title: Safety and tolerability of eltrombopag versus placebo for treatment of thrombocytopenia in patients with advanced myelodysplastic syndromes or acute myeloid leukaemia: a multicentre, randomised, placebo-controlled, double-blind, phase 1/2 trial.
abstract: BACKGROUND
  Patients with myelodysplastic syndrome or acute myeloid leukaemia who are thrombocytopenic and unable to receive disease-modifying therapy have few treatment options. Platelet transfusions provide transient benefit and are limited by alloimmunisation. Eltrombopag, an oral thrombopoietin receptor agonist, increases platelet counts and has preclinical antileukaemic activity. We aimed to assess the safety and tolerability of eltrombopag for the treatment of thrombocytopenia in adult patients with advanced myelodysplastic syndrome, secondary acute myeloid leukaemia after myelodysplastic syndrome, or de-novo acute myeloid leukaemia.
  
  
  METHODS
  We did this multicentre, randomised, placebo-controlled, double-blind, phase 1/2 trial at 37 centres in ten countries in Europe, east Asia, and the Americas. Patients aged 18 years or older who had relapsed or refractory disease or were ineligible for standard treatments; had platelet counts of less than 30 × 10(9) platelets per L; had 10-50% bone-marrow blasts; or were platelet transfusion dependent were randomly assigned (2:1), via a telephone-based interactive voice-response system (GlaxoSmithKline Registration and Medication Ordering System) with a permuted-block randomisation schedule (block size of three), to receive once-daily eltrombopag or matching placebo dose adjusted from 50 mg to a maximum dose of 300 mg. Randomisation was stratified by presence of poor-prognosis (complex) karyotype (presence of at least three abnormalities, or chromosome 7 abnormalities, vs absence) and bone-marrow blast count (<20% vs ≥20%). Patients and study personnel were masked to treatment allocation. The primary endpoint was safety and tolerability, including adverse events, non-haematological laboratory grade 3-4 toxic effects, and changes in bone-marrow blast counts from baseline. Analysis was by intention to treat. This trial is registered at ClinicalTrials.gov, number NCT00903422.
  
  
  RESULTS
  Between May 14, 2009, and May 9, 2013, we randomly assigned 98 patients to receive either eltrombopag (n=64) or placebo (n=34). 63 (98%) patients in the eltrombopag group and 32 (94%) patients in the placebo group had adverse events. The most common adverse events were pyrexia (27 [42%] vs 11 [32%]), nausea (20 [31%] vs 7 [21%]), diarrhoea (19 [30%] vs 6 [18%]), fatigue (16 [25%] vs 6 [18%]), decreased appetite (15 [23%] vs 5 [15%]), and pneumonia (14 [22%] vs 8 [24%]). Drug-related adverse events of grade 3 or higher were reported in six (9%) patients in the eltrombopag group and four (12%) patients in the placebo group. Increases in the proportion of peripheral blasts did not differ significantly between groups. Haemorrhage of grade 3 or higher was reported in ten (16%) patients given eltrombopag and nine (26%) patients given placebo. 21 (33%) patients receiving eltrombopag and 16 (47%) patients receiving placebo died while on treatment. No deaths in patients receiving eltrombopag and two deaths in patients receiving placebo were regarded as treatment related. Post-baseline bone-marrow examinations were done in 40 (63%) patients in the eltrombopag group and 17 (50%) patients in the placebo group. The most common reason for no examination was death before the scheduled 3 month assessment. There were no differences between median bone-marrow blast counts or proportions of peripheral blasts between groups.
  
  
  CONCLUSIONS
  Eltrombopag doses up to 300 mg daily had an acceptable safety profile in patients with advanced myelodysplastic syndrome or acute myeloid leukaemia. The role of eltrombopag in these patients warrants further investigation.
  
  
  BACKGROUND
  GlaxoSmithKline.
authors.affiliation: Department of Internal Medicine, University Hospital Carl Gustav Carus, Dresden, Germany. Electronic address: uwe.platzbecker@uniklinikum-dresden.de.
authors.forename: Uwe
authors.initials: U
authors.lastname: Platzbecker
authors.affiliation: Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, NT, Hong Kong.
authors.forename: Raymond S M
authors.initials: RS
authors.lastname: Wong
authors.affiliation: Division of Hematologic Malignancies, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY, USA.
authors.forename: Amit
authors.initials: A
authors.lastname: Verma
authors.affiliation: Division of Oncology, Bone Marrow Transplantation and Leukemia Section, Washington University Medical School, St Louis, MO, USA.
authors.forename: Camille
authors.initials: C
authors.lastname: Abboud
authors.affiliation: Hematology Unit, Hospital das Clínicas-UFMG, Belo Horizonte, Minas Gerais, Brazil.
authors.forename: Sergio
authors.initials: S
authors.lastname: Araujo
authors.affiliation: Division of Transfusion Medicine, Department of Medicine, Taipei Veterans General Hospital and National Yang-Ming University School of Medicine, Taipei, Taiwan.
authors.forename: Tzeon-Jye
authors.initials: TJ
authors.lastname: Chiou
authors.affiliation: Georgetown University Department of Medicine, Virginia Cancer Specialists, Arlington, VA, USA.
authors.forename: John
authors.initials: J
authors.lastname: Feigert
authors.affiliation: Department of Medicine, China Medical University Hospital, Taichung, Taiwan.
authors.forename: Su-Peng
authors.initials: SP
authors.lastname: Yeh
authors.affiliation: Department of Medicine, Technical University of Munich, Munich, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Götze
authors.affiliation: Department of Hematology and Cell Therapy, Hôpital Saint-Antoine, Paris, France.
authors.forename: Norbert-Claude
authors.initials: NC
authors.lastname: Gorin
authors.affiliation: Hematology Division, Stanford University Cancer Center, Stanford, CA, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Greenberg
authors.affiliation: Department of Internal Medicine, Division of Hematology and Oncology, University of Kansas Medical Center, Kansas City, KS, USA.
authors.forename: Suman
authors.initials: S
authors.lastname: Kambhampati
authors.affiliation: Division of Hematology, Department of Internal Medicine, Seoul St Mary's Hospital, Seocho-Gu, Seoul, South Korea.
authors.forename: Yoo-Jin
authors.initials: YJ
authors.lastname: Kim
authors.affiliation: Internal Medicine, Asan Medical Center, Songpa-Gu, Seoul, South Korea.
authors.forename: Je-Hwan
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Department of Hematology, Cancer Care Centers of South Texas-US Oncology Network, San Antonio, TX, USA.
authors.forename: Roger
authors.initials: R
authors.lastname: Lyons
authors.affiliation: Hematology Department, San Bortolo Hospital, Vicenza, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Ruggeri
authors.affiliation: Department of Experimental and Clinical Medicine, Azienda Ospedaliero Universitaria Careggi, University of Florence, Florence, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Santini
authors.affiliation: Faculty of Health Science, Macau University of Science and Technology Hospital, Taipa, Macau, China.
authors.forename: Gregory
authors.initials: G
authors.lastname: Cheng
authors.affiliation: Division of Hematology Oncology, Samsung Medical Center, Seoul, South Korea.
authors.forename: Jun Ho
authors.initials: JH
authors.lastname: Jang
authors.affiliation: Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Chien-Yuan
authors.initials: CY
authors.lastname: Chen
authors.affiliation: Clinical Pharmacology Modeling and Simulation, GlaxoSmithKline, Research Triangle Park, NC, USA.
authors.forename: Brendan
authors.initials: B
authors.lastname: Johnson
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: John
authors.initials: J
authors.lastname: Bennett
authors.affiliation: Oncology R&D, Projects Clinical Platforms and Sciences, GlaxoSmithKline, Collegeville, PA, USA.
authors.forename: Frank
authors.initials: F
authors.lastname: Mannino
authors.affiliation: Oncology Business Unit, GlaxoSmithKline, Stockley Park West, Uxbridge, UK.
authors.forename: Yasser Mostafa
authors.initials: YM
authors.lastname: Kamel
authors.affiliation: Oncology R&D, Projects Clinical Platforms and Sciences, GlaxoSmithKline, Collegeville, PA, USA.
authors.forename: Nicole
authors.initials: N
authors.lastname: Stone
authors.affiliation: Oncology R&D, Projects Clinical Platforms and Sciences, GlaxoSmithKline, Collegeville, PA, USA.
authors.forename: Souria
authors.initials: S
authors.lastname: Dougherty
authors.affiliation: Oncology R&D, Projects Clinical Platforms and Sciences, GlaxoSmithKline, Collegeville, PA, USA.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Chan
authors.affiliation: Department of Internal Medicine II, Marien Hospital, Düsseldorf, Germany.
authors.forename: Aristoteles
authors.initials: A
authors.lastname: Giagounidis
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001565:Benzoates / Q000627:therapeutic use*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D006834:Hydrazines / Q000627:therapeutic use*; D015470:Leukemia, Myeloid, Acute / Q000150:complications / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000150:complications / Q000188:drug therapy*; D011720:Pyrazoles / Q000627:therapeutic use*; D053628:Receptors, Thrombopoietin / Q000819:agonists; D013921:Thrombocytopenia / Q000150:complications / Q000188:drug therapy*; D016896:Treatment Outcome
chemical_list: D001565:Benzoates; D006834:Hydrazines; D011720:Pyrazoles; D053628:Receptors, Thrombopoietin; C520809:eltrombopag