Eltrombopag for Low-Risk Myelodysplastic Syndromes With Thrombocytopenia: Interim Results of a Phase II, Randomized, Placebo-Controlled Clinical Trial (EQOL-MDS)

Abstract

Purpose: In myelodysplastic syndromes (MDS), severe thrombocytopenia is associated with poor prognosis. This multicenter trial presents the second-part long-term efficacy and safety results of eltrombopag in patients with low-risk MDS and severe thrombocytopenia.

Methods: In this single-blind, randomized, placebo-controlled, phase-II trial of adult patients with International Prognostic Scoring System low- or intermediate-1-risk MDS, patients with a stable platelet (PLT) count (<30 × 10³/mm³) received eltrombopag or placebo until disease progression. Primary end points were duration of PLT response (PLT-R; calculated from the time of PLT-R to date of loss of PLT-R, defined as bleeding/PLT count <30 × 10³/mm³ or last date in observation) and long-term safety and tolerability. Secondary end points included incidence and severity of bleeding, PLT transfusions, quality of life, leukemia-free survival, progression-free survival, overall survival and pharmacokinetics.

Results: From 2011 to 2021, of 325 patients screened, 169 patients were randomly assigned oral eltrombopag (N = 112) or placebo (N = 57) at a starting dose of 50 mg once daily to maximum of 300 mg. PLT-R, with 25-week follow-up (IQR, 14-68) occurred in 47/111 (42.3%) eltrombopag patients versus 6/54 (11.1%) in placebo (odds ratio, 5.9; 95% CI, 2.3 to 14.9; P < .001). In eltrombopag patients, 12/47 (25.5%) lost the PLT-R, with cumulative thrombocytopenia relapse-free survival at 60 months of 63.6% (95% CI, 46.0 to 81.2). Clinically significant bleeding (WHO bleeding score ≥ 2) occurred less frequently in the eltrombopag arm than in the placebo group (incidence rate ratio, 0.54; 95% CI, 0.38 to 0.75; P = .0002). Although no difference in the frequency of grade 1-2 adverse events (AEs) was observed, a higher proportion of eltrombopag patients experienced grade 3-4 AEs (χ² = 9.5, P = .002). AML evolution and/or disease progression occurred in 17% (for both) of eltrombopag and placebo patients with no difference in survival times.

Conclusion: Eltrombopag was effective and relatively safe in low-risk MDS with severe thrombocytopenia. This trial is registered with ClinicalTrials.gov identifier: NCT02912208 and EU Clinical Trials Register: EudraCT No. 2010-022890-33.

FIG 1.

CONSORT diagram. Four patients (one in the eltrombopag arm and three in the control arm) withdrew from the trial before receiving the first dose of eltrombopag; thus, 165 patients (111 patients of the eltrombopag arm and 54 patients of the control arm) were considered in the modified ITT. The first patient was enrolled on June 13, 2011, and the last patient was enrolled on October 1, 2021. At the time of data extraction, 45 patients of 111 of the eltrombopag group and 17 patients of 54 of the placebo group entered the second part of the trial. AE, adverse event; ITT, intention-to-treat; MDS, myelodysplastic syndrome; PLT, platelet.

FIG 2.

Reverse Kaplan-Meier curves of platelet response in both treatment groups.

FIG 3.

(A) Box and whisker plot of PLT count over time. The horizontal line in the middle of each box represents the median, while the top and bottom of each box represent the 75th and 25th percentiles, respectively. The whiskers above and below the box plot mark the 97.5th and 2.5th percentiles, respectively. (B) Hemoglobin as an effect modifier of PLT response (log-transformed data) to eltrombopag. Data represent the ratio (and 95% CI) over the study period of the geometric mean of PLT count in eltrombopag-treated patients to the geometric mean of PLT count in patients in the placebo group. The numbers reported in parentheses (B) represent the number of observations with a hemoglobin value over time falling in a specific hemoglobin interval. LMM, linear mixed models; PLT, platelet.