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 5 125) was 92.7% vs 76.2% for MRD-positive patients (n 5 21) (log-rank P 5 .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. (Blood. 2017;129(25): 3304-3313)
Bibliographical noteFunding Information:
The authors thank Anders Kolb, Holly Pitman, and Vani Shanker for their constructive review of the manuscript. This work was supported by the National Cancer Institute of the National Institutes of Health National Clinical Trials Network (NCTN) Operations Center grant U10CA180886, NCTN Statistics and Data Center U10CA180899, Chair?s grant U10CA098543, Statistics and Data Center grant U10CA098413. The correlative biology studies were supported by grant R01 CA120772. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.