Immune checkpoint inhibitors (ICIs) have shown antitumor activity against a wide variety of malignancies. The anti-PD antibody pembrolizumab has become a standard treatment for PD-L1-positive nonsmall cell lung cancer (NSCLC) patients. ICIs have hematological side effects called hematological immune-related adverse events (hemirAEs), and ICI-induced immune-related thrombocytopenia is one of them. Several reports have described the clinical course and management of ICI-induced immune-related thrombocytopenia in melanoma patients and NSCLC patients, but there has been little evidence regarding refractory ICI-induced immune-related thrombocytopenia after initial treatment, for example, with a steroid and rituximab. Munehiro Ito and colleagues[1] report the case of a patient with advanced NSCLC complicated by pembrolizumab-induced refractory immune-related thrombocytopenia who showed remarkable improvement in the thrombocytopenia in response to eltrombopag olamine treatment.

Figure 1. Mechanism of Eltrombopag Olamine.[2]

Immune thrombocytopenia

Immune thrombocytopenia (ITP), formerly known as idiopathic thrombocytopenic purpura until the Vicenza Consensus Conference, is an autoimmune disorder characterized by an abnormally low number of circulating platelets, <100 × 103/μl, which promotes purpura, petechiae and bleeding episodes, whose seriousness depends on the location. The most severe manifestation is intracranial hemorrhage, whose frequency is estimated to be ~1.4% in adults and 0.4% in children, and occurs specially when the platelet count drops below 10 × 103/μl. The incidence of primary ITP in adults is 3.3/100,000/year. ITP incidence is multimodal and exhibits three peaks in children, young adults, women aged 30–40 years, and the elderly. 

Mechanism

Eltrombopag is a synthetic biphenyl hydrazone, nonpeptide, low molecular weight TPO-RA, which is presented as eltrombopag olamine [3′?-{(2Z)-2-[1(3,4-dimethylphenyl)-3-methyl-5-oxo-1,5-dihydro-4H-pyrazol-4-ylidene]hydrazino}-2′?-hydroxy-3-biphenylcarboxylic acid-2-aminoethanol (1:2); molecular weight: 564.65]. Unlike native TPO, which binds to the extracellular domain of TPO-R, eltrombopag interacts with the transmembrane domain of the latter. As a consequence, the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway stimulates megakaryocytopoiesis, while autoantibody generation is not detected. Furthermore, eltrombopag does not influence agonist-induced platelet aggregation or activation, and its oral bioavailability is excellent; circulating peaks are documented at 2–6 h after oral administration. Metabolism takes place in the liver via cytochrome P450 isoenzymes CYP1A, CYP2C8, and uridine diphosphate glucuronosyltransferase, and the half-life is in the range of 21–32 h.

Efficacy and safety

Three experiences with eltrombopag in daily clinical practice in the context of chronic ITP in refractory patients support the notion that this treatment may be effective and well tolerated in the long term. Although not frequent, thrombotic events are AEs whose consequences might be potentially serious. This means that the decision about treatment in patients with thrombosis risk factors should include careful consideration of whether or not the expected benefits outweigh the odds of thromboembolism.[2]

References

[1] Munehiro Ito . “Eltrombopag olamine for refractory immune-related thrombocytopenia induced by pembrolizumab in a non-small cell lung cancer patient.” Lung Cancer 146 (2020): Pages 362-365.

[2] Taylor Olmsted Kim;Michele P Lambert,;Jenny Despotovic. “Eltrombopag for use in children with immune thrombocytopenia.” Blood advances 2 4 (2018): 454–461.

[3] Jose Ramon Gonzalez-Porras, &nbsp;Jose Maria Bastida. “Eltrombopag in immune thrombocytopenia: efficacy review and update on drug safety.” Therapeutic Advances in Drug Safety 9 6 (2018): 263–285.