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M.D. Tarantino et al.
beyond two years of disease,5,6 and all major centers are familiar with patients with very long-term (i.e. of many years’ duration) refractory chronic ITP for whom they have no good treatment options.
Thrombopoietin (TPO) receptor agonists are an impor- tant second-line option in children with chronic ITP. The overall efficacy, safety, and tolerability profile compares favorably to other treatment options, with the major con- cern being that treatment may need to be continued indef- initely. While there are two large randomized, placebo- controlled trials of eltrombopag in children with chronic ITP,7,8 there are no long-term safety and efficacy data of eltrombopag in children with ITP. In phase I/II and III placebo-controlled studies in children with ITP for ≥6 months, the TPO receptor agonist romiplostim increased and maintained platelet counts in most patients.9,10 Children completing the placebo-controlled romiplostim studies could enroll in the open-label long-term extension study reported here. An interim report described data for 22 patients in the phase I/II study, including 12 who entered this extension study.11 This report includes final data from all 66 patients in the extension study, including 12 patients from the phase I/II study and 54 patients from the phase III study.
The objectives of this study were to describe the safety and efficacy of long-term use of romiplostim in children with ITP. End points included the occurrence of adverse events (AE), platelet responses, bleeding, reduced use of concurrent ITP medications, and a post hoc end point of treatment-free response, defined as maintaining platelet counts ≥50x109/L for at least six months with no ITP med- ications, including romiplostim. As this was not a predict- ed occurrence, there were no prospective immunological studies to explore markers of treatment-free response.
Methods
Patients were recruited from 28 sites in the US, Canada, Spain, and Australia. The study ran from 30th December 2009 (first patient enrolled) to 12th January 2017 (last visit). Study guidelines for romiplostim dosing and possible reasons for withholding romiplostim doses are summarized in Online Supplementary Figure S1. Romiplostim was administered weekly, starting at 1 mg/kg or continuing at the last dose from the previous study. The dose of romiplostim was adjusted to a maximum of 10 mg/kg based on platelet count. If, in the opinion of the investigator, the patient maintained acceptable platelet counts without weekly dosing, romiplostim could be withheld until the platelet count fell to <50x109/L. Dose reduction by 1 μg/kg was required for two con- secutive weekly platelet counts >200 and <400x109/L. If any platelet count was ≥400x109/L, romiplostim was withheld until the platelet count was <200x109/L, then decreased by 1 mg/kg. If the current dose was 1 mg/kg and a dose reduction was required for elevated platelet counts, then romiplostim was withheld until platelet counts fell to <50x109/L, when it was restarted at a dose of 1 mg/kg. Patients could receive other ITP medications at a stable dose and schedule, which could be reduced or withheld for platelet counts ≥50x109/L. Patients could receive rescue medica- tions [intravenous immunoglobulin (IVIg), anti-D, platelet transfu- sions, corticosteroids, or antifibrinolytics] for platelet counts <10x109/L, for bleeding/wet purpura, or per investigator (e.g. pre- procedure).
Eligible patients had completed a placebo-controlled romi- plostim ITP study,9,10 had ITP for ≥6 months (before initial study),
and were ≤18 years of age; those turning 18 after enrollment were allowed to stay on study. The studies were conducted in compli- ance with all regulatory obligations and institutional review board and informed consent regulations at each investigational site and the Declaration of Helsinki. All patients/legal representatives pro- vided written informed consent/assent.
Assessments included platelet count, blood smear, and review of AE (including bleeding) every four weeks; and physical exami- nation, vital signs, complete blood count, and serum chemistries every 12 weeks. Samples for binding antibodies against romi- plostim and TPO were tested yearly and at study end; positive samples were tested for neutralizing antibodies. Bone marrow aspirates/biopsies were not required but could be performed at the investigator’s discretion.
Efficacy outcomes included platelet counts and platelet response (≥50x109/L, no rescue medication use in the previous 4 weeks). Missing data for platelet counts were imputed using the average of neighboring values within ±1 week. Treatment-free response was defined post hoc as platelet counts ≥50x109/L in the absence of all ITP medications including romiplostim for ≥24 weeks.
Statistical analyses were descriptive. Categorical end points were summarized by the number and percentage of patients in each category. Continuous end points were summarized by num- ber of patients, mean, standard deviation, median, and 25th per- centile and 75th percentile, with minimum and maximum values. AE were also summarized as the number of events and rate per 100 patient-years of exposure. Proportional hazards models were used to evaluate factors correlating with time to treatment-free response; patients without treatment-free response were censored at their final platelet count. For the univariate model, each poten- tial factor was considered alone (analogous to a log-rank test). If the assumption of proportional hazards was violated, non-para- metric tests (Fisher exact test for categorical variables and Kruskal- Wallis test for continuous variables) were used. For multivariate models, a forward stepwise selection criterion was used with sig- nificance levels for entry and exit set at 0.05.
Results
Demographics and disposition
Sixty-six patients gave consent for this extension study; one withdrew before treatment and 65 received romi- plostim. Fifteen patients had received placebo previously and this study was their first exposure to romiplostim; patients already receiving romiplostim could enroll with- out interruption of dosing. At baseline, patient median age was 11 years (range: 3-18 years), 56% (37 of 66) were female, and median platelet count was 28 x109/L (range: 2- 458x109/L) (Table 1). Median ITP duration was 3.0 years (range: 1-13 years), past ITP treatments included IVIg, anti-D, corticosteroids, and rituximab, and 9% (6 of 66) had prior splenectomy (Table 2). There were no notable differences at baseline for patients achieving treatment- free response.
Investigators reported that 37 of 66 patients (56%) com- pleted romiplostim treatment (Figure 1). Reasons for dis- continuation of romiplostim treatment (28 of 66, 42%) included consent withdrawn (n=10), required other thera- py (n=5), non-compliance (n=4), per protocol (n=3), administrative decision (n=2), AE (n=2), and other (n=2). AE were asthenia, headache, dehydration, and vomiting in one patient and anxiety in the other; investigators did not consider these AE to be treatment-related.
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haematologica | 2019; 104(11)