, he underwent ulnar artery thrombectomy with reconstruction and arterial bypass grafting. His pain improved significantly postsurgically, and he was able to return to a normal routine. This case illustrates the classic presentation, examination, imaging findings and management options of HHS. HHS should be considered in patients with digital ischaemia and associated occupational exposures. Diagnosing the condition appropriately allows for optimal management, aiming at minimising symptoms and maximising quality of life.

Objectives: To deploy machine learning tools (random forests) to develop a model that reliably predicts hospital mortality in children with acute infections residing in low- and middle-income countries, using age and other variables collected at hospital admission. Design: Post hoc analysis of a single-center, prospective, before-and-after feasibility trial. Setting: Rural district hospital in Rwanda, a low-income country in Sub-Sahara Africa. Patients: Infants and children greater than 28 days and less than 18 years of life hospitalized because of an acute infection. Interventions: None. Measurements and Main Results: Age, vital signs (heart rate, respiratory rate, and temperature) capillary refill time, altered mental state collected at hospital admission, as well as survival status at hospital discharge were extracted from the trial database. This information was collected for 1,579 adult and pediatric patients admitted to a regional referral hospital with an acute infection in rural Rwanda. Nine-hundred forty-nine children were included in this analysis. We predicted survival in study subjects using random forests, a machine learning algorithm. Five prediction models, all including age plus two to five other variables, were tested. Three distinct optimization criteria of the algorithm were then compared. The in-hospital mortality was 1.5% (n = 14). All five models could predict in-hospital mortality with an area under the receiver operating characteristic curve ranging between 0.69 and 0.8. The model including age, respiratory rate, capillary refill time, altered mental state exhibited the highest predictive value area under the receiver operating characteristic curve 0.8 (95% CI, 0.78–0.8) with the lowest possible number of variables. Conclusions: A machine learning-based algorithm could reliably predict hospital mortality in a Sub-Sahara African population of 949 children with an acute infection using easily collected information at admission which includes age, respiratory rate, capillary refill time, and altered mental state. Future studies need to evaluate and strengthen this algorithm in larger pediatric populations, both in high- and low-/middle-income countries.

Current criteria for the diagnosis of CKD in adults include persistent signs of kidney damage, such as increased urine albumin-to-creatinine ratio or a GFR below the threshold of 60 ml/min per 1.73 m 2 . This threshold has important caveats because it does not separate kidney disease from kidney aging, and therefore does not hold for all ages. In an extensive review of the literature, we found that GFR declines with healthy aging without any overt signs of compensation (such as elevated single-nephron GFR) or kidney damage. Older living kidney donors, who are carefully selected based on good health, have a lower predonation GFR compared with younger donors. Furthermore, the results from the large meta-analyses conducted by the CKD Prognosis Consortium and from numerous other studies indicate that the GFR threshold above which the risk of mortality is increased is not consistent across all ages. Among younger persons, mortality is increased at GFR <75 ml/min per 1.73 m 2 , whereas in elderly people it is increased at levels <45 ml/min per 1.73 m 2 . Therefore, we suggest that amending the CKD definition to include age-specific thresholds for GFR. The implications of an updated definition are far reaching. Having fewer healthy elderly individuals diagnosed with CKD could help reduce inappropriate care and its associated adverse effects. Global prevalence estimates for CKD would be substantially reduced. Also, using an age-specific threshold for younger persons might lead to earlier identification of CKD onset for such individuals, at a point when progressive kidney damage may still be preventable.

Background: Prader-Willi syndrome (PWS) is a rare genetic disorder characterized by obesity, hypotonia, feeding difficulties, obesity, musculoskeletal manifestations including scoliosis, and hip dysplasia (HD). The aim of this study was to characterize the clinical and radiographic evolution of HD in the pediatric PWS population. Methods: The authors performed a retrospective cohort study of 72 patients (147 anteroposterior pelvic radiographs) between January 2004 and December 2016. Center-edge angle (CEA) of Wiberg, acetabular index (AI), and neck-shaft angle (NSA) were measures in all hips. The relationship between radiographic and demographic parameters of age, sex, and body mass index z-score (BMIzs) were assessed. Results: A total of 274 radiographic measurements were performed and analyzed in 72 patients. The mean CEA, AI, and NSA were 21.8±7.1 degrees (range, 5 to 35 degrees), 16.7±7 degrees (range, 5 to 45 degrees), and 142±8.5 degrees (range, 128 to 165 degrees), respectively. HD was diagnosed in 79 (29%) hip radiographs and varied significantly between the age groups (P<0.01). A statistically significant association was identified between age and CEA [β coef, 0.80; 95% confidence interval (CI), 0.6-1; P<0.01], AI (β coef, −0.90; 95% CI, −1.1 to −0.7; P<0.01), and NSA (β coef, −1.11; 95% CI, −1.4 to −0.9; P<0.01) angles. Sex and BMIzs were not identified as independent predictors of radiographic hip angles (P>0.1). Conclusions: The present study demonstrated favorable evolution of hip radiographic parameters in the PWS population treated with growth hormone early in development. This finding should prompt orthopedists to consider observation alone in the management algorithm for HD in patients with PWS. Levels of Evidence: Level III—a retrospective comparative study.

In this work related to familial aggregation of familial venous thromboembolism, the investigators report genomic and transcriptomic association of 16 novel susceptibility loci for venous thromboembolism.