Discussion
This systematic review identified 11 studies that reported a definition of pediatric rITP with wide variation between studies. After examining the reported definitions, there appears to be general agreement on the following criteria: (1) unresponsive to medical interventions, (2) persistent or recurrent platelet count <20 x109/L, and (3) requiring treatment to reduce clinically significant bleeding or risk of bleeding (Table 1). The ICON survey also demonstrates differences in provider definitions of rITP, even among those with expertise in the field (Figure 2A and 2B). A consensus definition would greatly aid researchers in clarifying eligibility and reporting in clinical trials, as well as clinicians in standardizing clinical practice and inter-professional communication.
In addition to the lack of consistency between rITP definitions, there was also no standardized treatment regimen noted. Of the studies that reported on treatment, rituximab was the most commonly prescribed therapy. The American Society of Hematology 2019 guidelines currently recommend rituximab for refractory pediatric ITP following: (1) failure of first line treatment and TPO-RAs in patients with ITP lasting ≥ 3 months, (2) patients who suffer from non-life-threatening mucosal bleeding and/or (3) diminished health-related quality of life and do not respond to first line treatments.1 Overall, response rates to rituximab in pediatric patients range from 23% to 69%.2 This wide range may be attributed to differences in patient demographics and disease characteristics (ie, prior therapies, duration of disease, severity of disease). Indeed, studies have identified potential predictors for rituximab response, such as gender (female as a positive predictor), patient age (older age as a positive predictor), and treatments prior to rituximab (prior positive response to steroids as a positive predictor).19,20 Further, variation in study methodology may also contribute to the wide-ranging response rate of rituximab. Although most patients received the standard dose of rituximab (375 mg/m2/week of rituximab for 4 weeks),9,13,17,18 some studies prescribed modified doses18 and infusion numbers, guided by blood cell count.13 These treatment schedules were inconsistent as studies failed to provide clear criteria for treatment escalation or tapering, and may likely have confounded the reported results. The comparability and interpretation of results were also complicated by the lack of consistency between studies’ criteria for complete and partial response. Although most studies referenced criterion outlined by the IWG,21 others constructed their own criteria, ranging from >75x109/L to >150x109/L.17,18Despite the variation in response, rituximab remains an efficacious monotherapy that warrants further exploration for this challenging patient population.
While most studies involve a single 4-week course of rituximab, one study investigated outcomes following multiple courses of rituximab.13 In addition, combination therapy involving rituximab, cyclophosphamide, and dexamethasone has been previously used in the treatment of autoimmune cytopenias in adults22 but it is not clear how well these results will translate to the pediatric setting.23
Other treatments that were used in rITP include dapsone, TPO-RAs, and splenectomy. Although it has not been as well-studied in pediatric populations, dapsone has historically been a safe and effective treatment for chronic ITP in adults.24 The response rate of dapsone ranges from 9-50%25–28 while that of splenectomy is 50-70%.29 Studies involving splenectomy consistently demonstrated partial to complete responses in patients who were refractory to prior treatments. Of note, some studies’ definition of rITP was contingent on patients having undergone splenectomy.8,9,11,14 Current ASH guidelines list splenectomy as a deferred treatment option after other treatment options have been attempted.1 Therefore, requiring that the patient failed prior splenectomy is not an appropriate criteria for children with ITP.
Romiplostim appeared in only one study with moderate success, as 5 out of 10 patients showed significant clinical improvement.14 Currently, TPO-RAs, such as romiplostim, are indicated in pediatric patients who have ITP > 3 months and are unresponsive to corticosteroids, immunoglobulins, or splenectomy.30,31 Most of the literature pre-dates the approval of TPO-RAs, which may have a role in combination regimens for rITP.