|Grant Number:||5R01CA133881-03 Interpret this number|
|Primary Investigator:||Aplenc, Richard|
|Organization:||Children'S Hosp Of Philadelphia|
|Project Title:||Genetic Predictors of Aml Treatment Response|
DESCRIPTION (provided by applicant): Although acute myeloid leukemia (AML) causes substantial treatment burden in both children and adults, AML treatment response remains incompletely understood. This application proposes a genome-wide association study (GWAS) of pediatric AML treatment response. Two hypotheses underlie this application. First, somatic genetic variation will modify AML relapse and treatment related infection risk. Second, clinical trial simulations (CTS) may define how genetic variation data may be used to modify AML treatment. These hypotheses will be tested in three specific aims. Aim 1 will use the Illumina Human 610 HH Bead Chip to perform a GWAS with 840 patients to identify genotypes associated with AML relapse and infectious complication risk. Aim 2 will use the Illumina Infinium" Chip to validate 4% of SNPs found in Aim 1 in 1,160 Caucasian patients and 750 non-Caucasian patients. Aim 3 will use CTS to test the clinical applicability of infection susceptibility genotypes discovered and validated in the first two aims. This application has significance both as the first GWAS in AML and as a novel step towards translating genetic variability data into the clinical care of patients. Furthermore, since pediatric and adult AML share common molecular pathologies and treatment strategies, this research may inform the care of both adult and pediatric AML patients. PUBLIC HEALTH RELEVANCE: Acute myeloid leukemia (AML) causes a substantial disease and treatment burden in both children and adults. This application will provide data on the role of somatic genetic variability in AML treatment response and will use clinical trial simulations to model the application of genotype data to clinical patient care. Thus, this application may not only inform the care of adult and pediatric AML patients, but may also provide important insights into the translation of genotype data into patient care.
Concordance of copy number alterations using a common analytic pipeline for genome-wide analysis of Illumina and Affymetrix genotyping data: a report from the Children's Oncology Group.
Authors: Vujkovic M, Attiyeh EF, Ries RE, Horn M, Goodman EK, Ding Y, Kavcic M, Alonzo TA, Gerbing RB, Hirsch B, Raimondi S, Gamis AS, Meshinchi S, Aplenc R
Source: Cancer Genet, 2015 Jul-Aug;208(7-8), p. 408-13.
EPub date: 2015 May 7.
TPMT and MTHFR genotype is not associated with altered risk of thioguanine-related sinusoidal obstruction syndrome in pediatric acute lymphoblastic leukemia: a report from the Children's Oncology Group.
Authors: Wray L, Vujkovic M, McWilliams T, Cannon S, Devidas M, Stork L, Aplenc R
Source: Pediatr Blood Cancer, 2014 Nov;61(11), p. 2086-8.
EPub date: 2014 Apr 16.
Dexrazoxane exposure and risk of secondary acute myeloid leukemia in pediatric oncology patients.
Authors: Seif AE, Walker DM, Li Y, Huang YS, Kavcic M, Torp K, Bagatell R, Fisher BT, Aplenc R
Source: Pediatr Blood Cancer, 2015 Apr;62(4), p. 704-9.
EPub date: 2014 Mar 26.
Antifungal prophylaxis associated with decreased induction mortality rates and resources utilized in children with new-onset acute myeloid leukemia.
Authors: Fisher BT, Kavcic M, Li Y, Seif AE, Bagatell R, Huang YS, Zaoutis T, Torp K, Leckerman KH, Aplenc R
Source: Clin Infect Dis, 2014 Feb;58(4), p. 502-8.
EPub date: 2013 Nov 23.
Patient and hospital factors associated with induction mortality in acute lymphoblastic leukemia.
Authors: Seif AE, Fisher BT, Li Y, Torp K, Rheam DP, Huang YS, Harris T, Shah A, Hall M, Fieldston ES, Kavcic M, Vujkovic M, Bailey LC, Kersun LS, Reilly AF, Rheingold SR, Walker DM, Aplenc R
Source: Pediatr Blood Cancer, 2014 May;61(5), p. 846-52.
EPub date: 2013 Nov 19.
Gene expression profiling to predict viridans group streptococcal and invasive fungal infection in pediatric acute myeloid leukemia: a brief report from the Children's Oncology Group.
Authors: Lee GE, Sung L, Fisher BT, Sullivan KE, McWilliams T, Tobias JW, Meshinchi S, Alonzo TA, Gamis A, Aplenc R
Source: Acta Haematol, 2014;131(3), p. 167-9.
EPub date: 2013 Nov 6.
Zoonotic infections in pediatric patients with acute leukemia.
Authors: Lothstein K, Fisher B, Li Y, Seif A, Harris T, Torp K, Kavcic M, Huang YS, Rheingold SR, Aplenc R
Source: Pediatr Blood Cancer, 2013 Dec;60(12), p. E160-2.
EPub date: 2013 Aug 19.
Induction mortality, ATRA administration, and resource utilization in a nationally representative cohort of children with acute promyelocytic leukemia in the United States from 1999 to 2009.
Authors: Fisher BT, Singh S, Huang YS, Li Y, Gregory J, Walker D, Seif AE, Kavcic M, Aplenc R
Source: Pediatr Blood Cancer, 2014 Jan;61(1), p. 68-73.
EPub date: 2013 Jul 18.
Trends in Clostridium difficile infection and risk factors for hospital acquisition of Clostridium difficile among children with cancer.
Authors: de Blank P, Zaoutis T, Fisher B, Troxel A, Kim J, Aplenc R
Source: J Pediatr, 2013 Sep;163(3), p. 699-705.e1.
EPub date: 2013 Mar 8.
Induction mortality and resource utilization in children treated for acute myeloid leukemia at free-standing pediatric hospitals in the United States.
Authors: Kavcic M, Fisher BT, Li Y, Seif AE, Torp K, Walker DM, Huang YS, Lee GE, Tasian SK, Vujkovic M, Bagatell R, Aplenc R
Source: Cancer, 2013 May 15;119(10), p. 1916-23.
EPub date: 2013 Feb 21.
Epidemiology of childhood acute myeloid leukemia.
Authors: Puumala SE, Ross JA, Aplenc R, Spector LG
Source: Pediatr Blood Cancer, 2013 May;60(5), p. 728-33.
EPub date: 2013 Jan 9.
Leveraging administrative data to monitor rituximab use in 2875 patients at 42 freestanding children's hospitals across the United States.
Authors: Kavcic M, Fisher BT, Seif AE, Li Y, Huang YS, Walker D, Aplenc R
Source: J Pediatr, 2013 Jun;162(6), p. 1252-8, 1258.e1.
EPub date: 2012 Dec 24.
Assembly of a cohort of children treated for acute myeloid leukemia at free-standing children's hospitals in the United States using an administrative database.
Authors: Kavcic M, Fisher BT, Torp K, Li Y, Huang YS, Seif AE, Vujkovic M, Aplenc R
Source: Pediatr Blood Cancer, 2013 Mar;60(3), p. 508-11.
EPub date: 2012 Nov 28.
Variation in hospital antibiotic prescribing practices for children with acute lymphoblastic leukemia.
Authors: Fisher BT, Gerber JS, Leckerman KH, Seif AE, Huang YS, Li Y, Harris T, Torp K, Douglas R, Shah A, Walker D, Aplenc R
Source: Leuk Lymphoma, 2013 Aug;54(8), p. 1633-9.
EPub date: 2012 Dec 26.
Dexrazoxane use in pediatric patients with acute lymphoblastic or myeloid leukemia from 1999 and 2009: analysis of a national cohort of patients in the Pediatric Health Information Systems database.
Authors: Walker DM, Fisher BT, Seif AE, Huang YS, Torp K, Li Y, Aplenc R
Source: Pediatr Blood Cancer, 2013 Apr;60(4), p. 616-20.
EPub date: 2012 Sep 4.
Merging of the National Cancer Institute-funded cooperative oncology group data with an administrative data source to develop a more effective platform for clinical trial analysis and comparative effectiveness research: a report from the Children's Oncology Group.
Authors: Aplenc R, Fisher BT, Huang YS, Li Y, Alonzo TA, Gerbing RB, Hall M, Bertoch D, Keren R, Seif AE, Sung L, Adamson PC, Gamis A
Source: Pharmacoepidemiol Drug Saf, 2012 May;21 Suppl 2, p. 37-43.
Establishment of an 11-year cohort of 8733 pediatric patients hospitalized at United States free-standing children's hospitals with de novo acute lymphoblastic leukemia from health care administrative data.
Authors: Fisher BT, Harris T, Torp K, Seif AE, Shah A, Huang YS, Bailey LC, Kersun LS, Reilly AF, Rheingold SR, Walker D, Li Y, Aplenc R
Source: Med Care, 2014 Jan;52(1), p. e1-6.
Risk factors for renal failure in pediatric patients with acute myeloid leukemia: a retrospective cohort study.
Authors: Fisher BT, Zaoutis TE, Leckerman KH, Localio R, Aplenc R
Source: Pediatr Blood Cancer, 2010 Oct;55(4), p. 655-61.