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Editorials
The child with immune thrombocytopenia: to treat or not to treat, is that still the question?
Nichola Cooper1 and Douglas B. Cines2
1Centre for Haematology, Department of Medicine, Imperial College, Hammersmith Hospital, London, UK and 2Departments of Pathology and Laboratory Medicine and Medicine, University of Pennsylvania-Perelman School of Medicine, Philadelphia, PA, USA
E-mail: DOUGLAS B. CINES - dcines@pennmedicine.upenn.edu doi:10.3324/haematol.2019.229179
In this issue of the Journal, Tarantino et al.1 describe their experience with the use of romiplostim to treat children with persistent immune thrombocytopenia (ITP). The results of this study also have implications for management of children who present with ITP.1
Eighty to 90% of children who present with ITP go into remission within 12 months and life-threatening bleeding is rare.2,3 However, this means that 10-20% do not go into remission, and even those whose disease eventually remits can experience bleeding symptoms and limitations in quality of life until this occurs. There is considerable heterogeneity in symptomatology and responsiveness that makes treatment decisions challenging for patients, families and clinicians alike.4 ITP presenting in very young children, with a peak around 3-4 years, is some- what more likely to be self-limiting, whereas ITP present- ing in the teen years is more likely to follow the more prolonged course seen in adults.2 Treatment decisions are further complicated by the fact that standard therapies are associated with burdensome adverse effects. Steroids cause metabolic and behavior problems that limit dosing and duration of treatment. Intravenous immunoglobulin (IVIG) can cause severe headaches, requires children to miss school, and its beneficial effects are transient. Splenectomy and immunosuppressive treatment, includ- ing rituximab, are used with caution in children because of the potential for increased risk of infection in an imma- ture immune system and the unknown potential for late effects such as secondary malignancies if immunosupres- sants are used persistently.5 In view of these adverse effects of treatment, the low incidence of internal bleed- ing, the high likelihood of remission, and the absence of data indicating an effect on durable remission, many guidelines recommend not treating children with ITP unless bleeding is severe (Figure 1, left).6,7 However, this clinical situation is not ideal. Episodic and unpredictable bleeding along with low platelet counts can lead to child and parental anxiety, restrictions on activities, and a sig- nificant negative impact on social and emotional develop- ment. Children with ITP and significant thrombocytope- nia can have reduced school attendance, fail to participate in athletic activities, and families may be reluctant to trav- el far from home.5,8
Therefore, there is an unmet need for less toxic and less invasive approaches to managing children with: a) symp- tomatic persistent/chronic ITP; b) those at significant risk of bleeding based on platelet count and/or comorbidities; and c) those with impaired health care related quality of life (HRQol) due to the need for considerable medical attention or because of the emotional impact associated with bleeding, the fear of bleeding, and the side effects of current treatments.
Thrombopoietin receptor agonists (TRA) have been
used successfully for these purposes in adults with ITP for approximately ten years.9 From 80% to 90% of adults show a response, almost all of which are durable with continued treatment. Response rates are even higher when crossovers from either agent to the other are included and less stringent response criteria, e.g. attaining a patient-specific hemostatic platelet count, are employed. There is now less concern over the risk of thrombosis and marrow fibrosis based on long-term safe- ty studies,10,11 and 20-30% of adult patients are able to dis- continue therapy by 2-3 years of treatment (reviewed by Ghanima et al.9).
Following upon from this track record in adults, it became important to assess whether similar efficacy and safety profiles would be seen in children with ITP. Smaller randomized studies showing efficacy and no major safety concerns led to the approval of romiplostim in 2018 for use in children with ITP who are over one year of age with ITP ≥6 months duration.12,13 Treatment was associated with improvement in child self-reported HRQol and reduced parental burden.14 However, there continued to be a need to establish whether efficacy was sustained, to investigate the long-term safety, and to assess the impact of romiplostim on the natural history of ITP in children.
In this issue, Tarantino et al. report the outcomes of an open-label extension study of romiplostim in 65 children with ITP of ≥6 months duration,1 15 of whom were receiving this treatment for the first time. Median dura- tion of disease was 3 years (range: 1-13 years) and median baseline age was 11 years (range: 3-18 years). Median duration of treatment was 2.6 years (range: 1-7 years), median average weekly dose 4.8 mg/kg (but was as low as 0.1 mg/kg in some), and the median response rate using previously published strict criteria (72% at ≥75% of vis- its; 58% at ≥90% of visits) was comparable to outcomes in adults. Fifty-nine (91%) of the 65 children or their caregivers “self-administered” treatment at home at least once starting at median study week 7. Fifty-seven report- ed miscellaneous bleeding adverse effects (AE) as would be expected in a trial in this population, but no thrombo- sis or other major drug-related AE were identified, although bone marrow examinations that might have revealed fibrosis were performed in only two subjects. Of note, 23 (35%) required rescue treatment on at least one occasion. Also, 29 (44%) left the study for a variety of reasons, including withdrawal of consent for unspeci- fied reasons, non-compliance, need for other treatment, and two for AE unrelated to treatment. Treatment-free responses were observed in 15 children (23%) who had ITP for a median of four years (range: 1-12 years), had received romiplostim for two years (range: 1-6 years), and the response was maintained in 14 for a median of one
haematologica | 2019; 104(11)