Efficacy of Eltrombopag in Patients With Lower-Risk Myelodysplastic Syndromes and Thrombocytopenia

Platelet transfusions are commonly administered to patients with myelodysplastic syndromes (MDS) who develop profound thrombocytopenia, but the short therapeutic effect and eventual transfusion refractoriness have prompted researchers to look for new treatment options.

In a study published in the Lancet Haematology, Esther N. Oliva, MD, from the Division of Hematology at Azienda Ospedaliera Bianchi-Melacrino-Morelli in Reggio Calabria, Italy, and co-authors assessed the safety and efficacy of eltrombopag, an oral thrombopoietin receptor (TPO-R) agonist, in 90 patients who were refractory to or ineligible for alternative treatments, finding that the drug was well tolerated and clinically effective in raising platelet counts and reducing bleeding events.

The randomized, single-blind, placebo-controlled, phase I/II superiority EQoL-MDS trial enrolled adult patients with low- or intermediate-risk MDS who had a stable platelet count (<30×109 platelets/L) but had relapsed, were refractory to, or ineligible for alternative treatment. Patients were enrolled from hospitals in Italy, France, Germany, and Slovenia between June 13, 2011, and June 17, 2016.

Patients were excluded from the trial if they had:

  • received previous chemoradiotherapy or TPO-R agonists
  • peripheral monocytosis of >1×109 cell/L or leukocytosis of ≥25×109 cell/L
  • an Eastern Cooperative Oncology Group performance status of >3
  • preexisting cardiovascular disease or arrhythmia associated with an increased risk of a thromboembolic event

Patients (mean age = 69±12 years) were randomized 2:1 to receive eltrombopag (ranging from 50-300 mg; n=59) or placebo (n=31) for at least 24 weeks and until disease progression.

The median follow-up time to assess platelet responses (defined according to International Working Group criteria) was 11 weeks (range = 4-24 weeks) in the entire patient cohort, but it was shorter in the eltrombopag cohort compared with the placebo cohort: 7 weeks (range = 2-21 weeks) and 17 weeks (range = 7-24 weeks; p values not reported).

In the eltrombopag cohort, the proportion of patients who achieved platelet responses within 24 weeks (primary endpoint) was 47 percent (n=28), including 11 partial responses (PRs) and 17 complete responses. In the placebo cohort, one patient (3%) responded with a PR (odds ratio [OR] = 27.1; 95% CI 3.5-211.9; p=0.0017).

The median daily dose at the time of response was 50 mg (range = 50-175 mg). Patients in the eltrombopag group responded quickly to treatment, with a median time to response of two weeks (range = 1-15 weeks).

All responders required dose titration increases or decreases in the first six months of treatment. “The platelet responses predominantly seen at the low dose of 50 mg might indicate that eltrombopag modulates aberrant immune pathways and thereby acts as both a thrombomimetic and an immunomodulatory drug,” Dr. Oliva and co-authors wrote.

During follow-up, 21 patients had at least one severe bleeding event (defined as a World Health Organization bleeding score of ≥2); more patients in the placebo cohort (n=13, 42%) than the eltrombopag arm (n=8, 14%; p=0.0025) experienced this type of bleeding event. The authors conducted a multivariate analysis to determine whether any baseline clinical factors were associated with platelet response, finding that a lower hemoglobin concentration conferred a worse prognosis (>12.0 g/dL vs. 81-100 g/dL; OR=1.38; 95% CI 1.12-1.70; p=0.0024).

“The increase in platelet count per se translates into a significant improvement in patient-reported outcomes,” Dr. Oliva told ASH Clinical News. “[Of note], there should not be concern about progression of MDS and acute myeloid leukemia evolution since these did not differ in patients receiving eltrombopag versus those allocated to placebo.”

Patients who received placebo experienced fewer grade 3/4 adverse events (AEs) than those in the eltrombopag group (16% vs. 46%; p=0.0053). Eight patients in the eltrombopag group permanently discontinued treatment because of persistent drug-related toxicity.

“Overall, no significant between-treatment difference was observed in the incidence of grade 1/2 non-hematologic AEs,” the authors wrote. Nausea/vomiting (n=11), pain (n=11), asthenia (n=6), skin lesions (n=6), fever (n=5), and hyperbilirubinemia (n=5) were the most common grade 1/2 AEs in the eltrombopag cohort, whereas asthenia (n=11), pain (n=4), fever (n=3), and nausea/vomiting (n=2) were the most common grade 1/2 AEs in the placebo group.

Four deaths and two deaths occurred in the eltrombopag (7%) and placebo (6%) cohorts, respectively, though none was deemed treatment related. Causes of death in the eltrombopag group included pneumonia (n=1), heart failure (n=2), and massive rectal hemorrhage (n=1); in the placebo cohort, deaths were related to heart failure (n=1) and pneumonia (n=1).

Disease progression, a concern in past trials of TPO-R agonists, occurred in seven eltrombopag-treated patients (12%) compared with five placebo-treated patients (16%; p=0.81). MDS evolved to acute myeloid leukemia in four patients treated with eltrombopag (7%) and one patient treated with placebo (3%; p=0.83).

The ongoing phase II portion of the study is assessing the long-term duration of response, safety, and tolerability of eltrombopag, with results to be reported at a later date.
Though Dr. Oliva suggested that “our findings might provide valuable evidence to support the approval of this new therapeutic option for the subset of patients with MDS and severe thrombocytopenia,” she also noted that the study is limited by a single-blind design. In addition, the results may not be generalizable to patients with higher-risk MDS, who were excluded from enrollment.


Oliva EN, Alati C, Santini V, et al. Eltrombopag versus placebo for low-risk myelodysplastic syndromes with thrombocytopenia (EQoL-MDS): phase 1 results of a single-blind, randomised, controlled, phase 2 superiority trial. Lancet Haematol. 2017;4:e127-36.