Myeloid Leukemia Associated with Down Syndrome

leukaemogenesis, presumably from a subclone of persisting TMD cells that acquire a selective advantage. This hypothesis can be verified by monitoring minimal residual disease, either by immunophenotype or quantitative GATA1[23] polymerase chain reaction.


Introduction
Children with Down syndrome (DS) have a 10-to 20-fold increased risk of developing acute leukemia. [1][2][3][4] The relative risk of developing acute megakaryoblastic leukemia (AMKL) is estimated to be 500 times higher in children with DS than in those without DS. Interestingly, five to 10 % of neonates with DS develop transient abnormal myelopoiesis (TAM). In most cases, it resolves spontaneously within 3 months. However, approximately 15% of the severe cases are fatal and 20% of patients develop AMKL until 3 year-old ( Fig.1). AMKL in DS has a number of distinct features and it is now considered a specific subtype of acute myeloid leukemia (AML) in the 4 th edition of the World Health Organization (WHO) classification called Myeloid Leukemia of Down syndrome (ML-DS).

Treatment for AML-DS
Conventional treatment of AML-DS has been associated with excessive treatment-related mortality (TRM), cardiac toxicity due to anthracyclines and serious infections. Zwaan et al demonstrated a 12-fold increase in sensitivity to cytarabine in DS-AML cells compared with non-DS AML cells, as well as increased sensitivity to anthracyclines (two-to seven-fold) and etoposide (20-fold). [11] Several collaborative study groups have adapted their standard AML protocol for AML-DS by reducing the dose of drugs (Table 1). [5,8,[12][13][14][15][16][17] In the Children's Oncology Group (COG) trial A2971 (n=132), [13] etoposide, dexamethasone, and the maintenance course were eliminated from the previous CCG2891 protocol. COG A2971 achieved a 5-year EFS rate of 79% plus or minus 7% (versus 77% plus or minus 7% in the CCG2891 trial) while maintaining a low induction failure rate of 6.4%, attaining a 0% CNS relapse rate, and sustaining an acceptably low 5-year postremission. In the AML-BFM98 study (n=66), [7] AML-DS patients were treated with reduced doses of anthracyclines and cytarabine compared with the previous AMLBFM93 protocol (n = 44). The cumulative doses of anthracyclines and cytarabine were 220 to 240mg/m2 and 23 to 29g/m2 in the BFM98 study, and 440mg/m2 and

Transient Abnormal Myelopoiesis (TAM)
Transient abnormal myelopoiesis (TAM), also known as transient leukemia (TL) or transient myeloproliferative disorder (TMD) occurs in approximately 10% of infants with DS. [1,4] TAM was considered to be ''self-limiting''; the prognosis of TAM was favorable, except for the risk of the subsequent development of acute leukemia. Most of newborns are asymptomatic and only present with circulating blast cells, with or without leucocytosis. Other clinical features include hepatomegaly, splenomegaly, serous effusions and, in up to 10% of patients, liver fibrosis due to blast cell infiltration that can rarely cause fulminant liver failure. Leucocytosis and thrombocytopenia are common. About a quarter of patients have abnormal liver transaminases and abnormal laboratory coagulation tests. The blast cells in TAM usually have the 'blebby' appearance characteristic of megakaryoblasts and typically express CD41, CD42b.
Most neonates with TAM do not need chemotherapy as the clinical and laboratory abnormalities spontaneously resolve within 3-6 months after birth. However, symptomatic babies with TAM, especially those with high blast counts or liver dysfunction, may benefit from low-dose cytarabine.
In 2006, Children's Oncology Group (COG) reported a prospective study of the natural history of 48 children with DS and TAM. [18] Early death occurred in 17% of infants and was significantly correlated with higher WBC count at diagnosis, increased bilirubin and liver enzymes, and failure to normalize the blood count. Recurrence of leukemia occurred in 19% of infants at a mean of 20 months. In the AML-BFM study, 22 children among total 146 children (15%) died within the first 6 months. The 5-year OS and EFS were 85% plus or minus 3% and 63% plus or minus 4%, respectively. [19]A total of 28 children received a short course of cytarabine treatment. Interestingly, EFS and OS did not differ significantly in the treated versus the untreated group. Among the 124 children who survived the first 6 months of life, 29 (23.4%) subsequently developed ML-DS. The 5-year EFS after diagnosis of ML-DS for all 29 patients was 91% plus or minus 5%, which is significantly higher than the 5-year EFS of those of ML-DS patients without documented TAM (70% plus or minus 4%). According to the retrospective study from Japan, estimated gestational age (EGA), higher WBC counts and higher direct bilirubin levels were significant predictive factors for poor prognosis. [20,21] Muramatsu et al devised a simple risk stratification system based on the EGA and the peak WBC count. The high-risk group (HR) was defined as preterm infants with WBC >100 x 10 9 /l, the intermediaterisk group (IR) was defined as preterm infants with WBC <100 x 10 9 /l and term infants with WBC >100 x 10 9 /l, and the low-risk group (LR) was defined as term infants with WBC< 100 x 10 9 /l. In the LR group, only three of 39 patients (7.7 %) died early. Based on their data, patients in the LR group should receive no interventions. However, since the probability of early death in patients in the HR group exceeded 50%, active intervention including low dose cytarabine should be tried in the context of a clinical trial for these patients.

Treatment for TAM
In patients with a severe form of TAM, the main causes of death in early life are progressive hepatic fibrosis, cardiopulmonary failure, and disseminated intravascular coagulation. These complications may be caused by blast cell infiltration into visceral organs. In the Pediatric Oncology Group (POG) study 9481, 10 mg/m2 per dose or 1.2-1.5 mg/kg per dose was given subcutaneously or intravenously by slow injection twice a day for 7 days (Table 2). [18] In the AML-BFM study, 0.5-1.5 mg/kg was administered for 3-12 days. [19] As TAM blasts are highly sensitive to cytarabine, there is generally a rapid response, characterized by the disappearance of peripheral blasts by day 7 of treatment.  Although TAM resolves in the majority of DS infants, 20-30% subsequently develop ML-DS, usually within in the first 4 years of life. [18][19][20][21][22] In the COG study 2971, twenty-one patients among total 135 TAM patients (16%) developed ML-DS, including 3 received cytarabine. [20] The development of AMKL after remission of TAM has been interested as a model of myeloid leukaemogenesis, presumably from a subclone of persisting TMD cells that acquire a selective advantage. This hypothesis can be verified by monitoring minimal residual disease, either by immunophenotype or quantitative GATA1 [23] polymerase chain reaction.