DISCUSSION
Extreme leukocytosis and peripheral blasts at the time of birth is generally concerning for either congenital acute leukemia or TMD. Congenital leukemia is an aggressive disease in which the bone marrow of an infant is overwhelmed and will typically present with leukocytosis and other cytopenia, this diagnosis is often fatal. In both of our cases, the infants had appropriate platelet and hemoglobin, making congenital leukemia less likely.
The diagnosis of TMD is based on the finding of blasts in the peripheral blood and/or organs of newborns with down syndrome or trisomy 21 mosaicism. Confirmation with a second blood sample or >5% blasts in the bone marrow is required. TMD commonly presents with hepatomegaly, splenomegaly, lymphadenopathy, or pericardial/pleural effusion 1,2. The incidence of TMD for neonates with trisomy 21 has mostly been reported as about 10%1,3-5. There are reports of intrauterine hepatomegaly noted on ultrasound, as with patient 1, indicating prenatal origin of the disease6,7.
TMD is associated with an acquired truncating GATA1 mutation, which results in the formation of blasts from the megakaryocyte lineage which will over-populate organs that produce fetal blood, namely the liver resulting in hepatomegaly 3,8,9. The majority of patients who develop TMD go on to achieve spontaneous resolution of blasts by 3 months of age. TMD can by complicated by liver failure, DIC, severe direct hyperbilirubinemia and, occasionally renal and cardiac failure3. One of the significant clinical concerns is potential for development of severe hepatic fibrosis, due to accumulation of peripheral myeloblasts in the liver. Patients with TMD need to be closely monitored as 20-30% of the cases can evolve into acute myeloid leukemia (AML) typically within the first five years of life1,3,4,10.
The mortality rate for those diagnosed with TMD is 10-20% so close monitoring is warranted and treatment with chemotherapy is occasionally required 1,3. Chemotherapy is indicated in the presence of a WBC count > 100×103/μL (100 ×109/L), liver failure with hepatomegaly, bleeding complications, or pleural/pericardial effusions not better explained by another disease process3.
Low dose cytarabine is an accepted treatment for TMD meeting the above criteria. Gamis et al. had attempted to treat TMD with a continuous cytarabine infusion of 3.33mg/kg/24hours for 5 days11. Since that time a cytarabine dosing schedules of 1.2-1.5 mg/kg per dose twice a day for 3-12 days has been reported2,10,12. The nuances of choosing the actual dose and duration of treatment are left to the treating physician’s discretion10,13,14.
Due to the significant leukocytosis and hepatomegaly in both of the presented cases, the decision was made to treat with low dose cytarabine. Patient 1 received 5 days of treatment and patient 2 received 4 days of cytarabine 1.5 mg/kg/dose BID. The decision to stop treatment was made based on down trending of peripheral blasts and WBC less than 100×103/μL (100 ×109/L). Even though peripheral blasts were still present in patient 2, cytarabine was discontinued due to myelosuppression, requiring transfusion support and with the knowledge of the continued effect of immunosuppression. Both patients had resolution of peripheral blasts prior to DOL 30.
Clinically, patient 2 had resolution of hepatomegaly and splenomegaly as well as decreased bilirubin while on Ursodiol. The patient was discharged at 1 month of age with no notable complications from treatment or TMD and he will be monitored closely for potential development of AML.
The severity of prenatal manifestations of hepatomegaly for patient 1 might indicate increased severity of TMD and despite timely interventions after birth complications from TMD and hepatic fibrosis is likely what resulted in the patient’s death.
Early recognition of TMD allows for early consultation with pediatric hematology-oncology for management. While observation is appropriate for most patients with TMD, both of these infants met criteria for treatment with cytarabine. TMD is treated with a range of cytarabine dosing, and dosing at the upper limit of the reported range of doses was decided on in attempts to aggressively treat the patients. Duration of chemotherapy was decided on to best balance toxicity and benefit. Physicians should screen for TMD in patients with trisomy 21 by obtaining a CBC with differential soon after birth.15 Early recognition is important so that associated complications can be monitored allowing for treatment to be initiated when indicated.