Low-Dose Cytosine Arabinoside Therapy for Neonates with Down Syndrome (DS) and Transient Leukemia (TL).

Transient leukemia (TL), which is also referred to as transient myeloproliferative disorder or transient abnormal myelopoiesis, occurs in approximately 10% of infants with Down syndrome (DS). This disorder is characterized by the appearance of blast cells with megakaryoblastic and/or erythroblastic characteristics in the peripheral blood. While most TL patients have a favorable clinical course and the blast cells disappear spontaneously, vital organ failure and early death occurs in some patients. In this group of patients, liver failure with hepatic fibrosis and cardiopulmonary failure are the major causes of death. Recently, low-dose cytosine arabinoside (Ara-C) therapy has been reported to be effective for improving the clinical outcome in TL patients with severe liver or cardiopulmonary disease. However, because the disease resolves spontaneously in most instances, it is not generally recommended that all patients receive antileukemic therapy. It is unknown whether the survival rate of certain TL patients could be improved by low-dose Ara-C. This study was conducted to clarify the safety and efficacy of low-dose Ara-C therapy for TL patients with DS.

A retrospective questionnaire survey of patients diagnosed with DS between 2003 and 2009 was conducted to identify all DS neonates with TL. The eligibility criteria for the analysis were infants with DS who were younger than 3 months and had circulating blast cells in the peripheral blood. A total of 153 patients (81 male, 72 female) were identified.

Thirty-four of the 153 patients (22%) died. Early death occurred in 31 of 153 patients (20%); the median age at death was 47 days (range, 9–241 days). The covariates that were significantly correlated with early death were examined further. On univariate analysis, the following covariates were identified: early estimated gestational age, WBC ≥ 100 × 10⁹/L, severe bleeding, and anasarca. On multivariate analysis, it was confirmed that WBC ≥ 100 × 10⁹/L and anasarca were independent risk factors for early death. Twenty of the 121 patients (16.5%) who survived for more than 9 months after birth subsequently developed acute myeloid leukemia at a median age of 16 months (range, 3–45 months). All 21 patients were diagnosed as having acute megakaryoblastic leukemia (AMKL) and received low intensity chemotherapy specific for AMKL in DS patients. Eighteen of 21 (86%) patients achieved a complete remission, and they are alive and well; whereas 3 patients who had refractory or relapsed leukemia died.

Twenty-eight of the 153 patients (18%) received low-dose Ara-C therapy. The median dose and duration of Ara-C were 0.95 mg/kg/day (range, 0.4–3.1 mg/kg/day) and 7 days (range, 2–15 days), respectively. The median duration of neutropenia (<0.5 × 10⁹/L) was 0 days (range, 0–14 days). All patients recovered from myelosuppression and safely accomplished the treatment, except in 1 patient who had received 11 days of Ara-C treatment and died of prolonged neutropenia-induced sepsis. Sixteen of 28 (57%) patients were started to receive Ara-C within 10 days after diagnosis, whereas 12 patients received Ara-C later.

While the median WBC count of early treated patients was significantly higher than that of other patients (133.5 × 10⁹/L; range, 16.0–356.9 □L 10⁹/L vs 31.9 × 10⁹/L; range, 4.4–341.5 × 10⁹/L.; p < 0.001), the probability of 1-year overall survival of patients who received low-dose Ara-C within 10 days after the initial diagnosis of TL was similar to that of patients who received Ara-C later or who did not receive Ara-C (69.4 ± 12.9%; n = 16 vs. 79.7 ± 3.5%; n = 137; p = 0.614). By subgroup analysis of patients with WBC ≥ 100 × 10⁹/L, the probability of 1-year overall survival of patients who received early Ara-C treatment was significantly higher than that of others (66.1 ± 13.9%; n = 13 vs. 33.3 ± 8.6%; n = 30; p = 0.035).

In summary, we found that low-dose Ara-C therapy for patients with TL and DS has a tolerable toxicity profile, and early intervention with this therapy could improve the clinical outcome of patients whose WBC count exceeds 100 × 10⁹/L. We plan to confirm the efficacy of low dose Ara-C treatment in a prospective clinical trial for high-risk patients with DS and TL.

No relevant conflicts of interest to declare.