Therapy reduction in patients with Down Syndrome Myeloid Leukemia: The international ML-DS 2006 trial

Madita Uffmann, Mareike Rasche, Martin Zimmermann, Christine von Neuhoff, Ursula Creutzig, Michael Dworzak, Lenie Scheffers, Henrik Hasle, C. Michel Zwaan, Dirk Reinhardt and Jan-Henning Klusmann

Key points

  • Reducing therapy intensity in the ML-DS 2006 trial did not impair the excellent prognosis in ML-DS compared to the historical control

  • Early treatment response and gain of chromosome 8 are independent prognostic factors


Children with Down syndrome and myeloid leukemia (ML-DS) have a superior outcome compared to non-DS patients, but suffer from higher constitutional susceptibility to cytotoxic drugs. We analyzed the outcome of 170 pediatric patients with ML-DS enrolled in the prospective, multi-center, open-label, non-randomized ML-DS 2006 trial, by the NOPHO, DCOG and AML-BFM study groups. In comparison to 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 mg/m2 to 450 mg/m2) and intrathecal CNS-prophylaxis while omitting maintenance therapy. Still, 5-year overall survival (5yr-OS; 89±;3% vs. 90±;4%, Plog-rank=0.64), event-free survival (5yr-EFS; 87±;3% vs. 89±;4%, Plog-rank=0.71) and cumulative incidence of relapse/non-response (CIR; 6±;3% vs. 6±;2%, PGray=0.03) did not significantly differ between the ML-DS 2006 trial and the historical control arm. Poor early treatment response (5yr-EFS 58±;16% vs. 88±;3% Plog rank=0.0008) and gain of chromosome 8 (CIR 16±;7% vs 3±;2%, PGray=0.02; 5yr-EFS 73±;8% vs 91±;4%, Plog rank=0.018) were identified as independent prognostic factors predicting a worse EFS. Five out of seven relapsed patients (71%) with cytogenetic data had trisomy 8. Thus, our study reveals prognostic markers for children with ML-DS and illustrates that reducing therapy did not impair the excellent outcome. The trial was registered at EudraCT as #2007-006219-2.

  • Submitted January 27, 2017.
  • Accepted March 29, 2017.