Background: Grade ≥ 3 thrombocytopenia occurs in 20-45% of patients with chronic myeloid leukemia (CML) treated with tyrosine kinase inhibitors (TKI). While most instances resolve with TKI transient interruptions and dose reductions, persistent or recurrent thrombocytopenia may adversely influence TKI efficacy. Similarly, patients with myelofibrosis (MF) treated with ruxolitinib may experience thromobocytopenia requiring dose adjustments and interruptions, also potentially affecting efficacy.

Methods: We initiated a pilot study to assess the efficacy of eltrombopag for patients with CML or MF with persistent or recurrent thrombocytopenia after ≥3 months of therapy with an approved TKI or ruxolitinib, respectively. The primary objective is recovery of platelet count. Secondary objectives include safety, TKI/ruxolitinib dose intensity and response to therapy after start of therapy with eltrombopag. Patients with grade ≥ 3 thrombocytopenia (platelets <50 x 109/L) for patients with CML or platelets <100 x 109/L for patients with MF after at least 3 months of therapy with TKI or ruxolitinib, or those with prior grade 3 thrombocytopenia requiring TKI/ruxolitinib dose reductions or interruptions interfering with response, were enrolled.

Starting dose for Eltrombopag is at 50 mg daily (25 mg for patients of East Asian ancestry) with dose escalation allowed every 2 weeks to a maximum of 300 mg daily according to platelet response. 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 CML, and ≥100 x 109/L for MF that is sustained for 3 months while continuing TKI therapy. This report is an interim analysis of futility and toxicity.

Results: Nineteen patients have been enrolled (CML=14, MF=5). Median age is 58 years (range, 29-97 years); median duration of disease 2.1 years (range, 0.5-29 years) for patients with CML and 2 years (range, 0.3-3.6 years) for patients with MF. At the time of enrollment, patients with CML were treated with following TKIs: dasatinib (4), nilotinib (3), ponatinib (3), bosutinib (3), and imatinib (1). Median platelet count for patients with CML was 37 (range, 14-51), and 60 (range, 25 to 91) for those with MF. Cytogenetic response for patients with CML at baseline were: partial=3, minor=6, and none=5. After a median duration of treatment of 17 months (range, 3-48.4 months), 11 of 14 patients with CML achieved complete platelet response at eltrombopag doses of 50 - 300 mg per day. One additional patient with CML had a transient response. Median peak platelet count among responders was 224 (range, 123-424) x 109/L. In addition 7 patients with CML have had improvement in cytogenetic responses: 1 from none to complete, 3 from minor to partial, 1 minor to complete, 2 from partial to complete. None of the 5 patients with MF had a sustained increase in platelet count to ≥ 100 x 109/L. Two patients (1 each of CML and MF) had improvement in hemoglobin of over 2 gm/dL from baseline (from 8.2 g/dl to 10.6 g/dl, and from 9.4 g/dl to 11.4 g/dl, respectively), and 1 patient with CML had absolute neutrophil count recovery to >1x109/L (baseline neutrophils 0.71 x109/L). In 2 patients with CML, TKI dose could be increased and maintained while continuing eltrombopag. Grade3/4 toxicities irrespective of attribution include infection (n=5, 3 MF and 2 CML), elevated liver enzymes (n=5, all in CML), hyperglycemia (n=2), fatigue (n=2), chest pain (n=1), and myocardial infarction (n=1). One patient with MF showed increase in bone marrow fibrosis from grade 2 to grade 3. No progression of disease has been documented in any patient. One patient died on study from septic and hemorrhagic shock not related to study drug. Seven of the 19 patients enrolled are still on study. One patient discontinued therapy secondary to toxicity (persistent transaminitis with accompanying lack of response).

Conclusion: Eltrombopag may alleviate thrombocytopenia in some patients with CML treated with TKI. This is frequently accompanied by a decrease in treatment interruptions, and improved response. No similar benefit has been observed in patients with MF treated with ruxolitinib. This study continues enrollment.


Cortes:ARIAD: Consultancy, Research Funding; Bristol-Myers Squib: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. Jain:Servier: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Genentech: Research Funding; Celgene: Research Funding; BMS: Research Funding; Incyte: Research Funding; Infinity: Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Novimmune: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Research Funding; Abbvie: Research Funding. Jabbour:ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. Kantarjian:Amgen: Research Funding; ARIAD: Research Funding; Bristol-Myers Squibb: Research Funding; Pfizer Inc: Research Funding; Delta-Fly Pharma: Research Funding; Novartis: Research Funding.

Author notes


Asterisk with author names denotes non-ASH members.