Improved outcomes for myeloid leukemia of Down syndrome: a report from the Children's Oncology Group AAML0431 trial

Improved outcomes for myeloid leukemia of Down syndrome: a report from the Children's Oncology Group AAML0431 trial
Children with Down syndrome have an increased risk of myeloid leukemia (ML), which generally has unique features such as a megakaryoblastic subtype, preceeding transient abnormal myelopoeisis, and association with mutations in the GATA1 transcription factor. Many have a myelodysplastic phase that preceeds the development of AML. Excellent cure rates have been achieved, but excessive deaths have been observed due to infection and cardiac dysfunction.
The Children's Oncology Group study aimed to adapt therapy for Down syndrome ML to capitalize on the sensitive of blasts to cytarabine (ARAC) and daunorubicin with more effective use of high-dose ARAC and reduced daunorubicin dosing. In the treatment protocol, high-dose ARAC was used earlier in the second induction cycle instead of daunorubicin, resulting in a 25% lower cumulative dose. Minimal residual disease (MRD) testing was performed as an optional biology study.
205 children were enrolled, with a 5 year OS of 93% and EFS of 89.9%. Kaplan-Meier curves demonstrated improved outcomes compared to historical controls for all patients, with statistically significant p-values. MRD showed worse outcomes for those patients with increased levels at the end of the first induction cycle. Toxicity was noted to be highest with the high-dose ARAC in Induction block II, accounting for two-thirds of all grade 3 or higher adverse events.
While outcomes were compared to historical controls, there was no corresponding analysis for toxicity. Although the authors speculated as to the impact of myelosuppression related to the high-dose ARAC, it is difficult to conclude whether the toxicity seen is a significant or important change.
Reduction in daunorubicin and changes in the administration of ARAC were associated with improved EFS and OS in patients with Down syndrome and ML. MRD at the end of Induction I was the only significant predictor of outcome.

Please see the other study published on the same topic by Uffmann et al. in the same issue of Blood.