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Romiplostim in pediatric ITP
Romiplostim exposure
Median romiplostim treatment duration was 2.6 years (range: 0.1-7.0 years) and total exposure to romiplostim was 182 patient-years. Median average weekly romi- plostim dose (i.e. cumulative romiplostim dose divided by duration of treatment) was 4.8 mg/kg (range: 0.1-10 mg/kg). The mean maximum weekly romiplostim dose was 6.9 mg/kg and the median maximum weekly dose was 8.0 mg/kg. Twenty patients started on 1 mg/kg of romiplostim, including the 15 patients who previously received placebo and five patients with >24 weeks since the last dose of romiplostim. The median weekly dose was typically between 4 and 5 mg/kg during the first two years (Figure 2A). The smaller number of patients continuing romi- plostim treatment for more than four years complicated median dose calculations at later visits. In a post hoc analy- sis, all 65 patients received their doses per protocol >90% of the time; 21 patients missed ≥1 dose as a result of non- compliance a total of 65 times.
Safety
The most common AE were headache and contusion (Table 3). Fifty-four serious AE occurred in 19 patients (Online Supplementary Table S1). One patient had treat- ment-related concurrent serious AE of grade 4 thrombocy- topenia, grade 3 epistaxis, and grade 2 anemia, using investigator-reported severity ratings from the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. Five patients with serious AE of low platelet counts had fluctuating platelet counts (Online Supplementary Figure S2). Bleeding AE occurred in 57 patients; only three of these AE were deemed treatment-related (injection site hemorrhage, injection site bruising, and epistaxis). The most frequent bleeding AE were contusion (51%, 33 of 65), epistaxis (49%, 32 of 65), and petechiae (31%, 20 of 65). There were no cases of intracranial hemorrhage; spe- cific bleeding events included menorrhagia (3 of 65, 5%), hematuria (3 of 65, 5%), rectal hemorrhage (3 of 65, 5%), hematochezia (2 of 65, 3%), hemoptysis (2 of 65, 3%), anal hemorrhage (1 of 65, 2%), and hematemesis (1 of 65, 2%) (Figure 2B). There were seven patients with serious or
grade 3 AE of bleeding (Online Supplementary Table S2). For one patient, the investigator considered the serious AE of worsening epistaxis (and serious AE of anemia and throm- bocytopenia) to be treatment-related; tests for the patient’s anti-drug binding antibodies were all negative. No arterial or venous thromboembolic AE were reported. Of note, the contusion rate dropped from 239 to 92 per 100 patient-years when one patient who had 499 AE was excluded from the analysis (Table 3). That patient, a 7- year old boy at baseline, was in the study for 3.4 years and had several serious AE: six of decreased platelet count, and one each of headache, head injury, vomiting, leukopenia, hematoma, pharyngitis streptococcal, and gastroenteritis. His platelet counts ranged from 10 to 872x109/L and his dose was increased to 7-10 mg/kg. Seventy percent of his reported AE were non-serious AE of contusion (271 events) or petechiae (78 events). Per the treating investiga- tor, he was a very active child who played multiple sports.
Post-dosing antibodies were assayed annually in 60 patients; data covered >200 patient-years of exposure (including parent studies). One girl had anti-romiplostim neutralizing antibody detected upon leaving the study to receive other therapy; the neutralizing antibody was absent on retesting three and six months later. She received multiple additional therapies and was stable on mycophenolate mofetil. No patients developed anti-TPO neutralizing antibody.
Bone marrow biopsies were performed in two patients with additional cytopenias; both were found to have iron- deficiency anemia and no abnormal cellularity, fibrosis, or malignancy. The first was a 17-year old girl who under- went a bone marrow biopsy after two years on study to evaluate her persistent anemia. With regular supplemental iron intake and lighter menstrual bleeding, her anemia improved. The second bone marrow biopsy, performed after six weeks on study, was in an 11-year old girl who developed neutropenia and anemia; she received iron for
Table 2. Patient immune thrombocytopenia (ITP) medication history.
Table 1. Baseline demographics.
enrolled N=66
Patients with treatment-free response N=15
9 (60)
10 (67) 3 (20) 1 (7) 1 (7) 0 (0)
8 (4-18)
2 (13) 8 (53) 5 (33)
14 (1-44)†
All patients enrolled N=66 n (%)
3.0 (1-13)
Patients with treatment-free response N=15
n (%)
4 (1-12)
All patients
Female, n (%)
Race/ethnicity, n (%) White
African American Hispanic/Latino Asian
Other
Age, years, median (range)
Age group, years, n (%) ≥1 to <6
≥6 to <12
≥12
Baseline platelet count,
x109/L, median (range)
37 (56)
40 (61) 9 (14) 9 (14) 6 (9) 2 (3)
11 (3-18)
12 (18) 25 (38) 29 (44)
28 (2-458)*
ITP duration, median (range), years
Number of prior ITP treatments 1
2 3 >3
Prior splenectomy
Received specific therapies in the past IVIg
Corticosteroid
Anti-D antibody Rituximab Vincristine/vinblastine Danazol
Azathioprine
Other*
7(11) 2(13)
17 (26) 15 (23) 26 (39)
6 (9)
60 (91) 54 (82) 24 (36) 24 (36) 4 (6)
4 (6)
4 (6)
26 (39)
4 (27) 3 (20) 6 (40)
0 (0)
15 (100) 12 (80) 5 (33) 5 (33) 0 (0) 1 (7) 0 (0) 5 (33)
*For extension study described in this paper (i.e. not parent studies); 19 of 21 patients with baseline platelet count >50x109/L had previous romiplostim treatment; only one had rescue medication use right before baseline. †At start of parent study.
IVIg: intravenous immunoglobulin. *Other includes aminocaproic acid, cyclosporine, dapsone,mercaptopurine,mycophenolate mofetil,platelets,sirolimus,and tranexamic acid. Designation of platelet transfusion as a rescue medication was per investigator.
haematologica | 2019; 104(11)
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