title: Therapy reduction in patients with Down syndrome and myeloid leukemia: the international ML-DS 2006 trial.
abstract: Children with myeloid leukemia associated with Down syndrome (ML-DS) have superior outcome compared with non-DS patients, but suffer from higher constitutional cytotoxic drug susceptibility. We analyzed the outcome of 170 pediatric patients with ML-DS enrolled in the prospective, multicenter, open-label, nonrandomized ML-DS 2006 trial by Nordic Society for Pediatric Hematology and Oncology (NOPHO), Dutch Childhood Oncology Group (DCOG), and Acute Myeloid Leukemia-Berlin-Frankfurt-Münster (AML-BFM) study group. Compared with the historical control arm (reduced-intensity protocol for ML-DS patients from the AML-BFM 98 trial), treatment intensity was reduced by lowering the cumulative dose of etoposide (950 to 450 mg/m2) and intrathecal central nervous system prophylaxis while omitting maintenance therapy. Still, 5-year overall survival (89% ± 3% vs 90% ± 4%;Plog-rank= .64), event-free survival (EFS; 87% ± 3% vs 89% ± 4%;Plog-rank= .71), and cumulative incidence of relapse/nonresponse (CIR/NR; 6% ± 3% vs 6% ± 2%;PGray= .03) did not significantly differ between the ML-DS 2006 trial and the historical control arm. Poor early treatment response (5-year EFS, 58% ± 16% vs 88% ± 3%;Plog rank= .0008) and gain of chromosome 8 (CIR/NR, 16% ± 7% vs 3% ± 2%,PGray= .02; 5-year EFS, 73% ± 8% vs 91% ± 4%,Plog rank= .018) were identified as independent prognostic factors predicting a worse EFS. Five of 7 relapsed patients (71%) with cytogenetic data had trisomy 8. Our study reveals prognostic markers for children with ML-DS and illustrates that reducing therapy did not impair excellent outcome. The trial was registered at EudraCT as #2007-006219-2.
authors.affiliation: Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.
authors.forename: Madita
authors.initials: M
authors.lastname: Uffmann
authors.affiliation: Pediatric Hematology and Oncology, Pediatrics III, Essen University Hospital, Essen, Germany.
authors.forename: Mareike
authors.initials: M
authors.lastname: Rasche
authors.affiliation: Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Zimmermann
authors.affiliation: Pediatric Hematology and Oncology, Pediatrics III, Essen University Hospital, Essen, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: von Neuhoff
authors.affiliation: Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.
authors.forename: Ursula
authors.initials: U
authors.lastname: Creutzig
authors.affiliation: Department of Pediatrics, St. Anna Children's Hospital/Children's Cancer Research Institute, Medical University of Vienna, Vienna, Austria.
authors.forename: Michael
authors.initials: M
authors.lastname: Dworzak
authors.affiliation: Dutch Childhood Oncology Group, The Hague, The Netherlands.
authors.forename: Lenie
authors.initials: L
authors.lastname: Scheffers
authors.affiliation: Department of Pediatrics, Aarhus University Hospital, Skejby, Denmark; and.
authors.forename: Henrik
authors.initials: H
authors.lastname: Hasle
authors.affiliation: Dutch Childhood Oncology Group, The Hague, The Netherlands.|Department of Pediatric Oncology/Hematology, Erasmus Medical Center/Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: C Michel
authors.initials: CM
authors.lastname: Zwaan
authors.affiliation: Pediatric Hematology and Oncology, Pediatrics III, Essen University Hospital, Essen, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Reinhardt
authors.affiliation: Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.
authors.forename: Jan-Henning
authors.identifier: 0000-0002-1070-0727
authors.initials: JH
authors.lastname: Klusmann
mesh_terms: D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D002675:Child, Preschool; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics; D003561:Cytarabine / Q000009:adverse effects / Q000627:therapeutic use; D020732:Cytogenetic Analysis; D018572:Disease-Free Survival; D004314:Down Syndrome / Q000150:complications* / Q000235:genetics; D005047:Etoposide / Q000009:adverse effects / Q000627:therapeutic use; D005260:Female; D006801:Humans; D015255:Idarubicin / Q000009:adverse effects / Q000627:therapeutic use; D007223:Infant; D007951:Leukemia, Myeloid / Q000150:complications* / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D011446:Prospective Studies; D016896:Treatment Outcome; D014314:Trisomy / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D003561:Cytarabine; D005047:Etoposide; D015255:Idarubicin