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W. Ghanima et al.
patients experiencing such platelet fluctuations with romi- plostim can be stabilized by switching to eltrombopag.74
Adverse events mainly associated with eltrombopag
Cataract
Treatment-related cataracts were observed in juvenile rodents on eltrombopag and were dose and time depend- ent. Cataracts have been reported with both eltrombopag and romiplostim. Given multiple confounding risk factors, e.g. steroid use, older age, smoking, no clinical study has unequivocally demonstrated this suspected risk with TPO-RA. In a 6-month study, the incidence of cataract in patients treated with eltrombopag was similar to place- bo.25 In the open-label EXTEND study, cataracts devel- oped in 28 patients (9%) in up to eight years of treatment. In 16 (5%), it was considered a severe adverse event, which led to withdrawal of eltrombopag in four (1.3%) patients.24 In the Pediatric Patients with Thrombocytopenia from Idiopathic Thrombocytopenic Purpura (PETIT2) study, two children developed cataracts, raising serious concern.33 The analysis of up to 1000 patients treated with romiplostim for ITP reported 37 events of cataracts, but only one case in patients with placebo or SoC, suggesting cataracts, given the big differ- ence in exposure, might also be associated with romi- plostim.46
An alternative option to routine ophthalmological eval- uation for all patients on eltrombopag is to reserve oph- thalmic examination for patients with one or more risk factors.
Transaminitis
Hepatocyte degeneration, associated with increased serum liver enzymes, was observed in animals at doses that were associated with morbidity and mortality. In humans, development of transaminitis occurs in up to 10%, especially on eltrombopag.22,25 Bilirubin elevations are also possible but involve mainly non-conjugated biliru- bin (not indicative of serious liver injury). Transaminitis is mostly asymptomatic and reversible with dose interrup- tion, reduction or discontinuation; only 3% of children and adults were unable to tolerate eltrombopag in large studies.24,25 Transaminitis occurs more in the first year of treatment, which justifies regular monitoring of liver enzymes at more frequent intervals particularly during the first years.
Adverse events mainly associated with romiplostim
Risk of antibody development
Romiplostim is a chimeric fusion protein produced by genetic engineering. Neutralizing antibodies directed against romiplostim have been reported. In contrast, because small molecules do not typically elicit an immune response, development of neutralizing antibod- ies is not considered to be a risk for eltrombopag. In an analysis of up to 1000 patients treated with romiplostim, neutralizing antibodies to romiplostim were reported in only six patients; importantly, none cross-reacted with endogenous TPO. All had a platelet response, and detec-
tion of neutralizing antibodies did not automatically result in loss of response.66 However, neutralizing anti- bodies were detected in a group of four patients treated with romiplostim who lost response.75 Current estimates, based on very limited data, suggest that these occur at a rate of up to 1%, more frequently in children than adults. Monitoring could be yearly and when response is lost.
Other indications for thrombopoietin receptor agonists
Treatment of severe aplastic anemia (SAA) with eltrom- bopag yielded multilineage clinical responses in certain patients with refractory severe aplastic anemia.11 Consequently, eltrombopag has been approved for use in patients with SAA failing immunosuppression who are not eligible for transplantation. A recent study has shown benefit when eltrombopag was used upfront together with immunosuppression, with more than one-third of the patients achieving a complete response by six months.57
Thrombocytopenia is a common complication of liver disease, and eltrombopag was licensed to support the platelet count in patients with hepatitis C undergoing treatment with interferon and ribavirin. However, improvements in current hepatitis C therapy have meant that interferon is no longer used.76
Studies into the use of TPO-RA in MDS are no longer actively pursued, perhaps not so much because of the risk of induction of leukemia, as because of failure to provide evidence of survival benefit.54,55
The major indication under study is in solid tumor chemotherapy. Studies are now available that demon- strate promising results. Schedule and dosing in solid tumor chemotherapy can be better maintained, but trans- lating this into a survival advantage still has to be clearly demonstrated.77
Treatment of inherited thrombocytopenias with eltrombopag has been studied in MYH9-related disorders and Wiskott-Aldrich syndrome, showing platelet response in both conditions.78-80
Other thrombopoietic agents
Two current studies with avatrombopag and lusutrom- bopag, both of which were recently approved for proce- dures in thrombocytopenic patients with liver disease in the US, were careful to verify adequate pre-procedure por- tal flow and use only several days of TPO-RA prior to and during the procedure to avoid risks of thrombosis, espe- cially that of the portal vein. Avatrombopag, an oral small molecule, apparently binds to the TPO-R similarly to eltrombopag, but does not have any dietary limitations.81 It was shown to be effective in a phase II study of ITP,81 and also in a recently published phase III trial, which con- firmed the superiority of avatrombopag (5-40 mg daily) over placebo with regard to acute and durable platelet response in patients with chronic ITP. Headache was the most frequent side effect.82 In view of the two RCT in ITP and the approved indication in liver disease, we expect that avatrombopag will be licensed for ITP.
A recombinant human thrombopoietin (rhTPO) has been licensed in China for many years in adults and children with ITP. Studies have also recently been performed in pregnant women, all with good results.83,84 One concern is the uncertainty regarding development of antibodies to the TPO agent which, unlike those seen with romiplostim, might cross-react with endogenous TPO and create lasting
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haematologica | 2019; 104(6)