Low-dose cytarabine treatment in children with down syndrome and transient myeloproliferative disorder to prevent ML-DS: AML-BFM TMD prevention 2007 study

Background: Approximately 10% of the children with Down syndrome are diagnosed with transient myeloproliferative disorder (TMD) within the first days of life. Previous studies have shown that TMD patients face an around 20% risk of early death and a 20% to 30% risk to develop myeloid leukemia during the first 4 years of life (ML-DS). Aims: The aim of the AML-BFM TMD Prevention 2007 trial was to analyze the outcome of patients diagnosed with TMD and to evaluate whether the application of a low-dose cytarabin treatment can prevent the progression to ML-DS. Methods: The AML-BFM TMD Prevention 2007 trial is a multi-center, non-randomized, historically controlled study. Patients with TMD were prospectively enrolled. They received a low-dose cytarabin treatment (1.5 mg/kg i.v./s.c. daily) for one week respectively if they met the following criteria: TMD-related symptoms (e.g. hyperleucocytosis, hepatopathy) at diagnosis, MRD-positivity (FACS≥10-3 or qPCR≥10-4) eight weeks after diagnosis. Patients could receive cytarabintreatment up to three weeks in case of failure to respond to the cytarabin-treatment (morphologic detection of blasts between week four and eight after diagnosis and/or MRD-positivity after treatment in week ten after diagnosis). Results: Here we report a cohort of 108 patients (male: 60, female:48) diagnosed with TMD. The median age at diagnosis was 4 days. As common in children with Down syndrome, many of the patients presented with comorbidities (cardiac defects: 68%, other malformations: 15%); 36% were delivered preterm. 45 patients received low-dose cytarabin treatment, 57 patients did not receive this treatment. Overall, patients in this trial do not show a significantly better event-free survival (EFS; 72±4% vs 63±4%, p=0.15) and overall survival (OS; 91±3% vs 85±3%, p=0.15) than the historic control group (n=146). The cumulative incidence (CI) of death was lower, (8±3% vs 15±3%) albeit not significantly (p=0.09). The CI of ML-DS was also similar (19±4% vs 22±4%, p=0.88). Patients that presented with TMD-related clinical symptoms (n=43; symptoms: hyperleucocytosis [WBC>100, 000], hepatopathy, ascites, hydrops fetalis) had a tendency for a better EFS (59±8% vs 44±8%, p=0.097), OS (80±6% vs 67±7% p=0.10) and CI of death (20±7% vs 33±7%, p=0.10) than patients with those symptoms in the historic control group (n=45). For the progression to ML-DS there is no significant difference between the two groups (21±7% vs 23%±7%, p=0.91). For patients that do not show any of the TMD-related symptoms (n=59), no significant differences were observed regarding EFS (81±5% vs 71±5%, p=0.27), OS (98% vs 93±3%, p=0.16) and CI of ML-DS (19±6% vs 22±4%, p=0.95) compared to patients without these symptoms in the historic control (n=101). Summary/Conclusions: The consequent treatment with low-dose cytarabine of symptomatic patients results in a trend towards reduced CI of death as compared to the historic control. However, progression to ML-DS remained unchanged suggesting that the treatment with low-dose chemotherapy does not seem to prevent the development of subsequent leukemia in TMD-patients. Therefore, a general preventive chemotherapeutic treatment of children diagnosed with TMD cannot be recommended. However, children with TMD-related symptoms should receive low-dose cytarabine to reduce disease-related mortality.