A pilot phase I dose finding safety study of the thrombopoietin-receptor agonist, eltrombopag, in patients with myelodysplastic syndrome treated with azacitidine

作者：Svensson Tobias^*; Chowdhury Onima; Garelius Hege; Lorenz Fryderyk; Saft Leonie; Jacobsen Sten Eirik; Hellstrom Lindberg Eva; Cherif Honar

来源：European Journal of Haematology, 2014, 93(5): 439-445.

DOI：10.1111/ejh.12383

• Myelodysplastic syndrome
• azacitidine
• eltrombopag
• thrombocytopenia
• thrombopoietin-receptor

ObjectivesThrombocytopenia is an independent adverse prognostic factor in patients with Myelodysplastic syndromes (MDS). Azacitidine, first-line treatment for the majority of patients with higher-risk MDS, is associated with aggravated thrombocytopenia during the first cycles. Eltrombopag is a novel thrombopoietin receptor agonist, which also has been shown to inhibit proliferation of leukaemia cell lines in vitro. This phase I clinical trial was designed to explore the safety and tolerability of combining eltrombopag with azacitidine in patients with MDS. In addition, we assessed the potential effects of eltrombopag on hematopoietic stem and progenitor cells (HSPCs) from included patients. %26lt;br%26gt;Patients and methodsPreviously untreated patients with MDS eligible for treatment with azacitidine and with a platelet count %26lt;75x10(9)/L were included. Patients received eltrombopag in dose escalation cohorts during three cycles of azacitidine. %26lt;br%26gt;ResultsTwelve patients, with a median age of 74yr, were included. Severe adverse events included infectious complications, deep vein thrombosis and transient ischaemic attack. The maximal tolerated eltrombopag dose was 200mg qd. Complete remission or bone marrow remission was achieved in 4 of 12 patients. Platelet counts improved or remained stable in 9 of 12 patients despite azacitidine treatment. No increase in blast count, disease progression, or bone marrow fibrosis related to study medication was reported. Eltrombopag did not induce cycling of HSPCs. %26lt;br%26gt;ConclusionThe combination of eltrombopag with azacitidine in high-risk MDS patients is feasible and well tolerated. Improvements in platelet counts and the potential antileukaemic effect of eltrombopag should be explored in a randomised study.

• 出版日期2014-11