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


METHODS
Previously untreated patients with MDS eligible for treatment with azacitidine and with a platelet count <75 × 10(9) /L were included. Patients received eltrombopag in dose escalation cohorts during three cycles of azacitidine.


RESULTS
Twelve patients, with a median age of 74 yr, were included. Severe adverse events included infectious complications, deep vein thrombosis and transient ischaemic attack. The maximal tolerated eltrombopag dose was 200 mg 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.


CONCLUSIONS
The 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.
Department of Medical Sciences, Section of Hematology, Uppsala University Hospital, Uppsala, Sweden.
Tobias
T
Svensson
Onima
O
Chowdhury
Hege
H
Garelius
Fryderyk
F
Lorenz
Leonie
L
Saft
Sten-Eirik
SE
Jacobsen
Eva
E
Hellström-Lindberg
Honar
H
Cherif
D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D001374:Azacitidine / Q000008:administration & dosage* / Q000009:adverse effects; D001565:Benzoates / Q000008:administration & dosage* / Q000009:adverse effects; D001792:Blood Platelets / Q000187:drug effects / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D006412:Hematopoietic Stem Cells / Q000187:drug effects; D006801:Humans; D006834:Hydrazines / Q000008:administration & dosage* / Q000009:adverse effects; D002546:Ischemic Attack, Transient / Q000209:etiology / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010865:Pilot Projects; D010976:Platelet Count; D011720:Pyrazoles / Q000008:administration & dosage* / Q000009:adverse effects; D053628:Receptors, Thrombopoietin / Q000819:agonists / Q000378:metabolism; D012074:Remission Induction; D013921:Thrombocytopenia / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016896:Treatment Outcome; D020246:Venous Thrombosis / Q000209:etiology / Q000473:pathology
D000970:Antineoplastic Agents; D001565:Benzoates; D006834:Hydrazines; D011720:Pyrazoles; D053628:Receptors, Thrombopoietin; D001374:Azacitidine; C520809:eltrombopag
Myelodysplastic syndrome; azacitidine; eltrombopag; thrombocytopenia; thrombopoietin-receptor