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Treatment of Pediatric Primary Immune Thrombocytopenia With Thrombopoietin Receptor Agonists
Treatment of Pediatric Primary Immune Thrombocytopenia With Thrombopoietin Receptor Agonists Thomas Kühne Chronic immune thrombocytopenia (ITP) occurs in approximately one fifth of children with primary ITP and is characterized by a significant lack of clinical data. A minority of these children exhibit bleeding and need treatment. Often standard therapy used for patients with newly diagnosed ITP is administered to stop bleeding and to increase the platelet count. These drugs are associated with adverse effects, which is particularly evident when used during long time. In adult patients with chronic ITP, thrombopoietin receptor agonists (TPO-RAs) demonstrated efficacy in approximately 80% of patients. These drugs have been studied intensely for registration purposes; however, for children and adolescents they are not yet approved and studies are ongoing. First experiences with these drugs show similar effects and safety as in adults, though based on very small numbers of children. These drugs have the potential to be used during long time, in order to increase platelets, to stop or prevent bleeding and to augment quality of life, making long-term safety an important issue. Semin Hematol 52:25–30. C 2014 Elsevier Inc. All rights reserved.
T
he management of children with primary immune thrombocytopenia (ITP) is debated since ITP is recognized as a disease entity. The controversy is caused by limited evidence-based clinical knowledge, the rarity of ITP, and the unpredictability of the natural history of ITP, including the bleeding risk. Most clinical trials were based on investigator-driven initiatives and included often a short-time period to study a drug intervention. The American Society of Hematology practice guidelines from 1996 revealed a lack of clinical trial data in children and adults with many clinical decisions being opinion rather than evidence based.1 The advent of thrombopoietin receptor agonists (TPORAs) offered new treatment strategies and are successful in adults with ITP, demonstrated by many prospective industry-sponsored phase I–III clinical trials for drug registration purposes. No other drugs, which are indicated for the treatment of patients with ITP, have been more intensely studied than TPO-RAs. The introduction and the mode of action of these drugs triggered many fruitful debates of the management of adults with ITP for whom Division of Oncology/Hematology, University Children’s Hospital, Basel, Switzerland. Financial disclosure/conflicts of interest: the author received research funds from Amgen and GlaxoSmithKline. Address correspondence to Thomas Kühne, MD, Division of Oncology/ Hematology, University Children’s Hospital, Postfach, Spitalstrasse 33, CH-4031 Basel, Switzerland.. E-mail: [email protected] 0037-1963/$ - see front matter & 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1053/j.seminhematol.2014.10.004
Seminars in Hematology, Vol 52, No 1, January 2015, pp 25–30
TPO-RAs are approved since 5 years. Clinical trials are ongoing to approve these drugs also for children. This report summarizes preliminary experiences of TPO-RAs in pediatrics.
THROMBOCYTOPENIA, BLEEDING, AND PEDIATRIC ITP Platelets as part of the primary hemostasis maintain vascular integrity. If they are reduced in number and/or in function, the vessel wall becomes permeable and bleeding occurs. Physiologically the number of platelets varies significantly (150–400 109/L),2 and their exact number to maintain vascular integrity is not well understood. Bleeding, bleeding severity, and cessation of bleeding appear to be the result of complex processes, which are clinically often difficult to be identified. This is of particular interest when estimating individual bleeding risk and in clinical decision-making for patients with ITP. ITP is a rare bleeding disorder of children and adults with premature platelet destruction of autoantibodybound platelets by Fc-receptor mediated phagocytosis of the monocytic–phagocytic system. This process may also affect megakaryocytes resulting in reduced platelet production and representing the rationale to treat patients with TPO-RAs. ITP occurs in approximately 1–6 of 100,000 children per year with a peak age of 1–6 years and a constant increase in adolescents and adults, suggesting different pathomechanisms.3,4 Children present frequently with an abrupt onset of bleeding and with a severe 25
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thrombocytopenia, often with a platelet count of less than 20 109/L.5 In approximately two thirds of the children a viral infection occurs days or weeks before bleeding. Although viral and platelet proteins may express similarities resulting in molecular mimicry, it is still not well understood whether these infections play a role in triggering thrombocytopenia. The peak of pediatric ITP is similar to that of the typical frequent viral infections during early childhood.
MANAGEMENT OF PEDIATRIC PRIMARY ITP The evolution of the management of children with ITP in recent years is reflected by various practice guidelines.1,6,7,8,9 In spite of the growing experience reflected by these guidelines, the management of children is still a highly individual endeavor requiring experienced pediatricians.10 Traditionally, the platelet count serves as a treatment endpoint with the goal to increase it by drugs as fast as possible, although there is no clinical basis to support this assumption. In recent years it has been realized that the platelet count has limited power to predict bleeding and therefore alternative endpoints are evaluated, including bleeding and health-related quality of life.11,12,13,14,15 Although these treatment endpoints are complex and not available as bedside tests, they are under investigation, because they are in the primary interest of the patients and may result in more adequate therapies. A milestone in recent years was the inclusion of the “watch and wait strategy” in children with mild or no bleeding in recent guidelines.8,9 Children with more bleeding and with mucous membrane bleeding are often treated because of the fear of life-threatening bleeding, although this complication is a rare event in children. Intracranial hemorrhage occurs in less than 0.5% of children with ITP. Standard therapy includes corticosteroids, intravenous immunoglobulins and anti-D. There is a minority of children with symptomatic chronic ITP. For these children standard therapy, ie, corticosteroids and immunoglobulins may be administered but are associated with many adverse reactions particularly when they are used during long time. Thus, new drugs are warranted for the management of these children. Reasons for searching new drugs in children with chronic ITP include drugs with high efficacy and safety profiles, splenectomy postponing strategies, as splenectomy is not a standard therapy in pediatrics, and improvement of quality of life. TPORAs appear to fulfill these requirements and are currently under investigation in pediatrics.
TPO-RAS Megakaryocytes and platelets are varying greatly in number in healthy individuals and are regulated primarily by thrombopoietin.16,17 However, in thrombocytopenic patients multiple mechanisms regulating thrombopoetin and c-mpl may be present.18 The presence of thrombopoietin
T. Kühne was first assumed in the 1950s in thrombocytopenic individuals.19 The thrombopoietin receptor (c-mpl) was discovered prior to the discovery of thrombopoietin,20 the cDNA of which was cloned in 1994 by five different laboratories.21,22,23,24,25 Thrombopoietin is synthesized and released at a constant rate without storage pools. The liver is the main source of thrombopoietin, although it is also found at much lower concentrations in the kidneys, spleen and bone marrow.26,27 Thrombopoietin activates several downstream signaling pathways and is a promoter of cellular maturation and proliferation. Whether there are functions of thrombopoietin other than interactions with megakaryocytes is not completely understood and subject of research.28 There are other factors, which stimulate megakaryocyte development and maturation, such as interleukin (IL)-3, IL-6, IL-11, and stem cell factor,29,30 without a clear understanding of the complex regulatory functions of these molecules.
EXPERIENCE OF TPO-RAS IN PEDIATRICS TPO-RAs have been successfully introduced for adult patients with chronic ITP with an excellent efficacy and safety profile.31,32,33,34 In children there is still limited experience with small studies and case series, but clinical trials are ongoing. The majority of the reported patients had chronic primary ITP and failed to one or more standard therapy for the treatment of ITP. The majority of the children were non-splenectomized. Bussel et al reported the first multicenter double-blind placebocontrolled study of 22 children aged 1–18 years (median, 10 years) with chronic ITP and a median of five different previous ITP treatments.35 There were six splenectomized children in the romiplostim group and two in the placebo group. The children received weekly subcutaneous injections of romiplostim (n ¼ 17) or placebo (n ¼ 5) for 12 weeks. Patients were stratified by age 1:2:2 (12 months–o3 years, 3–o12 years, 12–o18 years). The children received romiplostim or placebo randomly in a 3:1 ratio. Romiplostim was adjusted by an algorithm to achieve a target platelet count of 50–250 109/L, and the permitted doses ranged from 1–10 mg/kg. The dose could be increased every 2 weeks. Recommended rescue medications were intravenous immunoglobulins, platelet transfusions, and corticosteroids and were administered, if bleeding or wet purpura occurred or if the patient was believed to be at risk by the investigator. Almost all patients (15/17) achieved a platelet count Z50 109/L for 2 consecutive weeks in the romiplostim group in contrast to the placebo group (n ¼ 0). The median weekly dose of romiplostim was 5 mg/kg. No treatment-related serious adverse events were observed. Adverse events included headache (35%), epistaxis (35%), oropharyngeal pain (24%), pyrexia (24%), and others. Six patients of the romiplostim and two of the placebo group were splenectomized before study entry. The two nonresponders to romiplostim were splenectomized children.
Thrombopoietin receptor agonists for pediatric ITP
Splenectomized children received slightly higher doses of romiplostim than non-splenectomized children; however, platelet counts did not differ significantly between these two groups. In a similar single-center study performed in Egypt 18 children with chronic ITP received randomly romiplostim or placebo 2:1 for 12 weeks.36 Age ranges were 2.5–16 years in the romiplostim group and 4–15 years in the placebo group. Romiplostim was started at a dose of 1 mg/kg and was escalated to 5 mg/kg. The median weekly dose of romiplostim was 2 mg/kg. A platelet count of 450 109/L was achieved by 10 patients (83.3%). The peak platelet count was reached by the fifth week of treatment. Rescue treatment with immunoglobulins was administered to one child in the romiplostim group and two in the placebo group. Romiplostim was well tolerated without serious adverse events. The most common reported adverse events were headache, epistaxis, cough, and vomiting. Three non-splenectomized children aged 4, 10, and 13 years were reported in a single-center retrospective longitudinal study of romiplostim with an observation period of 27–39 weeks.37 One of the children had newly diagnosed and the other two had chronic ITP. The patient with newly diagnosed ITP had a complex history of heart transplantation at 4 months of age and received several drugs including immunosuppressives and acetylsalicylic acid. In all patients bone marrow examinations were performed, which was compatible with the diagnosis of ITP. Initial romiplostim dose was 1 mg/kg. The median platelet count was 40–215 109/L. Platelet responses were achieved after 7–28 days. Adverse effects included headache, asthenia, and mucocutaneous bleeding. Eight non-splenectomized patients aged 3.4–15.2 years with chronic ITP participated in a single-center uncontrolled prospective study.38 Romiplostim was started at 1 mg/kg and escalated by 1 mg/kg/wk if the platelet count was o50 109/L. The median duration of romiplostim therapy was 12 (range, 1–22) weeks. One female patient aged 6 years was excluded at screening because of increased bone marrow reticulin and hepatitis C infection. Variable responses were achieved in four of seven children. Addition of corticosteroids in four patients resulted in a rapid platelet response. Adverse events were mild and transient. A national multicenter French retrospective analysis of 10 children with refractory or non-responsive chronic severe ITP aged 1–18 years and treated with romiplostim was recently reported.39 All children had a bone marrow aspiration at diagnosis, which was compatible with ITP. The children were treated for 3–36 months with a romiplostim dose between 4–10 mg/kg, starting at 1 mg/kg with weekly escalation to a maximum of 10 mg/kg. Median duration of thrombocytopenia was 1.9 (range, 0.8–15) years before romiplostim was administered and the median number of previous treatments including splenectomy (two patients) was four (range, 2-11). Concomitant drugs and rescue medication including immunoglobulins and corticosteroids were recorded. A clinical
27 improvement with the Buchanan score12 with disappearance of mucosal bleeding was recorded in five patients. Of those, one patient achieved a complete response (platelet count 4100 109/L) and four patients achieved a response (platelet count 30–100 109/L). In five patients no clinical response was seen with persistent severe bleeding and no platelet response. Serious adverse events were not seen and adverse events were observed in six children. A retrospective analysis of children with chronic ITP who were not on-study was reported with 21 children treated with romiplostim (two centers), and 12 children treated with eltrombopag (single center).40 The mean age of children treated with romiplostim was 11.4 years and with eltrombopag was 14.5 years. Children received one to seven previous treatments and the mean number was identical between the two groups. Immunoglobulines or intravenous anti-D was given in seven patients 1 week before start of TPO-RAs because of very low platelet counts. Major hemorrhage was absent in all children before and during treatment with TPO-RAs. There were three splenectomized children (two on romiplostim and one on eltrombopag). Median starting dose was 5.0 mg/kg weekly for romiplostim and 50 mg daily for eltrombopag. Dose escalation to the maximum of 10 mg/kg romiplostim was performed in 21 children (overall mean maximum weekly dose: 8.1 mg/kg). In the eltrombopag group, eight of 12 children received the maximum dose of 75 mg (overall mean maximum dose: 66.7 mg). The median dose at best response was 6.8 mg/kg (romiplostim) and 75 mg (eltrombopag). Main efficacy end points were defined as platelet count Z50 109/L on 2 consecutive weeks, an increase in platelets Z20 109/L over baseline on 2 consecutive weeks, and the percentage of weeks with platelet counts Z50 109/L. The percentage of patients achieving these three primary end points was similar between the two TPO-RAs. Twenty-seven (82%) of the children responded to TPO-RAs, 18 on romiplostim and nine on eltrombopag. The average time to achieve a platelet count of Z50 109/L was 2.3 weeks (romiplostim) and 2.8 weeks (eltrombopag). The age of the children did not affect the rate of the platelet increase. Duration of successful romiplostim use ranged from 6–44 months, with 11 of the 18 responders ongoing. Duration of successful eltrombopag use ranged from 23–53 months with seven of the 12 responders ongoing. Eighteen children were treated with TPO-RAs for more than 2 years. Serious adverse events related to treatment did not occur, and treatment was not terminated because of study treatment. Adverse events included lacy rash, nausea, and headaches (romiplostim), and headache, epistaxis, and mild rectal bleeding (eltrombopag). Thrombosis occurred in one patient with a provoked deep vein thrombosis at the site of an ankle fracture. This study also examined bone marrow samples with a low grade of changes. Eleven patients had bone marrow examinations before and during treatment with TPO-RAs (10 on romiplostim and one on
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eltrombopag). Nine were on maximal doses of romiplostim (n ¼ 8) and eltrombopag (n ¼ 1). Seven children did not change their degree of reticulin, three increased from bone marrow myelofibrosis (MF) consensus grades MF grade 0 to MF grade 1 on treatment.41,42 Thirty bone marrow examinations (18 romiplostim and 12 eltrombopag) were performed at or after 1 year on treatment and 17 of these (12 romiplostim and five eltrombopag) were performed after more than 2 years of treatment. One patient with an MF grade 1 marrow after 21 months of treatment progressed to MF grade 2 after 40 months of romiplostim and then eltrombopag. In a 12-week, multicenter, randomized, double-blind, placebo-controlled pilot study health-related quality of life and parental burden of children treated with romiplostim were investigated in 17 children and five children who received placebo.43 The study was designed to determine safety, tolerability, and efficacy of romiplostim.35 A reduced parental burden was revealed, but was not as clear for health-related quality of life, probably due to the low patient number. In adults it has been demonstrated that patients receiving romiplostim had greater healthrelated quality-of-life improvements than patients on standard of care; however, the clinical benefit was not clear.44 Further studies in the development of tools and their assessments are needed. At the annual meeting of the European Hematology Association, two studies were presented with eltrombopag in children with chronic ITP. First, a phase II multicenter, placebo-controlled trial with 15 children on eltrombopag in part 1 (13 weeks, open-label dose finding) and 45 children on eltrombopag and 22 on placebo in part 2 (7 weeks, double-blind) with an open-label part 3 for up to 24 weeks.45 In the double-blind phase 81% of children responded at least once, and 36% had platelet counts of Z50 109/L for Z60% of assessments, and 43% had responses for 412/24 weeks in the open-label phase. In the eltrombopag group, there were four serious adverse events (anemia, febrile neutropenia, neutropenia, and urinary tract infection and pyrexia) in the double-blind phase and four additional subjects had alanineaminotransferase (ALT) increase, epistaxis, lenticular opacities, and vitreous opacities in the open-label phase. Most common adverse events included headache, upper respiratory tract infection, diarrhea, nausea, pyrexia, and oropharyngeal pain. Second, in a phase III multicenter, placebo-controlled trial 63 children received eltrombopag and 29 placebo.46 In part 1 with 13 weeks, children were randomized 2:1 to receive either eltrombopag or placebo, followed by part 2, which was an open-label phase for 24 weeks. The ages of the children were 1–17 and 4–17 years on eltrombopag and placebo, respectively. Primary endpoint was met by the study including 40% of children who achieved platelet counts Z50 109/L (without rescue) for Z6 out of 8 weeks between weeks 5–12 during the double-blind phase, and 44% achieved response in Z75 % of assessments in the last 12 weeks of the open-label
T. Kühne
phase. Also, clinical responses were observed including reduction in bleeding from 71% at baseline to 37% at week 12 and 24% at week 24, reduction in baseline ITP medication in 52% of children, and reduction in rescue therapy from 19% at baseline to 13% in the open-label phase. In the eltrombopag group, four serious adverse events including epistaxis, petechiae, hemorrhage, and hypertensive crisis were reported and the most common adverse events included nasopharyngitis, rhinitis, and epistaxis. Aspartate-aminotransferase (ASAT) elevations were reported 4 times.
CONSIDERATIONS OF THE SAFETY PROFILE OF TPO-RAS IN PEDIATRICS The first experience with these drugs in children suggests that immediate adverse events are similar in grade and duration to adults. However, the long-term safety profile has not been studied sufficiently, although it appears to be acceptable in adults, which has been demonstrated in two long-term studies.47,48 There are unanswered questions of potential adverse events, such as thromboembolic events either evoked directly by the drugs or in relationship to comorbidity and use of concomitant drugs,49 bone marrow reticulin and collagen changes,50 stimulation of malignant cells and induction of malignancy or leukemic transformation,51 extramyeloid reactions, reduction in threshold for platelet activation, and stem cell depletion. It must be demonstrated that children exposed to TPO-RAs are not vulnerable or even more vulnerable than adults to these potential side effects. In a recent single-center retrospective, and later prospective study the extent of MF, its clinical relevance, and incidence of phenotypic and karyotypic abnormalities of 16 children and 50 adults with ITP were reported.50 Patients were included if they had at least one bone marrow aspiration and biopsy performed after the initiation of treatment with a TPO-RA. In this center patients undergo bone marrow examination while on TPO-RAs every 1 or 2 years. Patients were treated with romiplostim, eltrombopag, AKR501 (Eisai, Tokyo, Japan), or a nowdiscontinued Shionogi agent. The study revealed that myelofibrosis may be induced by TPO-RAs of grades 2/3 in approximately one fifth of patients. Older age was associated with higher grades of bone marrow fibrosis, and duration of treatment appeared to affect the grade, although this was statistically not significant. No relationship was identified between the grade of fibrosis and any of the following factors: initial marrow fibrosis grade, duration of disease, immature platelet fraction, the dose of TPO-RA, or the type of TPO-RA agent. Of 12 patients with MF grade 2/3, eight were on eltrombopag and four on romiplostim, suggesting that fibrosis could occur with either agent. The number of children was probably too small and interpretation of results is therefore limited. Children tended to have lower degrees of reticulin fibrosis, and collagen fibrosis was absent. The authors concluded
Thrombopoietin receptor agonists for pediatric ITP
that patients should be evaluated regularly with bone marrow examinations in order to identify bone marrow grades 2/3 MF, which should prompt the clinician to stop therapy with TPO-RA, as it appeared in this study that discontinuation of TPO-RAs may prevent development of clinical manifestations.
OUTLOOK AND CONCLUSIONS Clinical information of children with chronic ITP will remain limited because of the rarity of these patients. Thus, clinical research of these children is important, as it has been shown that the platelet count, bleeding and health-related quality of life can be improved by TPORAs. As for adult patients, there may be also alternative indications for TPO-RAs in children with inherited and acquired platelet disorders.52,53 It appears that TPO-RAs for children and adolescents are as efficacious as they are in adult patients with chronic ITP and that the safety profile is similar in both groups. There is still limited information of trial data in children and the safety of long-term use of these drugs remains unknown in children. A close collaboration of pediatric with adult hematology is an important prerequisite to use limited resources for clinical research, to exchange clinical trial data and to plan future research. Extrapolation of adult data to children needs very careful and critical assessments and interpretations and does not substitute pediatric clinical research. In neonatology for example it has been proposed to perform again preclinical research to study TPO-RAs.54
REFERENCES 1. George JN, Woolf SH, Raskob GE, et al. Idiopathic thrombocytopenic purpura: a practice guideline developed by explicit methods for The American Society of Hematology. Blood. 1996;88:3-40. 2. Sloan AW. The normal platelet count in man. J Clin Pathol. 1951;14:78-83. 3. Kühne T. Immune thrombocytopenia (ITP), 2nd edition Bremen: UNI-MED, 2013 4. Schoonen WM, Kucera G, Coalson J, et al. Epidemiology of immune thrombocytopenic purpura in the General Practice Research Database. Br J Haematol. 2009;145:235-44. 5. Kühne T, Imbach P, Bolton-Maggs PHB, Berchtold W, Blanchette V, Buchanan GR. Newly diagnosed idiopathic thrombocytopenic purpura in childhood: an observational study. Lancet. 2001;358:2122-5. 6. Eden OB, Lilleyman JS. Guidelines for management of idiopathic thrombocytopenic purpura. The British Paediatric Haematology Group. Arch Dis Child. 1992;67:1056-8. 7. British Committee for Standards in Haematology General Haematology Task Force. Guidelines for the investigation and management of idiopathic thrombocytopenic purpura in adults, children and in pregnancy. Br J Haematol. 2003;120:574-96. 8. Provan D, Stasi R, Newland AC, et al. International consensus report on the investigation and management of primary immune thrombocytopenia. Blood. 2010;115:168-86.
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9. Neunert C, Lim W, Crowther M, Cohen A, Solberg L Jr., Crowther MA. The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia. Blood. 2011;117:4190-207. 10. Kühne T, Imbach P. Management of children and adolescents with primary immune thrombocytopenia: controversies and solutions. Vox Sang. 2013;104:55-66. 11. Bolton-Maggs PH. Severe bleeding in idiopathic thrombocytopenic purpura. J Pediatr Hematol Oncol. 2003;25(Suppl 1): S47-51. 12. Buchanan GR, Adix L. Grading of hemorrhage in children with idiopathic thrombocytopenic purpura. J Pediatr. 2002;141:683-8. 13. Edslev PW, Rosthøj S, Treutiger I, Rajantie J, Zeller B, Jonsson OG. A clinical score predicting a brief and uneventful course of newly diagnosed idiopathic trombocytopenic purpura in children. Br J Hematol. 2007;138:513-6. 14. Rodeghiero F, Michel M, Gernsheimer T, et al. Standardization of bleeding assessment in immune thrombocytopenia: report from the International Working Group. Blood. 2013;121:2596-606. 15. Klaassen RJ, Blanchette VS, Barnard D, et al. Validity, reliability, and responsiveness of a new measure of healthrelated quality of life in children with immune thrombocytopenic purpura: the Kids' ITP Tools. J Pediatr. 2007;150:510-5. 16. Gurney AL, Carver Moore K, de Sauvage FJ, Moore MW. Thrombocytopenia in c-mpl-deficient mice. Science. 1994;265:1445-7. 17. Carver-Moore K, Broxmeyer HE, Luoh SM, et al. Low levels of erythroid and myeloid progenitors in thrombopoietin- and c-mpl-deficient mice. Blood. 1996;88:803-8. 18. Vianello F, Vettore S, Tezza F, et al. Serum thrombopietin and cMpl expression in thrombocytopenia of different etiologies. Hematol Rep. 2014;6:4996. 19. Kelemen E, Cserhati I, Tanos B. Demonstration and some properties of human thrombopoietin in thrombocythaemic sera. Acta Haematol. 1958;20:350-5. 20. Souyri M, Vigon I, Penciolelli JF, Heard JM, Tambourin P, Wendling F. A putative truncated cytokine receptor gene transduced by the myeloproliferative leukemia virus immortalizes hematopoietic progenitors. Cell. 1990;63:1137-47. 21. Bartley TD, Bogenberger J, Hunt P, et al. Identification and cloning of a megakaryocyte growth and development factor that is a ligand for the cytokine receptor Mpl. Cell. 1994;77:1117-24. 22. de Sauvage FJ, Hass PE, Spencer SD, et al. Stimulation of megakaryocytopoiesis and thrombopoiesis by the c-Mpl ligand. Nature. 1994;369:533-8. 23. Kaushansky K, Lok S, Holly RD, et al. Promotion of megakaryocyte progenitor expansion and differentiation by the c-Mpl ligand thrombopoietin. Nature. 1994;369:568-71. 24. Kuter DJ, Beeler DL, Rosenberg RD. The purification of megapoietin: a physiological regulator of megakaryocyte growth and platelet production. Proc Natl Acad Sci U S A. 1994;91:11104-8. 25. Lok S, Kaushansky K, Holly RD, et al. Cloning and expression of murine thrombopoietin cDNA and stimulation of platelet production in vivo. Nature. 1994;369:565-8. 26. Wolber EM, Dame C, Fahnenstich H, et al. Expression of the thrombopoietin gene in human fetal and neonatal tissues. Blood. 1999;94:97-105.
30
27. Sungaran R, Markovic B, Chong BH. Localization and regulation of thrombopoietin mRNa expression in human kidney, liver, bone marrow, and spleen using in situ hybridization. Blood. 1997;89:101-7. 28. Hitchcock IS, Kaushansky K. Thrombopoietin from beginning to end. Br J Haematol. 2014;165:259-68. 29. Angchaisuksiri P, Carlson PL, Dessypris EN. Effects of recombinant human thrombopoietin on megakaryocyte colony formation and megakaryocyte ploidy by human CD34þ cells in a serum-free system. Br J Haematol. 1996;93:13-7. 30. Kaushansky K, Lin N, Grossmann A, Humes J, Sprugel KH, Broudy VC. Thrombopoietin expands erythroid, granulocyte-macrophage, and megakaryocytic progenitor cells in normal and myelosuppressed mice. Exp Hematol. 1996;24:265-9. 31. Stasi R, Bosworth J, Rhodes E, Shannon MS, Willis F, Gordon-Smith EC. Thrombopoietic agents. Blood Rev. 2010;24:179-90. 32. Hallam S, Provan D, Newland AC. Immune thrombocytopenia—what are the new treatment options? Expert Opin Biol Ther. 2013;13:1173-85. 33. Kuter DJ. The biology of thrombopoietin and thrombopoietin receptor agonists. Int J Hematol. 2013;98:10-23. 34. Bussel JB, Lakkaraja M. Thrombopoietic agents: there is still much to learn. Presse Med. 2014;43:e69-78. 35. Bussel JB, Buchanan GR, Nugent DJ, et al. A randomized, double-blind study of romiplostim to determine its safety and efficacy in children with immune thrombocytopenia. Blood. 2011;118:28-36. 36. Elalfy MS, Abdelmaksoud AA, Eltonbary KY. Romiplostim in children with chronic refractory ITP: randomized placebo controlled study. Ann Hematol. 2011;90:1341-4. 37. Vilaplana VE, Aragonés JH, Fernández-Llamazares CM, Bieler CB, Rodríguez SM, Sáez MS. Use of romiplostim for primary immune thrombocytopenia in children. Pediatr Hematol Oncol. 2012;29:197-205. 38. Mokhtar GM, Tantawy AA, El Sherif NH. Romiplostim therapy in children with unresponsive chronic immune thrombocytopenia. Platelets. 2012;23:264-73. 39. Pasquet M, Aladjidi N, Guiton C, et al. Romiplostim in children with chronic immune thrombocytopenia (ITP): the French experience. Br J Haematol. 2014;164:266-71. 40. Ramaswamy K, Hsieh L, Leven E, Thompson MV, Nugent D, Bussel JB. Thrombopoietic agents for the treatment of persistent and chronic immune thrombocytopenia in children. J Pediatr. Epub 2014 May 22, 10.1016/j.jpeds.2014.03.060. Available from www.jpeds.com. 41. Thiele J, Kvasnicka HM, Facchetti F, Franco V, van der Walt J, Orazi A. European consensus on grading bone marrow fibrosis and assessment of cellularity. Haematologica. 2005;90:1128-32. 42. Kuter DJ, Mufti GJ, Bain BJ, Hasserjian RP, Davis W, Stustein M. Evaluation of bone marrow reticulin formation
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in chronic immune thrombocytopenia patients treated with Romiplostim. Blood. 2009;114:3748-56. Klaassen RJ, Mathias SD, Buchanan G, et al. Pilot study of the effect of romiplostim on childh health-related quality of life (HRQoL) and parental burden in immune thrombocytopenia (ITP). Pediatr Blood Cancer. 2012;58:395-8. Kuter DJ, Mathias SD, Rummel M, et al. Health-related quality of life in nonsplenectomized immune thrombocytopenia patients receiving romiplostim or medical standard of care. Am J Hematol. 2012;87:558-61. Bussel JB, de Miguel PG, Despotovic J, et al. Eltrombopag treatment of childhood persistent and chronic immune thrombocytopenia: final results of the PETIT study (TRA108062), a phase 2, placebo-controlled clinical trial. 19th Congress of the European Hematology Association, Milan, Italy, 12-15 June 2014. Available from: www.ehaweb.org. Grainger JD, Locatelli F, Chotsampancharoen T, et al. Results from PETIT2 (TRA1155450): a randomized placebo-controlled trial of eltrombopag treatment in pediatric patients with chronic immune thrombocytopenia. 19th Congress of the European Hematology Association, Milan, Italy, 12-15 June 2014. Available from: www.ehaweb.org. Kuter DJ, Bussel JB, Newland A, et al. Long-term treatment with romiplostim in patients with chronic immune thrombocytopenia: safety and efficacy. Br J Haematol. 2013;161: 411-23. Saleh MN, Bussel JB, Cheng G, et al. Safety and efficacy of eltrombopag for treatment of chronic immune thrombocytopenia: results of the long-term, open-label EXTEND study. Blood. 2013;121:537-45. Ruggeri M, Tosetto A, Palandri F, et al. Thrombotic risk in patients with primary immune thrombocytopenia is only mildly increased and explained by personal and treatmentrelated risk factors. J Thromb Haemost. 2014;12:1266-73. Ghanima W, Geyer JT, Lee CS, et al. Bone marrow fibrosis in 66 patients with immune thrombocytopenia treated with thrombopoietin-receptor agonists: a single-center, long-term follow-up. Haematologica. 2014;99:937-44. Oshima Y, Yuji K, Tanimoto T, Hinomura Y, Tojo A. Association between acute myelogenous leukemia and thrombopoietin receptor agonists in patients with immune thrombocytopenia. Intern Med. 2013;52:2193-201. Pecci A, Gresele P, Klersy C. Eltrombopag for the treatment of the inherited thrombocytopenia deriving from MYH9 mutations. Blood. 2010;116:5832-7. Favier R, Joffrey F, Favier M, Denoyelle F, Martignetti JA. First successful use of eltrombopag before surgery in a child with MYH9-related thrombocytopenia. Pediatrics. 2013;132: e793-795. Sallmon H, Gutti RK, Ferrer-Marin F, Liu Z-J, Sola-Visner MC. Increasing platelets without transfusion: is it time to introduce novel thrombopoietic agents in neonatal care? J Perinatol. 2010;30:765-9.
T
he management of children with primary immune thrombocytopenia (ITP) is debated since ITP is recognized as a disease entity. The controversy is caused by limited evidence-based clinical knowledge, the rarity of ITP, and the unpredictability of the natural history of ITP, including the bleeding risk. Most clinical trials were based on investigator-driven initiatives and included often a short-time period to study a drug intervention. The American Society of Hematology practice guidelines from 1996 revealed a lack of clinical trial data in children and adults with many clinical decisions being opinion rather than evidence based.1 The advent of thrombopoietin receptor agonists (TPORAs) offered new treatment strategies and are successful in adults with ITP, demonstrated by many prospective industry-sponsored phase I–III clinical trials for drug registration purposes. No other drugs, which are indicated for the treatment of patients with ITP, have been more intensely studied than TPO-RAs. The introduction and the mode of action of these drugs triggered many fruitful debates of the management of adults with ITP for whom Division of Oncology/Hematology, University Children’s Hospital, Basel, Switzerland. Financial disclosure/conflicts of interest: the author received research funds from Amgen and GlaxoSmithKline. Address correspondence to Thomas Kühne, MD, Division of Oncology/ Hematology, University Children’s Hospital, Postfach, Spitalstrasse 33, CH-4031 Basel, Switzerland.. E-mail: [email protected] 0037-1963/$ - see front matter & 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1053/j.seminhematol.2014.10.004
Seminars in Hematology, Vol 52, No 1, January 2015, pp 25–30
TPO-RAs are approved since 5 years. Clinical trials are ongoing to approve these drugs also for children. This report summarizes preliminary experiences of TPO-RAs in pediatrics.
THROMBOCYTOPENIA, BLEEDING, AND PEDIATRIC ITP Platelets as part of the primary hemostasis maintain vascular integrity. If they are reduced in number and/or in function, the vessel wall becomes permeable and bleeding occurs. Physiologically the number of platelets varies significantly (150–400 109/L),2 and their exact number to maintain vascular integrity is not well understood. Bleeding, bleeding severity, and cessation of bleeding appear to be the result of complex processes, which are clinically often difficult to be identified. This is of particular interest when estimating individual bleeding risk and in clinical decision-making for patients with ITP. ITP is a rare bleeding disorder of children and adults with premature platelet destruction of autoantibodybound platelets by Fc-receptor mediated phagocytosis of the monocytic–phagocytic system. This process may also affect megakaryocytes resulting in reduced platelet production and representing the rationale to treat patients with TPO-RAs. ITP occurs in approximately 1–6 of 100,000 children per year with a peak age of 1–6 years and a constant increase in adolescents and adults, suggesting different pathomechanisms.3,4 Children present frequently with an abrupt onset of bleeding and with a severe 25
26
thrombocytopenia, often with a platelet count of less than 20 109/L.5 In approximately two thirds of the children a viral infection occurs days or weeks before bleeding. Although viral and platelet proteins may express similarities resulting in molecular mimicry, it is still not well understood whether these infections play a role in triggering thrombocytopenia. The peak of pediatric ITP is similar to that of the typical frequent viral infections during early childhood.
MANAGEMENT OF PEDIATRIC PRIMARY ITP The evolution of the management of children with ITP in recent years is reflected by various practice guidelines.1,6,7,8,9 In spite of the growing experience reflected by these guidelines, the management of children is still a highly individual endeavor requiring experienced pediatricians.10 Traditionally, the platelet count serves as a treatment endpoint with the goal to increase it by drugs as fast as possible, although there is no clinical basis to support this assumption. In recent years it has been realized that the platelet count has limited power to predict bleeding and therefore alternative endpoints are evaluated, including bleeding and health-related quality of life.11,12,13,14,15 Although these treatment endpoints are complex and not available as bedside tests, they are under investigation, because they are in the primary interest of the patients and may result in more adequate therapies. A milestone in recent years was the inclusion of the “watch and wait strategy” in children with mild or no bleeding in recent guidelines.8,9 Children with more bleeding and with mucous membrane bleeding are often treated because of the fear of life-threatening bleeding, although this complication is a rare event in children. Intracranial hemorrhage occurs in less than 0.5% of children with ITP. Standard therapy includes corticosteroids, intravenous immunoglobulins and anti-D. There is a minority of children with symptomatic chronic ITP. For these children standard therapy, ie, corticosteroids and immunoglobulins may be administered but are associated with many adverse reactions particularly when they are used during long time. Thus, new drugs are warranted for the management of these children. Reasons for searching new drugs in children with chronic ITP include drugs with high efficacy and safety profiles, splenectomy postponing strategies, as splenectomy is not a standard therapy in pediatrics, and improvement of quality of life. TPORAs appear to fulfill these requirements and are currently under investigation in pediatrics.
TPO-RAS Megakaryocytes and platelets are varying greatly in number in healthy individuals and are regulated primarily by thrombopoietin.16,17 However, in thrombocytopenic patients multiple mechanisms regulating thrombopoetin and c-mpl may be present.18 The presence of thrombopoietin
T. Kühne was first assumed in the 1950s in thrombocytopenic individuals.19 The thrombopoietin receptor (c-mpl) was discovered prior to the discovery of thrombopoietin,20 the cDNA of which was cloned in 1994 by five different laboratories.21,22,23,24,25 Thrombopoietin is synthesized and released at a constant rate without storage pools. The liver is the main source of thrombopoietin, although it is also found at much lower concentrations in the kidneys, spleen and bone marrow.26,27 Thrombopoietin activates several downstream signaling pathways and is a promoter of cellular maturation and proliferation. Whether there are functions of thrombopoietin other than interactions with megakaryocytes is not completely understood and subject of research.28 There are other factors, which stimulate megakaryocyte development and maturation, such as interleukin (IL)-3, IL-6, IL-11, and stem cell factor,29,30 without a clear understanding of the complex regulatory functions of these molecules.
EXPERIENCE OF TPO-RAS IN PEDIATRICS TPO-RAs have been successfully introduced for adult patients with chronic ITP with an excellent efficacy and safety profile.31,32,33,34 In children there is still limited experience with small studies and case series, but clinical trials are ongoing. The majority of the reported patients had chronic primary ITP and failed to one or more standard therapy for the treatment of ITP. The majority of the children were non-splenectomized. Bussel et al reported the first multicenter double-blind placebocontrolled study of 22 children aged 1–18 years (median, 10 years) with chronic ITP and a median of five different previous ITP treatments.35 There were six splenectomized children in the romiplostim group and two in the placebo group. The children received weekly subcutaneous injections of romiplostim (n ¼ 17) or placebo (n ¼ 5) for 12 weeks. Patients were stratified by age 1:2:2 (12 months–o3 years, 3–o12 years, 12–o18 years). The children received romiplostim or placebo randomly in a 3:1 ratio. Romiplostim was adjusted by an algorithm to achieve a target platelet count of 50–250 109/L, and the permitted doses ranged from 1–10 mg/kg. The dose could be increased every 2 weeks. Recommended rescue medications were intravenous immunoglobulins, platelet transfusions, and corticosteroids and were administered, if bleeding or wet purpura occurred or if the patient was believed to be at risk by the investigator. Almost all patients (15/17) achieved a platelet count Z50 109/L for 2 consecutive weeks in the romiplostim group in contrast to the placebo group (n ¼ 0). The median weekly dose of romiplostim was 5 mg/kg. No treatment-related serious adverse events were observed. Adverse events included headache (35%), epistaxis (35%), oropharyngeal pain (24%), pyrexia (24%), and others. Six patients of the romiplostim and two of the placebo group were splenectomized before study entry. The two nonresponders to romiplostim were splenectomized children.
Thrombopoietin receptor agonists for pediatric ITP
Splenectomized children received slightly higher doses of romiplostim than non-splenectomized children; however, platelet counts did not differ significantly between these two groups. In a similar single-center study performed in Egypt 18 children with chronic ITP received randomly romiplostim or placebo 2:1 for 12 weeks.36 Age ranges were 2.5–16 years in the romiplostim group and 4–15 years in the placebo group. Romiplostim was started at a dose of 1 mg/kg and was escalated to 5 mg/kg. The median weekly dose of romiplostim was 2 mg/kg. A platelet count of 450 109/L was achieved by 10 patients (83.3%). The peak platelet count was reached by the fifth week of treatment. Rescue treatment with immunoglobulins was administered to one child in the romiplostim group and two in the placebo group. Romiplostim was well tolerated without serious adverse events. The most common reported adverse events were headache, epistaxis, cough, and vomiting. Three non-splenectomized children aged 4, 10, and 13 years were reported in a single-center retrospective longitudinal study of romiplostim with an observation period of 27–39 weeks.37 One of the children had newly diagnosed and the other two had chronic ITP. The patient with newly diagnosed ITP had a complex history of heart transplantation at 4 months of age and received several drugs including immunosuppressives and acetylsalicylic acid. In all patients bone marrow examinations were performed, which was compatible with the diagnosis of ITP. Initial romiplostim dose was 1 mg/kg. The median platelet count was 40–215 109/L. Platelet responses were achieved after 7–28 days. Adverse effects included headache, asthenia, and mucocutaneous bleeding. Eight non-splenectomized patients aged 3.4–15.2 years with chronic ITP participated in a single-center uncontrolled prospective study.38 Romiplostim was started at 1 mg/kg and escalated by 1 mg/kg/wk if the platelet count was o50 109/L. The median duration of romiplostim therapy was 12 (range, 1–22) weeks. One female patient aged 6 years was excluded at screening because of increased bone marrow reticulin and hepatitis C infection. Variable responses were achieved in four of seven children. Addition of corticosteroids in four patients resulted in a rapid platelet response. Adverse events were mild and transient. A national multicenter French retrospective analysis of 10 children with refractory or non-responsive chronic severe ITP aged 1–18 years and treated with romiplostim was recently reported.39 All children had a bone marrow aspiration at diagnosis, which was compatible with ITP. The children were treated for 3–36 months with a romiplostim dose between 4–10 mg/kg, starting at 1 mg/kg with weekly escalation to a maximum of 10 mg/kg. Median duration of thrombocytopenia was 1.9 (range, 0.8–15) years before romiplostim was administered and the median number of previous treatments including splenectomy (two patients) was four (range, 2-11). Concomitant drugs and rescue medication including immunoglobulins and corticosteroids were recorded. A clinical
27 improvement with the Buchanan score12 with disappearance of mucosal bleeding was recorded in five patients. Of those, one patient achieved a complete response (platelet count 4100 109/L) and four patients achieved a response (platelet count 30–100 109/L). In five patients no clinical response was seen with persistent severe bleeding and no platelet response. Serious adverse events were not seen and adverse events were observed in six children. A retrospective analysis of children with chronic ITP who were not on-study was reported with 21 children treated with romiplostim (two centers), and 12 children treated with eltrombopag (single center).40 The mean age of children treated with romiplostim was 11.4 years and with eltrombopag was 14.5 years. Children received one to seven previous treatments and the mean number was identical between the two groups. Immunoglobulines or intravenous anti-D was given in seven patients 1 week before start of TPO-RAs because of very low platelet counts. Major hemorrhage was absent in all children before and during treatment with TPO-RAs. There were three splenectomized children (two on romiplostim and one on eltrombopag). Median starting dose was 5.0 mg/kg weekly for romiplostim and 50 mg daily for eltrombopag. Dose escalation to the maximum of 10 mg/kg romiplostim was performed in 21 children (overall mean maximum weekly dose: 8.1 mg/kg). In the eltrombopag group, eight of 12 children received the maximum dose of 75 mg (overall mean maximum dose: 66.7 mg). The median dose at best response was 6.8 mg/kg (romiplostim) and 75 mg (eltrombopag). Main efficacy end points were defined as platelet count Z50 109/L on 2 consecutive weeks, an increase in platelets Z20 109/L over baseline on 2 consecutive weeks, and the percentage of weeks with platelet counts Z50 109/L. The percentage of patients achieving these three primary end points was similar between the two TPO-RAs. Twenty-seven (82%) of the children responded to TPO-RAs, 18 on romiplostim and nine on eltrombopag. The average time to achieve a platelet count of Z50 109/L was 2.3 weeks (romiplostim) and 2.8 weeks (eltrombopag). The age of the children did not affect the rate of the platelet increase. Duration of successful romiplostim use ranged from 6–44 months, with 11 of the 18 responders ongoing. Duration of successful eltrombopag use ranged from 23–53 months with seven of the 12 responders ongoing. Eighteen children were treated with TPO-RAs for more than 2 years. Serious adverse events related to treatment did not occur, and treatment was not terminated because of study treatment. Adverse events included lacy rash, nausea, and headaches (romiplostim), and headache, epistaxis, and mild rectal bleeding (eltrombopag). Thrombosis occurred in one patient with a provoked deep vein thrombosis at the site of an ankle fracture. This study also examined bone marrow samples with a low grade of changes. Eleven patients had bone marrow examinations before and during treatment with TPO-RAs (10 on romiplostim and one on
28
eltrombopag). Nine were on maximal doses of romiplostim (n ¼ 8) and eltrombopag (n ¼ 1). Seven children did not change their degree of reticulin, three increased from bone marrow myelofibrosis (MF) consensus grades MF grade 0 to MF grade 1 on treatment.41,42 Thirty bone marrow examinations (18 romiplostim and 12 eltrombopag) were performed at or after 1 year on treatment and 17 of these (12 romiplostim and five eltrombopag) were performed after more than 2 years of treatment. One patient with an MF grade 1 marrow after 21 months of treatment progressed to MF grade 2 after 40 months of romiplostim and then eltrombopag. In a 12-week, multicenter, randomized, double-blind, placebo-controlled pilot study health-related quality of life and parental burden of children treated with romiplostim were investigated in 17 children and five children who received placebo.43 The study was designed to determine safety, tolerability, and efficacy of romiplostim.35 A reduced parental burden was revealed, but was not as clear for health-related quality of life, probably due to the low patient number. In adults it has been demonstrated that patients receiving romiplostim had greater healthrelated quality-of-life improvements than patients on standard of care; however, the clinical benefit was not clear.44 Further studies in the development of tools and their assessments are needed. At the annual meeting of the European Hematology Association, two studies were presented with eltrombopag in children with chronic ITP. First, a phase II multicenter, placebo-controlled trial with 15 children on eltrombopag in part 1 (13 weeks, open-label dose finding) and 45 children on eltrombopag and 22 on placebo in part 2 (7 weeks, double-blind) with an open-label part 3 for up to 24 weeks.45 In the double-blind phase 81% of children responded at least once, and 36% had platelet counts of Z50 109/L for Z60% of assessments, and 43% had responses for 412/24 weeks in the open-label phase. In the eltrombopag group, there were four serious adverse events (anemia, febrile neutropenia, neutropenia, and urinary tract infection and pyrexia) in the double-blind phase and four additional subjects had alanineaminotransferase (ALT) increase, epistaxis, lenticular opacities, and vitreous opacities in the open-label phase. Most common adverse events included headache, upper respiratory tract infection, diarrhea, nausea, pyrexia, and oropharyngeal pain. Second, in a phase III multicenter, placebo-controlled trial 63 children received eltrombopag and 29 placebo.46 In part 1 with 13 weeks, children were randomized 2:1 to receive either eltrombopag or placebo, followed by part 2, which was an open-label phase for 24 weeks. The ages of the children were 1–17 and 4–17 years on eltrombopag and placebo, respectively. Primary endpoint was met by the study including 40% of children who achieved platelet counts Z50 109/L (without rescue) for Z6 out of 8 weeks between weeks 5–12 during the double-blind phase, and 44% achieved response in Z75 % of assessments in the last 12 weeks of the open-label
T. Kühne
phase. Also, clinical responses were observed including reduction in bleeding from 71% at baseline to 37% at week 12 and 24% at week 24, reduction in baseline ITP medication in 52% of children, and reduction in rescue therapy from 19% at baseline to 13% in the open-label phase. In the eltrombopag group, four serious adverse events including epistaxis, petechiae, hemorrhage, and hypertensive crisis were reported and the most common adverse events included nasopharyngitis, rhinitis, and epistaxis. Aspartate-aminotransferase (ASAT) elevations were reported 4 times.
CONSIDERATIONS OF THE SAFETY PROFILE OF TPO-RAS IN PEDIATRICS The first experience with these drugs in children suggests that immediate adverse events are similar in grade and duration to adults. However, the long-term safety profile has not been studied sufficiently, although it appears to be acceptable in adults, which has been demonstrated in two long-term studies.47,48 There are unanswered questions of potential adverse events, such as thromboembolic events either evoked directly by the drugs or in relationship to comorbidity and use of concomitant drugs,49 bone marrow reticulin and collagen changes,50 stimulation of malignant cells and induction of malignancy or leukemic transformation,51 extramyeloid reactions, reduction in threshold for platelet activation, and stem cell depletion. It must be demonstrated that children exposed to TPO-RAs are not vulnerable or even more vulnerable than adults to these potential side effects. In a recent single-center retrospective, and later prospective study the extent of MF, its clinical relevance, and incidence of phenotypic and karyotypic abnormalities of 16 children and 50 adults with ITP were reported.50 Patients were included if they had at least one bone marrow aspiration and biopsy performed after the initiation of treatment with a TPO-RA. In this center patients undergo bone marrow examination while on TPO-RAs every 1 or 2 years. Patients were treated with romiplostim, eltrombopag, AKR501 (Eisai, Tokyo, Japan), or a nowdiscontinued Shionogi agent. The study revealed that myelofibrosis may be induced by TPO-RAs of grades 2/3 in approximately one fifth of patients. Older age was associated with higher grades of bone marrow fibrosis, and duration of treatment appeared to affect the grade, although this was statistically not significant. No relationship was identified between the grade of fibrosis and any of the following factors: initial marrow fibrosis grade, duration of disease, immature platelet fraction, the dose of TPO-RA, or the type of TPO-RA agent. Of 12 patients with MF grade 2/3, eight were on eltrombopag and four on romiplostim, suggesting that fibrosis could occur with either agent. The number of children was probably too small and interpretation of results is therefore limited. Children tended to have lower degrees of reticulin fibrosis, and collagen fibrosis was absent. The authors concluded
Thrombopoietin receptor agonists for pediatric ITP
that patients should be evaluated regularly with bone marrow examinations in order to identify bone marrow grades 2/3 MF, which should prompt the clinician to stop therapy with TPO-RA, as it appeared in this study that discontinuation of TPO-RAs may prevent development of clinical manifestations.
OUTLOOK AND CONCLUSIONS Clinical information of children with chronic ITP will remain limited because of the rarity of these patients. Thus, clinical research of these children is important, as it has been shown that the platelet count, bleeding and health-related quality of life can be improved by TPORAs. As for adult patients, there may be also alternative indications for TPO-RAs in children with inherited and acquired platelet disorders.52,53 It appears that TPO-RAs for children and adolescents are as efficacious as they are in adult patients with chronic ITP and that the safety profile is similar in both groups. There is still limited information of trial data in children and the safety of long-term use of these drugs remains unknown in children. A close collaboration of pediatric with adult hematology is an important prerequisite to use limited resources for clinical research, to exchange clinical trial data and to plan future research. Extrapolation of adult data to children needs very careful and critical assessments and interpretations and does not substitute pediatric clinical research. In neonatology for example it has been proposed to perform again preclinical research to study TPO-RAs.54
REFERENCES 1. George JN, Woolf SH, Raskob GE, et al. Idiopathic thrombocytopenic purpura: a practice guideline developed by explicit methods for The American Society of Hematology. Blood. 1996;88:3-40. 2. Sloan AW. The normal platelet count in man. J Clin Pathol. 1951;14:78-83. 3. Kühne T. Immune thrombocytopenia (ITP), 2nd edition Bremen: UNI-MED, 2013 4. Schoonen WM, Kucera G, Coalson J, et al. Epidemiology of immune thrombocytopenic purpura in the General Practice Research Database. Br J Haematol. 2009;145:235-44. 5. Kühne T, Imbach P, Bolton-Maggs PHB, Berchtold W, Blanchette V, Buchanan GR. Newly diagnosed idiopathic thrombocytopenic purpura in childhood: an observational study. Lancet. 2001;358:2122-5. 6. Eden OB, Lilleyman JS. Guidelines for management of idiopathic thrombocytopenic purpura. The British Paediatric Haematology Group. Arch Dis Child. 1992;67:1056-8. 7. British Committee for Standards in Haematology General Haematology Task Force. Guidelines for the investigation and management of idiopathic thrombocytopenic purpura in adults, children and in pregnancy. Br J Haematol. 2003;120:574-96. 8. Provan D, Stasi R, Newland AC, et al. International consensus report on the investigation and management of primary immune thrombocytopenia. Blood. 2010;115:168-86.
29
9. Neunert C, Lim W, Crowther M, Cohen A, Solberg L Jr., Crowther MA. The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia. Blood. 2011;117:4190-207. 10. Kühne T, Imbach P. Management of children and adolescents with primary immune thrombocytopenia: controversies and solutions. Vox Sang. 2013;104:55-66. 11. Bolton-Maggs PH. Severe bleeding in idiopathic thrombocytopenic purpura. J Pediatr Hematol Oncol. 2003;25(Suppl 1): S47-51. 12. Buchanan GR, Adix L. Grading of hemorrhage in children with idiopathic thrombocytopenic purpura. J Pediatr. 2002;141:683-8. 13. Edslev PW, Rosthøj S, Treutiger I, Rajantie J, Zeller B, Jonsson OG. A clinical score predicting a brief and uneventful course of newly diagnosed idiopathic trombocytopenic purpura in children. Br J Hematol. 2007;138:513-6. 14. Rodeghiero F, Michel M, Gernsheimer T, et al. Standardization of bleeding assessment in immune thrombocytopenia: report from the International Working Group. Blood. 2013;121:2596-606. 15. Klaassen RJ, Blanchette VS, Barnard D, et al. Validity, reliability, and responsiveness of a new measure of healthrelated quality of life in children with immune thrombocytopenic purpura: the Kids' ITP Tools. J Pediatr. 2007;150:510-5. 16. Gurney AL, Carver Moore K, de Sauvage FJ, Moore MW. Thrombocytopenia in c-mpl-deficient mice. Science. 1994;265:1445-7. 17. Carver-Moore K, Broxmeyer HE, Luoh SM, et al. Low levels of erythroid and myeloid progenitors in thrombopoietin- and c-mpl-deficient mice. Blood. 1996;88:803-8. 18. Vianello F, Vettore S, Tezza F, et al. Serum thrombopietin and cMpl expression in thrombocytopenia of different etiologies. Hematol Rep. 2014;6:4996. 19. Kelemen E, Cserhati I, Tanos B. Demonstration and some properties of human thrombopoietin in thrombocythaemic sera. Acta Haematol. 1958;20:350-5. 20. Souyri M, Vigon I, Penciolelli JF, Heard JM, Tambourin P, Wendling F. A putative truncated cytokine receptor gene transduced by the myeloproliferative leukemia virus immortalizes hematopoietic progenitors. Cell. 1990;63:1137-47. 21. Bartley TD, Bogenberger J, Hunt P, et al. Identification and cloning of a megakaryocyte growth and development factor that is a ligand for the cytokine receptor Mpl. Cell. 1994;77:1117-24. 22. de Sauvage FJ, Hass PE, Spencer SD, et al. Stimulation of megakaryocytopoiesis and thrombopoiesis by the c-Mpl ligand. Nature. 1994;369:533-8. 23. Kaushansky K, Lok S, Holly RD, et al. Promotion of megakaryocyte progenitor expansion and differentiation by the c-Mpl ligand thrombopoietin. Nature. 1994;369:568-71. 24. Kuter DJ, Beeler DL, Rosenberg RD. The purification of megapoietin: a physiological regulator of megakaryocyte growth and platelet production. Proc Natl Acad Sci U S A. 1994;91:11104-8. 25. Lok S, Kaushansky K, Holly RD, et al. Cloning and expression of murine thrombopoietin cDNA and stimulation of platelet production in vivo. Nature. 1994;369:565-8. 26. Wolber EM, Dame C, Fahnenstich H, et al. Expression of the thrombopoietin gene in human fetal and neonatal tissues. Blood. 1999;94:97-105.
30
27. Sungaran R, Markovic B, Chong BH. Localization and regulation of thrombopoietin mRNa expression in human kidney, liver, bone marrow, and spleen using in situ hybridization. Blood. 1997;89:101-7. 28. Hitchcock IS, Kaushansky K. Thrombopoietin from beginning to end. Br J Haematol. 2014;165:259-68. 29. Angchaisuksiri P, Carlson PL, Dessypris EN. Effects of recombinant human thrombopoietin on megakaryocyte colony formation and megakaryocyte ploidy by human CD34þ cells in a serum-free system. Br J Haematol. 1996;93:13-7. 30. Kaushansky K, Lin N, Grossmann A, Humes J, Sprugel KH, Broudy VC. Thrombopoietin expands erythroid, granulocyte-macrophage, and megakaryocytic progenitor cells in normal and myelosuppressed mice. Exp Hematol. 1996;24:265-9. 31. Stasi R, Bosworth J, Rhodes E, Shannon MS, Willis F, Gordon-Smith EC. Thrombopoietic agents. Blood Rev. 2010;24:179-90. 32. Hallam S, Provan D, Newland AC. Immune thrombocytopenia—what are the new treatment options? Expert Opin Biol Ther. 2013;13:1173-85. 33. Kuter DJ. The biology of thrombopoietin and thrombopoietin receptor agonists. Int J Hematol. 2013;98:10-23. 34. Bussel JB, Lakkaraja M. Thrombopoietic agents: there is still much to learn. Presse Med. 2014;43:e69-78. 35. Bussel JB, Buchanan GR, Nugent DJ, et al. A randomized, double-blind study of romiplostim to determine its safety and efficacy in children with immune thrombocytopenia. Blood. 2011;118:28-36. 36. Elalfy MS, Abdelmaksoud AA, Eltonbary KY. Romiplostim in children with chronic refractory ITP: randomized placebo controlled study. Ann Hematol. 2011;90:1341-4. 37. Vilaplana VE, Aragonés JH, Fernández-Llamazares CM, Bieler CB, Rodríguez SM, Sáez MS. Use of romiplostim for primary immune thrombocytopenia in children. Pediatr Hematol Oncol. 2012;29:197-205. 38. Mokhtar GM, Tantawy AA, El Sherif NH. Romiplostim therapy in children with unresponsive chronic immune thrombocytopenia. Platelets. 2012;23:264-73. 39. Pasquet M, Aladjidi N, Guiton C, et al. Romiplostim in children with chronic immune thrombocytopenia (ITP): the French experience. Br J Haematol. 2014;164:266-71. 40. Ramaswamy K, Hsieh L, Leven E, Thompson MV, Nugent D, Bussel JB. Thrombopoietic agents for the treatment of persistent and chronic immune thrombocytopenia in children. J Pediatr. Epub 2014 May 22, 10.1016/j.jpeds.2014.03.060. Available from www.jpeds.com. 41. Thiele J, Kvasnicka HM, Facchetti F, Franco V, van der Walt J, Orazi A. European consensus on grading bone marrow fibrosis and assessment of cellularity. Haematologica. 2005;90:1128-32. 42. Kuter DJ, Mufti GJ, Bain BJ, Hasserjian RP, Davis W, Stustein M. Evaluation of bone marrow reticulin formation
T. Kühne
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
in chronic immune thrombocytopenia patients treated with Romiplostim. Blood. 2009;114:3748-56. Klaassen RJ, Mathias SD, Buchanan G, et al. Pilot study of the effect of romiplostim on childh health-related quality of life (HRQoL) and parental burden in immune thrombocytopenia (ITP). Pediatr Blood Cancer. 2012;58:395-8. Kuter DJ, Mathias SD, Rummel M, et al. Health-related quality of life in nonsplenectomized immune thrombocytopenia patients receiving romiplostim or medical standard of care. Am J Hematol. 2012;87:558-61. Bussel JB, de Miguel PG, Despotovic J, et al. Eltrombopag treatment of childhood persistent and chronic immune thrombocytopenia: final results of the PETIT study (TRA108062), a phase 2, placebo-controlled clinical trial. 19th Congress of the European Hematology Association, Milan, Italy, 12-15 June 2014. Available from: www.ehaweb.org. Grainger JD, Locatelli F, Chotsampancharoen T, et al. Results from PETIT2 (TRA1155450): a randomized placebo-controlled trial of eltrombopag treatment in pediatric patients with chronic immune thrombocytopenia. 19th Congress of the European Hematology Association, Milan, Italy, 12-15 June 2014. Available from: www.ehaweb.org. Kuter DJ, Bussel JB, Newland A, et al. Long-term treatment with romiplostim in patients with chronic immune thrombocytopenia: safety and efficacy. Br J Haematol. 2013;161: 411-23. Saleh MN, Bussel JB, Cheng G, et al. Safety and efficacy of eltrombopag for treatment of chronic immune thrombocytopenia: results of the long-term, open-label EXTEND study. Blood. 2013;121:537-45. Ruggeri M, Tosetto A, Palandri F, et al. Thrombotic risk in patients with primary immune thrombocytopenia is only mildly increased and explained by personal and treatmentrelated risk factors. J Thromb Haemost. 2014;12:1266-73. Ghanima W, Geyer JT, Lee CS, et al. Bone marrow fibrosis in 66 patients with immune thrombocytopenia treated with thrombopoietin-receptor agonists: a single-center, long-term follow-up. Haematologica. 2014;99:937-44. Oshima Y, Yuji K, Tanimoto T, Hinomura Y, Tojo A. Association between acute myelogenous leukemia and thrombopoietin receptor agonists in patients with immune thrombocytopenia. Intern Med. 2013;52:2193-201. Pecci A, Gresele P, Klersy C. Eltrombopag for the treatment of the inherited thrombocytopenia deriving from MYH9 mutations. Blood. 2010;116:5832-7. Favier R, Joffrey F, Favier M, Denoyelle F, Martignetti JA. First successful use of eltrombopag before surgery in a child with MYH9-related thrombocytopenia. Pediatrics. 2013;132: e793-795. Sallmon H, Gutti RK, Ferrer-Marin F, Liu Z-J, Sola-Visner MC. Increasing platelets without transfusion: is it time to introduce novel thrombopoietic agents in neonatal care? J Perinatol. 2010;30:765-9.