Immune Thrombocytopenia during Childhood: New Approaches to Classification and Management

Abstract

See related article, p 600Immune thrombocytopenia (ITP), which was previously called idiopathic thrombocytopenic purpura, is one of the most common primary hematologic disorders encountered by pediatricians, its prevalence being approximately 8 per 100 000 children.1Terrell D.R. Beebe L.A. Neas B.R. Vesely S.K. Segal J.B. George J.N. Prevalence of primary immune thrombocytopenia in Oklahoma.Am J Hematol. 2012; 87 ([Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't]): 848-852Crossref PubMed Scopus (50) Google Scholar ITP usually occurs in an otherwise well child whose blood count is normal except for isolated but sometimes quite severe thrombocytopenia. Conventional wisdom holds that ITP is an immune-mediated condition attributable to antibodies directed against platelet membrane antigens, which cause the child's sensitized platelets to be engulfed and destroyed by macrophages in the liver and spleen. The specific “trigger” for such a process may be a recent infection or receipt of measles, mumps, and rubella vaccine2Mantadakis E. Farmaki E. Buchanan G.R. Thrombocytopenic purpura after measles-mumps-rubella vaccination: a systematic review of the literature and guidance for management.J Pediatr. 2010; 156 ([Review]): 623-628Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar but is frequently undefined.Most children with ITP suddenly develop petechiae, bruises, and sometimes mucous membrane bleeding (especially from the nose and mouth), so parents and physicians alike are usually alarmed. Fortunately, ITP often resolves within a few weeks without treatment, but prominent hemorrhage in the setting of severe thrombocytopenia (platelet count ≤10 000 per mm3) necessitates drug treatment to inhibit the rapid destruction of the child's platelets. In such circumstances, corticosteroids, intravenous immunoglobulin, or anti-D immunoglobulin are employed as “first line” therapy on a short-term basis to control bleeding until spontaneous recovery ensues. In contrast, approximately 20%-25% of children with ITP present less dramatically with mild bruising and petechiae over a period of weeks or months. Most of them do not require initial drug treatment.Several recent developments include new meaning to the abbreviation “ITP”,3Rodeghiero F. Stasi R. Gernsheimer T. Michel M. Provan D. Arnold D.M. et al.Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children: report from an international working group.Blood. 2009; 113 ([Consensus Development Conference Research Support, Non-U.S. Gov't]): 2386-2393Crossref PubMed Scopus (1761) Google Scholar a novel treatment option for some children affected by it,4Bussel J.B. Buchanan G.R. Nugent D.J. Gnarra D.J. Bomgaars L.R. Blanchette V.S. et al.A randomized, double-blind study of romiplostim to determine its safety and efficacy in children with immune thrombocytopenia.Blood. 2011; 118 ([Multicenter Study Randomized Controlled Trial Research Support, Non-U.S. Gov't]): 28-36Crossref PubMed Scopus (168) Google Scholar and an excellent evidence-based guideline for practitioners.5Neunert C. Lim W. Crowther M. Cohen A. Solberg Jr., L. Crowther M.A. American Society of HematologyThe American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia.Blood. 2011; 117 ([Practice Guideline Review]): 4190-4207Crossref PubMed Scopus (1320) Google Scholar Some of these features are nicely exemplified in an article published in this issue of The Journal.6Ramaswamy K. Hsieh L. Leven E. Thompson M.V. Nugent D. Bussel J.B. Thrombopoietic agents for the treatment of persistent and chronic immune thrombocytopenia (ITP) in children.J Pediatr. 2014; 165: 600-605Abstract Full Text Full Text PDF PubMed Scopus (38) Google ScholarNew TerminologyAmong the advances impacting the diagnosis and management of ITP is the adoption of new descriptive terminology. Historically, ITP was considered as being either “acute” (beginning suddenly but resolving within 6 months) or “chronic” (lasting more than 6 months, regardless of the time course and severity of bleeding). Yet such a classification was awkward. Many children initially diagnosed with “acute” ITP continue to have thrombocytopenia beyond 6 months and thus were then labeled as having chronic ITP. Others were designated as having “chronic” disease nevertheless fully recovered by 12 months following diagnosis or even years later. A more attractive and descriptive terminology, recently formulated by an ITP International Working Group,3Rodeghiero F. Stasi R. Gernsheimer T. Michel M. Provan D. Arnold D.M. et al.Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children: report from an international working group.Blood. 2009; 113 ([Consensus Development Conference Research Support, Non-U.S. Gov't]): 2386-2393Crossref PubMed Scopus (1761) Google Scholar has instead categorized ITP as being either newly diagnosed, persistent (lasting more than 3 months following diagnosis), or chronic (still present 12 or more months from diagnosis). Moreover, “idiopathic” was logically replaced by “immune,” and “purpura” was eliminated altogether, given that many mildly affected children actually have no or little purpura. Fortunately, the long-standing abbreviation for what is now called ITP is still valid. These more logical definitions, which are appropriate for children as well as adults with ITP,7Grace R.F. Long M. Kalish L.A. Neufeld E.J. Applicability of 2009 international consensus terminology and criteria for immune thrombocytopenia to a clinical pediatric population.Pediatr Blood Cancer. 2012; 58 ([Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't]): 216-220Crossref PubMed Scopus (16) Google Scholar have since been broadly endorsed by the international community of ITP experts.New Treatment StrategiesA second recent advance benefitting both children and adults with ITP is a better understanding of disease mechanisms and resultant treatment strategies. In ITP, not only are the platelets rapidly destroyed by immunologic processes, but their production by bone marrow megakaryocytes can be reduced as well. This latter observation resulted in the discovery of a new class of drugs, so-called thrombopoietin (TPO) receptor agonists (TPO agents), which stimulate platelet production. A series of careful prospective studies beginning over a decade ago resulted in Food and Drug Administration approval of 2 such drugs, romiplostim and eltrombopag, for adults with chronic refractory ITP and platelet counts below 30 000 per mm3.5Neunert C. Lim W. Crowther M. Cohen A. Solberg Jr., L. Crowther M.A. American Society of HematologyThe American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia.Blood. 2011; 117 ([Practice Guideline Review]): 4190-4207Crossref PubMed Scopus (1320) Google Scholar, 8Provan D. Stasi R. Newland A.C. Blanchette V.S. Bolton-Maggs P. Bussel J.B. et al.International consensus report on the investigation and management of primary immune thrombocytopenia.Blood. 2010; 15 ([Consensus Development Conference Practice Guideline Research Support, Non-U.S. Gov't Review]): 168-186Crossref Scopus (1438) Google Scholar Substantial experience with these agents has demonstrated their efficacy in raising the platelet count as well as their overall safety. Yet to date, use of TPO agents in children with ITP has been limited to several industry-sponsored clinical trials4Bussel J.B. Buchanan G.R. Nugent D.J. Gnarra D.J. Bomgaars L.R. Blanchette V.S. et al.A randomized, double-blind study of romiplostim to determine its safety and efficacy in children with immune thrombocytopenia.Blood. 2011; 118 ([Multicenter Study Randomized Controlled Trial Research Support, Non-U.S. Gov't]): 28-36Crossref PubMed Scopus (168) Google Scholar and small case series.9Elalfy M.S. Abdelmaksoud A.A. Eltonbary K.Y. Romiplostim in children with chronic refractory ITP: randomized placebo controlled study.Ann Hematol. 2011; 90 ([Randomized Controlled Trial]): 1341-1344Crossref PubMed Scopus (62) Google Scholar, 10Mokhtar G.M. Tantawy A.A. El Sherif N.H. Romiplostim therapy in children with unresponsive chronic immune thrombocytopenia.Platelets. 2012; 23 ([Clinical Trial]): 264-273Crossref PubMed Scopus (27) Google Scholar, 11Vilaplana V.E. Aragones J.H. Fernandez-Llamazares C.M. Bieler C.B. Rodriguez S.M. Saez M.S. Use of romiplostim for primary immune thrombocytopenia in children.Pediatr Hematol Oncol. 2012; 29 ([Case Reports]): 197-205Crossref PubMed Scopus (22) Google Scholar, 12Pasquet M. Aladjidi N. Guiton C. Courcoux M.F. Munzer M. Auvrignon A. et al.Centre de Reference National des Cytopenies Auto-immunes de l'Enfant (CEREVANCE)Romiplostim in children with chronic immune thrombocytopenia (ITP): the French experience.Br J Haematol. 2014; 164 ([Research Support, Non-U.S. Gov't]): 266-271Crossref PubMed Scopus (29) Google Scholar Although the preliminary results are promising with regard to efficacy, safety, and acceptability, neither romiplostim nor eltrombopag are have yet been approved for use in children.In this issue of The Journal,6Ramaswamy K. Hsieh L. Leven E. Thompson M.V. Nugent D. Bussel J.B. Thrombopoietic agents for the treatment of persistent and chronic immune thrombocytopenia (ITP) in children.J Pediatr. 2014; 165: 600-605Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar two groups of investigators, highly experienced in the diagnosis and management of ITP, retrospectively report their clinical use of these TPO agents as “second line” therapy in a heterogeneous cohort of 33 children with persistent or chronic ITP. The authors point out the similarities and differences between these two drugs. Both bind to and activate the TPO receptor on the platelet surface, albeit by slightly different mechanisms. Romiplostim is administered by subcutaneous injection once weekly, whereas eltrombopag is given by mouth once daily on an empty stomach. Both drugs are well tolerated, and the current study demonstrates a clinically significant platelet response in over two-thirds of the treated children. In fact, 7 of the authors' 33 patients had a sustained platelet increment and were able to discontinue the TPO agent. Although not specifically reported by the authors, the choice of initial drug was determined in part by the patient and parent deciding whether they desired a weekly “shot” or a daily “pill” that required an empty stomach for four hours. The authors closely monitored their patients according to the same standards employed in the prior and ongoing industry-sponsored studies. The adverse effects occasionally observed in adult patients (ie, bone marrow fibrosis and venous or arterial thrombosis) were not noted in the current pediatric series.The experience of Ramaswamy et al described here6Ramaswamy K. Hsieh L. Leven E. Thompson M.V. Nugent D. Bussel J.B. Thrombopoietic agents for the treatment of persistent and chronic immune thrombocytopenia (ITP) in children.J Pediatr. 2014; 165: 600-605Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar and the limited data reported by others are highly promising. Practitioners who treat children with ITP should consider prescribing these drugs off-label for highly selected young patients with severe and/or refractory ITP. However, in doing so, some pitfalls and barriers are likely to be encountered. Both agents are costly ($50-$75 000 annually for an adult), and in some cases payers may deny their use in children. Also, neither agent “cures” ITP, thus differing in certain respects from splenectomy and immunosuppressive drugs, such as rituximab, which potentially foster long-term or even permanent remissions. Thus, these TPO agents are similar to intravenous immunoglobulin and pulses of corticosteroids in that a single dose or treatment course usually offers only short-term benefits. Also, severe “rebound” thrombocytopenia has been noted following abrupt discontinuation of TPO agents in adults. It seems unlikely that these drugs “induce” a clinical remission but, instead, may help maintain a satisfactory platelet count until the child's ITP remits spontaneously. The primary objective of drug treatment in children and adolescents with ITP continues to be increasing the platelet count to a level where spontaneous bleeding is absent, thus allowing resumption of normal activities. Although the platelet count is more objectively measured than bleeding severity, it is this latter goal that is truly most important to children with ITP and their parents.To date, study of these TPO agents has been described only for patients with persistent or chronic “refractory” ITP. Yet, perhaps another indication that should be explored is severe thrombocytopenia in patients with newly diagnosed ITP and major bleeding who have failed to respond to intravenous immunoglobulin and corticosteroids. Given that an initial clinically meaningful response to TPO agents can occur within just 1-2 weeks, future studies should explore the merits of romiplostim and eltrombopag in such newly diagnosed children as potentially effective “bridge” therapy until spontaneous remission occurs or more conventional second line immunosuppressive therapy or splenectomy is undertaken.Evidence-Based GuidelinesA final noteworthy advance in ITP management was the 2011 publication of an evidence-based guideline by the American Society of Hematology.5Neunert C. Lim W. Crowther M. Cohen A. Solberg Jr., L. Crowther M.A. American Society of HematologyThe American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia.Blood. 2011; 117 ([Practice Guideline Review]): 4190-4207Crossref PubMed Scopus (1320) Google Scholar Understandably, it featured no specific recommendations regarding TPO agent use in children. Yet, in many other ways, the guideline was groundbreaking in its objective and rigorous review of the literature and its patient-centered (as opposed to platelet count-centered) focus.The favorable experience with TPO agents reported in this issue of The Journal by Ramaswamy et al6Ramaswamy K. Hsieh L. Leven E. Thompson M.V. Nugent D. Bussel J.B. Thrombopoietic agents for the treatment of persistent and chronic immune thrombocytopenia (ITP) in children.J Pediatr. 2014; 165: 600-605Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar should raise the profile of this important treatment strategy and foster the design and execution of prospective studies aimed at further exploring this treatment modality in selected young patients with ITP. See related article, p 600Immune thrombocytopenia (ITP), which was previously called idiopathic thrombocytopenic purpura, is one of the most common primary hematologic disorders encountered by pediatricians, its prevalence being approximately 8 per 100 000 children.1Terrell D.R. Beebe L.A. Neas B.R. Vesely S.K. Segal J.B. George J.N. Prevalence of primary immune thrombocytopenia in Oklahoma.Am J Hematol. 2012; 87 ([Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't]): 848-852Crossref PubMed Scopus (50) Google Scholar ITP usually occurs in an otherwise well child whose blood count is normal except for isolated but sometimes quite severe thrombocytopenia. Conventional wisdom holds that ITP is an immune-mediated condition attributable to antibodies directed against platelet membrane antigens, which cause the child's sensitized platelets to be engulfed and destroyed by macrophages in the liver and spleen. The specific “trigger” for such a process may be a recent infection or receipt of measles, mumps, and rubella vaccine2Mantadakis E. Farmaki E. Buchanan G.R. Thrombocytopenic purpura after measles-mumps-rubella vaccination: a systematic review of the literature and guidance for management.J Pediatr. 2010; 156 ([Review]): 623-628Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar but is frequently undefined. See related article, p 600 See related article, p 600 Most children with ITP suddenly develop petechiae, bruises, and sometimes mucous membrane bleeding (especially from the nose and mouth), so parents and physicians alike are usually alarmed. Fortunately, ITP often resolves within a few weeks without treatment, but prominent hemorrhage in the setting of severe thrombocytopenia (platelet count ≤10 000 per mm3) necessitates drug treatment to inhibit the rapid destruction of the child's platelets. In such circumstances, corticosteroids, intravenous immunoglobulin, or anti-D immunoglobulin are employed as “first line” therapy on a short-term basis to control bleeding until spontaneous recovery ensues. In contrast, approximately 20%-25% of children with ITP present less dramatically with mild bruising and petechiae over a period of weeks or months. Most of them do not require initial drug treatment. Several recent developments include new meaning to the abbreviation “ITP”,3Rodeghiero F. Stasi R. Gernsheimer T. Michel M. Provan D. Arnold D.M. et al.Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children: report from an international working group.Blood. 2009; 113 ([Consensus Development Conference Research Support, Non-U.S. Gov't]): 2386-2393Crossref PubMed Scopus (1761) Google Scholar a novel treatment option for some children affected by it,4Bussel J.B. Buchanan G.R. Nugent D.J. Gnarra D.J. Bomgaars L.R. Blanchette V.S. et al.A randomized, double-blind study of romiplostim to determine its safety and efficacy in children with immune thrombocytopenia.Blood. 2011; 118 ([Multicenter Study Randomized Controlled Trial Research Support, Non-U.S. Gov't]): 28-36Crossref PubMed Scopus (168) Google Scholar and an excellent evidence-based guideline for practitioners.5Neunert C. Lim W. Crowther M. Cohen A. Solberg Jr., L. Crowther M.A. American Society of HematologyThe American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia.Blood. 2011; 117 ([Practice Guideline Review]): 4190-4207Crossref PubMed Scopus (1320) Google Scholar Some of these features are nicely exemplified in an article published in this issue of The Journal.6Ramaswamy K. Hsieh L. Leven E. Thompson M.V. Nugent D. Bussel J.B. Thrombopoietic agents for the treatment of persistent and chronic immune thrombocytopenia (ITP) in children.J Pediatr. 2014; 165: 600-605Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar New TerminologyAmong the advances impacting the diagnosis and management of ITP is the adoption of new descriptive terminology. Historically, ITP was considered as being either “acute” (beginning suddenly but resolving within 6 months) or “chronic” (lasting more than 6 months, regardless of the time course and severity of bleeding). Yet such a classification was awkward. Many children initially diagnosed with “acute” ITP continue to have thrombocytopenia beyond 6 months and thus were then labeled as having chronic ITP. Others were designated as having “chronic” disease nevertheless fully recovered by 12 months following diagnosis or even years later. A more attractive and descriptive terminology, recently formulated by an ITP International Working Group,3Rodeghiero F. Stasi R. Gernsheimer T. Michel M. Provan D. Arnold D.M. et al.Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children: report from an international working group.Blood. 2009; 113 ([Consensus Development Conference Research Support, Non-U.S. Gov't]): 2386-2393Crossref PubMed Scopus (1761) Google Scholar has instead categorized ITP as being either newly diagnosed, persistent (lasting more than 3 months following diagnosis), or chronic (still present 12 or more months from diagnosis). Moreover, “idiopathic” was logically replaced by “immune,” and “purpura” was eliminated altogether, given that many mildly affected children actually have no or little purpura. Fortunately, the long-standing abbreviation for what is now called ITP is still valid. These more logical definitions, which are appropriate for children as well as adults with ITP,7Grace R.F. Long M. Kalish L.A. Neufeld E.J. Applicability of 2009 international consensus terminology and criteria for immune thrombocytopenia to a clinical pediatric population.Pediatr Blood Cancer. 2012; 58 ([Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't]): 216-220Crossref PubMed Scopus (16) Google Scholar have since been broadly endorsed by the international community of ITP experts. Among the advances impacting the diagnosis and management of ITP is the adoption of new descriptive terminology. Historically, ITP was considered as being either “acute” (beginning suddenly but resolving within 6 months) or “chronic” (lasting more than 6 months, regardless of the time course and severity of bleeding). Yet such a classification was awkward. Many children initially diagnosed with “acute” ITP continue to have thrombocytopenia beyond 6 months and thus were then labeled as having chronic ITP. Others were designated as having “chronic” disease nevertheless fully recovered by 12 months following diagnosis or even years later. A more attractive and descriptive terminology, recently formulated by an ITP International Working Group,3Rodeghiero F. Stasi R. Gernsheimer T. Michel M. Provan D. Arnold D.M. et al.Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children: report from an international working group.Blood. 2009; 113 ([Consensus Development Conference Research Support, Non-U.S. Gov't]): 2386-2393Crossref PubMed Scopus (1761) Google Scholar has instead categorized ITP as being either newly diagnosed, persistent (lasting more than 3 months following diagnosis), or chronic (still present 12 or more months from diagnosis). Moreover, “idiopathic” was logically replaced by “immune,” and “purpura” was eliminated altogether, given that many mildly affected children actually have no or little purpura. Fortunately, the long-standing abbreviation for what is now called ITP is still valid. These more logical definitions, which are appropriate for children as well as adults with ITP,7Grace R.F. Long M. Kalish L.A. Neufeld E.J. Applicability of 2009 international consensus terminology and criteria for immune thrombocytopenia to a clinical pediatric population.Pediatr Blood Cancer. 2012; 58 ([Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't]): 216-220Crossref PubMed Scopus (16) Google Scholar have since been broadly endorsed by the international community of ITP experts. New Treatment StrategiesA second recent advance benefitting both children and adults with ITP is a better understanding of disease mechanisms and resultant treatment strategies. In ITP, not only are the platelets rapidly destroyed by immunologic processes, but their production by bone marrow megakaryocytes can be reduced as well. This latter observation resulted in the discovery of a new class of drugs, so-called thrombopoietin (TPO) receptor agonists (TPO agents), which stimulate platelet production. A series of careful prospective studies beginning over a decade ago resulted in Food and Drug Administration approval of 2 such drugs, romiplostim and eltrombopag, for adults with chronic refractory ITP and platelet counts below 30 000 per mm3.5Neunert C. Lim W. Crowther M. Cohen A. Solberg Jr., L. Crowther M.A. American Society of HematologyThe American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia.Blood. 2011; 117 ([Practice Guideline Review]): 4190-4207Crossref PubMed Scopus (1320) Google Scholar, 8Provan D. Stasi R. Newland A.C. Blanchette V.S. Bolton-Maggs P. Bussel J.B. et al.International consensus report on the investigation and management of primary immune thrombocytopenia.Blood. 2010; 15 ([Consensus Development Conference Practice Guideline Research Support, Non-U.S. Gov't Review]): 168-186Crossref Scopus (1438) Google Scholar Substantial experience with these agents has demonstrated their efficacy in raising the platelet count as well as their overall safety. Yet to date, use of TPO agents in children with ITP has been limited to several industry-sponsored clinical trials4Bussel J.B. Buchanan G.R. Nugent D.J. Gnarra D.J. Bomgaars L.R. Blanchette V.S. et al.A randomized, double-blind study of romiplostim to determine its safety and efficacy in children with immune thrombocytopenia.Blood. 2011; 118 ([Multicenter Study Randomized Controlled Trial Research Support, Non-U.S. Gov't]): 28-36Crossref PubMed Scopus (168) Google Scholar and small case series.9Elalfy M.S. Abdelmaksoud A.A. Eltonbary K.Y. Romiplostim in children with chronic refractory ITP: randomized placebo controlled study.Ann Hematol. 2011; 90 ([Randomized Controlled Trial]): 1341-1344Crossref PubMed Scopus (62) Google Scholar, 10Mokhtar G.M. Tantawy A.A. El Sherif N.H. Romiplostim therapy in children with unresponsive chronic immune thrombocytopenia.Platelets. 2012; 23 ([Clinical Trial]): 264-273Crossref PubMed Scopus (27) Google Scholar, 11Vilaplana V.E. Aragones J.H. Fernandez-Llamazares C.M. Bieler C.B. Rodriguez S.M. Saez M.S. Use of romiplostim for primary immune thrombocytopenia in children.Pediatr Hematol Oncol. 2012; 29 ([Case Reports]): 197-205Crossref PubMed Scopus (22) Google Scholar, 12Pasquet M. Aladjidi N. Guiton C. Courcoux M.F. Munzer M. Auvrignon A. et al.Centre de Reference National des Cytopenies Auto-immunes de l'Enfant (CEREVANCE)Romiplostim in children with chronic immune thrombocytopenia (ITP): the French experience.Br J Haematol. 2014; 164 ([Research Support, Non-U.S. Gov't]): 266-271Crossref PubMed Scopus (29) Google Scholar Although the preliminary results are promising with regard to efficacy, safety, and acceptability, neither romiplostim nor eltrombopag are have yet been approved for use in children.In this issue of The Journal,6Ramaswamy K. Hsieh L. Leven E. Thompson M.V. Nugent D. Bussel J.B. Thrombopoietic agents for the treatment of persistent and chronic immune thrombocytopenia (ITP) in children.J Pediatr. 2014; 165: 600-605Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar two groups of investigators, highly experienced in the diagnosis and management of ITP, retrospectively report their clinical use of these TPO agents as “second line” therapy in a heterogeneous cohort of 33 children with persistent or chronic ITP. The authors point out the similarities and differences between these two drugs. Both bind to and activate the TPO receptor on the platelet surface, albeit by slightly different mechanisms. Romiplostim is administered by subcutaneous injection once weekly, whereas eltrombopag is given by mouth once daily on an empty stomach. Both drugs are well tolerated, and the current study demonstrates a clinically significant platelet response in over two-thirds of the treated children. In fact, 7 of the authors' 33 patients had a sustained platelet increment and were able to discontinue the TPO agent. Although not specifically reported by the authors, the choice of initial drug was determined in part by the patient and parent deciding whether they desired a weekly “shot” or a daily “pill” that required an empty stomach for four hours. The authors closely monitored their patients according to the same standards employed in the prior and ongoing industry-sponsored studies. The adverse effects occasionally observed in adult patients (ie, bone marrow fibrosis and venous or arterial thrombosis) were not noted in the current pediatric series.The experience of Ramaswamy et al described here6Ramaswamy K. Hsieh L. Leven E. Thompson M.V. Nugent D. Bussel J.B. Thrombopoietic agents for the treatment of persistent and chronic immune thrombocytopenia (ITP) in children.J Pediatr. 2014; 165: 600-605Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar and the limited data reported by others are highly promising. Practitioners who treat children with ITP should consider prescribing these drugs off-label for highly selected young patients with severe and/or refractory ITP. However, in doing so, some pitfalls and barriers are likely to be encountered. Both agents are costly ($50-$75 000 annually for an adult), and in some cases payers may deny their use in children. Also, neither agent “cures” ITP, thus differing in certain respects from splenectomy and immunosuppressive drugs, such as rituximab, which potentially foster long-term or even permanent remissions. Thus, these TPO agents are similar to intravenous immunoglobulin and pulses of corticosteroids in that a single dose or treatment course usually offers only short-term benefits. Also, severe “rebound” thrombocytopenia has been noted following abrupt discontinuation of TPO agents in adults. It seems unlikely that these drugs “induce” a clinical remission but, instead, may help maintain a satisfactory platelet count until the child's ITP remits spontaneously. The primary objective of drug treatment in children and adolescents with ITP continues to be increasing the platelet count to a level where spontaneous bleeding is absent, thus allowing resumption of normal activities. Although the platelet count is more objectively measured than bleeding severity, it is this latter goal that is truly most important to children with ITP and their parents.To date, study of these TPO agents has been described only for patients with persistent or chronic “refractory” ITP. Yet, perhaps another indication that should be explored is severe thrombocytopenia in patients with newly diagnosed ITP and major bleeding who have failed to respond to intravenous immunoglobulin and corticosteroids. Given that an initial clinically meaningful response to TPO agents can occur within just 1-2 weeks, future studies should explore the merits of romiplostim and eltrombopag in such newly diagnosed children as potentially effective “bridge” therapy until spontaneous remission occurs or more conventional second line immunosuppressive therapy or splenectomy is undertaken. A second recent advance benefitting both children and adults with ITP is a better understanding of disease mechanisms and resultant treatment strategies. In ITP, not only are the platelets rapidly destroyed by immunologic processes, but their production by bone marrow megakaryocytes can be reduced as well. This latter observation resulted in the discovery of a new class of drugs, so-called thrombopoietin (TPO) receptor agonists (TPO agents), which stimulate platelet production. A series of careful prospective studies beginning over a decade ago resulted in Food and Drug Administration approval of 2 such drugs, romiplostim and eltrombopag, for adults with chronic refractory ITP and platelet counts below 30 000 per mm3.5Neunert C. Lim W. Crowther M. Cohen A. Solberg Jr., L. Crowther M.A. American Society of HematologyThe American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia.Blood. 2011; 117 ([Practice Guideline Review]): 4190-4207Crossref PubMed Scopus (1320) Google Scholar, 8Provan D. Stasi R. Newland A.C. Blanchette V.S. Bolton-Maggs P. Bussel J.B. et al.International consensus report on the investigation and management of primary immune thrombocytopenia.Blood. 2010; 15 ([Consensus Development Conference Practice Guideline Research Support, Non-U.S. Gov't Review]): 168-186Crossref Scopus (1438) Google Scholar Substantial experience with these agents has demonstrated their efficacy in raising the platelet count as well as their overall safety. Yet to date, use of TPO agents in children with ITP has been limited to several industry-sponsored clinical trials4Bussel J.B. Buchanan G.R. Nugent D.J. Gnarra D.J. Bomgaars L.R. Blanchette V.S. et al.A randomized, double-blind study of romiplostim to determine its safety and efficacy in children with immune thrombocytopenia.Blood. 2011; 118 ([Multicenter Study Randomized Controlled Trial Research Support, Non-U.S. Gov't]): 28-36Crossref PubMed Scopus (168) Google Scholar and small case series.9Elalfy M.S. Abdelmaksoud A.A. Eltonbary K.Y. Romiplostim in children with chronic refractory ITP: randomized placebo controlled study.Ann Hematol. 2011; 90 ([Randomized Controlled Trial]): 1341-1344Crossref PubMed Scopus (62) Google Scholar, 10Mokhtar G.M. Tantawy A.A. El Sherif N.H. Romiplostim therapy in children with unresponsive chronic immune thrombocytopenia.Platelets. 2012; 23 ([Clinical Trial]): 264-273Crossref PubMed Scopus (27) Google Scholar, 11Vilaplana V.E. Aragones J.H. Fernandez-Llamazares C.M. Bieler C.B. Rodriguez S.M. Saez M.S. Use of romiplostim for primary immune thrombocytopenia in children.Pediatr Hematol Oncol. 2012; 29 ([Case Reports]): 197-205Crossref PubMed Scopus (22) Google Scholar, 12Pasquet M. Aladjidi N. Guiton C. Courcoux M.F. Munzer M. Auvrignon A. et al.Centre de Reference National des Cytopenies Auto-immunes de l'Enfant (CEREVANCE)Romiplostim in children with chronic immune thrombocytopenia (ITP): the French experience.Br J Haematol. 2014; 164 ([Research Support, Non-U.S. Gov't]): 266-271Crossref PubMed Scopus (29) Google Scholar Although the preliminary results are promising with regard to efficacy, safety, and acceptability, neither romiplostim nor eltrombopag are have yet been approved for use in children. In this issue of The Journal,6Ramaswamy K. Hsieh L. Leven E. Thompson M.V. Nugent D. Bussel J.B. Thrombopoietic agents for the treatment of persistent and chronic immune thrombocytopenia (ITP) in children.J Pediatr. 2014; 165: 600-605Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar two groups of investigators, highly experienced in the diagnosis and management of ITP, retrospectively report their clinical use of these TPO agents as “second line” therapy in a heterogeneous cohort of 33 children with persistent or chronic ITP. The authors point out the similarities and differences between these two drugs. Both bind to and activate the TPO receptor on the platelet surface, albeit by slightly different mechanisms. Romiplostim is administered by subcutaneous injection once weekly, whereas eltrombopag is given by mouth once daily on an empty stomach. Both drugs are well tolerated, and the current study demonstrates a clinically significant platelet response in over two-thirds of the treated children. In fact, 7 of the authors' 33 patients had a sustained platelet increment and were able to discontinue the TPO agent. Although not specifically reported by the authors, the choice of initial drug was determined in part by the patient and parent deciding whether they desired a weekly “shot” or a daily “pill” that required an empty stomach for four hours. The authors closely monitored their patients according to the same standards employed in the prior and ongoing industry-sponsored studies. The adverse effects occasionally observed in adult patients (ie, bone marrow fibrosis and venous or arterial thrombosis) were not noted in the current pediatric series. The experience of Ramaswamy et al described here6Ramaswamy K. Hsieh L. Leven E. Thompson M.V. Nugent D. Bussel J.B. Thrombopoietic agents for the treatment of persistent and chronic immune thrombocytopenia (ITP) in children.J Pediatr. 2014; 165: 600-605Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar and the limited data reported by others are highly promising. Practitioners who treat children with ITP should consider prescribing these drugs off-label for highly selected young patients with severe and/or refractory ITP. However, in doing so, some pitfalls and barriers are likely to be encountered. Both agents are costly ($50-$75 000 annually for an adult), and in some cases payers may deny their use in children. Also, neither agent “cures” ITP, thus differing in certain respects from splenectomy and immunosuppressive drugs, such as rituximab, which potentially foster long-term or even permanent remissions. Thus, these TPO agents are similar to intravenous immunoglobulin and pulses of corticosteroids in that a single dose or treatment course usually offers only short-term benefits. Also, severe “rebound” thrombocytopenia has been noted following abrupt discontinuation of TPO agents in adults. It seems unlikely that these drugs “induce” a clinical remission but, instead, may help maintain a satisfactory platelet count until the child's ITP remits spontaneously. The primary objective of drug treatment in children and adolescents with ITP continues to be increasing the platelet count to a level where spontaneous bleeding is absent, thus allowing resumption of normal activities. Although the platelet count is more objectively measured than bleeding severity, it is this latter goal that is truly most important to children with ITP and their parents. To date, study of these TPO agents has been described only for patients with persistent or chronic “refractory” ITP. Yet, perhaps another indication that should be explored is severe thrombocytopenia in patients with newly diagnosed ITP and major bleeding who have failed to respond to intravenous immunoglobulin and corticosteroids. Given that an initial clinically meaningful response to TPO agents can occur within just 1-2 weeks, future studies should explore the merits of romiplostim and eltrombopag in such newly diagnosed children as potentially effective “bridge” therapy until spontaneous remission occurs or more conventional second line immunosuppressive therapy or splenectomy is undertaken. Evidence-Based GuidelinesA final noteworthy advance in ITP management was the 2011 publication of an evidence-based guideline by the American Society of Hematology.5Neunert C. Lim W. Crowther M. Cohen A. Solberg Jr., L. Crowther M.A. American Society of HematologyThe American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia.Blood. 2011; 117 ([Practice Guideline Review]): 4190-4207Crossref PubMed Scopus (1320) Google Scholar Understandably, it featured no specific recommendations regarding TPO agent use in children. Yet, in many other ways, the guideline was groundbreaking in its objective and rigorous review of the literature and its patient-centered (as opposed to platelet count-centered) focus.The favorable experience with TPO agents reported in this issue of The Journal by Ramaswamy et al6Ramaswamy K. Hsieh L. Leven E. Thompson M.V. Nugent D. Bussel J.B. Thrombopoietic agents for the treatment of persistent and chronic immune thrombocytopenia (ITP) in children.J Pediatr. 2014; 165: 600-605Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar should raise the profile of this important treatment strategy and foster the design and execution of prospective studies aimed at further exploring this treatment modality in selected young patients with ITP. A final noteworthy advance in ITP management was the 2011 publication of an evidence-based guideline by the American Society of Hematology.5Neunert C. Lim W. Crowther M. Cohen A. Solberg Jr., L. Crowther M.A. American Society of HematologyThe American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia.Blood. 2011; 117 ([Practice Guideline Review]): 4190-4207Crossref PubMed Scopus (1320) Google Scholar Understandably, it featured no specific recommendations regarding TPO agent use in children. Yet, in many other ways, the guideline was groundbreaking in its objective and rigorous review of the literature and its patient-centered (as opposed to platelet count-centered) focus. The favorable experience with TPO agents reported in this issue of The Journal by Ramaswamy et al6Ramaswamy K. Hsieh L. Leven E. Thompson M.V. Nugent D. Bussel J.B. Thrombopoietic agents for the treatment of persistent and chronic immune thrombocytopenia (ITP) in children.J Pediatr. 2014; 165: 600-605Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar should raise the profile of this important treatment strategy and foster the design and execution of prospective studies aimed at further exploring this treatment modality in selected young patients with ITP. Thrombopoietic Agents for the Treatment of Persistent and Chronic Immune Thrombocytopenia in ChildrenThe Journal of PediatricsVol. 165Issue 3PreviewTo determine the safety, tolerability, or efficacy of 2 licensed thrombopoietic agents in children with persistent and chronic immune thrombocytopenia (ITP). Full-Text PDF