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Eltrombopag safe, effective for children with chronic immune thrombocytopenia
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Eltrombopag appeared to be a suitable therapeutic option for children with chronic immune thrombocytopenia, according to findings from an international phase 3 study.
Between 13% and 36% of children with immune thrombocytopenia experience it chronically, or for longer than 12 months. Treatment options for these children — which include immunosuppression via corticosteroids, rituximab (Rituxan; Genentech, Biogen Idec) or a splenectomy — are associated with short-term and long-term adverse effects.
John D. Grainger, MBChB, MRCP, FRCPath, MD, a pediatric hematologist at Royal Manchester Children’s Hospital in Manchester, U.K., and colleagues of the PETIT2 trial investigated the safety and efficacy of eltrombopag (Promacta, Novartis) — a thrombopoietin receptor agonist shown to be safe, tolerable and effective in adults — in children using doses from the dose-finding phase of the PETIT study, a precursor to this trial.
The analysis included 92 patients aged 1 to 17 years who had chronic immune thrombocytopenia and platelet counts less than 30 x 109/L.
Researchers stratified patients by age into one of three cohorts — ages 12 to 17 years, ages 6 to 11 years or ages 1 to 5 years — and randomly assigned patients 2:1 to receive eltrombopag (n = 63) or placebo (n = 29).
The study consisted of two parts. The first part of the study was a 13-week, double-blind period with dosages based on body weight and ethnic origin. Those patients who completed the 13-week period then went into an open-label treatment period for 24 weeks, during which all patients received eltrombopag at either the starting dose (if they were formerly on placebo) or their established dose.
The proportion of patients who achieved platelet counts of at least 50 x 10⁹/L in absence of rescue therapy for 6 weeks or more from 5 to 12 weeks of the double-blind period served as the primary outcome measure.
Three patients discontinued therapy because of adverse events during the double-blind phase. Two patients in the eltrombopag group withdrew because of increased liver aminotransferases and one patient in the placebo group withdrew due to an abdominal hemorrhage.
Twenty-five patients (40%) in the eltrombopag group achieved the primary outcome in 6 of the last 8 weeks of the double-blind period compared with one patient (3%) from the placebo group (OR = 18; 95% CI, 1.3-140.9).
A greater proportion of patients in the eltrombopag arm responded to treatment than patients in the placebo arm in the 12-17 age group (39% vs. 10%), 6-11 age group (42% vs. 0%) and 1-5 age group (36% vs. 0%).
A smaller proportion of the patients who received eltrombopag had WHO grades 1 to 4 bleeding at the end of the double-blind period than those who received placebo (37% vs. 55%); however, occurred of grade 2 to grade 4 bleeding was similar (5% vs. 7%).
During the open-label period, 80% of patients (n = 70 of 87) reached the primary outcome threshold or better at least once.
Adverse events that occurred more frequently in this portion of the study among patients in the eltrombopag arm included nasopharyngitis (17%), rhinitis (16%), upper respiratory tract infection (11%) and cough (11%).
Serious adverse events occurred in 8% of the eltrombopag arm and 14% of the placebo arm; however, no deaths, malignancies or thrombosis occurred during the trial.
“The responses seen in this study are consistent with those seen in PETIT and the adult studies of eltrombopag for treatment of chronic immune thrombocytopenia,” the researchers wrote. “[This study] provides evidence for the use of thrombopoietin receptor agonists in pediatric patients with chronic immune thrombocytopenia.”
Based in part on the results of this trial, the FDA approved eltrombopag for pediatric patients aged 6 years and older with chronic immune thrombocytopenia in a second-line setting.
Although these data are promising, more research is needed comparing the effectiveness of eltrombopag and other standard options in children, Cindy E. Neunert, MD, of the department of pediatrics hematology/oncology/bone marrow transplant at Columbia University, and Rachael F. Grace, MD, director of the hematology clinic at Boston Children’s Cancer and Blood Disorder Center and assistant professor of pediatrics at Harvard Medical School wrote in an invited commentary.
“Studies that use comparative effectiveness research methods are crucial and should focus on assessment of patient-reported outcomes,” Neunert and Grace wrote. “Although [this study] clearly shows the efficacy of eltrombopag against placebo, further data are needed to establish its effectiveness in clinical practice where thought must be given to cost, availability of more curative options and patient adherence to long-term daily medication.” – by Anthony SanFilippo
Disclosure: The study was funded by GlaxoSmithKline. Grainger reports research funding from Baxter and honoraria from Amgen, Baxter and GlaxoSmithKline. Neunert reports a safety board role with Genzyme. Please see the full study for a list of all other researchers’ relevant financial disclosures.
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