Long-term treatment with romiplostim and treatment-free platelet responses in children with chronic immune thrombocytopenia

Abstract

Children with immune thrombocytopenia for ≥6 months completing a romiplostim study received weekly subcutaneous romiplostim (1-10 μg/kg targeting platelet counts of 50-200×109/L) in this extension to examine romiplostim's long-term safety and efficacy. Sixty-five children received romiplostim for a median of 2.6 years (range: 0.1-7.0 years). Median baseline age was 11 years (range: 3-18 years) and platelet count was 28×109/L (range: 2-458×109/L). No patient discontinued treatment for an adverse event. Median average weekly dose was 4.8 mg/kg (range: 0.1-10 mg/kg); median platelet counts remained >50×109/L, starting at week 2. Nearly all patients (94%) had ≥1 platelet response (≥50×109/L, no rescue medication in the previous 4 weeks), 72% had responded at ≥75% of visits, and 58% had responded at ≥90% of visits. Treatment-free response (platelets ≥50×109/L ≥24 weeks without immune thrombocytopenia treatment) was seen in 15 of 65 patients while withholding romiplostim doses. At onset of treatment-free response, the nine girls and six boys had a median immune thrombocytopenia duration of four years (range: 1-12 years) and had received romiplostim for two years (range: 1-6 years). At last observation, treatment-free responses lasted for a median of one year (range: 0.4-2.1 years), with 14 of 15 patients still in treatment-free response. Younger age at first dose and platelet count >200×109/L in the first four weeks were associated with treatment-free responses. In this 7-year open-label extension, three-quarters of the patients responded ≥75% of the time, and romiplostim was well tolerated, with no substantial treatment-related adverse events. Importantly, 23% of children maintained treatment-free platelet responses while withholding romiplostim and all other immune thrombocytopenia medications for ≥6 months. (Registered at clinicaltrials.gov identifier: 01071954).

Trial registration: ClinicalTrials.gov NCT01071954.

Copyright© 2019 Ferrata Storti Foundation.

Figures

Figure 1.

Study flow and patient disposition. Reasons for discontinuing romiplostim are provided. *Of the 21 patients who entered the first extension, one withdrew consent before treatment. †Of the 66 patients who enrolled on the second extension, one withdrew consent before treatment. ‡Of these three patients, two had treatment-free response and one had platelet counts <30×109/L despite ten weeks on 10 mg/kg. §Other reasons were that the study ended and treatment-free response. ¶Received romiplostim until study end January 2017 (12 months after the last patient enrolled). #: number of; PBO: placebo; Q1, Q3: 25th and 75th percentiles.

Figure 2.

Dose, bleeding adverse events, and platelet counts over time. Shown are median dose (A), rate of bleeding adverse events per 100 patient-year (all and grade ≥2) (B), and median platelet counts (C) over time. (C) The area marked by the dotted lines indicates the target platelet count of 50-200×109/L. Patients received weekly subcutaneous romiplostim, starting with the same dose as the final dose in the parent study or 1 mg/kg [if previously on placebo (n=15) or >24 weeks since the last dose (n=5)]. The dose was adjusted weekly by 1 mg/kg from 1-10 mg/kg to target platelet counts of 50-200×109/L. Bleeding was assessed per Common Terminology Criteria for Adverse Events version 3.0 grading of adverse events: 1, mild; 2, moderate; 3, severe; 4, life-threatening; 5, fatal. pt-yr: patient-years; Q1, Q3: 25th and 75th percentiles.

Figure 3.

Treatment-free response for at least six months. Shown are time to onset (A) and modeling of characteristics associated with treatment-free response (B). 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 9/L. If the platelet count was >200 to <400×109/L for two consecutive weeks, the dose was reduced by 1 mg/kg at the next scheduled dose. If the platelet count was ≥400×109/L, the dose was withheld and reduced on the next scheduled day of dosing when the platelet count was <200×109/L. Red boxes indicate factors significant in the univariate analyses; yellow highlighting indicates those significant in the multivariate analyses. Hazard ratios for age at first dose and age at immune thrombocytopenia (ITP) diagnosis are per year of age, the hazard ratio for baseline platelet count is per 1×109/L, and the hazard ratio for mean platelet count in the first four weeks is per 10×109/L. Hazard ratios greater than 1 indicate an increased likelihood of developing treatment-free response. Note: the univariate models for prior rituximab use (P=1.0) and prior splenectomy (P=0.32) had non-proportional hazards, hence neither factor has a hazard ratio. #: number of; meds: medications.