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.