ArticlesEltrombopag for the treatment of children with persistent and chronic immune thrombocytopenia (PETIT): a randomised, multicentre, placebo-controlled study
Introduction
Immune thrombocytopenia, which results from antibody-mediated platelet destruction and impaired platelet production, is a common cause of childhood thrombocytopenia.1, 2 Most patients have bruising and petechiae,3 but a few develop clinically significant bleeding, especially when platelet counts are less than 10–20 × 109 per L.3, 4, 5
For many children, immune thrombocytopenia improves spontaneously;4, 6 however, 13–36% of paediatric patients develop immune thrombocytopenia lasting for more than 6 months.6 The most severely affected children have very low platelet counts and ongoing bleeding, and are at risk of serious haemorrhage.
Despite the fact that consensus guidelines exist, treatment of persistent (ie, lasting for 3–12 months), and especially chronic (>12 months), immune thrombocytopenia in children is controversial because of the absence of evidence from randomised clinical trials.7, 8 Treatment options include long-term use of corticosteroids or intravenous immunoglobulin, rituximab, other immunosuppressive drugs, or splenectomy.8, 9, 10, 11, 12, 13, 14, 15 The side-effects from these treatments can be concerning, and responses, if seen, might only be transient.8, 9, 10, 11, 12, 13, 14, 15 However, immune thrombocytopenia can resolve spontaneously even during the chronic phase.6 Therefore, children are sometimes managed with a watch-and-wait approach, even for long periods of time. However, for these children, persistently low platelet counts might curtail normal childhood activities, which could affect their quality of life.16
Eltrombopag is an oral non-peptide thrombopoietin receptor agonist that leads to signal transduction through the JAK/STAT, MAPK, and AKT pathways, resulting in proliferation and differentiation of megakaryocytes and increased platelet production.17, 18 Eltrombopag is approved for chronic immune thrombocytopenia in adults; however, data are scarce for children with immune thrombocytopenia treated with thrombopoietin receptor agonists.19, 20
The PETIT study is the first randomised, double-blind, placebo-controlled trial in patients aged 1–17 years with immune thrombocytopenia lasting for 6 months or more (persistent or chronic immune thrombocytopenia). We aimed to investigate the efficacy and safety of 24 weeks of eltrombopag in these children.
Section snippets
Study design
PETIT was a three-part, randomised, multicentre, placebo-controlled study (figure 1) done at 22 centres in the USA, UK, Canada, Spain, France, and the Netherlands. The study consisted of a dose-finding phase; a randomised, placebo-controlled double-blind phase; and an open-label phase.
The study protocol was approved by national, regional, or investigational centre ethics committee or institutional review boards accordingly. The trial protocol is available online.
Patients
Patients aged 1–17 years with a
Results
Between Oct 2, 2009, and June 22, 2011, we recruited 15 patients, with five patients in each age cohort (table 1), into the open-label dose-finding phase. Patients in the dose-finding phase did not enter the double-blind phase. Between March 17, 2010, and Jan 15, 2013, we assessed 82 additional patients for eligibility in the double-blind phase. Patients were enrolled in the double-blind starting with those aged 12–17 years, and the double-blind phase ran in parallel with the dose-finding phase
Discussion
Our results show that eltrombopag can be effective to increase platelet counts in children with persistent and chronic immune thrombocytopenia. The primary efficacy outcome was met: significantly more patients achieved a response, as defined as a platelet count of at least 50 × 109 per L without rescue therapy, with eltrombopag than with placebo during the 6 week randomised phase. Responses were similar (at about 60% of patients) in the three age cohorts. Clinical benefit was shown by
References (39)
- et al.
Immune thrombocytopenic purpura (ITP) plasma and purified ITP monoclonal autoantibodies inhibit megakaryocytopoiesis in vitro
Blood
(2003) - et al.
Bleeding manifestations and management of children with persistent and chronic immune thrombocytopenia: data from the Intercontinental Cooperative ITP Study Group (ICIS)
Blood
(2013) - et al.
Idiopathic thrombocytopenic purpura: a practice guideline developed by explicit methods for the American Society of Hematology
Blood
(1996) - et al.
The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia
Blood
(2011) - et al.
Randomised trial of intravenous immunoglobulin G, intravenous anti-D, and oral prednisone in childhood acute immune thrombocytopenic purpura
Lancet
(1994) - et al.
Outcomes 5 years after response to rituximab therapy in children and adults with immune thrombocytopenia
Blood
(2012) - et al.
Prospective phase 1/2 study of rituximab in childhood and adolescent chronic immune thrombocytopenic purpura
Blood
(2006) - et al.
Splenectomy and the incidence of venous thromboembolism and sepsis in patients with immune thrombocytopenia
Blood
(2013) - et al.
Discovery and characterization of a selective, nonpeptidyl thrombopoietin receptor agonist
Exp Hematol
(2005) - et al.
Eltrombopag for management of chronic immune thrombocytopenia (RAISE): a 6-month, randomised, phase 3 study
Lancet
(2011)