The thrombopoietin‒receptor agonist romiplostim is approved for adults with chronic immune thrombocytopenia (ITP). Several phase 1/2 and 3 studies have been conducted to investigate the efficacy and safety of romiplostim in children with ITP; the current single-arm, open-label, global study evaluated subcutaneous romiplostim for ≤3 years in 204 children with ITP.
Eligible children must have had ITP for ≥6 months, received ≥1 prior ITP therapies, and had a platelet count ≤30 × 109/L or uncontrolled bleeding at screening. Treatment consisted of weekly subcutaneous dosing initiated at 1 μg/kg and titrated weekly in 1-μg/kg increments up to 10 μg/kg to target platelet counts of 50 to 200 × 109/L. The primary end point was the percentage of time with a platelet response in months 0 to 6, with response defined as a platelet count ≥50 × 109/L with no rescue medications in the past 4 weeks.
At the interim data cutoff, 203 patients received ≥1 doses. The median age of the study population was 10 years (range, 1-17 years), 51% were female. The median ITP duration was 1.8 years (range, 0.5-13.8 years); median baseline platelet count was 14 × 109/L. Patients had received a median of 2 (range, 1-7) prior ITP treatments, 34 (17%) patients were receiving concurrent ITP medications, and 10 (5%) patients had had prior splenectomy.
During the first 6 months, the median percentage of time with a platelet response was 50% (17%, 83%); the percentage of time ≥100 × 109/L was 17% (0%, 33%). During months 7-12, the median percentage of time with platelet response was 83% (50%, 100%). Over the course of the study, 88% of patients responded; the median percentage of time ≥100 × 109/L was 26% (5%, 48%). The median percentage of time with an increase in platelet counts ≥20 × 109/L above baseline was 74% (39%, 90%). From week 12 onward, median platelet counts were >50 × 109/L. There was no variation in platelet response and dose by age. Four patients had treatment-free periods and maintained platelet counts ≥50 × 109/L with no ITP medications (including romiplostim) for ≥24 weeks. Fifty-two (26%) patients received rescue medications; 3 patients had splenectomy on study.
Median treatment duration was 53 (range, 8-119) weeks for a total exposure time of 226 patient-years. Over the course of the study, patients received a median average weekly romiplostim dose of 6.9 (0.2-9.5) µg/kg; the median dose was 9 μg/kg at 1 year (n = 106) and 10 μg/kg at 2 years (n = 17). The majority (63%) of patients initiated self-administration because their platelet count was ≥50 × 109/L. The most common adverse events of any grade included epistaxis (32%), headache (31%), and viral upper respiratory tract infection (28%). Serious adverse events occurred in 41 (20%) patients, including epistaxis (5%), decreased platelet count (3%), and thrombocytopenia (1%); of these, 5 serious adverse events were deemed treatment-related: 2 headaches, 2 abdominal pain, and 1 each of presyncope and neutralizing antibodies. Overall, 64 (31%) patients discontinued treatment, mostly due to lack of efficacy (n = 38); 7 patients discontinued due to adverse events, including headaches (n = 2), abdominal pain (n = 1), dizziness (n = 1), interstitial lung disease (n = 1), mixed connective tissue disease (n = 1), neutralizing antibody (n = 1), lupus (n = 1), and vomiting (n = 1). Bleeding occurred in 62% of patients, with grade ≥3 bleeding noted in 17 (8%) patients, including epistaxis (4%), ecchymosis (1%), and contusion (1%); grade 4 bleeding events were reported in 2 patients.
There were 6 cases of neutralizing antibody to romiplostim (of 201 patients tested), but none to thrombopoietin; all discontinued due to antibodies, 5/6 had continued elevated platelet counts, and in 2/6 cases, antibodies were not found on retesting. Of 30 patients with baseline bone marrow biopsies (all with modified Bauermeister scores of grade 0 [no reticulin], 1 [fine fibers], or 2 [fine fiber network]), 27 had evaluable on-study biopsies after 1 year; 1 patient had an increase from grade 0 to 2. There was no follow-up biopsy for this patient; once at a steady dose of 10 μg/kg, most (10/16) of his platelet counts were ≥30 × 109/L. Four patients had an increase in 1 grade, 1 patient had a decrease in 2 grades, and 3 had a decrease in 1 grade. There were no findings of collagen or abnormalities.
These results demonstrated that the majority of children with ITP who received open-label romiplostim for ≥6 months achieved a platelet response, with median platelet counts >50 × 109/L from week 12 onward; no new safety signals were observed over 226 patient-years.
Grainger JD, et al. ASH 2017. Abstract 2334