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.