Eltrombopag For The Management Of Thrombocytopenia Associated With Tyrosine Kinase Therapy In Patients With Chronic Myeloid Leukemia and Myelofibrosis

Abstract

Incidence of grade ≥ 3 thrombocytopenia is 20-45% among patients with chronic myeloid leukemia (CML) treated with tyrosine kinase inhibitors (TKI). While most thrombocytopenias resolve on continued TKI therapy with dose adjustments, sustained thrombocytopenia is cause for dose reductions and interruptions. Similarly among patients with myelofibrosis (MF), dose reduction of ruxolitinib is recommended for thromobocytopenia. As suboptimal dosing of TKI may lead to inadequate response, we initiated a study to assess the efficacy of eltrombopag for patients with CML or MF who are persistently thrombocytopenic after at least 3 months of therapy with an approved TKI. The primary objective is recovery of platelet count. Secondary objectives include safety, TKI dose intensity and response to TKI after start of therapy with eltrombopag. Patients with grade ≥ 3 thrombocytopenia (platelets <50 x 109/L) for patients with CML and platelets<100 x 109/L for patients with MF after at least 3 months of therapy with TKI, are being enrolled.Starting dose for Eltrombopag is at 50 mg daily with dose escalation allowed every 2 weeks up to a maximum of 300 mg daily according to platelet response. For patients of East Asian ancestry, eltrombopag starting dose is 25 mg daily with dose escalation every two weeks. Safety monitoring includes liver enzymes and periodic evaluation of bone marrow fibrosis. Planned accrual is for 39 patients (29 patients with CML and 10 with MF). The target response is at least 30% of subjects to have a complete (platelet) response, which is defined as platelet count ≥ 50 x 109/L for patients with CML and ≥ 100 x 109/L for patients with MF that is sustained for 3 months while continuing TKI therapy. This report is of a planned interim analysis of futility and toxicity.Eleven patients have been accrued to the study (CML=7, MF=4). Median age is 59 years (range, 30-97 years) and median duration of disease was 2.5 years (range, 2-17 years) for patients with CML and 2.3 years (range, 0.4-3 years) for patients with MF. At the time of enrollment patients with CML were treated with following TKIs: nilotinib (2), ponatinib (2), dasatinib (2) and bosutinib (1). Median platelet count for patients with CML was 47 (range, 29-48) and was 60 (range, 25-72) for patients with MF. Cytogenetic response for patients with CML at baseline were; major=3, minor=2, none=2. After a median duration of treatment for 8 months (range, 3-12 months), 5 out of 7 patients with CML achieved complete platelet response at eltrombopag doses 50 – 300 mg per day. Median peak platelet count among responders was 115 (range, 64-205) x 109/L. In addition 3 patients with CML had improvement in cytogenetic responses; 1 minor to complete, 2 minor to major. Two out of four patients with MF had non sustained increases in platelet count to ≥ 100 x 109/L. In addition to improvement in platelet counts, 2 patients (1 each of CML and MF) had improvement in hemoglobin of over 2 gm/dL from baseline and 1 patient with CML had absolute neutrophil count recover to> 1x109/L. In 3 patients, 2 with CML and 1 with MF, TKI dose could be increased while continuing eltrombopag. Grade3/4 toxicities irrespective of attribution include infection (N=5, 4 MF and 1 CML), hyperglycemia, fatigue, chest pain, myocardial infarction, elevated liver enzymes (N=1 for each). Follow up bone marrow biopsies have not shown any increase in bone marrow fibrosis or evidence of disease acceleration.In conclusion, early evidence of activity of eltrombopag in alleviating persistent TKI induced thrombocytopenia in chronic phase CML is quite encouraging while its activity in MF appears to be limited. Disclosures:Borthakur:GSK: Research Funding.