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.