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Thrombopoietin-receptor agonists in children with immune thrombocytopenia
Comment
Thrombopoietin-receptor agonists in children with immune thrombocytopenia Paediatric immune thrombocytopenia is usually a benign condition that results in spontaneous remission within 6–12 months for most of children. Despite severe thrombocytopenia, clinically significant bleeding events are rare. Thus, a common treatment approach for many children is close observation.1 However, a small proportion of children have severe haemorrhage, develop chronic immune thrombocytopenia, are refractory to first-line therapy, or report low healthrelated quality of life. For these children, development of novel drugs could bring a substantial benefit. Historically, second-line treatment options for immune thrombocytopenia were scarce. Early understanding was based on knowledge of immune destruction of antibody-coated platelets in the spleen. Therefore, splenectomy was one of the earliest options for refractory patients.2 An appreciation for the long-term risk of sepsis associated with splenectomy, coupled with a more refined understanding of the pathophysiology of immune thrombocytopenia, resulted in therapeutic developments with immunosuppressant agents such as rituximab.3 A major advancement was the discovery that antibodies in patients with immune thrombocytopenia cause apoptosis-like changes in megakaryocytes, which leads to reduced platelet production.4 This finding led to investigations of thrombopoietin, the main megakaryocyte growth factor, as a potential non-immunosuppressant treatment option for patients with immune thrombocytopenia. Two recombinant thrombopoietin-receptor agonists, eltrombopag and romiplostim, are currently approved by the US Food and Drug Administration (FDA) for adults with chronic immune thrombocytopenia. Both drugs increase the platelet count, reduce bleeding events, and improve health-related quality of life in adults.5–9 Although data are accumulating in the adult population, little prospective data have been reported for paediatric patients.10,11 Because of this shortage of data, the 2011 immune thrombocytopenia guidelines of the American Society of Hematology were unable to comment on the use of thrombopoietin-receptor agonists in children.1 The Lancet and The Lancet Haematology report two parallel randomised, multicentre, placebo-
controlled trials of eltrombopag in children with chronic immune thrombocytopenia.12,13 John Grainger and colleagues12 report the findings from PETIT2, a phase 3 trial, in The Lancet, and James Bussel and colleagues13 describe the results of PETIT, a phase 2 trial, in The Lancet Haematology. Together, these studies report important findings for 15 children enrolled in the PETIT dose-finding study and 159 children randomly assigned to receive eltrombopag or placebo (n=67 in PETIT, n=92 in PETIT2). The studies enrolled similar patient cohorts: patients aged 1–17 years with platelet counts less than 30 × 10⁹ per L. Most patients had received more than two previous treatments, few had undergone splenectomy, and most had chronic immune thrombocytopenia. Patients in the randomised phases received doubleblind treatment for 7 weeks in PETIT and 13 weeks in PETIT2, followed by a 24 week open-label phase. Overall, the findings of both trials showed the efficacy of eltrombopag. During the double-blind phase of PETIT, 16 (36%) patients who received eltrombopag achieved a platelet count of 50 × 10⁹ per L or more for 60% or more of the visits from weeks 2–6 compared with no patients among those who received placebo (odds ratio [OR] 5·84, 95% CI 1·18–28·90).13 Similarly, in the PETIT2 doubleblind phase, 25 (40%) patients given eltrombopag achieved a platelet count of at least 50 × 10⁹ per L for 75% or more of the visits between weeks 5–12, compared with one (3%) patient who received placebo (OR 18·0, 95% CI 2·3–1·40).12 A platelet count of 50 × 10⁹ per L or more was detected at least once in 62% (n=28 in PETIT; n=39 in PETIT2) of patients who received eltrombopag during the first 6 weeks of both studies. Furthermore, clinical data showed that treatment with eltrombopag resulted in a proportional reduction in WHO grade 1–4 bleeding events (eltrombopag vs placebo: 14 [31%] vs 18 [82%] patients in PETIT; 23 [37%] vs 16 [55%] patients in PETIT2) and need for rescue treatments (eltrombopag vs placebo: six [13%] vs 11 [50%] patients in PETIT; 12 [19%] vs seven [24%] patients in PETIT2) compared with placebo. During the open-label phase, about 80% of patients (54 [81%] patients in PETIT and 70 [80%] patients in PETIT2) achieved a platelet count of 50 × 10⁹ per L or more at least once in both studies.
www.thelancet.com Published online July 29, 2015 http://dx.doi.org/10.1016/S0140-6736(15)61223-5
Published Online July 29, 2015 http://dx.doi.org/10.1016/ S0140-6736(15)61223-5 See Online/Articles http://dx.doi.org/10.1016/ S0140-6736(15)61107-2 See Online/Articles Lancet Haem 2015; published online July 29. http://dx.doi.org/10.1016/ S2352-3026(15)00114-3
1
Comment
Duration
Efficacy outcomes based on platelet count
Results
Platelet count ≥50 × 10⁹ per L for ≥6 weeks from week 5–12 of the DBP Proportion of patients achieving platelet count ≥50 × 10⁹ per L in the absence of rescue therapy at any time during DBP Proportion of patients achieving platelet count ≥50 × 10⁹ per L at any time of the OLP Maximum period of continuous platelet counts ≥50 × 10⁹ per L in patients receiving eltrombopag (mean [SD], weeks)
25 (40%) eltrombopag, 1 (3%) placebo 47 (75%) eltrombopag, 6 (21%) placebo
Platelet count ≥50 × 10⁹ per L for ≥60% of assessments from weeks 2–6 of the DBP Proportion of patients achieving platelet count ≥50 × 10⁹ per L in the absence of rescue therapy during weeks 1–6 of the DBP Proportion of patients achieving platelet count ≥50 × 10⁹ per L at any time of the OLP
16 (36%) eltrombopag, 0 (0%) placebo
Eltrombopag Grainger, 201512 13 week DBP and (n=92) 24 week OLP
Bussel, 201513 (n=67)
7 week DBP and 24 week OLP
70 (80%) DBP: 3·3 (3·1) weeks OLP: 8·6 (7·8) weeks
28 (62%) eltrombopag, 7 (32%) placebo 54 (81%)
Romiplostim Bussel, 201511 (n=22)
≤109 week OLP
Median percentage of weeks patients had a platelet count ≥50 × 10⁹ per L Percentage of patients with a peak platelet count ≥150 × 10⁹ per L
84·3% (IQR 69·9–90·8) 21 (95·5%)
Bussel, 201110 (n=22)
12 week DBP
Platelet count ≥50 × 10⁹ per L for 2 consecutive weeks and an increase of platelet count ≥20 × 10⁹ per L above baseline from weeks 1–12 Proportion of patients with a platelet count >100 × 10⁹ per L at any time in the absence of rescue medication Median number of weeks platelet counts were ≥50 × 10⁹ per L in patients receiving romiplostim
15 (88%) romiplostim, 0 placebo 12 (71%) romiplostim, 0 placebo 7 weeks (range 0–11)
DBP=double-blind phase. OLP=open-label phase.
Table: Variability in response reporting across prospective thrombopoeitin-receptor agonist trials in children
Direct comparison of these responses with other trials of thrombopoietin-receptor agonists is challenging because the primary outcome varies among studies and dosing strategies are different (table). Nevertheless, the proportions of patients with responses in the double-blind and open-label phases of PETIT and PETIT2 seem to be similar to the findings reported in adult studies of thrombopoietin-receptor agonists.7–9 The paediatric romiplostim phase 1/2 trial10 reported responses in 15 [88%] of 17 patients, with the primary outcome as a platelet count of at least 50 × 10⁹ per L on 2 consecutive weeks. This result is similar to those seen in the double-blind and open-label phases of the two PETIT studies, with the outcome defined as a platelet count of at least 50 × 10⁹ per L once. Because of the associated difficulties and expense needed for studies of rare diseases, it is crucial that consistent and standardised response criteria14 are applied to allow for direct comparisons. A strength of these studies is the 24-week open label phase, which showed maintenance of the platelet count and reduction in concomitant treatments for immune thrombocytopenia and bleeding events with long-term use of eltrombopag. In view of the fact that eltrombopag is not a curative therapy, patients might need ongoing therapy until they naturally enter 2
remission. Therefore, confirmation of the long-term efficacy, tolerability, and safety of eltrombopag is just as important as the short-term findings. Similar to findings in adult studies, adverse events were mostly mild and serious adverse events were infrequent. The most common drug-related adverse event in both studies was transaminitis (n=5 in PETIT; n=11 in PETIT2), which led to drug discontinuation in seven patients across the two studies. As seen in the adult studies, this event was reversible with drug discontinuation. Notably, two patients receiving eltrombopag and corticosteroids in PETIT2 developed cataracts, which supports previous findings in adult trials.6 Ongoing surveillance data will be necessary to inform the need for ophthalmology examinations. Grade 4 neutropenia events (n=3 overall for both PETIT and PETIT2), which had not been reported in previous trials of thrombopoietin-receptor agonists, were reported in both studies. Unlike the adult trials, no thrombotic events occurred in either PETIT or PETIT2, suggesting that these events might be related to additional thrombophilia risk factors in the adult population. Findings from early studies of thrombopoietin-receptor agonists raised concerns about the development of bone marrow reticulin in treated patients. A study of bone marrow findings in
www.thelancet.com Published online July 29, 2015 http://dx.doi.org/10.1016/S0140-6736(15)61223-5
Comment
115 adult patients treated with eltrombopag noted only two patients who had developed significant bone marrow reticulin during 5·5 years of treatment.15 Prospective data on bone marrow reticulin are scarce for paediatric trials; therefore, this safety data will probably have to be extrapolated from adult findings. PETIT and PETIT2 provide key data to help to inform decision making for paediatric immune thrombocytopenia by showing the safety and efficacy of eltrombopag in children. With this data, the FDA has now approved eltrombopag for the treatment of children aged 6 years or older who have chronic immune thrombocytopenia with an insufficient response to corticosteroids, intravenous immunoglobulins, or splenectomy.16 With so many treatment choices and so few direct comparisons, how should clinicians and patients select from available treatment options? Adequately powered comparative randomised clinical trials are difficult to do, especially in view of individual preference, cost, differences in routes of administration, and the surgical considerations of splenectomy. Therefore, studies that use comparative effectiveness research methods are crucial and should focus on assessment of patient-reported outcomes. Although the PETIT and PETIT2 studies clearly show the efficacy of eltrombopag against placebo,12,13 further data are needed to establish its effectiveness in clinical practice where thought must be given to cost, availability of more curative options, and patient adherence to longterm daily medication. Bussel and colleagues report that during the 24 week PETIT study, no significant changes in health-related quality of life occurred. They point out that drug delivery was problematic for some families, possibly offsetting some of the clinical benefits. Furthermore, continued long-term safety data are needed because paediatric patients with chronic refractory immune thrombocytopenia might need years of pharmacological therapy. Ongoing analysis from both trials will provide valuable information to guide clinicians. Lastly, existing prospective trials of thrombopoietin-receptor agonists in paediatrics have focused only on patients with chronic primary immune thrombocytopenia with no data about patients who need early escalation of therapy, use before surgery, or treatment for secondary immune thrombocytopenia. In view of the short-acting, reversible properties of thrombopoietin-receptor agonists, these patients might
be likely to receive them in clinical practice. Despite these gaps, when viewed alongside the paediatric data for romiplostim,10,11 evidence to provide a rationale for thrombopoietin-receptor agonist use in children with immune thrombocytopenia continues to grow. *Cindy E Neunert, Rachael F Grace Department of Pediatrics Hematology/Oncology/Bone Marrow Transplant, Columbia University, New York, NY 10032, USA (CEN); and Department of Pediatric Hematology/Oncology, Dana-Farber/ Boston Children’s Cancer and Blood Disorder Center, Boston, MA, USA (RFG) [email protected] CEN has served on a safety board for Genzyme. RFG was a co-investigator at Boston Children’s Hospital, where one participant in PETIT was enrolled. 1
2 3 4
5 6
7
8
9 10
11
12
13
14
15
16
Neunert C, Lim W, Crowther M, et al. The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia. Blood 2011; 117: 4190–207. Schulman I. Diagnosis and treatment: management of idiopathic thrombocytopenic purpura. Pediatrics 1964; 33: 979–80. Liang Y, Zhang L, Gao J, Hu D, Ai Y. Rituximab for children with immune thrombocytopenia: a systematic review. PLoS One 2012; 7: e36698. Houwerzijl EJ, Blom NR, van der Want JJ, et al. Ultrastructural study shows morphologic features of apoptosis and para-apoptosis in megakaryocytes from patients with idiopathic thrombocytopenic purpura. Blood 2004; 103: 500–06. Bussel JB, Cheng G, Saleh MN, et al. Eltrombopag for the treatment of chronic idiopathic thrombocytopenic purpura. N Engl J Med 2007; 357: 2237–47. Bussel JB, Provan D, Shamsi T, et al. Effect of eltrombopag on platelet counts and bleeding during treatment of chronic idiopathic thrombocytopenic purpura: a randomised, double-blind, placebo-controlled trial. Lancet 2009; 373: 641–48. Cheng G, Saleh MN, Marcher C, et al. Eltrombopag for management of chronic immune thrombocytopenia (RAISE): a 6-month, randomised, phase 3 study. Lancet 2011; 377: 393–402. Kuter DJ, Bussel JB, Lyons RM, et al. Efficacy of romiplostim in patients with chronic immune thrombocytopenic purpura: a double-blind randomised controlled trial. Lancet 2008; 371: 395–403. Kuter DJ, Rummel M, Boccia R, et al. Romiplostim or standard of care in patients with immune thrombocytopenia. N Engl J Med 2010; 363: 1889–99. 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. Bussel JB, Hsieh L, Buchanan GR, et al. Long-term use of the thrombopoietin-mimetic romiplostim in children with severe chronic immune thrombocytopenia (ITP). Pediatr Blood Cancer 2014; published online Oct 24. DOI:10.1002/pbc.25136. Grainger JD, Locatelli F, Chotsampancharoen T, et al. Eltrombopag for children with chronic immune thrombocytopenia (PETIT2): a randomised, multicentre, placebo-controlled trial. Lancet 2015; published online July 29. http://dx.doi.org/10.1016/S0140-6736(15)61107-2. Bussel JB, Garcia de Miguel P, Despotovic JM, et al. Eltrombopag for the treatment of children with persistent and chronic immune thrombocytopenia (PETIT): a randomised, multicentre, placebo-controlled study. Lancet Haematol 2015; published online July 29. http://dx.doi. org/10.1016/ S2352-3026(15)00114-3. Rodeghiero F, Stasi R, Gernsheimer T, 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: 2386–93. Brynes RK, Orazi A, Theodore D, et al. Evaluation of bone marrow reticulin in patients with chronic immune thrombocytopenia treated with eltrombopag: data from the EXTEND study. Am J Hematol 2015; 90: 598–601. US Food and Drug Administration. Highlights of prescribing information. June, 2015. www.accessdata.fda.gov/drugsatfda_docs/ label/2015/022291s015lbl.pdf (accessed July 24, 2015).
www.thelancet.com Published online July 29, 2015 http://dx.doi.org/10.1016/S0140-6736(15)61223-5
3
Thrombopoietin-receptor agonists in children with immune thrombocytopenia Paediatric immune thrombocytopenia is usually a benign condition that results in spontaneous remission within 6–12 months for most of children. Despite severe thrombocytopenia, clinically significant bleeding events are rare. Thus, a common treatment approach for many children is close observation.1 However, a small proportion of children have severe haemorrhage, develop chronic immune thrombocytopenia, are refractory to first-line therapy, or report low healthrelated quality of life. For these children, development of novel drugs could bring a substantial benefit. Historically, second-line treatment options for immune thrombocytopenia were scarce. Early understanding was based on knowledge of immune destruction of antibody-coated platelets in the spleen. Therefore, splenectomy was one of the earliest options for refractory patients.2 An appreciation for the long-term risk of sepsis associated with splenectomy, coupled with a more refined understanding of the pathophysiology of immune thrombocytopenia, resulted in therapeutic developments with immunosuppressant agents such as rituximab.3 A major advancement was the discovery that antibodies in patients with immune thrombocytopenia cause apoptosis-like changes in megakaryocytes, which leads to reduced platelet production.4 This finding led to investigations of thrombopoietin, the main megakaryocyte growth factor, as a potential non-immunosuppressant treatment option for patients with immune thrombocytopenia. Two recombinant thrombopoietin-receptor agonists, eltrombopag and romiplostim, are currently approved by the US Food and Drug Administration (FDA) for adults with chronic immune thrombocytopenia. Both drugs increase the platelet count, reduce bleeding events, and improve health-related quality of life in adults.5–9 Although data are accumulating in the adult population, little prospective data have been reported for paediatric patients.10,11 Because of this shortage of data, the 2011 immune thrombocytopenia guidelines of the American Society of Hematology were unable to comment on the use of thrombopoietin-receptor agonists in children.1 The Lancet and The Lancet Haematology report two parallel randomised, multicentre, placebo-
controlled trials of eltrombopag in children with chronic immune thrombocytopenia.12,13 John Grainger and colleagues12 report the findings from PETIT2, a phase 3 trial, in The Lancet, and James Bussel and colleagues13 describe the results of PETIT, a phase 2 trial, in The Lancet Haematology. Together, these studies report important findings for 15 children enrolled in the PETIT dose-finding study and 159 children randomly assigned to receive eltrombopag or placebo (n=67 in PETIT, n=92 in PETIT2). The studies enrolled similar patient cohorts: patients aged 1–17 years with platelet counts less than 30 × 10⁹ per L. Most patients had received more than two previous treatments, few had undergone splenectomy, and most had chronic immune thrombocytopenia. Patients in the randomised phases received doubleblind treatment for 7 weeks in PETIT and 13 weeks in PETIT2, followed by a 24 week open-label phase. Overall, the findings of both trials showed the efficacy of eltrombopag. During the double-blind phase of PETIT, 16 (36%) patients who received eltrombopag achieved a platelet count of 50 × 10⁹ per L or more for 60% or more of the visits from weeks 2–6 compared with no patients among those who received placebo (odds ratio [OR] 5·84, 95% CI 1·18–28·90).13 Similarly, in the PETIT2 doubleblind phase, 25 (40%) patients given eltrombopag achieved a platelet count of at least 50 × 10⁹ per L for 75% or more of the visits between weeks 5–12, compared with one (3%) patient who received placebo (OR 18·0, 95% CI 2·3–1·40).12 A platelet count of 50 × 10⁹ per L or more was detected at least once in 62% (n=28 in PETIT; n=39 in PETIT2) of patients who received eltrombopag during the first 6 weeks of both studies. Furthermore, clinical data showed that treatment with eltrombopag resulted in a proportional reduction in WHO grade 1–4 bleeding events (eltrombopag vs placebo: 14 [31%] vs 18 [82%] patients in PETIT; 23 [37%] vs 16 [55%] patients in PETIT2) and need for rescue treatments (eltrombopag vs placebo: six [13%] vs 11 [50%] patients in PETIT; 12 [19%] vs seven [24%] patients in PETIT2) compared with placebo. During the open-label phase, about 80% of patients (54 [81%] patients in PETIT and 70 [80%] patients in PETIT2) achieved a platelet count of 50 × 10⁹ per L or more at least once in both studies.
www.thelancet.com Published online July 29, 2015 http://dx.doi.org/10.1016/S0140-6736(15)61223-5
Published Online July 29, 2015 http://dx.doi.org/10.1016/ S0140-6736(15)61223-5 See Online/Articles http://dx.doi.org/10.1016/ S0140-6736(15)61107-2 See Online/Articles Lancet Haem 2015; published online July 29. http://dx.doi.org/10.1016/ S2352-3026(15)00114-3
1
Comment
Duration
Efficacy outcomes based on platelet count
Results
Platelet count ≥50 × 10⁹ per L for ≥6 weeks from week 5–12 of the DBP Proportion of patients achieving platelet count ≥50 × 10⁹ per L in the absence of rescue therapy at any time during DBP Proportion of patients achieving platelet count ≥50 × 10⁹ per L at any time of the OLP Maximum period of continuous platelet counts ≥50 × 10⁹ per L in patients receiving eltrombopag (mean [SD], weeks)
25 (40%) eltrombopag, 1 (3%) placebo 47 (75%) eltrombopag, 6 (21%) placebo
Platelet count ≥50 × 10⁹ per L for ≥60% of assessments from weeks 2–6 of the DBP Proportion of patients achieving platelet count ≥50 × 10⁹ per L in the absence of rescue therapy during weeks 1–6 of the DBP Proportion of patients achieving platelet count ≥50 × 10⁹ per L at any time of the OLP
16 (36%) eltrombopag, 0 (0%) placebo
Eltrombopag Grainger, 201512 13 week DBP and (n=92) 24 week OLP
Bussel, 201513 (n=67)
7 week DBP and 24 week OLP
70 (80%) DBP: 3·3 (3·1) weeks OLP: 8·6 (7·8) weeks
28 (62%) eltrombopag, 7 (32%) placebo 54 (81%)
Romiplostim Bussel, 201511 (n=22)
≤109 week OLP
Median percentage of weeks patients had a platelet count ≥50 × 10⁹ per L Percentage of patients with a peak platelet count ≥150 × 10⁹ per L
84·3% (IQR 69·9–90·8) 21 (95·5%)
Bussel, 201110 (n=22)
12 week DBP
Platelet count ≥50 × 10⁹ per L for 2 consecutive weeks and an increase of platelet count ≥20 × 10⁹ per L above baseline from weeks 1–12 Proportion of patients with a platelet count >100 × 10⁹ per L at any time in the absence of rescue medication Median number of weeks platelet counts were ≥50 × 10⁹ per L in patients receiving romiplostim
15 (88%) romiplostim, 0 placebo 12 (71%) romiplostim, 0 placebo 7 weeks (range 0–11)
DBP=double-blind phase. OLP=open-label phase.
Table: Variability in response reporting across prospective thrombopoeitin-receptor agonist trials in children
Direct comparison of these responses with other trials of thrombopoietin-receptor agonists is challenging because the primary outcome varies among studies and dosing strategies are different (table). Nevertheless, the proportions of patients with responses in the double-blind and open-label phases of PETIT and PETIT2 seem to be similar to the findings reported in adult studies of thrombopoietin-receptor agonists.7–9 The paediatric romiplostim phase 1/2 trial10 reported responses in 15 [88%] of 17 patients, with the primary outcome as a platelet count of at least 50 × 10⁹ per L on 2 consecutive weeks. This result is similar to those seen in the double-blind and open-label phases of the two PETIT studies, with the outcome defined as a platelet count of at least 50 × 10⁹ per L once. Because of the associated difficulties and expense needed for studies of rare diseases, it is crucial that consistent and standardised response criteria14 are applied to allow for direct comparisons. A strength of these studies is the 24-week open label phase, which showed maintenance of the platelet count and reduction in concomitant treatments for immune thrombocytopenia and bleeding events with long-term use of eltrombopag. In view of the fact that eltrombopag is not a curative therapy, patients might need ongoing therapy until they naturally enter 2
remission. Therefore, confirmation of the long-term efficacy, tolerability, and safety of eltrombopag is just as important as the short-term findings. Similar to findings in adult studies, adverse events were mostly mild and serious adverse events were infrequent. The most common drug-related adverse event in both studies was transaminitis (n=5 in PETIT; n=11 in PETIT2), which led to drug discontinuation in seven patients across the two studies. As seen in the adult studies, this event was reversible with drug discontinuation. Notably, two patients receiving eltrombopag and corticosteroids in PETIT2 developed cataracts, which supports previous findings in adult trials.6 Ongoing surveillance data will be necessary to inform the need for ophthalmology examinations. Grade 4 neutropenia events (n=3 overall for both PETIT and PETIT2), which had not been reported in previous trials of thrombopoietin-receptor agonists, were reported in both studies. Unlike the adult trials, no thrombotic events occurred in either PETIT or PETIT2, suggesting that these events might be related to additional thrombophilia risk factors in the adult population. Findings from early studies of thrombopoietin-receptor agonists raised concerns about the development of bone marrow reticulin in treated patients. A study of bone marrow findings in
www.thelancet.com Published online July 29, 2015 http://dx.doi.org/10.1016/S0140-6736(15)61223-5
Comment
115 adult patients treated with eltrombopag noted only two patients who had developed significant bone marrow reticulin during 5·5 years of treatment.15 Prospective data on bone marrow reticulin are scarce for paediatric trials; therefore, this safety data will probably have to be extrapolated from adult findings. PETIT and PETIT2 provide key data to help to inform decision making for paediatric immune thrombocytopenia by showing the safety and efficacy of eltrombopag in children. With this data, the FDA has now approved eltrombopag for the treatment of children aged 6 years or older who have chronic immune thrombocytopenia with an insufficient response to corticosteroids, intravenous immunoglobulins, or splenectomy.16 With so many treatment choices and so few direct comparisons, how should clinicians and patients select from available treatment options? Adequately powered comparative randomised clinical trials are difficult to do, especially in view of individual preference, cost, differences in routes of administration, and the surgical considerations of splenectomy. Therefore, studies that use comparative effectiveness research methods are crucial and should focus on assessment of patient-reported outcomes. Although the PETIT and PETIT2 studies clearly show the efficacy of eltrombopag against placebo,12,13 further data are needed to establish its effectiveness in clinical practice where thought must be given to cost, availability of more curative options, and patient adherence to longterm daily medication. Bussel and colleagues report that during the 24 week PETIT study, no significant changes in health-related quality of life occurred. They point out that drug delivery was problematic for some families, possibly offsetting some of the clinical benefits. Furthermore, continued long-term safety data are needed because paediatric patients with chronic refractory immune thrombocytopenia might need years of pharmacological therapy. Ongoing analysis from both trials will provide valuable information to guide clinicians. Lastly, existing prospective trials of thrombopoietin-receptor agonists in paediatrics have focused only on patients with chronic primary immune thrombocytopenia with no data about patients who need early escalation of therapy, use before surgery, or treatment for secondary immune thrombocytopenia. In view of the short-acting, reversible properties of thrombopoietin-receptor agonists, these patients might
be likely to receive them in clinical practice. Despite these gaps, when viewed alongside the paediatric data for romiplostim,10,11 evidence to provide a rationale for thrombopoietin-receptor agonist use in children with immune thrombocytopenia continues to grow. *Cindy E Neunert, Rachael F Grace Department of Pediatrics Hematology/Oncology/Bone Marrow Transplant, Columbia University, New York, NY 10032, USA (CEN); and Department of Pediatric Hematology/Oncology, Dana-Farber/ Boston Children’s Cancer and Blood Disorder Center, Boston, MA, USA (RFG) [email protected] CEN has served on a safety board for Genzyme. RFG was a co-investigator at Boston Children’s Hospital, where one participant in PETIT was enrolled. 1
2 3 4
5 6
7
8
9 10
11
12
13
14
15
16
Neunert C, Lim W, Crowther M, et al. The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia. Blood 2011; 117: 4190–207. Schulman I. Diagnosis and treatment: management of idiopathic thrombocytopenic purpura. Pediatrics 1964; 33: 979–80. Liang Y, Zhang L, Gao J, Hu D, Ai Y. Rituximab for children with immune thrombocytopenia: a systematic review. PLoS One 2012; 7: e36698. Houwerzijl EJ, Blom NR, van der Want JJ, et al. Ultrastructural study shows morphologic features of apoptosis and para-apoptosis in megakaryocytes from patients with idiopathic thrombocytopenic purpura. Blood 2004; 103: 500–06. Bussel JB, Cheng G, Saleh MN, et al. Eltrombopag for the treatment of chronic idiopathic thrombocytopenic purpura. N Engl J Med 2007; 357: 2237–47. Bussel JB, Provan D, Shamsi T, et al. Effect of eltrombopag on platelet counts and bleeding during treatment of chronic idiopathic thrombocytopenic purpura: a randomised, double-blind, placebo-controlled trial. Lancet 2009; 373: 641–48. Cheng G, Saleh MN, Marcher C, et al. Eltrombopag for management of chronic immune thrombocytopenia (RAISE): a 6-month, randomised, phase 3 study. Lancet 2011; 377: 393–402. Kuter DJ, Bussel JB, Lyons RM, et al. Efficacy of romiplostim in patients with chronic immune thrombocytopenic purpura: a double-blind randomised controlled trial. Lancet 2008; 371: 395–403. Kuter DJ, Rummel M, Boccia R, et al. Romiplostim or standard of care in patients with immune thrombocytopenia. N Engl J Med 2010; 363: 1889–99. 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. Bussel JB, Hsieh L, Buchanan GR, et al. Long-term use of the thrombopoietin-mimetic romiplostim in children with severe chronic immune thrombocytopenia (ITP). Pediatr Blood Cancer 2014; published online Oct 24. DOI:10.1002/pbc.25136. Grainger JD, Locatelli F, Chotsampancharoen T, et al. Eltrombopag for children with chronic immune thrombocytopenia (PETIT2): a randomised, multicentre, placebo-controlled trial. Lancet 2015; published online July 29. http://dx.doi.org/10.1016/S0140-6736(15)61107-2. Bussel JB, Garcia de Miguel P, Despotovic JM, et al. Eltrombopag for the treatment of children with persistent and chronic immune thrombocytopenia (PETIT): a randomised, multicentre, placebo-controlled study. Lancet Haematol 2015; published online July 29. http://dx.doi. org/10.1016/ S2352-3026(15)00114-3. Rodeghiero F, Stasi R, Gernsheimer T, 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: 2386–93. Brynes RK, Orazi A, Theodore D, et al. Evaluation of bone marrow reticulin in patients with chronic immune thrombocytopenia treated with eltrombopag: data from the EXTEND study. Am J Hematol 2015; 90: 598–601. US Food and Drug Administration. Highlights of prescribing information. June, 2015. www.accessdata.fda.gov/drugsatfda_docs/ label/2015/022291s015lbl.pdf (accessed July 24, 2015).
www.thelancet.com Published online July 29, 2015 http://dx.doi.org/10.1016/S0140-6736(15)61223-5
3