Immune thrombocytopenia (ITP) is usually acute and self-limited in children, although bleeding symptoms are occasionally severe and do not respond to conventional therapy. In this issue of Blood, Bussel and colleagues report initial phase 1/2 safety and efficacy data using romiplostim, a novel agent that increases thrombopoiesis, for the treatment of childhood ITP.1
The success of targeted therapy designed to directly stimulate megakaryocytes through the thrombopoietin (TPO) receptor to produce more platelets, most notably using second-generation thrombopoietic agents eltrombopag and romiplostim,2 suggests that a new treatment paradigm for immune-mediated thrombocytopenia could soon be on the horizon.
ITP is a common and familiar hematologic disorder, especially to pediatric hematologists. The clinical presentation of childhood ITP is typically dramatic, with an abrupt onset of severe thrombocytopenia and widespread mucocutaneous bleeding symptoms. Fortunately, the vast majority of children with ITP will improve spontaneously over weeks to months and resolve without long-term sequelae. However, many newly diagnosed children receive intravenous immunoglobulin, anti-D immunoglobulin, or corticosteroids to treat or prevent bleeding, and to minimize the rare but real risks of life-threatening bleeding, including intracranial hemorrhage.
In less than 5% of cases, the thrombocytopenia of childhood ITP is severe or responds poorly to such front-line therapy. In these cases, more aggressive therapy such as splenectomy or potent immunosuppressants including rituximab (anti-CD20 monoclonal antibody) can be used with some success, although the benefits must be weighed against the serious adverse event profiles of these interventions.3 In about 20% to 30% of cases, the clinical course becomes chronic and may require frequent therapy. A novel, safe, and efficacious therapeutic agent would represent a welcome addition to the existing pharmacologic armamentarium for children with chronic, severe, or recalcitrant ITP.
Recently, Kuter et al described the results of a large, randomized, controlled trial of romiplostim, a TPO peptide mimetic that functions as a thrombopoietin receptor (TPO-R) agonist, for the treatment of adults with chronic immune thrombocytopenia.4 Romiplostim directly stimulates the bone marrow megakaryocytes through TPO-R to increase thrombopoiesis, thereby increasing production of new platelets for circulation. However, splenic production of autoantibodies that hamper thrombopoiesis and facilitate destruction of platelets by splenic macrophages continues to occur (see figure). Bussel et al now report on a randomized, double blind, placebo-controlled study that includes the first efficacy and safety data of a TPO-R agonist in children. Using a dose-escalation treatment plan, romiplostim administered in 12 weekly doses was successful for achieving a platelet count of more than 50 × 109/L for 2 consecutive weeks, at a median dose of 5 μg/kg/day, in 15 of 17 children (88%) compared with 0 of 5 (0%) who received placebo (P = .0008).1
In addition, important short-term safety data are provided, with no treatment-related serious adverse events noted, and only headache and epistaxis observed more commonly among children receiving romiplostim. Although almost all subjects (94%) had at least 1 adverse event, most were mild and none led to withdrawal or removal from the study. Drug pharmacokinetics in those children who had favorable responses were also obtained. Considering the fact that these patients were severely affected and often refractory to other therapies, the superiority of romiplostim over placebo suggests that this will become a valuable treatment option for patients who have failed standard front-line therapies. These results are important for practicing hematologists caring for children with severe and refractory ITP, as well as researchers seeking to better understand the role of this class of drugs in the treatment of immune-mediated thrombocytopenia.
Despite these exciting and encouraging data, there are long-term risks that must be addressed in future studies. First is the issue of antibody production against endogenous TPO (eTPO), which led to the discontinuation of first-generation TPO-R agonists. The second-generation agonist romiplostim has no sequence homology with eTPO, resulting in a significantly decreased incidence of anti-eTPO antibody development. The development of anti-romiplostim antibodies has also been reported, but there have been no reports of neutralizing eTPO activity. Although the current study contains a relatively small sample size (22 patients) and only short-term data, the lack of antibody production is promising. The second issue is marrow reticulin formation and potential marrow fibrosis; studies in rats suggest romiplostim does alter marrow fiber content,5 although careful serial measurements in humans have not been conducted. Especially in young patients for whom long-term therapy would be considered based on adult ITP data,6 this safety concern must be addressed prospectively in future clinical trials. It will be especially important to gather long-term safety data in children, who could potentially receive this therapy for many years. However, these pediatric data are consistent with a growing amount of data in adults, and suggest that this treatment may be a safe, well-tolerated, and efficacious option for the most severely affected children with refractory ITP.
Conflict-of-interest disclosure: J.M.D. receives honorarium from Cangene. R.E.W. declares no competing financial interests. ■