title: Improved outcomes for myeloid leukemia of Down syndrome: a report from the Children's Oncology Group AAML0431 trial.
abstract: Patients with myeloid leukemia of Down syndrome (ML-DS) have favorable event-free survival (EFS), but experience significant treatment-related morbidity and mortality. ML-DS blast cells ex vivo have increased sensitivity to cytarabine (araC) and daunorubicin, suggesting that optimizing drug dosing may improve outcomes while reducing toxicity. The Children's Oncology Group (COG) AAML0431 trial consisted of 4 cycles of induction and 2 cycles of intensification therapy based on the treatment schema of the previous COG A2971 trial with several modifications. High-dose araC (HD-araC) was used in the second induction cycle instead of the intensification cycle, and 1 of 4 daunorubicin-containing induction cycles was eliminated. For 204 eligible patients, 5-year EFS was 89.9% and overall survival (OS) was 93.0%. The 5-year OS for 17 patients with refractory/relapsed leukemia was 34.3%. We determined the clinical significance of minimal residual disease (MRD) levels as measured by flow cytometry on day 28 of induction I. MRD measurements, available for 146 of the 204 patients, were highly predictive of treatment outcome; 5-year disease-free survival for MRD-negative patients (n = 125) was 92.7% vs 76.2% for MRD-positive patients (n = 21) (log-rankP= .011). Our results indicated that earlier use of HD-araC led to better EFS and OS in AAML0431 than in past COG studies. A 25% reduction in the cumulative daunorubicin dose did not impact outcome. MRD, identified as a new prognostic factor for ML-DS patients, can be used for risk stratification in future clinical trials. This trial was registered at www.clinicaltrials.gov as #NCT00369317.
authors.affiliation: Division of Hematology/Oncology, Children's Hospital of Michigan, Wayne State University, Detroit, MI.
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Taub
authors.affiliation: IWK Health Centre, Dalhousie University, Halifax, NS, Canada.
authors.forename: Jason N
authors.initials: JN
authors.lastname: Berman
authors.affiliation: Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.
authors.forename: Johann K
authors.initials: JK
authors.lastname: Hitzler
authors.affiliation: Children's Hospital of San Antonio, Baylor College of Medicine, San Antonio, TX.
authors.forename: April D
authors.initials: AD
authors.lastname: Sorrell
authors.affiliation: Lucile Packard Children's Hospital, Stanford University, Palo Alto, CA.
authors.forename: Norman J
authors.initials: NJ
authors.lastname: Lacayo
authors.affiliation: Vanderbilt-Ingram Cancer Center, Nashville, TN.
authors.forename: Kelley
authors.initials: K
authors.lastname: Mast
authors.affiliation: Vanderbilt-Ingram Cancer Center, Nashville, TN.
authors.forename: David
authors.initials: D
authors.lastname: Head
authors.affiliation: St. Jude Children's Research Hospital, Memphis, TN.
authors.forename: Susana
authors.initials: S
authors.lastname: Raimondi
authors.affiliation: Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, MN.
authors.forename: Betsy
authors.initials: B
authors.lastname: Hirsch
authors.affiliation: Department of Oncology and.|Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI.
authors.forename: Yubin
authors.initials: Y
authors.lastname: Ge
authors.affiliation: Children's Oncology Group, Monrovia, CA.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Gerbing
authors.affiliation: Children's Oncology Group, Monrovia, CA.
authors.forename: Yi-Cheng
authors.initials: YC
authors.lastname: Wang
authors.affiliation: Children's Oncology Group, Monrovia, CA.|Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA.
authors.forename: Todd A
authors.initials: TA
authors.lastname: Alonzo
authors.affiliation: St. Jude Children's Research Hospital, Memphis, TN.|Department of Pediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Dario
authors.initials: D
authors.lastname: Campana
authors.affiliation: St. Jude Children's Research Hospital, Memphis, TN.|Department of Pediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Elaine
authors.initials: E
authors.lastname: Coustan-Smith
authors.affiliation: Department of Pediatrics, University of New Mexico, Albuquerque, NM; and.
authors.forename: Prasad
authors.initials: P
authors.lastname: Mathew
authors.affiliation: Division of Hematology/Oncology, Children's Mercy Hospitals and Clinics, Kansas City, MO.
authors.forename: Alan S
authors.initials: AS
authors.lastname: Gamis
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D002675:Child, Preschool; D003561:Cytarabine / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D020732:Cytogenetic Analysis; D003630:Daunorubicin / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D018572:Disease-Free Survival; D004314:Down Syndrome / Q000150:complications* / Q000235:genetics; D005260:Female; D006801:Humans; D007223:Infant; D015470:Leukemia, Myeloid, Acute / Q000150:complications / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D009190:Myelodysplastic Syndromes / Q000150:complications / Q000188:drug therapy* / Q000235:genetics; D018365:Neoplasm, Residual / Q000175:diagnosis / Q000235:genetics; D016896:Treatment Outcome
chemical_list: D000903:Antibiotics, Antineoplastic; D000964:Antimetabolites, Antineoplastic; D003561:Cytarabine; D003630:Daunorubicin