Abstract: Immune thrombocytopenia (ITP) is an acquired autoimmune bleeding disorder which presents with isolated thrombocytopenia and risk of hemorrhage. While most children with ITP promptly recover with or without drug therapy, ITP is persistent or chronic in others. When needed, how to select second‐line therapies is not clear. ICON1, conducted within the Pediatric ITP Consortium of North America (ICON), is a prospective, observational, longitudinal cohort study of 120 children from 21 centers starting second‐line treatments for ITP which examined treatment decisions. Treating physicians reported reasons for selecting therapies, ranking the top three. In a propensity weighted model, the most important factors were patient/parental preference (53%) and treatment‐related factors: side effect profile (58%), long‐term toxicity (54%), ease of administration (46%), possibility of remission (45%), and perceived efficacy (30%). Physician, health system, and clinical factors rarely influenced decision‐making. Patient/parent preferences were selected as reasons more often in chronic ITP (85.7%) than in newly diagnosed (0%) or persistent ITP (14.3%, P  = .003). Splenectomy and rituximab were chosen for the possibility of inducing long‐term remission ( P   〈  .001). Oral agents, such as eltrombopag and immunosuppressants, were chosen for ease of administration and expected adherence ( P   〈  .001). Physicians chose rituximab in patients with lower expected adherence ( P  = .017). Treatment choice showed some physician and treatment center bias. This study illustrates the complexity and many factors involved in decision‐making in selecting second‐line ITP treatments, given the absence of comparative trials. It highlights shared decision‐making and the need for well‐conducted, comparative effectiveness studies to allow for informed discussion between patients and clinicians.

Abstract: Background: Decision-making in selecting second-line therapies for pediatric patients with immune thrombocytopenia (ITP) has not been studied. Using data collected from physicians experienced in treating ITP, we developed a conceptual model of factors that informed treatment choice. This study was a component of ICON1, a prospective, observational, longitudinal cohort study of second line treatments for childhood ITP performed by the Pediatric ITP Consortium of North America (ICON). Methods: Physicians who enrolled patients in ICON1 were asked to rank the top three reasons they chose a specific treatment so as to weight each factor. Those choices that were ranked 1, 2, or 3 were weighted to develop a propensity scored decisional model. In other questions, physicians were asked about all factors that may have influenced decisions to begin a particular second line therapy and this data was then used to examine additional factors that influenced therapy choices and to compare between therapies. Results: ICON1 enrolled 118 patients; 101 had primary ITP and 53 were receiving their first second line therapy. The majority of physicians in the study saw eleven or more patients per year, and the time since completion of fellowship ranged from 1 to 44 years (mean 12.5 (SD 11)). The most important factors guiding treatment decisions in propensity weighted modeling were "patient preference factors": patient/parental preference (40%), and treatment-related factors: possibility of remission (38%), side effect profile (36%), efficacy (27%), long-term toxicity (33%), and ease of administration (30%). Physician factors, such as experience and adhering to published guidelines, rarely influenced decision-making with only 2% of physicians giving published guidelines as a reason for choice of therapy, and there being no difference in choice based on years since fellowship or experience in treating ITP patients. However, 28% of physicians stated their comfort level with a treatment strongly influenced their choice. Additionally, 38% of physicians did not endorse any patient clinical factors (e.g. frequency of bleeding, expected compliance, response to other therapies, age, comorbidities) as key in their decision-making. Health system factors, such as insurance approval or distance from the closest medical center, rarely influenced treatment choice. Treatments could be categorized into five groups: oral immunosuppressive agents, rituximab, romiplostim, eltrombopag or splenectomy. A significant determinant of choosing splenectomy or rituximab was the "possibility of long-term remission" (p 〈 0.001). A high percentage of treatment factors impacted the decision to prescribe: for rituximab 92% of physicians endorsed at least one treatment factor; for oral immunosuppressants, and romiplostim and eltrombopag, 100% of physicians endorsed at least one treatment factor. Among the top 3 choices for each medication, treatment related factors were major determinants (Table). Oral agents, were significantly more likely to be chosen for ease of administration and expected adherence (p 〈 0.001). When examining the reasons physicians chose particular therapies, physicians indicated "this agent is most efficacious" most frequently for romiplostim, but not for eltrombopag (p 〈 0.001) and were more likely to choose rituximab in patients in whom there was lower expected compliance (p=0.017). Conclusions: This first analysis of physician decision making regarding second line therapies shows that patient preference and physician perception of treatment characteristics (efficacy, side effects, possibility of long term remission) are primary drivers of physician choice in contrast to guidelines, clinical characteristics and health system factors. Future comparative effectiveness studies are necessary to better inform patient and physician choice. Disclosures Lambert: Novartis: Consultancy. Grace:Agios Pharmaceuticals: Other: Scientific Advisor, Research Funding. Bussel:Cangene: Research Funding; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sysmex: Research Funding; Symphogen: Membership on an entity's Board of Directors or advisory committees; BiologicTx: Research Funding; Shionogi: Membership on an entity's Board of Directors or advisory committees; Physicians Education Resource: Speakers Bureau; Protalex: Membership on an entity's Board of Directors or advisory committees, Research Funding; Immunomedics: Research Funding; Rigel Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer Ingelheim: Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; UpToDate: Patents & Royalties; Momenta Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Prophylix Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genzyme: Research Funding; Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Haley:Baxalta: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Honoraria. Neufeld:Novartis: Consultancy.

Abstract: Background: Children with ITP who are prescribedsecond line treatments vary in terms of their clinical phenotype, prior treatments, and health related quality of life (HRQoL). Objective: To describe the clinical characteristics and HRQoL of North American pediatric patients with ITP initiating second line treatments. Methods: A longitudinal observational cohort of 118 children with ITP starting second line treatments was enrolled from 2013-2015 at 21 ICON centers. Enrollment requirements included age 1-17y and starting a second line treatment (not IVIG, steroids or anti-D) as monotherapy. Baseline demographic and clinical characteristics were recorded, including response to prior treatments, worst bleeding scores, and baseline platelet counts. Fisher's exact test was used to compare treatment with phase of ITP, age cohort, and gender. HRQoL was measured by patient/caregiver report using the Kids ITP Tool (KIT) where 0 is worst and 100 is best, while physicians assessed the perceived effect of ITP on patient HRQoL using a 5-point scale. Spearman correlations were used to test for association between bleeding, HRQoL, and duration of ITP. ANOVA was used to compare the mean KIT scores of the treatment groups. Results: The clinical characteristics of the cohort are shown in the Table. Median age at enrollment was 11.4 y and 15% had newly diagnosed ITP, 31% had persistent ITP, and 54% had chronic ITP. The median number of prior treatments was 3 (range: 1-9). The prior response rate (platelet 〉 30 x 109/µL and no bleeding) to prednisone was 59% and IVIG 66%. Fifty-five (47%) patients had received at least one prior second line treatment. At enrollment, physicians reported that ITP had impacted the patients' HRQoL severely in 15%, significantly in 44%, moderately in 38%, and almost not at all in 3%. The mean score of the child KIT report was 71.4 (SD 17.2), the parent proxy KIT was 64.7 (SD 16.4), and the parent impact KIT was 36.1 (SD 19.2). The physician's assessment of the patient's HRQoL significantly correlated with the child report (p 〈 .001) and parent proxy report (p 〈 .001). The number of prior treatments and the worst bleeding score did not significantly correlate with the child or parent proxy KIT scores with the exception of gynecologic bleeding on the parent proxy report (p=.002). The duration of ITP significantly correlated with child (p=0.001) and parent proxy KIT scores (p=0.005) where a longer duration was associated with better HRQoL. The number of prior treatments, worst bleeding, and phase of ITP did not correlate with the parent impact KIT score. Treatments selected for second line treatment included: rituximab (n=42), romiplostim (n=31), eltrombopag (n=20), oral immunosuppressants (n=16), splenectomy (n=4), and dapsone (n=3). The selected treatment was not significantly different by age, gender, baseline child KIT score, or duration of ITP. Baseline parent proxy KIT scores varied significantly between selected treatments (p=0.03) and were significantly lower in children starting on eltrombopag in comparison to romiplostim (56.4 (SD 15.1) vs. 70.3 (SD 15.1), respectively; p=0.03). Conclusions: Children with ITP starting on new second line treatments often have received multiple prior treatments and nearly half start these treatments prior to being diagnosed with chronic ITP, including 15% who were in the newly diagnosed phase. Physician assessment of patient HRQoL correlates well with child and parent proxy report of HRQoL. The number of prior treatments and worst bleeding score did not correlate with HRQoL. Longer duration of ITP was associated with a better HRQoL, suggesting that the level of concern related to ITP may lessen over time. Baseline KIT scores were significantly different in children starting on specific treatments. Future analysis will compare the change from baseline in HRQoL in children treated with second line therapies. Disclosures Grace: Agios Pharmaceuticals: Other: Scientific Advisor, Research Funding. Neufeld:Novartis: Consultancy. Bussel:Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Symphogen: Membership on an entity's Board of Directors or advisory committees; Shionogi: Membership on an entity's Board of Directors or advisory committees; Protalex: Membership on an entity's Board of Directors or advisory committees, Research Funding; Physicians Education Resource: Speakers Bureau; Prophylix Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Rigel Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Immunomedics: Research Funding; Cangene: Research Funding; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer Ingelheim: Research Funding; Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding; UpToDate: Patents & Royalties; Genzyme: Research Funding; BiologicTx: Research Funding; Momenta Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Sysmex: Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Haley:Baxalta: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Honoraria. Thompson:Baxalta (now part of Shire): Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; bluebird bio: Consultancy, Research Funding; Baxalta (now part of Shire): Research Funding; ApoPharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; bluebird bio: Consultancy, Research Funding; Amgen: Research Funding; Mast: Research Funding; Mast: Research Funding; Celgene: Research Funding; Celgene: Research Funding; Eli Lily: Research Funding; Eli Lily: Research Funding.

Abstract: Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder with isolated thrombocytopenia and hemorrhagic risk. While many children with ITP can be safely observed, treatments are often needed for various reasons, including to decrease bleeding, or to improve health related quality of life (HRQoL). There are a number of available second‐line treatments, including rituximab, thrombopoietin‐receptor agonists, oral immunosuppressive agents, and splenectomy, but data comparing treatment outcomes are lacking. ICON1 is a prospective, multi‐center, observational study of 120 children starting second‐line treatments for ITP designed to compare treatment outcomes including platelet count, bleeding, and HRQoL utilizing the Kids ITP Tool (KIT). While all treatments resulted in increased platelet counts, romiplostim had the most pronounced effect at 6 months ( P  = .04). Only patients on romiplostim and rituximab had a significant reduction in both skin‐related (84% to 48%, P  = .01 and 81% to 43%, P  = .004) and non‐skin‐related bleeding symptoms (58% to 14%, P  = .0001 and 54% to 17%, P  = .0006) after 1 month of treatment. HRQoL significantly improved on all treatments. However, only patients treated with eltrombopag had a median improvement in KIT scores at 1 month that met the minimal important difference (MID). Bleeding, platelet count, and HRQoL improved in each treatment group, but the extent and timing of the effect varied among treatments. These results are hypothesis generating and help to improve our understanding of the effect of each treatment on specific patient outcomes. Combined with future randomized trials, these findings will help clinicians select the optimal second‐line treatment for an individual child with ITP.

Abstract: Background: The impact of second line therapies on health related quality of life (HRQoL) and fatigue in pediatric patients with ITP is not well studied. Objective: To describe the impact of second line therapies on HRQoL and fatigue in North American pediatric patients with ITP. Methods: A longitudinal observational cohort of 120 children with ITP starting second line treatments was enrolled from 2013-2015 at 21 ICON centers. Enrollment requirements included age 1-17y and starting a second line treatment (not IVIG, corticosteroids or anti-D immunoglobulin) as monotherapy. HRQoL (Kids ITP Tool - KIT) and fatigue (Hockenberry Fatigue Scale - FS) surveys were completed prior to starting treatment (baseline) and 1 and 12 months after starting treatment by patient/caregiver. KIT is scored from 0 (worst) to 100 (best), and the FS scores were re-scaled so that 0 is no fatigue and 100 is highest fatigue. At the same time points as the patient/caregiver surveys, physicians assessed the perceived effect of treatment on patient HRQoL using a 7-point scale. ANOVA was used to compare the baseline means of the treatment groups. This study specifically compared change from baseline to 1 month in the KIT and FS using paired t-tests within each treatment group. The 12 month timepoint was not used in the paired analysis of individual treatments due to attrition between 1 and 12 months. Results: The median age at enrollment was 11.3 y (1.2-17.8), and 16% (19/120) had newly diagnosed ITP, 31% (37/120) had persistent ITP, and 53% (64/120) had chronic ITP. The median number of prior treatments was 3 (range: 1-9). Fifty-eight (48%) patients had received at least one prior second line treatment. Treatments selected for second line treatment included: rituximab (n=43), romiplostim (n=31), eltrombopag (n=20), oral immunosuppressants (n=19), splenectomy (n=4), and dapsone (n=3). The child and parent proxy KIT scores significantly improved on rituximab (p & lt;0.001 for both), oral immunosuppressants (p=0.02, p=0.001), and eltrombopag (p=0.01 for both). Child KIT scores also significantly improved on romiplostim (p=0.003); however, there was no significant change in the parent proxy score (p=0.29). The parent impact KIT scores significantly improved from baseline to 1 month on all treatments (p & lt;0.001), although the scores were not significantly different between treatment types (p=0.67). Child, parent proxy, and parent impact KIT scores significantly increased between 1 month and 12 months in paired analysis combining treatments (p & lt;0.001). As previously described, at enrollment, physicians reported that ITP had impacted the patients' HRQoL severely in 15%, significantly in 45%, moderately in 38%, and almost not at all in 3%. Physicians reported that HRQoL improved in 68% (range: 64-75%) of patients while on treatment from baseline to 1 month with no significant difference by treatment group (p=0.46). The physician's assessment of the patient's baseline HRQoL significantly correlated with the child and parent proxy KIT report (p & lt;0.0001); however, after 1 month of treatment, the physician's assessment no longer correlated with the child (p=0.26) or parent proxy KIT report (p=0.11). At enrollment, the median FS-Child score (n=54) was 18.5 (range 0-85), the median FS-Adolescent score (n=42) was 20.2 (0-73), and the median FS-Parent (n= 100) score was 35 (7-81). One month FS-Child improved for those who were treated with rituximab (p=0.03); there was no significant change in fatigue on the other treatments. One month FS-Parent significantly improved for those treated with rituximab (p=0.015) and eltrombopag (p=0.009). Conclusions: In this pediatric cohort, all second line treatments appear to significantly improve HRQoL in ITP. Rituximab had the greatest impact in decreasing fatigue at one month. Physician assessment of patient HRQoL did not correlate well with patient assessment after treatment was started, suggesting there may be challenges in ascertaining the effect of treatment on HRQoL. Future analysis of ICON1 will consider the impact of treatment on HRQoL and fatigue while also accounting for the treatment effect on bleeding and platelet count. Disclosures Grace: Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Klaassen: Amgen: Consultancy; Hoffman-La Roche LTD: Consultancy; Octapharma: Honoraria; Baxalta: Honoraria; Biogen Canada LTD: Consultancy; Agios Pharmaceuticals: Consultancy. Despotovic: Sanofi: Consultancy; Schell Cooley LLP: Other: Expert witness. Bussel: Protalex: Membership on an entity's Board of Directors or advisory committees, Research Funding; Momenta: Membership on an entity's Board of Directors or advisory committees; Rigel: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Rothman: Pfizer: Consultancy; Agios Pharmaceuticals: Honoraria. Haley: Genentech: Honoraria; Baxalta: Honoraria; CSL Behring: Honoraria. Neufeld: Octapharma: Consultancy, Honoraria; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Lambert: Educational Concepts in Medicine: Honoraria; Novartis: Honoraria; AstraZeneca: Research Funding.

Abstract: Background: The indications for treating children with immune thrombocytopenia (ITP) remain controversial. A valid and reliable bleeding assessment tool could assist in objectively quantifying bleeding and influence treatment decisions. Both the ITP Bleeding Score (IBLS) and the ITP-Bleeding Assessment Tool (BAT) have been developed to assess bleeding severity in ITP. The IBLS scores bleeding severity using an 11-item tool with grading from 0 to 2 and the 18-item BAT grades from 0 to 3 or 4. The BAT includes some types of bleeding not represented on the IBLS, such has intramuscular hematomas. To date, no data describe how these two measures compare when measuring bleeding associated with ITP. Objective: To describe and compare bleeding as assessed by both the IBLS and BAT and to correlate bleeding severity with platelet counts in a cohort of children with ITP. Methods: A longitudinal observational cohort of children ages 〉 1 and 〈 18 years with ITP, were enrolled from 2013-2015 in the Pediatric ITP Consortium of North America ICON1 trial. All children were enrolled prior to starting a new second line monotherapy (not IVIG, steroids or anti-D). At enrollment, bleeding was assessed using the IBLS in all children. A subset of children also underwent a BAT assessment. Grades of bleeding were described and compared between tools and agreement in grading was assessed. Severity was correlated with platelet count using Spearman's correlation calculation. Results: 118 children were enrolled from 21 ICON centers. 54% had chronic ITP and the median age was 11.4y (range 1.2-17.8). The mean platelet count was 28 x 109/l (SD 57) and 88% had a baseline platelet count of 〈 30 x 109/l. The burden of skin and oral bleeding was high. Table 1 compares bleeding scores for the 78 patients with both measures. Agreement for grades 0, 1, and 2 between the measures was highest for urinary bleeding (97%), gastrointestinal (95%), subconjunctival (95%), and epistaxis (91%). Agreement between IBLS oral bleeding by historyand BAT gum bleeding was 78% and with BAT oral cavity bleeding was 79%. IBLS oral bleeding by physical examination and BAT gum bleeding was 73% and BAT oral cavity bleeding was 79%. The lowest agreement was seen for skin manifestations. IBLS skin bleeding by history showed only 54% and 62% agreement with the BAT ecchymoses and petechiae items respectively. IBLS skin bleeding by physical examination showed 59% agreement with both the BAT ecchymoses and petechiae items. Grades 3 and 4 scores from the BAT did not provide additional information beyond the IBLS for most sites of bleeding. For sites included on the BAT but not represented on the IBLS, only 1 child had an intramuscular hematoma, 1 suffered an ocular bleed, and none experienced hemarthrosis. Bleeding from minor wounds and bleeding with tooth loss captured additional bleeding symptoms in 9 and 4 children, respectively. There were no episodes of pulmonary or intracranial hemorrhage in the cohort. Table 2 shows the correlation between bleeding severity and platelet count for all items on each measure. Conclusion: The IBLS and BAT were similarly effective at identifying bleeding symptoms, although neither tool showed strong correlation with the platelet count. There were moderate correlations noted between skin bleeding scores and platelet counts for both tools. A major limitation of this comparison is the different definitions of bleeding severity between the two measures. For sites where the items were more detailed, agreement declined (i.e. adding specificity reduced generalizability). While no patients in our cohort exhibited significant grade 3 or 4 bleeding outside of skin findings, we conclude that in the setting of clinical trials, the ability to capture very severe bleeding might be an important distinction that supports using the more complicated BAT, but for clinical practice, a simplified assessment such as the IBLS may suffice. Disclosures Grace: Agios Pharmaceuticals: Other: Scientific Advisor, Research Funding. Neufeld:Novartis: Consultancy. Bussel:Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; UpToDate: Patents & Royalties; Protalex: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genzyme: Research Funding; Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding; Symphogen: Membership on an entity's Board of Directors or advisory committees; Rigel Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Shionogi: Membership on an entity's Board of Directors or advisory committees; Sysmex: Research Funding; Momenta Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Immunomedics: Research Funding; Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer Ingelheim: Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cangene: Research Funding; Prophylix Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Physicians Education Resource: Speakers Bureau; BiologicTx: Research Funding. Haley:CSL Behring: Honoraria; Baxalta: Membership on an entity's Board of Directors or advisory committees. Thompson:Celgene: Research Funding; ApoPharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Mast: Research Funding; Amgen: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Amgen: Research Funding; Baxalta (now part of Shire): Research Funding; bluebird bio: Consultancy, Research Funding; Baxalta (now part of Shire): Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; bluebird bio: Consultancy, Research Funding; Mast: Research Funding; ApoPharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Eli Lily: Research Funding; Eli Lily: Research Funding.