Paediatric ITP Philip Connor

Brief Background autoimmune disorder of platelet destruction, mucocutaneous bleeding episodes with a platelet count <100x109/L. majority of paediatric patients will spontaneously recover with conservative management. minority require treatment for bleeding, usually occurring at a platelet count of <20x109/L. Peaks of new cases in Winter months – driven by viral URTIs Persistence/Chronicity in 30% children vs. 70% of adults Similar incidence as Paediatric ALL - 2-3/100000 person years – about 400/year in UK Persistent if > 3 months, Chronic if >12 months ITP registries in the UK for both Adult and Paediatric age groups Both are NIHR portfolio adopted studies Other international registries exist – International Cooperative Study Group (ICIS) the biggest 131 centres in multiple countries

Dr John Grainger, Eilish Hannah The natural course of Childhood immune thrombocytopenia: results from the paediatric ITP registry Dr John Grainger, Eilish Hannah

About This Study This is the second large prospective study to follow children with ITP for longer than 12 months It is the first national prospective study to follow children with ITP for longer than 12 months Intercontinental cooperative ITP study group (ICIS produced the first) This study adds further knowledge to the natural course of the disease that was not reflected in the ICIS study. The UK registry captures patients of all severities whereas the ICIS cohort may reflect patients with more severe ITP. this study is more likely to have uniform management for each patient The UK registry captures patients from teaching hospitals and district general hospitals whereas ICIS patients are more from centres with a specialist interest in ITP. This is particulary important as the ICIS paper may reflect patients with more severe ITP this study is more likely to have uniform management for each patient due to one set of guidelines being used in the UK. However with the ICIS paper, research data was obtained from several different countries each of which may differ in their approach to the management of paediatric ITP.

Objectives To map the natural course of paediatric ITP with regards to: Recovery Platelet counts at specific time intervals Bleeding risk and bleeding severity

Methods This study used data collected from the UK paediatric ITP registry between January 2007 and February 2013. The registry has input from 80 different sites across the UK 564 patients were included aged 2 months to 16 years Mild, moderate, severe and life-threatening bleeding severity was defined by the Bolton-Maggs bleeding score. This study defined recovered as three consecutive platelet readings over 150x109/L. If a patient had a reading over 150x109/L and then a further reading below 150x109/L they were not classed as recovered.

Definitions Newly diagnosed ITP is from diagnosis to 3 months. Persistent ITP is ongoing ITP from 3 months after presentation until 12 months. Chronic ITP is ongoing ITP of more than 12 months duration.

Key Differences between this Study and the ICIS study. We had a smaller percentage of patients recovering at each time interval. Our study found patients had much lower platelet counts in the initial 6 months, 12 months and 24 months. This is mainly explained by the differences in management between the two cohort of patients. . The first key difference is; at established time intervals (6 months, 12 months and 24 months) our patients had comparatively lower platelet counts than the ICIS study. For a platelet count less than 10x109/L this study found the following; 9%, 10% and 10% at 6, 12 and 24 months respectivly compared to 2% at 6 months, 2% at 12 months and 1% at 24 months in the ICIS study. For a platelet count less than 20x109/L this study found 15%, 18% and 22% at 6 months, 12 months and 24 months respectively compared to 7% at 6 months, 7% at 12 months and 4% at 24 months in the ICIS study. This could be partly because some patients in our study had missing data at these time intervals hence, making the percentage with these platelet counts appear larger than they are. However it is most likely due to the higher treatment rates in the ICIS study compared to UK patients.

Ways Our Study Supported the ICIS study Platelet counts despite the differences mentioned earlier did follow a similar pattern, of an inverse relationship; as time progressed the percentage of patients with a low platelet count decreased. Like the ICIS study we also found the most common bleeding site to be the skin The percentage that developed chronic ITP was similar.

Response to First Line Treatment in Childhood ITP John D. Grainger, MD, BMBch, MRCP, FRCPATH1, Paula H. B Bolton-Maggs, BMBCh, DM, FRCP, FRCPath2 and Pearce Elizabeth A retrospective review of treatment episodes entered into the UKITP Registry between Jan 2007-May 2016 was performed. 1043 patients were identified. Bleeding severity Description Mild (grade 1) Bruising and petechiae; minor epistaxis Little or no interference with daily living Moderate (grade 2) More severe skin manifestations, some mucosal lesions Moderate epistaxis; Moderate menorrhagia More significant impact on daily life. Severe (grade 3) Bleeding episodes that require hospital admissions &/or blood transfusions: Epistaxis; Melena; Menorrhagia Symptoms seriously interfere with quality of life.

Response to First Line Treatment in Childhood ITP 798 patients were untreated other than supportive care. 245 patients (23%) had 422 treatment episodes for bleeding episodes. Of these 351 were single therapies and 71 were combination therapies. Treatment 136 treatments were with IVIG 152 treatments were Prednisolone 92 Regimen 1: 1-2mg/kg/day for 7-14 days 60 Regimen 2: 4mg/kg/day for 4 days. 71 treatments were with combination therapy

Response to First Line Treatment in Childhood ITP No Treatment n=615 Steroid Regimen 1 n=92 Steroid Regimen 2 n=60 IVIG n=1 36 Combination Therapy n=71 Mean Age 4.7 7.3 6.5 5.9 7.5 Mean platelet count 14.4 8.9 7.6 8.7 10.8 Mean Bleed Severity 1.5 1.7 2.1 2.0 2.5 Mean No. of bleeding sites 1.62 1.97 1.98 1.61 2.70 Bleed Severity   Number and percentage of cases with bleed severity Mean age at diagnosis (years)  Mean platelet count x109/L at diagnosis Mean no. of bleed sites Proportion receiving treatment Mild n=445, 42% 4.6 14.4 1.4 n= 67, 15% Moderate n=538, 51% 5.9 10.3 2.0 n=187, 35% Severe n=69, 6.5% 6.7 9.6 2.8 n= 58, 84% Life Threatening n=5,0.5% 8.1 4.7 2.9 n= 5, 100%

Response to First Line Treatment in Childhood ITP

Response to First Line Treatment in Childhood ITP   Time. Days after start of treatment 1 3 5 7 14 28 42 Median platelet count x109/L Steroid Regimen 1 6 11 50 34 30.5 45 24 Steroid Regimen 2 18 62 21 36 100 IVIG 10 37 61 84 47 30 Combination Treatments 16 43 91 101 225 235 Platelet response to therapy No significant difference was found between platelet count of treated and untreated groups over first 3 months A more rapid platelet response (platelet >30) was observed following IVIG or combination therapy and was maintained to 6 weeks Both steroid regimens took until Day 5 to achieve a platelet count >30. Regimen 2 produced a higher platelet count at Day 5 but this effect is transient.

Response to First Line Treatment in Childhood ITP In the UK, 23% of children with ITP are receiving treatment. A higher proportion required treatment with increasing bleeding severity and number of bleeding sites. IVIG demonstrated a superior response to steroid therapy and should be considered preferable for more significant bleeding. A higher dose, short duration steroid regimen was associated with a slightly faster response compared to lower dose treatment and may be preferable to longer duration steroids for milder bleeding that requires therapy.

Change Natural History Our registry data suggests no change  ‘Treatment with or without IVIg for Kids with ITP’ (TIKI) trial (NTR study ID TC1563) Between May 2009 and May 2015, 200 patients were enrolled, 109 males and 91 females. After randomization, 100 received IVIg and 100 received careful observation No statistically significant differences were seen regarding development of chronic ITP (currently defined as a platelet count <100 x 109/L at 12 months) between both groups: 10.2% in the IVIg group and 10.4% in the observation group

New Agents TPO mimetics used in cITP in children. Eltrombopag – efficacy shown in the PETIT Studies Licensed in USA and Europe Romiplstim Current study underway “A Single-Arm, Open-Label, Long-Term Efficacy and Safety Study of Subcutaneous (SC) Romiplostim in Children with Immune Thrombocytopenia (ITP)”

New Agents Empiric observation that the TPO mimetics seem to change the natural history of Chronic ITP 30% remission rate per year (vs. 10% expected) ?Upfront use in acute ITP?

Acknowledgments Slides from John Grainger ITP Support Association for their on going funding of the ITP registry. The UK Paediatric ITP Registry is currently supported by 80 treatment centres across the UK. Details of all centres are available at www.uk-itp.org . Medicines for children research network University of Manchester