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Thrombopoietin Receptor Agonists as a Novel Treatment for Immune Thrombocytopenia Safety

No serious adverse events were reported during the phase I study in healthy adults. Within the controlled clinical studies, adverse events were mostly mild to moderate.49

The rate of serious adverse

events was similar between the study groups (12% in the placebo group and 11% in the eltrombopag group).

Headache was the most common adverse event in both groups (≥30%). A higher incidence of serum liver test abnormalities, more specifically alanine transferase (ALT) elevations, was reported in the eltrombopag group. Approximately 5% of eltrombopag-treated patients experienced ALT ≥3 times the upper limit of normal compared with 2% of placebo-treated patients.59 Approximately 2% of patients withdrew from the study due to elevations in ALT or bilirubin.

Aggregate results from the placebo-controlled clinical trials reveal that patients in the eltrombopag arm were more likely to experience nausea (6 versus 4%), vomiting (4 versus 3%) and menorrhagia (4 versus 1%).51

Liver toxicities were typically mild, reversible and unaccompanied by clinical symptoms; some patients had more marked elevations and discontinued therapy. For this reason, it is prudent to monitor liver function tests periodically, every four weeks or so, even in patients on long-term eltrombopag.

In the controlled studies, one thrombotic/thromboembolic complication was reported within the groups that received eltrombopag and none within the placebo groups.53

Seven patients experienced

thrombotic/thromboembolic complications in the extension study.60 Data collection across all ITP studies indicate that the frequency of thromboembolic events observed during eltrombopag treatment (3.8%) is similar to that reported in the literature and prior to enrolment in the eltrombopag programme (3.2%).61

Importantly, no correlation has been

observed between platelet count increases or maximum platelet counts and thromboembolic events.

Serious haemorrhages occurred in two patients receiving eltrombopag, one patient receiving placebo and five patients following discontinuation of eltrombopag. Most of these patients had developed rebound worsening of thrombocytopenia (platelet counts <10x109/l) prior to the serious haemorrhagic episode.51

A recent consensus report on the diagnosis and management of ITP is the first official document trying to position these new drugs in therapy.10

However, from

a recent analysis of safety data from the ITP programme 8% of patients treated with eltrombopag (n=20) and 8% of patients treated with placebo (n=10) experienced drops in platelet counts to <10x109/l.62

Eltrombopag and romiplostim are the only drugs for which efficacy has been demonstrated in randomised phase III trials. They are therefore recommended with the strongest level of evidence as medical second-line treatment options for adult ITP patients (as opposed to the surgical option, i.e. splenectomy). They are also recommended as the subsequent line of therapy for adult patients failing first- and second-line therapies.

It is unclear at this time whether these decreases may be related to study medication or may represent normal fluctuations in platelet counts in patients with chronic ITP.

There were no clinical or laboratory symptoms suggestive of bone marrow fibrosis. Adverse reactions reported in the extension study occurred in a pattern similar to those reported in the placebo-controlled studies. There were no significant changes in blood coagulation, platelet aggregation, electrocardiographic findings or preliminary results of ophthalmic examinations in any of the studies.51


Stimulation of platelet production is a new approach to treating patients with chronic ITP, which has traditionally aimed to decrease platelet destruction. The rationale underlying this approach resides in


Apart from their efficacy prior to and after splenectomy, the new thrombopoietic agents are appealing for a number of reasons. These include the fact that:

• • •

they are not blood products, thereby avoiding the potential risk of infectious diseases;

unlike most of the current conventional therapies they are not immunosuppressive; and

they do not have the undesirable and often invalidating long-term side-effects of corticosteroids.

Several other TPO-R agonists are being developed. Ongoing studies will reveal how these agents actually impact the current management of patients with chronic ITP. The results of the studies are expected to lead to an expansion of the armamentarium of drugs available for ITP in the near future and may revolutionise the therapeutic approach to this autoimmune disorder. n


the evidence of both impaired platelet production and low TPO levels. While the inhibitory role of platelet autoantibodies can account for the ineffective megakaryopoiesis, the reason why endogenous TPO levels are below adequate levels in ITP is not yet clear. There is a poor correlation with megakaryocyte mass. Despite this, it was hypothesised that the use of the new thrombopoietic agents could fix the disturbed balance of platelet destruction and platelet production.

The results of randomised clinical trials investigating romiplostim and eltrombopag provide compelling evidence supporting platelet production stimulation in chronic ITP. These novel agents appear to be very effective in a high percentage of refractory adult patients with chronic ITP. The drugs are well tolerated, at least in the first six months of treatment. Due to the efficacy data, both drugs have been approved by the US Food and Drug Administration (FDA) for use in adult patients with chronic ITP, although only available on a restricted programme called Risk Evaluation and Mitigation Strategies (REMS). REMS is the term used to identify drugs or biological products that require additional procedures or documentation to ensure their safe use. The Network of EXperts Understanding and Supporting Nplate and patients (NEXUS) programme for romiplostim and PROMACTA CARES for eltrombopag are multifaceted REMS programmes. They aim to provide comprehensive access, support and education for chronic ITP patients, their caregivers and healthcare providers.

The major concern about the use of these new drugs beyond six months is the lack of long-term safety data. As a matter of fact, the European Medicines Agency has restricted the use of these agents to patients refractory to splenectomy or in those with contraindications to splenectomy.

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