Abdelrahman H Elsayed1, Xueyuan Cao2, Amit K Mitra3, Huiyun Wu4, Susana Raimondi5, Christopher Cogle6, Zeina Al-Mansour6, Raul C Ribeiro7, Alan Gamis8, Edward Anders Kolb9, Richard Aplenc10, Todd A Alonzo11,12, Soheil Meshinchi13, Jeffrey Rubnitz7, Stanley Pounds4, Jatinder K Lamba1,14,15. 1. Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Gainesville, FL. 2. Department of Acute and Tertiary Care, University of Tennessee Health Science Center, Memphis, TN. 3. Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL. 4. Department of Biostatistics, St Jude Children's Research Hospital, Memphis, TN. 5. Department of Pathology, St Jude Children's Research Hospital, Memphis, TN. 6. College of Medicine, University of Florida, Gainesville, FL. 7. Department of Oncology, St Jude Children's Research Hospital, Memphis, TN. 8. Department of Hematology-Oncology, Children's Mercy Hospitals and Clinics, Kansas City, MO. 9. Nemours Children's Health, Wilmington, DE. 10. Division of Pediatric Oncology/Stem Cell Transplant, Children's Hospital of Philadelphia, Philadelphia, PA. 11. COG Statistics and Data Center, Monrovia, CA. 12. Biostatistics Division, University of Southern California, Los Angeles, CA. 13. Fred Hutchinson Cancer Research Center, Seattle, WA. 14. University of Florida Health Cancer Center, University of Florida, Gainesville, FL. 15. Center for Pharmacogenomics and Precision Medicine, College of Pharmacy, University of Florida, Gainesville, FL.
Abstract
PURPOSE: To establish a patient-specific polygenic score derived from cytarabine (ara-C) pathway pharmacogenomic evaluation to personalize acute myeloid leukemia (AML) treatment. MATERIALS AND METHODS: Single nucleotide polymorphisms (SNPs) in the ara-C-pathway genes were analyzed with outcome in patients from the multicenter-AML02 trial (N = 166). Multi-SNP predictor modeling was used to develop 10-SNP Ara-C_SNP score (ACS10) using top SNPs predictive of minimal residual disease and event-free survival (EFS) from the AML02-cohort and four SNPs previously associated with ara-C triphosphate levels in the AML97 trial. ACS10 was evaluated for association with outcomes in each clinical trial arms: the standard low-dose ara-C (LDAC, n = 91) and augmented high-dose ara-C (HDAC, n = 75) arms of AML02 and the standard Ara-C, daunorubicin and etoposide (ADE) (n = 465) and the augmented ADE + gemtuzumab ozogamicin (GO; n = 466) arms of AAML0531 trial. RESULTS: In the standard LDAC-arm of AML02 cohort, the low-ACS10 score group (≤ 0) had significantly worse EFS (ACS10 low v high hazard ratio [HR] = 2.81; 95% CI, 1.45 to 5.43; P = .002) and overall survival (OS; HR = 2.98; 95% CI, 1.32 to 6.75; P = .009) compared with the high-ACS10 group (score > 0). These results were validated in the standard-ADE arm of AAML0531, with poor outcome in the low-ASC10 group compared with the high-ACS10 group (EFS: HR = 1.35, 95% CI, 1.04 to 1.75, P = .026; OS: HR = 1.64, 95% CI, 1.2 to 2.22, P = .002). Within the augmented arms (AML02-HDAC and AAML0531-ADE + GO), EFS and OS did not differ between low- and high-ACS10 score groups. In both cohorts, patients with low-ACS10 consistently showed a 10-percentage point improvement in 5-year EFS with augmented therapy (AML02-HDAC or AAML0531-ADE + GO arms) than with standard therapy (AML02-LDAC or AAML0531-ADE arms). CONCLUSION: Patients with low-ACS10 score experienced significantly poor outcome when treated on standard regimen. Augmentation with either high-dose ara-C or GO addition improved outcome in low-ACS10 group. A polygenic ACS10 score can identify patients with unfavorable pharmacogenetic characteristics and offers a potential for an elective augmented therapy option.
PURPOSE: To establish a patient-specific polygenic score derived from cytarabine (ara-C) pathway pharmacogenomic evaluation to personalize acute myeloid leukemia (AML) treatment. MATERIALS AND METHODS: Single nucleotide polymorphisms (SNPs) in the ara-C-pathway genes were analyzed with outcome in patients from the multicenter-AML02 trial (N = 166). Multi-SNP predictor modeling was used to develop 10-SNP Ara-C_SNP score (ACS10) using top SNPs predictive of minimal residual disease and event-free survival (EFS) from the AML02-cohort and four SNPs previously associated with ara-C triphosphate levels in the AML97 trial. ACS10 was evaluated for association with outcomes in each clinical trial arms: the standard low-dose ara-C (LDAC, n = 91) and augmented high-dose ara-C (HDAC, n = 75) arms of AML02 and the standard Ara-C, daunorubicin and etoposide (ADE) (n = 465) and the augmented ADE + gemtuzumab ozogamicin (GO; n = 466) arms of AAML0531 trial. RESULTS: In the standard LDAC-arm of AML02 cohort, the low-ACS10 score group (≤ 0) had significantly worse EFS (ACS10 low v high hazard ratio [HR] = 2.81; 95% CI, 1.45 to 5.43; P = .002) and overall survival (OS; HR = 2.98; 95% CI, 1.32 to 6.75; P = .009) compared with the high-ACS10 group (score > 0). These results were validated in the standard-ADE arm of AAML0531, with poor outcome in the low-ASC10 group compared with the high-ACS10 group (EFS: HR = 1.35, 95% CI, 1.04 to 1.75, P = .026; OS: HR = 1.64, 95% CI, 1.2 to 2.22, P = .002). Within the augmented arms (AML02-HDAC and AAML0531-ADE + GO), EFS and OS did not differ between low- and high-ACS10 score groups. In both cohorts, patients with low-ACS10 consistently showed a 10-percentage point improvement in 5-year EFS with augmented therapy (AML02-HDAC or AAML0531-ADE + GO arms) than with standard therapy (AML02-LDAC or AAML0531-ADE arms). CONCLUSION: Patients with low-ACS10 score experienced significantly poor outcome when treated on standard regimen. Augmentation with either high-dose ara-C or GO addition improved outcome in low-ACS10 group. A polygenic ACS10 score can identify patients with unfavorable pharmacogenetic characteristics and offers a potential for an elective augmented therapy option.
Authors: Jeffrey E Rubnitz; Hiroto Inaba; Gary Dahl; Raul C Ribeiro; W Paul Bowman; Jeffrey Taub; Stanley Pounds; Bassem I Razzouk; Norman J Lacayo; Xueyuan Cao; Soheil Meshinchi; Barbara Degar; Gladstone Airewele; Susana C Raimondi; Mihaela Onciu; Elaine Coustan-Smith; James R Downing; Wing Leung; Ching-Hon Pui; Dario Campana Journal: Lancet Oncol Date: 2010-05-05 Impact factor: 41.316
Authors: Amit K Mitra; Kristine R Crews; Stanley Pounds; Xueyuan Cao; Tanya Feldberg; Yogita Ghodke; Varsha Gandhi; William Plunkett; M Eileen Dolan; Christine Hartford; Susana Raimondi; Dario Campana; James Downing; Jeffrey E Rubnitz; Raul C Ribeiro; Jatinder K Lamba Journal: J Pharmacol Exp Ther Date: 2011-06-28 Impact factor: 4.030
Authors: Abdelrahman H Elsayed; Xueyuan Cao; Kristine R Crews; Varsha Gandhi; William Plunkett; Jeffrey E Rubnitz; Raul C Ribeiro; Stanley B Pounds; Jatinder K Lamba Journal: Pharmacogenomics Date: 2018-08-08 Impact factor: 2.533
Authors: J E Rubnitz; K R Crews; S Pounds; S Yang; D Campana; V V Gandhi; S C Raimondi; J R Downing; B I Razzouk; C-H Pui; R C Ribeiro Journal: Leukemia Date: 2009-02-26 Impact factor: 11.528