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

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.

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.

BACKGROUND: In myelodysplastic syndromes, thrombocytopenia is associated with mortality, but treatments in this setting are scarce. We tested whether eltrombopag, a thrombopoietin receptor agonist, might be effective in improving thrombocytopenia in lower-risk myelodysplastic syndromes and severe thrombocytopenia. METHODS: EQoL-MDS was a single-blind, randomised, controlled, phase 2 superiority trial of adult patients with low-risk or International Prognostic Scoring System intermediate-1-risk myelodysplastic syndromes and severe thrombocytopenia. Patients with a stable platelet count of lower than 30 × 109 platelets per L, aged at least 18 years, with refractoriness, ineligibility to receive treatment with alternative medications, or relapse while receiving treatment with alternative medications were included in this trial. Patients were randomly assigned (2:1) to receive eltrombopag (50 mg to 300 mg) or placebo for at least 24 weeks and until disease progression and were masked to treatment allocation. Here, we report the results in the intention-to-treat population of the first phase of the trial, for which the primary endpoints were the proportion of patients achieving a platelet response within 24 weeks and safety. The interim analysis presented here was protocol-specified and used a two-sided significance level of 0·001 and a p value at or below this limit for both primary endpoints to indicate the need for early trial termination. Duration of platelet transfusion independence, duration of response, overall survival, leukaemia-free survival, and pharmacokinetics will be reported at the end of the phase 2 portion of the trial. This trial is registered with EudraCT, number 2010-022890-33. FINDINGS: Between June 13, 2011, and June 17, 2016, we enrolled 90 participants for the first phase of the trial. The median follow-up time to assess platelet responses was 11 weeks (IQR 4-24). Platelet responses occurred in 28 (47%) of 59 patients in the eltrombopag group versus one (3%) of 31 patients in the placebo group (odds ratio 27·1 [95% CI 3·5-211·9], p=0·0017). During the follow-up, 21 patients had at least one severe bleeding event (WHO bleeding score ≥2). There were a higher number of bleeders in the placebo (13 [42%] of 31 patients) than in the eltrombopag arm (eight [14%] of 59 patients; p=0·0025). 52 grade 3-4 adverse events occurred in 27 (46%) of 59 patients in the eltrombopag group versus nine events in five (16%) of 31 patients in the placebo group (χ2=7·8, p=0·0053, stopping rule not reached). The outcome acute myeloid leukaemia evolution or disease progression occurred in seven (12%) of 59 patients in the eltrombopag group versus five (16%) of 31 patients in the placebo group (χ2=0·06, p=0·81). INTERPRETATION: Eltrombopag is well-tolerated in patients with lower-risk myelodysplastic syndromes and severe thrombocytopenia and is clinically effective in raising platelet counts and reducing bleeding events. The assessment of long-term safety and efficacy of eltrombopag and its effect on survival (phase 2 part of study) is still ongoing. FUNDING: Associazione QOL-ONE.

Quality of life and physicians' perception in myelodysplastic syndromes.

To detect factors associated with quality of life (QOL) of patients with myelodysplastic syndrome (MDS) and to compare the MDS patients' self-assessed QOL with that perceived by their physicians. In an observational, non-interventional, prospective, multicentre study, QOL was evaluated in 148 patients with newly diagnosed low- and intermediate-risk IPSS MDS. QOL measures (QOL-E v.2, LASA and EQ-5D) and patient-related candidate determinants of QOL were assessed for up to 18 months. Patients' QOL scores were compared with those obtained by appointed hematologists' assessment and with ECOG performance status (PS). Fatigue was not prevalent at diagnosis, though physical QOL and energy levels were low. Transfusion-dependent patients had worse QOL scores. In multivariate analysis, Hb levels and comorbidities were a major determinant of QOL. Physicians' perception of patients' well-being correlated with patients' QOL. Physicians underestimated the impact of disturbances on patients' QOL, mainly in the MDS-specific components. ECOG PS did not discriminate patients according to QOL status. In conclusion, the association of anemia with QOL is confirmed, while co-morbidities emerge as an independent predictor of QOL in MDS. Fatigue is not a major concern. ECOG PS is not a valuable surrogate of patient's QOL, thus highlighting that physician's judgment of patient's well-being must not substitute patient-reported outcomes. Appropriate questionnaires should be used to assess MDS patients' QOL in order to improve communication and therapeutic choice.