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

E.N. Oliva, C. Alati, V. Santini, A. Poloni, A. Molteni, P. Niscola, F. Salvi, G. Sanpaolo, E. Balleari, U. Germing, P. Fenaux, A. Stamatoullas, G.A. Palumbo, P. Salutari, S. Impera, P. Avanzini, A. Cortelezzi, A.M. Liberati, P. Carluccio, F. BuccisanoM.T. Voso, S. Mancini, A. Kulasekararaj, F. Morabito, M. Bocchia, P. Cufari, M.A.A. Spiriti, I. Santacaterina, M.G. D'Errigo, I. Bova, G. Zini, R. Latagliata

Research output: Contribution to journalArticlepeer-review

Abstract

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. © 2017 Elsevier Ltd
Original languageEnglish
Pages (from-to)e127-e136
JournalThe Lancet Haematology
Volume4
Issue number3
DOIs
Publication statusPublished - 2017

Keywords

  • creatinine
  • eltrombopag
  • hemoglobin
  • placebo
  • thrombopoietin receptor, acute myeloid leukemia
  • aged
  • Article
  • ascites
  • asthenia
  • bronchopneumonia
  • constipation
  • controlled study
  • coughing
  • cytogenetics
  • diarrhea
  • disease course
  • disease free survival
  • disease severity
  • drug dose increase
  • drug dose reduction
  • drug efficacy
  • drug safety
  • drug tolerability
  • drug withdrawal
  • eye jaundice
  • faintness
  • female
  • fever
  • follow up
  • headache
  • heart arrhythmia
  • heart failure
  • herpes virus infection
  • human
  • hyperbilirubinemia
  • hypertransaminasemia
  • intention to treat analysis
  • intermediate risk patient
  • International Prognostic Scoring System
  • kidney failure
  • limb disease
  • low risk patient
  • lower respiratory tract infection
  • major clinical study
  • male
  • microembolism
  • muscle cramp
  • myalgia
  • myelodysplastic syndrome
  • myelofibrosis
  • nausea
  • osteoarthritis
  • overall survival
  • pain
  • pancreatitis
  • paresthesia
  • phase 1 clinical trial
  • phase 2 clinical trial
  • priority journal
  • pruritus
  • quality of life
  • questionnaire
  • randomized controlled trial
  • rectum hemorrhage
  • respiratory failure
  • sepsis
  • single blind procedure
  • skin defect
  • skin discoloration
  • solid tumor
  • stomach hemorrhage
  • stomach pain
  • thrombocyte count
  • thrombocyte transfusion
  • thrombocytopenia
  • treatment outcome
  • treatment response
  • urinary tract infection
  • vomiting

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