ALBERT

Description: Background: In pediatric B-precursor acute lymphoblastic leukemia (ALL), hyperdiploidy (51 to 65 chromosomes and/or DNA index 〉 1.16) comprises approximately 25% of cases and is associated with a favorable prognosis. Aim: To evaluate the clinical and relapse characteristics of children with hyperdiploid (HY) ALL treated at Children’s Hospital of Michigan from 1991 to 2002. Methodology: Children were treated per several successive Pediatric Oncology Group ALL studies. Data was obtained by retrospective chart review. Study end-points were "relapse" or "death" whichever came first. Univariate and multivariate analysis was performed to study the association of various clinical and biological factors on outcome. Survival curves were drawn using Log-rank test. Results: 139 children diagnosed with ALL were included in the study: 31 (22%) HY-ALL; 108 (88%) non-HY-ALL (Table). In HY-ALL, 11(35%) relapsed: 3 (27%) isolated hematopoietic (HEM); 8 (73%) extra-medullary (EM) [TESTES: 4; TESTIS+HEM: 1; CNS+HEM: 3]. Two (18%) relapsed while on treatment. Non-HY-ALL relapses occurred in 25 (23%): HEM 16 (64%); EM 9 (46%) [TESTIS: 1; TESTIS+HEM: 1; CNS: 6; CNS+HEM: 1]. Thus, HY-ALL children were predisposed to EM involvement at relapse compared to non-HY-ALL (p10 years and Caucasian race were associated with poor EFS (p10 yr) with HY-ALL may require more intensive treatment and monitoring of sanctuary sites to prevent treatment failures. Figure Figure Patient Characterisitcs at Diagnosis Patient characterisitcs Hyperdiploid ALL (n=31) Non-Hyperdiploid ALL (n=108) CAUC: Caucasian; AA: African American; O: Other Median age (yrs) 3.9 (1.3–16.0) 5.8 (3.0–17.0) Race: CAUC/AA/O 21(69%)/ 6(19%)/ 4(12%) 66(61%)/ 28(26%)/ 14(12%) Age〉10 yr 5 (16%) 13 (12%) Male:Female 20 (65%):11(35%) 58 (54%):50(46%) Median follow up (yrs) 5.9 ± 4.0 5.3 ±3.4 Events 11 (35%) 30 (28%)

Description: Abstract 2987 Poster Board II-963 Background: Thrombosis in children, though rare, is being increasingly recognized in pediatric tertiary care centers. Most data on children have largely been extrapolated from adults. Comprehensive data about the incidence and risk factors for recurrence of pediatric thrombosis are scarce. Aim: 1) To estimate the incidence of recurrence of thrombosis at a single pediatric tertiary care center and 2) To determine the risk factors for recurrent thrombosis in children. Methods: After local IRB approval, charts of patients (pts) with documented venous or arterial thrombosis admitted or referred to the hematology service from 2001-2008, were reviewed and pertinent data obtained. Data were analyzed using the 17.0 version of SPSS. Results: Preliminary analysis revealed 238 pts (ages 0-30 years) with 183 deep venous (DVT, 75%), 53 arterial (22%) and 2 combined (0.8%) episodes of thrombosis at initial presentation. Of the 183 pts with DVT there were 110 females, 128 males; of pts with arterial strokes there were 21 females, 32 males. Overall 11 pts (4.6%, 6 females, 5 males) had a recurrence, with 91% venous and 9% arterial. Three (27%; 2 females, 1 male) out of the 11 pts had a third recurrence, which were all venous. Sites for recurrence were lower extremity (82%), neck (9%) and thorax (9%). Risk factors for recurrence were positive family history of DVT (7/11; 63.6%), elevation in factor VIII (5/11; 45.5%), proximal lower extremity thrombosis as primary site (5/11; 45.5%), obesity (4/11; 36.4%), the presence of PTTLA (4/11; 36.4%) and the presence of inflammatory bowel disease (27.3%). Heterozygous factor V Leiden and congenital AT III deficiency was present in one pt each (9%) with recurrence. Other congenital thrombophilia traits were not seen in patients with recurrent events. Interestingly, gender, duration of treatment and residual clot after treatment (partial resolution) were not significantly associated with risk of recurrence. Conclusion: Recurrent thrombosis is infrequent in children and a positive family history, elevated factor VIII, and other acquired factors such as obesity and inflammatory bowel disease were identified as risk factors for recurrence. Inherited thrombophilia and partial resolution of thrombosis were not associated with recurrence in this series of patients. Larger multi-center trials are needed to identify risk factors for recurrence in children. To our knowledge this is the first pediatric study that has systematically evaluated the incidence and risk factors associated with recurrent pediatric thrombosis. Disclosures: No relevant conflicts of interest to declare.

Description: Background: Von Willebrand Disease (VWD) is the most common bleeding disorder. Current gold standard diagnostic testing includes: VWF Activity (VWF:RCo), VWF Antigen (VWF:Ag) and Factor VIII Activity (FVIII). There are many difficulties associated with the current diagnostic methods. Thromboelastography (TEG) is a viscoelastic method of measuring coagulation function. The standard TEG assay has not been thought to be of use in VWD because of the lack of shear stress which is essential for the activation of VWF. Modified TEG using Ristocetin activation has been found to be useful in the diagnosis of VWD. The aims of this study were to evaluate the different parameters of Tissue factor (TF) initiated TEG in patients with VWD, to determine if this assay is sensitive to dysfunctional/low levels of VWF, as this does not require any significant change in procedure except for the use of TF as the activator instead of Kaolin. Methods: A retrospective chart review of patients who presented for a bleeding disorder workup that had TF initiated TEG analysis and Von Willebrand laboratory tests completed between January 2007 and December 2015 was performed. IRB approval was obtained, and current diagnostic tests for Von Willebrand Disease (CBC with platelet count, VWF:RCo and VWF:Ag, FVIII, ABO blood type; PT, PTT, Fibrinogen) and TF initiated TEG parameters, specifically K-Time and MRTG (Maximum rate of thrombin generation), were compared. To perform the TEG analysis, the citrated whole blood samples were activated using 20mL of 1:10,000 dilution of recombinant human tissue factor (Innovin, Dade Behring) and CaCl2. Results: A total sample size of 160 patients (ages ranging 2 weeks to 18 years) who had a workup for a bleeding disorder that included Von Willebrand studies and TEG were reviewed. Of these 160 patients, 75 patients had a VWF:RCo

Description: Abstract 4118 Background Acute lymphoblastic leukaemia (ALL) is the most common form of childhood cancer in the United States. The incidence of ALL is approximately 2-3-fold higher in Caucasian compared to African American (AA) children, suggesting potential differences in genetic susceptibility and/or exogenous exposures. Multiple epidemiologic studies have examined both genetic and environmental factors linked to the development of childhood ALL, primarily in Caucasian populations. Hence, identifying factors associated with racial differences in incidence of leukemia may provide new insights into the role of endogenous versus exogenous factors in the development of leukemia. A number of studies have reported relationships between folate metabolism and the risk of developing ALL including: i)maternal folate supplementation during pregnancy (reduced risk of ALL in offspring); and ii)polymorphisms of genes encoding enzymes involved in folate metabolism, including 5,10-methylenetetrahydrofolate reductase (MTHFR) (increased and decreased risks). To date, no studies have been performed specifically examining the role of folate metabolism in AA children. The objective of this study was to identify factors associated with folate metabolism which may be linked to the development of ALL in AA children compared to healthy controls. Patients and Methods AA children with B-precursor (BP) ALL were enrolled from the Hematology/Oncology Division of Children's Hospital of Michigan, while healthy AA children were enrolled as controls. Patients' racial backgrounds were based on parental reporting. The frequencies of polymorphisms in the MTHFR [677C〉T, 1298A〉C], thymidylate synthase [TS 2R3R], cystathionine-β-synthase [CBS 844ins(68)], and reduced folate carrier [RFC 80G〉A] genes were determined by genotyping between AA childhood BP-ALL [n=26; 14 males] and healthy AA children [n=87; 47 males]. The distributions of genotypes between cases and controls were compared using Fisher's exact test. Results The genotype distributions of the polymorphisms of the folate pathway genes are summarized in Table 1. The frequencies of the MTHFR gene variants 677 CT/TT were 2-fold higher in the ALL cohort than that in the healthy control cohort. MTHFR 677 CT/TT was significantly associated with a risk of developing ALL in the AA patients. There were no significant differences in the distributions of the TS, CBS, or RFC polymorphisms between the groups. High birth weight has been associated with an increased risk of developing ALL, though we found no significant difference in birth weights between ALL and control groups. Conclusion Our study is the first to demonstrate that there is a higher frequency of the variant MTHFR C677T polymorphism (associated with reduced enzyme activity and altered distribution of folate forms) in AA children with ALL compared to healthy controls. Low MTHFR enzyme activity leads to imbalances in the thymidylate and de novo purine biosynthetic pathways, ultimately affecting DNA synthesis and repair and likely increasing the risk of leukemia. Thus, the role of altered folate metabolism may contribute to the development of ALL in AA children similar to Caucasian children, although additional studies are still required to identify factors linked to the higher incidence of ALL in Caucasian children and/or low incidence in AA children. Disclosures: No relevant conflicts of interest to declare.