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 × 109platelets 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.


RESULTS
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).


CONCLUSIONS
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.


BACKGROUND
Associazione QOL-ONE.
Azienda Ospedaliera "Bianchi Melacrino Morelli", Reggio Calabria, Italy. Electronic address: estheroliva@hotmail.com.
Esther N
EN
Oliva
Azienda Ospedaliera "Bianchi Melacrino Morelli", Reggio Calabria, Italy.
Caterina
C
Alati
Azienda Ospedaliero-Universitaria Careggi, University of Florence, Florence, Italy.
Valeria
V
Santini
Universita Politecnica delle Marche, Ancona, Italy.
Antonella
A
Poloni
ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy.
Alfredo
A
Molteni
Sant'Eugenio Hospital, Rome, Italy.
Pasquale
P
Niscola
SS.Antonio e Biagio, Alessandria, Italy.
Flavia
F
Salvi
IRCCS Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.
Grazia
G
Sanpaolo
IRCCS Azienda Ospedaliera Universitaria San Martino IST, Genova, Italy.
Enrico
E
Balleari
Heinrich-Heine-University Düsseldorf, Germany.
Ulrich
U
Germing
Hôpital St Louis/Université Paris, France.
Pierre
P
Fenaux
Centre Henri Becquerel, Rouen, France.
Aspasia
A
Stamatoullas
AOU Policlinico Vittorio Emanuele, Catania, Italy.
Giuseppe A
GA
Palumbo
Ospedale Civile, Pescara, Italy.
Prassede
P
Salutari
A.R.N.A.S. Garibaldi, Catania, Italy.
Stefana
S
Impera
S Maria Nuova IRCCS, Reggio Emilia, Italy.
Paolo
P
Avanzini
Fondazione IRCCS Caa' Granda Ospedale Maggiore Policlinico and University of Milan, Milan, Italy.
Agostino
A
Cortelezzi
Universita degli studi di Perugia, Terni, Italy.
Anna Marina
AM
Liberati
University of Bari, Bari, Italy.
Paola
P
Carluccio
Tor Vergata University of Rome, Rome, Italy.
Francesco
F
Buccisano
Tor Vergata University of Rome, Rome, Italy.
Maria Teresa
MT
Voso
San Camillo Hospital, Rome, Italy.
Stefano
S
Mancini
King's College Hospital NHS Foundation Trust, London, UK.
Austin
A
Kulasekararaj
Unità Operativa Complessa di Ematologia A.O. di Cosenza, Cosenza, Italy.
Fortunato
F
Morabito
Azienda Ospedaliera Universitaria Senese, University of Siena, Siena, Italy.
Monica
M
Bocchia
A.O. Bianchi-Melacrino-Morelli-Divisione di Ematologia, Reggio Calabria, Italy.
Patrizia
P
Cufari
University of Rome Sapienza, Rome, Italy.
Maria Antonietta Aloe
MA
Spiriti
Azienda Ospedaliera "Bianchi Melacrino Morelli", Reggio Calabria, Italy.
Irene
I
Santacaterina
Azienda Ospedaliera "Bianchi Melacrino Morelli", Reggio Calabria, Italy.
Maria Grazia
MG
D'Errigo
Azienda Ospedaliera "Bianchi Melacrino Morelli", Reggio Calabria, Italy.
Irene
I
Bova
Fondazione Policlinico Gemelli-Università Cattolica del Sacro Cuore, Rome, Italy.
Gina
G
Zini
Policlinico Umberto I, Rome, Italy.
Roberto
R
Latagliata
D000368:Aged; D000369:Aged, 80 and over; D001565:Benzoates / Q000627:therapeutic use*; D018450:Disease Progression; D005260:Female; D006801:Humans; D006834:Hydrazines / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000150:complications*; D010976:Platelet Count; D011720:Pyrazoles / Q000627:therapeutic use*; D053628:Receptors, Thrombopoietin / Q000819:agonists*; D016037:Single-Blind Method; D013921:Thrombocytopenia / Q000150:complications* / Q000188:drug therapy*; D016896:Treatment Outcome
D001565:Benzoates; D006834:Hydrazines; D011720:Pyrazoles; D053628:Receptors, Thrombopoietin; C520809:eltrombopag