Case 2
A 5-month-old boy was admitted to our hospital following the abrupt
onset of diffuse cutaneous petechiae, conjunctival hemorrhage and
epistaxis (B.A.b.s. 3). Blood exams showed thrombocytopenia (platelet
count 3.000/microL). The baby was promptly started on IVIg (800
mg/Kg/dose for two consequent days) without success (platelet count
15.000/microL).
Bone marrow examination was performed confirming a diagnosis of ITP and
steroids were started (Prednisone 2 mg/kg/die for two weeks followed by
three consecutive days of Methylprednisolone at 30 mg/Kg/dose) without
success (platelet count 5.000 micro/L) and persistent symptoms. Since no
clinical response was obtained, we suggested an off-label use of
Eltrombopag. The parents’ consent was obtained.
Clinical response was observed after one month of treatment (B.A.b.s.
0-1) and, five weeks later, platelet count started to rise (platelet
count 127.000/microL) just a few days before hitting three-months from
the onset.
After five weeks from platelet count normalization Eltrombopag was
tapered down to 0.7 mg/kg/die; the following month the dose was further
reduced and finally, one month later, Eltrombopag was suspended.
The patient is currently at 9 months of follow-up from ITP onset and
with a normal platelet count (367.000/microL) (Figure 2).
DiscussionITP rarely presents in infants and, to the best of our knowledge, these
are the first two reported cases of children younger than 1-year
successfully treated with Eltrombopag. According to ASH guidelines, the
treatment of choice in patients with ITP requiring medical intervention
is IVIg [5][10] . Compared to steroids, IVIg elicit a faster
response [11] but neither of them guarantee a long term
remission[6]. In the reported cases IVIg was the first-line
treatment; having obtained no response, both children were started on a
course of steroids, also without success.
Steroids are well known to have significant side effects including
growth impairment, weight gain, mood disturbances, osteopenia, and other
metabolic effects [6]. Considering the very young age of our
patients, these side effects were even more concerning [12]. In
consideration of the extremely low platelet count, the persistence of
symptoms and the significant impact on the QoL of these patients we
started both infants on Eltrombopag.
The efficacy of Eltrombopag has been studied in two large pediatric
randomized clinical trials, PETIT and PETIT2, and in a longitudinal
observational study, ICON1[12]. None of these studies included
children younger than 1 year of age.
The adverse events related to Eltrombopag mainly consist in reversible
hepatotoxicity and iron deficiency anemia (due to the iron-chelating
effect of Eltrombopag)[12].
It has also been speculated that, following the possible thrombocytosis,
thromboembolic events may occur but there is currently no evidence
suggesting that these are related to TPO-ARs. Similarly, increase in
bone marrow reticuline and bone marrow fibrosis are theoretical - though
unproven - risks of Eltrombopag treatment. Conversely, rebound
thrombocytopenia is a known risk of abrupt TPO-RAs discontinuation [6,
13]. However, because of the recent wide use of this molecule,
possible long-term effects of TPO-RAs could be still unknown, and this
is particularly concerning when treating very young children.
Both children had already failed two treatment lines, showed
persistently low platelet count, along with bleeding symptoms. According
to the approved guidelines for management, the patients would have
remained off-therapy for months, during this period their motor skills
development (such as crawling and walking) would have increased the risk
of trauma and bleeding. These factors made it also particularly
difficult to discharge them home, with a severe impact on their families
QoL.
The low risk of significant side effects of Eltrombopag made the
decision easier to take; we carefully monitored the liver function,
hemoglobin and the iron levels for both infants and no abnormalities
were detected.
Currently, Eltrombopag is only available in tablets hence administering
a fractioned dose can be challenging in infants; in this context, it is
advisable to consider the weekly dosage over the daily one. Also, a more
practical formulation in oral solution might be useful. Eltrombopag also
needs not to be administered with milk and dairy products[6], making
it challenging to find the right time of administration in infants. In
conclusion, we report two cases of children younger than 1 year with
acute and persistent ITP successfully and safely treated with
Eltrombopag.
We believe further evidence is needed to define optimal dosage and drug
administration in infants along with its long-term safety.