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Anticoagulant treatment of pediatric cerebral venous thrombosis has not been evaluated in randomized trials. We evaluated the safety and efficacy of rivaroxaban and standard anticoagulants in the predefined subgroup of children with cerebral venous thrombosis (CVT) who participated in the EINSTEIN-Jr trial. Children with CVT were randomized (2:1), after initial heparinization, to treatment with rivaroxaban or standard anticoagulants (continued on heparin or switched to vitamin K antagonist). The main treatment period was 3 months. The primary efficacy outcome, symptomatic recurrent venous thromboembolism (VTE), and principal safety outcome, major or clinically relevant nonmajor bleeding,were centrally evaluated by blinded investigators. Sinus recanalization on repeat brain imaging was a secondary outcome. Statistical analyses were exploratory. In total, 114 children with confirmed CVT were randomized. All children completed the follow-up. None of the 73 rivaroxaban recipients and 1 (2.4%; CVT) of the 41 standard anticoagulant recipients had symptomatic, recurrent VTE after 3 months (absolute difference, 2.4%; 95% confidence interval [CI], 22.6% to 13.5%). Clinically relevant bleeding occurred in 5 (6.8%; all nonmajor and noncerebral) rivaroxaban recipients and in 1 (2.5%; major [subdural] bleeding) standard anticoagulant recipient (absolute difference, 4.4%; 95% CI, 26.7% to 13.4%). Complete or partial sinus recanalization occurred in 18 (25%) and 39 (53%) rivaroxaban recipients and in 6 (15%) and 24 (59%) standard anticoagulant recipients, respectively. In summary, in this substudy of a randomized trial with a limited sample size, children with CVT treated with rivaroxaban or standard anticoagulation had a low risk of recurrent VTE and clinically relevant bleeding. This trial was registered at clinicaltrials.gov as #NCT02234843. © 2020 by The American Society of Hematology This study was supported by Bayer AG and Janssen Research and Development.

Increased awareness of von Willebrand Disease (VWD) has led to more frequent diagnostic laboratory testing, which insurers often dictate be performed at a facility with off-site laboratory processing, instead of a coagulation facility with onsite processing. Off-site processing is more prone to preanalytical variables causing falsely low levels of von Willebrand Factor (VWF) due to the additional transport required. Our aim was to determine the percentage of discordance between off-site and onsite specimen processing for VWD in this multicenter, retrospective study. We enrolled females aged 12 to 50 years who had off-site specimen processing for VWF assays, and repeat testing performed at a consulting institution with onsite coagulation phlebotomy and processing. A total of 263 females from 17 institutions were included in the analysis. There were 251 subjects with both off-site and onsite VWF antigen (VWF:Ag) processing with 96 (38IU/dL) being low off-site and 56 (22IU/dL) low onsite; 223 subjects had VWF ristocetin co-factor (VWF:RCo), 122 (55IU/dL) were low off-site and 71 (32IU/dL) were low onsite. Similarly, 229 subjects had a Factor VIII (FVIII) assay, and 67 (29IU/dL) were low off-site with less than half, 29 (13IU/dL) confirmed low with onsite processing. Higher proportions of patients demonstrated low VWF:Ag, VWF:RCo, and/or FVIII with off-site processing compared to onsite (McNemar's test P-value

How old is too old? In vivo engraftment of human peripheral blood stem cells cryopreserved for up to 18 years - implications for clinical transplantation and stability programs

Background: Recently, the randomized EINSTEIN-Jr study showed similar efficacy and safety for rivaroxaban and standard anticoagulation for treatment of pediatric venous thromboembolism (VTE). The rivaroxaban dosing strategy was established based on phase 1 and 2 data in children and through pharmacokinetic (PK) modeling. Methods: Rivaroxaban treatment with tablets or the newly developed granules-for-oral suspension formulation was bodyweight-adjusted and administered once-daily, twice-daily, or thrice-daily for children with bodyweights of ≥30, ≥12 to (0-24)ss] and trough [C trough,ss] and maximum [C max,ss] steady-state plasma concentrations were derived using population PK modeling. Exposure-response graphs were generated to evaluate the potential relationship of individual PK parameters with recurrent VTE, repeat imaging outcomes, and bleeding or adverse events. A taste-and-texture questionnaire was collected for suspension-recipients. Results: Of the 335 children (aged 0-17 years) allocated to rivaroxaban, 316 (94.3%) were evaluable for PK analyses. Rivaroxaban exposures were within the adult exposure range. No clustering was observed for any of the PK parameters with efficacy, bleeding, or adverse event outcomes. Results were similar for the tablet and suspension formulation. Acceptability and palatability of the suspension were favorable. Discussion: Based on this analysis and the recently documented similar efficacy and safety of rivaroxaban compared with standard anticoagulation, we conclude that bodyweight-adjusted pediatric rivaroxaban regimens with either tablets or suspension are validated and provide for appropriate treatment of children with VTE.

Background: Recently, the randomised EINSTEIN-Jr. study showed similar efficacy and safety for rivaroxaban and standard anticoagulation for acute and continued treatment of paediatric venous thromboembolism (VTE). The rivaroxaban dosing strategy was established based on phase 1 and 2 data in children and through pharmacokinetic (PK) modeling. Methods: Rivaroxaban treatment with tablets or the newly-developed granules-for-oral suspension formulation was bodyweight-adjusted and administered once-daily, twice-daily or thrice-daily for children with bodyweights of ≥30, ≥12

Contains fulltext : 219893.pdf (Publisher’s version ) (Closed access) BACKGROUND: Treatment of venous thromboembolism in children is based on data obtained in adults with little direct documentation of its efficacy and safety in children. The aim of our study was to compare the efficacy and safety of rivaroxaban versus standard anticoagulants in children with venous thromboembolism. METHODS: In a multicentre, parallel-group, open-label, randomised study, children (aged 0-17 years) attending 107 paediatric hospitals in 28 countries with documented acute venous thromboembolism who had started heparinisation were assigned (2:1) to bodyweight-adjusted rivaroxaban (tablets or suspension) in a 20-mg equivalent dose or standard anticoagulants (heparin or switched to vitamin K antagonist). Randomisation was stratified by age and venous thromboembolism site. The main treatment period was 3 months (1 month in children /=1 dose), were centrally assessed by investigators who were unaware of treatment assignment. Repeat imaging was obtained at the end of the main treatment period and compared with baseline imaging tests. This trial is registered with ClinicalTrials.gov, number NCT02234843 and has been completed. FINDINGS: From Nov 14, 2014, to Sept 28, 2018, 500 (96%) of the 520 children screened for eligibility were enrolled. After a median follow-up of 91 days (IQR 87-95) in children who had a study treatment period of 3 months (n=463) and 31 days (IQR 29-35) in children who had a study treatment period of 1 month (n=37), symptomatic recurrent venous thromboembolism occurred in four (1%) of 335 children receiving rivaroxaban and five (3%) of 165 receiving standard anticoagulants (hazard ratio [HR] 0.40, 95% CI 0.11-1.41). Repeat imaging showed an improved effect of rivaroxaban on thrombotic burden as compared with standard anticoagulants (p=0.012). Major or clinically relevant non-major bleeding in participants who received >/=1 dose occurred in ten (3%) of 329 children (all non-major) receiving rivaroxaban and in three (2%) of 162 children (two major and one non-major) receiving standard anticoagulants (HR 1.58, 95% CI 0.51-6.27). Absolute and relative efficacy and safety estimates of rivaroxaban versus standard anticoagulation estimates were similar to those in rivaroxaban studies in adults. There were no treatment-related deaths. INTERPRETATION: In children with acute venous thromboembolism, treatment with rivaroxaban resulted in a similarly low recurrence risk and reduced thrombotic burden without increased bleeding, as compared with standard anticoagulants. FUNDING: Bayer AG and Janssen Research & Development. 01 januari 2020

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.

For decades, the monogenetic bleeding disorders hemophilia A and B (coagulation factor VIII and IX deficiency) have been treated with systemic protein replacement therapy. Now, diverse molecular medicines, ranging from antibody to gene to RNA therapy, are transforming treatment. Traditional replacement therapy requires twice to thrice weekly intravenous infusions of factor. While extended half-life products may reduce the frequency of injections, patients continue to face a lifelong burden of the therapy, suboptimal protection from bleeding and joint damage, and potential development of neutralizing anti-drug antibodies (inhibitors) that require less efficacious bypassing agents and further reduce quality of life. Novel non-replacement and gene therapies aim to address these remaining issues. A recently approved factor VIII-mimetic antibody accomplishes hemostatic correction in patients both with and without inhibitors. Antibodies against tissue factor pathway inhibitor (TFPI) and antithrombin-specific small interfering RNA (siRNA) target natural anticoagulant pathways to rebalance hemostasis. Adeno-associated virus (AAV) gene therapy provides lasting clotting factor replacement and can also be used to induce immune tolerance. Multiple gene-editing techniques are under clinical or preclinical investigation. Here, we provide a comprehensive overview of these approaches, explain how they differ from standard therapies, and predict how the hemophilia treatment landscape will be reshaped.

Background: Treatment of venous thromboembolism (VTE) in children is based on data obtained in adults with little direct documentation of its efficacy and safety in children. Methods: In a parallel-group open-label randomised study, 500 children aged birth to 17 years with documented acute VTE who had started heparinisation were assigned, in a 2:1 ratio, to receive bodyweight-adjusted rivaroxaban (tablets or suspension) in a 20-mg equivalent dose or standard anticoagulants. The main treatment period was 3 months (1 month in children under 2 years with catheter-related VTE). Symptomatic recurrent VTE and bleeding were centrally assessed unaware of treatment assignment. Repeat imaging was obtained at the end of the treatment period. Findings: Recurrent VTE was the primary efficacy outcome and occurred in 4 of the 335 (1.2%) children allocated to rivaroxaban and in 5 of the 165 (3.0%) children allocated to standard anticoagulants (64.2% of whom received subcutaneous heparins only), for a hazard ratio of 0.40 (95% confidence interval, 0.11 to 1.41). Repeat imaging showed an improved effect of rivaroxaban on thrombotic burden as compared with standard anticoagulants (P=0.012). Major or clinically relevant non-major bleeding was the principal safety outcome and occurred in 10 children (3.0%; all non-major) with rivaroxaban and in 3 children (1.9%; two major and 1 non-major) with standard anticoagulants. Absolute and relative efficacy and safety estimates of rivaroxaban versus standard anticoagulation estimates were comparable those obtained in rivaroxaban studies in adults. Interpretation: In children with acute VTE, treatment with rivaroxaban resulted in a low recurrence risk and a reduced thrombotic burden without increased bleeding, as compared to standard anticoagulants. Trial Registration: This trial is registered with ClinicalTrials.gov, number NCT02234843. Funding Statement: Bayer AG and Janssen Research & Development, LLC. Declaration of Interests: CM reports receiving personal fees and fees, paid to his institution, from Bayer, Bristol-Myers-Squibb, Pfizer and fees, paid to his institution, from BoehringerIngelheim; AWAL being employed by Bayer; RK receiving personal fees from Bayer, CSL Behring, and Kedrion; DB receiving personal fees and grant support from Actelion Pharmaceuticals, Bayer, Eli Lilly, BMS, and Novartis and grant support from AbbVie; PC receiving personal fees from Onyx Health Limited; AKC receiving personal fees from Bayer and fees, paid to his institution, from Bayer, Pfizer, Daiichi Sankyo, and Bristol-Myers-Squibb; GK receiving personal fees from Bayer, Boehringer Ingelheim, and Daiichi-Sankyo and fees, paid to her institution from Pfizer; SH receiving personal fees from P and fees, paid to her institution, from Bayer, Pfizer, and Daiichi Sankyo; AS receiving personal fees from Bayer, Pfizer, Daiichi Sankyo and Boehringer Ingelheim; PA receiving personal fees and fees, paid to his institution, from Abbvie and Bayer, and fees paid to his institution from Actelion, Novartis, and Daiichi Sankyo; EC receiving personal fees from Boehringer Ingelheim and Bristol-Myers-Squibb, and fees, paid to her institution from Bayer, Pfizer, and Daiichi Sankyo; DLY receiving fees, paid to his institution, from Bayer, Pfizer, and Bristol-Myers Squibb; OL receiving personal fees from Bayer, Pfizer, Boehringer Ingelheim, and Novartis, and fees, paid to her institution, from Bayer; JB-W receiving personal fees and fees, paid to his institution, from Bayer, Daiichi Sankyo, DOASENSE and Portola and fees, paid to his institution, from Pfizer; TTB receiving fees from Boehringer Ingelheim and Bayer, and grant support from Leo Pharma; IM receiving fees from Sanofi and Bayer; MP receiving grant support from Pfizer and Sobi; MPM receiving personal fees from Bayer; GY receiving receiving personal fees from GlaxoSmithKline and Portola and personal fees and fees paid to his institution from Bayer and Daiichi Sankyo; AFP, MM, WTS, SDB, KT, DK being employed by Bayer; JH was employed by Bayer; MC receiving grant support from and serving on a data and safety monitoring board for Bayer, receiving advisory board fees from Shionogi, Octapharma, Bristol-Myers Squibb Canada, and Asahi Kasei, receiving educational funding from Alexion Pharmaceuticals, Pfizer, CSL Behring, and Diagnostica Stago, receiving grant support, paid to his institution, from Leo Pharma, serving on a data and safety monitoring board for Daiichi Sankyo, owning stock in Alnylam Pharmaceuticals, and receiving educational funding and advisory board fees from Servier Canada; MHP receiving personal fees from Bayer; no other potential conflict of interest relevant to this article was reported. Ethics Approval Statement: The protocol was approved by the institutional review board at each participating center. Written permission from a parent or guardian and, when appropriate, child assent, were obtained.

Study Objective Heavy menstrual bleeding (HMB) occurs in up to 40% of adolescent girls, significantly affecting their daily activities. Identifying alternative treatment strategies for HMB is particularly important for adolescents who prefer not to take hormonal contraception. Our objective was to determine whether use of tranexamic acid (TA) would increase health-related quality of life and decrease menstrual blood loss (MBL) in adolescents with HMB. Design, Setting, Participants, Interventions, and Main Outcome Measures In an open-label, multi-institutional, single-arm, efficacy study, patients 18 years of age or younger with HMB were treated with oral TA 1300 mg 3 times daily during the first 5 days of menses and monitored over the course of 4 menstrual cycles (1 baseline; 3 treatment cycles). Assessment of MBL was performed using the Menorrhagia Impact Questionnaire (MIQ) and the Pictorial Blood Assessment Chart. The MIQ includes Likert scale items, validated to assess the influence of HMB on quality of life. In previous studies, a 1-point decrease or more in score correlated with clinically significant improvement. Results Thirty-two patients enrolled in the study, and 25 had sufficient follow-up data to be deemed evaluable. The mean age of the participants was 14.7 years (range, 11-18 years). There was an overall improvement in all items of the MIQ, with a greater than 1-point improvement in the MIQ perceived blood loss scale. When using TA, mean Pictorial Blood Assessment Chart score improved by 100 points. There were no medication-related serious adverse events. Conclusion Use of TA in female adolescents with HMB is well tolerated and leads to clinically meaningful reduction in MBL.

Objectives Thrombosis is a cause of morbidity in 4-15% of children who undergo pediatric cardiac surgery. Data on how to prevent this complication are sorely needed. We aimed to identify risk factors for thrombosis following pediatric cardiac surgery and determine if use of low molecular weight heparin prophylaxis is associated with a reduction in thrombosis risk. Design Retrospective cohort study. Setting Tertiary pediatric cardiovascular ICU. Patients Patients who underwent cardiac surgery between June 2014 and December 2015. Interventions None. Measurements and main results Data from patients with venous or arterial thrombosis confirmed by radiologic studies were matched two-to-one to controls based on age, Society of Thoracic Surgeons-European Association for Cardio-Thoracic Surgery mortality category, and gender. Thrombosis was detected in 33 patients (6.2%): 25 patients (76%) had venous thromboses, five patients (15%) had arterial thromboses, and three patients (9%) had both. Median time to thrombosis detection was 13 days (25-75%; 7-31 d). On multivariate analysis, which included adjustment for postoperative disease severity, fresh frozen plasma exposure was independently associated with thrombosis (odds ratio, 3.7; 95% CI, 1.4-9.4). Twenty-eight patients (85%) had central venous catheter-related thromboses. Low molecular weight heparin prophylaxis use in this subset of patients was not statistically different from controls (50% vs 45%, respectively; p = 0.47). On multivariable analysis, fresh frozen plasma exposure was also independently associated with central venous catheter-related thrombosis (odds ratio, 3.6; 95% CI, 1.2-10.6). Conclusions The occurrence of thrombosis after pediatric cardiac surgery at our institution was 6.2%, similar to what has been reported in other studies, despite frequent use of low molecular weight heparin. Further study is needed to determine the role of low molecular weight heparin for thromboprophylaxis and the relationship between fresh frozen plasma and thrombosis risk in children who undergo cardiac surgery.

Background: Immune thrombocytopenia (ITP) is an immune mediated bleeding disorder characterized by isolated thrombocytopenia. ITP can have a variety of presentations from asymptomatic to life threatening bleeding. Although childhood ITP is most often a self-resolving illness which can be closely observed without intervention, it can be associated with significant impact on quality of life (QoL). Prospective studies of QoL in ITP patients show that there is not always a correlation with treatment or disease severity. The pathway from initial presentation to final diagnosis varies and may include encounters with emergency room, primary care or specialty providers. There have been no published studies to date showing the impact of factors prior to the diagnosis of ITP on treatment decision making and QoL. Objective: To identify the role of physician-patient and physician-caregiver interactions on the QoL and emotional well-being of patients and their families. Ascertaining the impact of pre-diagnosis factors may provide an opportunity to improve access and quality of care provided. Methods: The ITP Consortium of North America (ICON) "Pathways" study was a multicenter observational prospective cohort study focused on the pathways to diagnosis of ITP. The study was supported by a Foundation for Morristown Medical Center Research Fund Grant. Subjects were included if they had presumed primary ITP and were age >12 months to Results: Sixty subjects and caregivers were enrolled at 6 ICON centers; 52 were eligible for inclusion. The majority (40%) had Grade 1 bleeding. Most patients (82%) were seen in outpatient hematology clinic by the hematologist and had been referred by the emergency room (73%). The median time to consultation with a hematologist from onset of symptoms was 7 days (1-199) and the median time to diagnosis by hematologist from initial contact with a health care provider was 5 days (0-154). Most subjects had seen 2 health care providers prior to the hematologist. KIT proxy report cumulative scores were a mean of 76.03 (SD 14.72). There was no significant difference between the time to diagnosis or the time from initial encounter with health care provider to hematologist and initial level of worry (p=0.70 and 0.90, respectively). There was also no significant difference between the time to diagnosis or the time from initial encounter with health care provider to hematologist and KIT proxy scores (p=0.96 and 0.50, respectively). However, there was a significant decline in level of worry (scale 0-10) prior to the hematologist visit (median 8, range 1-10) to after the visit (median 4, range 1-10). The association between number of medical providers encountered prior to diagnosis and KIT proxy scores was not significant (p=0.45) (Table). Conclusions: In this study at 6 teaching institutions, we were unable to detect a significant difference in proxy-reported KIT scores relative to the number of health care providers seen or time from diagnosis until the first encounter with the hematologist. We were, however, able to detect a significant change in the level of caregiver worry pre- and post- visit with the pediatric hematologist, supporting a benefit of specialist care to the caregivers of children with ITP. This study was limited by its small sample size and retrospective design. ITP is considered a benign disease but is associated with a significant amount of worry and impact on QoL for patients and caregivers which warrants further investigation. Disclosures Lambert: CSL Behring: Consultancy; Amgen: Consultancy, Other; Bayer: Other: Ad boards; Novartis: Other: Ad boards, Research Funding; Shionogi: Consultancy; Kedrion: Consultancy; Sysmex: Consultancy; AstraZeneca: Research Funding; PDSA: Research Funding. Grace:Agios Pharmaceuticals, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding.

Graft failure occurs at relatively low frequency, but commonly in hemophagocytic lymphohistiocytosis (HLH), especially with umbilical cord blood transplant (UCBT). No standard approaches to management of graft failure exist. We present a challenging case of relapsed HLH following first UCBT with primary graft failure following second UCBT. We report a novel reduced intensity conditioning regimen of alemtuzumab, 4 Gy total body irradiation and fludarabine for salvage of primary graft failure followed by double UCBT. The reported patient successfully engrafted with 100% donor chimerism following salvage UCBT with no occurrence of acute or chronic graft-versus-host disease.

The mortality in the ICU for pediatric HSCT recipients remains high. Early pulmonary complications continue to be an obstacle to the survival. We hypothesize OI is a predictor for mortality in critically ill pediatric HSCT recipients. Retrospective review of pediatric HSCT recipients between 2002 and 2010 who required intensive care during the same hospital admission as their transplant. Twenty-eight patients accounted for 31 ICU admissions. Twenty-six (84%) admissions required mechanical ventilation. Ten (38%) mechanically ventilated admissions were placed on HFOV. Mortality of those mechanically ventilated was 70%. An OI ≥ 20 at any point during ventilation was associated with 94% mortality, while an OI ≥ 25 had 100% mortality. There was a significant association between maximum OI at any point during mechanical ventilation and ICU mortality, with the odds of dying increasing by 13% for each unit increase of max OI (OR = 1.13, 95% CI = 1.01-1.26, p = 0.03). An OI of 20 had a sensitivity of 0.89 and specificity of 0.83 for predicting mortality. OI has a strong association with ICU mortality among pediatric stem cell recipients.

Graft failure occurs at relatively low frequency, but commonly in hemophagocytic lymphohistiocytosis (HLH), especially with umbilical cord blood transplant (UCBT). No standard approaches to management of graft failure exist. We present a challenging case of relapsed HLH following first UCBT with primary graft failure following second UCBT. We report a novel reduced intensity conditioning regimen of alemtuzumab, 4 Gy total body irradiation and fludarabine for salvage of primary graft failure followed by double UCBT. The reported patient successfully engrafted with 100% donor chimerism following salvage UCBT with no occurrence of acute or chronic graft-versus-host disease.

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 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 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.

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 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.

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 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.

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 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.