Therapy reduction in patients with Down syndrome and myeloid leukemia: the international ML-DS 2006 trial
Children with Down syndrome have an increased risk of myeloid leukemia (ML), the majority of which show a megakaryoblastic subtype and may evolve from transient abnormal myelopoeisis. They are associated with mutations in the GATA1 transcription factor. Excellent cure rates have been achieved, felt to be due to enhanced drug sensitivity in the blasts, but treatment-related mortality remains the major cause of death.
Building on a reduced intensity therapy for children with ML and Down syndrome, the treatment in this BFM trial was further intensity-reduced by excluding etoposide from the consolidation phase of therapy (450 mg/m2 cumulative dose rather than 950 mg/m2), decreased intrathecal cytarabine therapy, and the elimination of maintenance chemotherapy. The aim was to reduce treatment-related toxicity while preserving a high EFS.
170 patients were enrolled from 2006 to 2015, and had an excellent outcome with a 5-year OS of 89% and EFS of 87%. This was not significantly different than the historical control. There was no correlation of outcome noted with cytogenetic abnormalities, although poor early response to therapy (by morphologic assessment) and trisomy 8 was associated with worse prognosis. There were less infectious complications observed compared to the historical control, and the overall treatment related mortality was 2.9% compared to 5%.
The authors comment that there is still no clear evidence of the role of high-dose cytarabine and anthracycline dosing in ML in Down syndrome, such that the approach to risk-adapted therapy used here is only one possible option.