A Phase I Clinical Trial Using Eltrombopag in Patients with Acute Myelogenous Leukemia
Authors: Frey Noelle V. , Hexner Elizabeth O. , Porter David L , Mangan James K. , Loren Alison W. , Hatem Joseph , Bagg Adam , Perl Alexander E , Tsai Donald E , DiNardo Courtney D. , Heitjian Daniel , Luger Selina M. , Carroll Martin 
Published: October 2019

Abstract
Abstract 3576
Eltrombopag, a non-peptide, small molecule, thrombopoietin receptor agonist, has been shown to increase platelet counts in patients with idiopathic thrombocytopenic purpura (ITP), hepatitis C associated thrombocytopenia and severe aplastic anemia. Pre-clinical studies show that eltrombopag stimulates megakaryopoiesis in bone marrow samples from patients with acute myelogenous leukemia (AML) and inhibits leukemic cell growth. The clinical use of eltrombopag in the AML patient population has not been previously explored. We report the results of an investigator-initiated, phase I dose escalation clinical trial to evaluate the safety and efficacy of eltrombopag monotherapy in older patients with AML.
Eligible patients were ≥ 60 years old with non-M3 AML and a baseline platelet count ≤75,000/ul. A standard 3+3 design was used employing dose escalation in 4 sequential cohorts of 50mg, 100mg, 200mg and 300mg of eltrombopag daily. Subjects who did not complete at least one cycle of therapy (4 weeks) or experience a dose-limiting toxicity (DLT) were replaced. The primary endpoint was safety. Secondary endpoints included platelet and disease response. Bone marrow biopsies to evaluate for disease response and fibrosis were planned at one month, 3 months and 6 months.
Twenty-three subjects were enrolled from June 2010 to February 2012 at the Hospital of the University of Pennsylvania and received at least one dose of study drug. The median patient age was 73 (range 60–86). Twenty-one of 23 subjects were relapsed or refractory after prior therapy. Two of 23 subjects (ages 85 and 86) were previously untreated. Nineteen subjects were platelet transfusion-dependent. Thirteen subjects had a history of antecedent myelodysplastic syndrome (MDS) and 6 were requiring hydroxyurea at time of study entry.
Fourteen of 23 subjects completed the first cycle of therapy. Three remained on study for the entire 6-month study period. At the time of this report one subject remains on eltrombopag in an extension phase (8+ months of therapy). Indications for drug cessation included: possible DLT=1; progressive disease=5; death due to sepsis=5; lack of response=6, loss of response=1; and pursuit of hospice or alternative therapy=4. Overall eltrombopag was well tolerated at all doses studied and a maximally tolerated dose (MTD) was not reached. One subject at the 300mg dose level developed Grade 4 hepatic laboratory abnormalities possibly related to study drug, which met criteria for a DLT. The subject had concurrent polymicrobial sepsis and subsequently died. No other grade 3 or greater liver function abnormalities were observed. Asymptomatic skin discoloration with associated abnormal serum pigmentation was noted in subjects at the 200mg and 300mg dose levels.
There were no platelet responses in the 50 mg or 100 mg cohorts (7 subjects total). Two of 7 subjects treated at the 200mg dose level and 2 of 9 subjects treated at the 300mg dose level achieved a platelet response (25% platelet response rate at these higher dose levels). All 4 of these subjects became platelet transfusion independent. The duration of platelet responses were 5 weeks, 12 weeks, 6 months and 8+ months (ongoing at time of this report).
One subject with primary refractory AML, associated with monosomy 7, obtained a complete morphologic and cytogenetic response by 3 months of therapy at the 300mg dose level. This response was sustained at most recent bone marrow biopsy at 6 months of therapy and the patient remains on study drug. Increased reticulin fibrosis was also observed in this subject over time. No other subjects experienced a PR or CR. 6 patients had stable disease (SD) at one month, which was maintained at 3 months for 4 patients.
Our study shows that eltrombopag is well tolerated in patients with AML at doses well above those typically used to treat ITP. At higher doses, we observed clinically meaningful platelet and antileukemic responses. Further exploration of eltrombopag as both a platelet agonist and disease-modifying agent in the treatment of AML is justified.

Disclosures:
Frey: GSK: Consultancy, Research Funding. Porter:Novatis: Patents & Royalties; Celgene: Honoraria; Genentech: Employment; Pfizer: Research Funding. Perl:Astellas: Consultancy. Carroll:GlaxoSmithKlein: Research Funding.