Search

Pyruvate kinase deficiency (PKD) is the most common cause of congenital nonspherocytic hemolytic anemia. Although recognition of the disease spectrum has recently expanded, data describing its impact on health-related quality of life (HRQoL) are limited. In this prospective international cohort of 254 patients (131 adults and 123 children) with PKD, we used validated measures to assess the impact of disease on HRQoL (EuroQol 5-Dimension Questionnaire, Pediatric Quality of Life Inventory Generic Core Scale version 4.0, and Functional Assessment of Cancer Therapy-Anemia) and fatigue (Patient Reported Outcomes Measurement Information System Fatigue and Pediatric Functional Assessment of Chronic Illness Therapy-Fatigue). Significant variability in HRQoL and fatigue was reported for adults and children, although individual scores were stable over a 2-year interval. Although adults who were regularly transfused reported worse HRQoL and fatigue compared with those who were not (EuroQol-visual analog scale, 58 vs 80; P = .01), this difference was not seen in children. Regularly transfused adults reported lower physical, emotional, and functional well-being and more anemia symptoms. HRQoL and fatigue significantly differed in children by genotype, with the worst scores in those with 2 severe PKLR mutations; this difference was not seen in adults. However, iron chelation was associated with significantly worse HRQoL scores in children and adults. Pulmonary hypertension was also associated with significantly worse HRQoL. Additionally, 59% of adults and 35% of children reported that their jaundice upset them, identifying this as an important symptom for consideration. Although current treatments for PKD are limited to supportive care, new therapies are in clinical trials. Understanding the impact of PKD on HRQoL is important to assess the utility of these treatments. This trial was registered at www.clinicaltrials.gov as #NCT02053480.

Background Parents of children newly diagnosed with cancer are required to understand a significant amount of new information during a time of distress. Parents of children with cancer have expressed that concise information with visual cues, which can be repeated, positively influences their ability to understand. Objectives The primary objective was to develop 2 concise, video-based education modules that are understandable to parents of children with cancer. A secondary objective was to determine feasibility of a future trial evaluating efficacy of video-based education. Methods The study was conducted in phases: script development, video creation, and feasibility testing. Topics were "managing fever at home" and "giving medications at home." Content was developed by pediatric oncology experts and turned into video scripts. Scripts were refined through cognitive interviews with parents of children with cancer. Feasibility testing included recruitment of 20 parents of a child given a diagnosis of cancer within 4 weeks. Parents watched both videos and answered questions that assessed their understanding and perceived confidence. Results Final scripts were reviewed by 25 participants. Feasibility was achieved with 20 parents recruited within 7 weeks, with 100% watching both videos and answering knowledge and confidence questions. Conclusions We successfully developed 2 educational videos for parents of children newly diagnosed with cancer. A future trial to test the efficacy of video-based education modules is feasible. Implications to practice Delivering quality education to parents of children newly diagnosed with cancer can decrease parental distress and improve safe care during a high-risk time for treatment-related morbidity and mortality.

Background Immune thrombocytopenia (ITP) is an autoimmune disease characterized by low platelet counts and increased risk of bleeding. In preparation for an upcoming guideline, the ITP Emergency Management Guideline Panel, including clinical experts in hematology, emergency medicine, research methodology, and patient representatives, identified the need for a standardized definition of a critical ITP bleed. The goal of the definition was to distinguish critical bleeds from bleeds that may not require urgent treatment, typically in the context of severe thrombocytopenia. Methods The panel met in person and virtually to achieve consensus on the criteria for critical bleeding events among patients with ITP. Existing ITP bleeding scores and published definitions of major bleeds in patients receiving anticoagulation informed the definition of a critical ITP bleed. The Platelet Immunology Scientific Standardization Committee (SSC) of the International Society on Thrombosis and Haemostasis endorsed the definition. Results A critical ITP bleed was defined as: (a) a bleed in a critical anatomical site including intracranial, intraspinal, intraocular, retroperitoneal, pericardial, or intramuscular with compartment syndrome; or (2) an ongoing bleed that results in hemodynamic instability or respiratory compromise. Conclusion The definition of a critical ITP bleed was developed by the ITP Emergency Management Guideline Panel and endorsed by the Platelet Immunology SSC. It incorporates both anatomic and physiologic risk and pertains to patients with confirmed or suspected ITP who typically have severe thrombocytopenia (platelet count below 20 × 109 /L).

Avoidant/restrictive food intake disorder (ARFID) is a feeding and eating disorder that results in nutritional inadequacies, weight loss, and/or dependence on enteral feeds, and for which three clinical subtypes have been described. We present a unique case of an 11-year-old boy with rigid ARFID since infancy and features of all three ARFID subtypes. The patient presented with a life-long history of sensory aversion, limited intake and phobia of vomiting resulting in restriction to a single food item (yogurt) for more than 5 years. He presented with severe iron-deficiency anaemia, and deficiencies of vitamins A, C, D, E and zinc. We employed a multimodal therapeutic approach that incorporated elements of cognitive-behavioural therapy (CBT), family-based therapy (FBT) and pharmacological management with an antidepressant medication (sertraline) and an atypical antipsychotic agent (olanzapine). Over the course of a 7-week admission, our approach assisted the patient in successful weight restoration and incorporation of at least three new food items into his daily diet. While there are currently no first-line recommendations for ARFID management, our study lends support to the efficacy of CBT, FBT and pharmacological management for ARFID patients, including complex cases with multiple subtype features. Further research is needed to strengthen ARFID clinical guidelines.

Immune thrombocytopenia (ITP), an acquired autoimmune disorder of low platelets and risk of bleeding, has a substantial impact on health-related quality of life (HRQoL). Patients with ITP often report significant fatigue, although the pathophysiology of this is poorly understood. In this observational cohort of 120 children receiving second-line therapies for ITP, we assessed reports of fatigue using the Hockenberry Fatigue Scale. Children and adolescents with ITP reported a similarly high level of fatigue with 54% (29/54) of children and 62% (26/42) of adolescents reporting moderate-to-severe fatigue. There was no correlation between fatigue and age or gender. Adolescents with newly diagnosed and persistent ITP had higher mean fatigue scores than those with chronic ITP (P = 0·03). Fatigue significantly improved in children and adolescents by 1 month after starting second-line treatments, and this improvement continued to be present at 12 months after starting treatment. Fatigue scores at all time-points correlated with general HRQoL using the Kids ITP Tool, but did not correlate with bleeding symptoms, platelet count, or platelet response to treatment. Fatigue is common in children and adolescents with ITP and may benefit from ITP-directed treatment even in the absence of bleeding symptoms.

Purpose: To compare the Cancer Distress Scales for Adolescents and Young Adults (CDS-AYA)—Emotional and Impact scales—with the Edmonton Symptom Assessment Scale–revised (ESAS-r), Hospital Anxiety a...

Progressive cytopenia is a serious complication among paediatric patients with inherited bone marrow failure syndromes (IBMFS). Androgens have been used to improve blood counts in different bone marrow failure conditions. Little is known about efficacy and toxicity with new androgens (i.e., danazol) in different types of IBMFS. We identified 29 patients from the Canadian Inherited Marrow Failure Registry, who received oxymetholone or danazol. Sixteen (55%) had haematological response including patients with unclassified IBMFS (45%). Danazol showed a better toxicity profile and similar efficacy compared to oxymetholone. Androgens are an effective and safe option to ameliorate bone marrow failure in IBMFS.

Purpose: The use of valid and reliable screening tools to measure distress may help to identify adolescent and young adults (AYA) with cancer who need additional support. Our study describes a two-phase approach to adapt the Australian AYA oncology and survivorship distress screening tools for use in Canada. Methods: Phase 1 involved refining the Australian AYA oncology and survivorship screening tools using cognitive interviews with AYA with cancer and feedback from experts. In phase 2, a field-test study was performed, and Rasch Measurement Theory (RMT) analysis was used for item reduction and to examine reliability and validity. Results: Cognitive interviews with 45 AYA with cancer and feedback from 25 experts resulted in a field-test version of the Cancer Distress Scales for AYA (CDS-AYA) consisting of 91 items that measure 9 constructs. The field-test sample included 515 participants. RMT analysis identified five scales (impact of cancer, physical, emotional, cancer worry, and cognitive) with ordered thresholds, good item fit (-3.70 to 2.82), and acceptable reliability (0.85-0.94). Reliability for the remaining four scales (employment, education, practical, and social) was low, and the scales were retained as checklists, with the exception of the social scale that was dropped. Conclusion: The final item-reduced CDS-AYA consist of 48 items in 5 scales, with 2 stand-alone items in the physical and emotional scales and 23 items in 3 checklists. The CDS-AYA can be used in research and in clinical practice to measure distress in AYA with cancer.

Purpose: Distress is an important issue facing adolescent and young adults (AYA) with cancer due to their stage of development. Metrics are necessary to help improve psychosocial outcomes in this population. This study determined cut-points for the newly developed Cancer Distress Scales (CDS)-AYA. Methods: The CDS-AYA is a new patient-reported outcomes measure that comprises five independently functioning scales, including the following: Impact of Cancer (12 items), Physical (12 items), Emotional (11 items), Cognitive (8 items), and Cancer Worry (5 items). Canadian AYA with cancer 15-39 years of age completed the CDS-AYA and the Hospital Anxiety and Depression Scale (HADS), as part of the CDS-AYA field test. Only patients who had completed responses to the CDS-AYA and HADS were included in these analyses. Receiver operating characteristic (ROC) curve analysis was used to generate cut-points for five CDS-AYA scales based on distress defined by the HADS anxiety and HADS depression scale. Results: In total 453 of 515 respondents had complete data for the CDS-AYA and HADS were included in analyses. Area under the curve (AUC) in the ROC analyses ranged from 0.75 to 0.85. The CDS-AYA Emotional scale had the greatest AUC. The cutoff value for the Emotional scale was 27 based on the HADS anxiety scores (78.3% and 78.9%). Conclusions: The five CDS-AYA scales had fair to good accuracy when classifying the none/low and moderate/severe distress categories based on HADS anxiety and depression scales. For screening purposes, it is recommended that the Emotional scale or Impact of Cancer scale be utilized.

BACKGROUND Therapy for childhood acute lymphoblastic leukemia (ALL) is associated with substantial health care utilization and burden on families. Little is known about health care utilization during specific treatment phases. PROCEDURES We identified children with ALL diagnosed during 2002-2012 in Ontario, Canada and treated according to Children's Oncology Group (COG) protocols. Disease and treatment data were chart abstracted. Population-based health care databases identified all outpatient visits, emergency department (ED) visits, and hospitalizations. In addition to comparing standard and intensified versions of treatment phases, we compared patients receiving different steroids (dexamethasone vs. prednisone) and different versions of interim maintenance (IM) (Capizzi vs. high-dose methotrexate [HD-MTX]). RESULTS Six hundred thirty-seven children met inclusion criteria. During intensified consolidation, 76.2% of patients were hospitalized at least once, compared to only 32.3% of patients receiving standard consolidation (p

Pyruvate kinase deficiency (PKD) is a rare, autosomal recessive red blood cell enzyme disorder, which leads to lifelong hemolytic anemia and associated complications from the disease and its management.An international, multicenter registry enrolled 124 individuals younger than 18 years old with molecularly confirmed PKD from 29 centers. Retrospective and prospective clinical data were collected.There was a wide range in the age at diagnosis from 0 to 16 years. Presentation in the newborn period ranged from asymptomatic to neonatal jaundice to fulminant presentations of fetal distress, myocardial depression, and/or liver failure. Children5 years old were significantly more likely to be transfused than children12 to18 years (53% vs. 14%, p = .0006), which correlated with the timing of splenectomy. Regular transfusions were most common in children with two severe PKLR variants. In regularly transfused children, the nadir hemoglobin goal varied considerably. Impact on quality of life was a common reason for treatment with regular blood transfusions and splenectomy. Splenectomy increased the hemoglobin and decreased transfusion burden in most children but was associated with infection or sepsis (12%) and thrombosis (1.3%) even during childhood. Complication rates were high, including iron overload (48%), perinatal complications (31%), and gallstones (20%).There is a high burden of disease in children with PKD, with wide practice variation in monitoring and treatment. Clinicians must recognize the spectrum of the manifestations of PKD for early diagnostic testing, close monitoring, and management to avoid serious complications in childhood.

Purpose: Distress in cancer is defined as multifactorial unpleasant experience of an emotional, psychological, social, or spiritual nature that interferes with ones' ability to cope with cancer and...

Although different treatment protocols for childhood acute lymphoblastic leukaemia (ALL) all achieve high cure rates, their health care utilisation and costs have not been rigorously compared.Disease, treatment, and outcome data were chart abstracted for all children with ALL in Ontario, Canada, diagnosed 2002-2012. Linkage to population-based databases identified health care utilisation. Utilisation-associated costs were determined through validated algorithms. Chemotherapy-associated costs were calculated separately. Health care utilisation and costs were compared between patients receiving Children's Oncology Group (COG) versus Dana-Farber Cancer Institute (DFCI)-based treatment.Of 802 patients, 146 (18.2%) were treated on DFCI-based protocols. COG patients experienced significantly higher rates of emergency department (ED) visits (adjusted rate ratio [aRR]: 1.3, 95% confidence interval [CI]: 1.1-1.5; p = 0·01), whereas outpatient visit rates were 60% higher among DFCI patients (aRR: 1.6, 95% CI: 1.5-1.7, p 0.0001). In adjusted analyses, DFCI-associated cost intensity was 70% higher (aRR: 1.7, 95% CI: 1.5-1.9; p 0.0001), mainly attributable to outpatient visit costs. Total chemotherapy costs were higher among COG-treated patients ($39,400 ± $1100 versus $33,400 ± $2800; p = 0.02). Among PEG-ASNase-treated patients, total chemotherapy costs were highest among DFCI patients (median $54,200 ± $7400; p = 0.003 versus COG patients).COG and DFCI treatments were associated with higher ED visit rates and higher outpatient visit rates, respectively. Overall utilisation-associated costs were increased in DFCI-treated patients. Administration of some intravenous chemotherapy at home and decreases in PEG-ASNase cost would decrease health care utilisation and costs for all patients and mitigate differences between COG and DFCI protocols.C

Background: Pyruvate kinase deficiency (PKD) is the most common cause of chronic hereditary non-spherocytic hemolytic anemia. The spectrum of disease in PKD is broad, ranging from an incidentally discovered mild anemia to a severe transfusion-dependent anemia. Splenectomy partially ameliorates the anemia and reduces the transfusion burden in the majority of patients. Because hemoglobin poorly correlates with symptoms in PKD, transfusion requirements are typically used clinically to classify disease severity with those who are regularly transfused despite splenectomy recognized as the most severely affected subgroup. Aim: To compare demographics, complications, and laboratory results between the most severely-affected PKD patients (those that are splenectomized and regularly transfused) with non-regularly transfused splenectomized PKD patients. Methods: After ethics committee approval, patients were enrolled on the PKD Natural History Study, a prospective 30 site international study. All patients had molecularly confirmed PKD. Only splenectomized patients were included in the analysis. Transfusion frequency was observed over a 3-year period. Patients were divided into two groups based on transfusion frequency: the severe phenotype group was defined as those who receive regular transfusions (≥6 discrete red cell transfusion episodes per year) and the control group did not receive regular transfusions. Phenotype stability over the 3-year period was also assessed. Results: 154 splenectomized patients with PKD were included: 30 patients in the severe PKD phenotype group and 124 patients in the comparison PKD group. Results of the analysis comparing the two groups are described in the Table. Severely affected patients were more likely to be female (77% versus 51%, p=0.013), older at the time of splenectomy (median age: 5 versus 3.6, p=0.011), have iron overload (93% vs. 51%, p Conclusions: Patients with PKD who are regularly transfused despite splenectomy appeared to have similar rates of PKD-associated complications (except for iron overload) and similar relevant laboratory values and genotypes when compared to those who are not regularly transfused after splenectomy. The similarity observed between severe phenotype patients and comparison patients with PKD may result from a protective effect of transfusion (e.g. reduction of bone fractures and extramedullary hematopoiesis) or could suggest transfusion-dependence is an artificial signifier of disease severity, reflective of provider practices and patient symptoms rather than an actual distinct phenotype. Transfusion requirements in severe PKD appear to fluctuate significantly over time. Download : Download high-res image (830KB) Download : Download full-size image Disclosures Al-Samkari: Dova: Consultancy, Research Funding; Agios: Consultancy, Research Funding; Moderna: Consultancy. van Beers: RR Mechatronics: Research Funding; Agios Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Research Funding. Barcellini: Agios: Consultancy, Other: Advisory board; Apellis: Consultancy; Incyte: Consultancy, Other: Advisory board; Bioverativ: Consultancy, Other: Advisory board; Novartis: Research Funding, Speakers Bureau; Alexion: Consultancy, Research Funding, Speakers Bureau. Eber: Agios Pharmaceuticals, Inc.: Consultancy. Glader: Agios Pharmaceuticals, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Chonat: Alexion: Other: advisory board; Agios Pharmaceuticals, Inc.: Other: advisory board. Kuo: Pfizer: Consultancy; Novartis: Consultancy, Honoraria; Celgene: Consultancy; Agios: Consultancy; Alexion: Consultancy, Honoraria; Apellis: Consultancy; Bioverativ: Other: Data Safety Monitoring Board; Bluebird Bio: Consultancy. Despotovic: Dova: Honoraria; Novartis: Research Funding; Amgen: Research Funding. Kwiatkowski: Celgene: Consultancy; Terumo: Research Funding; Apopharma: Research Funding; bluebird bio, Inc.: Consultancy, Research Funding; Agios: Consultancy; Imara: Consultancy; Novartis: Research Funding. Thompson: Baxalta: Research Funding; Novartis: Consultancy, Research Funding; bluebird bio, Inc.: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Ravindranath: Agios Pharmaceuticals, Inc.: Other: I am site PI on several Agios-sponsored studies, Research Funding. Rothman: Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Agios: Honoraria, Research Funding. Verhovsek: Sickle Cell Awareness Group of Ontario: Membership on an entity's Board of Directors or advisory committees; Sickle Cell Disease Association of Canada: Membership on an entity's Board of Directors or advisory committees, Research Funding; Canadian Haemoglobinopathy Association: Membership on an entity's Board of Directors or advisory committees; Vertex: Consultancy. Kunz: Novartis: Membership on an entity's Board of Directors or advisory committees. Sheth: CRSPR/Vertex: Other: Clinical Trial Steering committee; Apopharma: Other: Clinical trial DSMB; Celgene: Consultancy. London: United Therapeutics: Consultancy; ArQule, Inc: Consultancy. Grace: Novartis: Research Funding; Agios Pharmaceuticals, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

A term infant girl was admitted for evaluation of severe thrombocytopenia. She also had purpura-like skin lesions. A complete blood count showed a platelet count of 40×10/L (normal value: 150 to 400×10/L). She received random donor platelet transfusions and intravenous immunoglobulin therapy; however, thrombocytopenia persisted. She developed bloody stools on day 5 of life and hematemesis on day 9. Upper gastrointestinal endoscopy revealed multiple small, 2 to 5 mm, vascular lesions throughout the stomach body and proximal duodenum. Our multidisciplinary team will discuss an approach towards a term infant with thrombocytopenia and gastrointestinal bleeding, the diagnostic challenges, and patient management.

IntroductionPain negatively affects the health-related quality of life (HRQL) of adolescents with cancer. The Pain Squad+ smartphone-based application (app), has been developed to provide adolescents with real-time pain self-management support. The app uses a validated pain assessment and personalised pain treatment advice with centralised decision support via a registered nurse to enable real-time pain treatment in all settings. The algorithm informing pain treatment advice is evidence-based and expert-vetted. This trial will longitudinally evaluate the impact of Pain Squad+, with or without the addition of nurse support, on adolescent health and cost outcomes.Methods and analysisThis will be a pragmatic, multicentre, waitlist controlled, 3-arm parallel-group superiority randomised trial with 1:1:1 allocation enrolling 74 adolescents with cancer per arm from nine cancer centres. Participants will be 12 to 18 years, English-speaking and with ≥3/10 pain. Exclusion criteria are significant comorbidities, end-of-life status or enrolment in a concurrent pain study. The primary aim is to determine the effect of Pain Squad+, with and without nurse support, on pain intensity in adolescents with cancer, when compared with a waitlist control group. The secondary aims are to determine the immediate and sustained effect over time of using Pain Squad+, with and without nurse support, as per prospective outcome measurements of pain interference, HRQL, pain self-efficacy and cost. Linear mixed models with baseline scores as a covariate will be used. Qualitative interviews with adolescents from all trial arms will be conducted and analysed.Ethics and disseminationThis trial is approved by the Hospital for Sick Children Research Ethics Board. Results will provide data to guide adolescents with cancer and healthcare teams in treating pain. Dissemination will occur through partnerships with stakeholder groups, scientific meetings, publications, mass media releases and consumer detailing.Trial registration numberNCT03632343(ClinicalTrials.gov).

Evans syndrome (ES) describes an immune dysregulation syndrome manifesting as multilineage autoimmune cytopenias, most often autoimmune hemolytic anemia (AIHA) and immune thrombocytopenia (ITP), but also autoimmune neutropenia (AIN) in some cases. Since Evans and colleagues first described this phenomenon in the 1940s–1950s, this syndrome of immune cytopenias is increasingly identified to be secondary to underlying systemic immune dysregulation rather than idiopathic pathology. Some of the most common pathologies now known to drive ES include autoimmune lymphoproliferative syndrome (ALPS), common variable immunodeficiency (CVID), and other systemic autoimmune diseases such as systemic lupus erythematosus (SLE), particularly in adolescent females. These pathologies share the commonality of a dysregulated immune system in which autoreactive lymphocytes are poorly controlled, ultimately predisposing to autoimmunity. Importantly, clinical outcomes for patients with ES can be optimized by targeting specific immune dysregulation pathologies, underscoring the need for thorough individualized diagnostic and treatment strategies.

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.

Introduction: Though ideal models of survivorship care are not definitively established, it has been suggested that childhood acute lymphoblastic leukemia (ALL) survivors can be cared for by properly informed primary care physicians (PCP - e.g. family physicians, community pediatricians) given low risks of late effects. PCP-driven models of care are dependent on the willingness of families to re-engage with their PCPs after a prolonged period of treatment delivered by pediatric oncologists during which PCP involvement may be minimal. We thus aimed to identify rates and predictors of PCP visits both during and after treatment among a population-based cohort of children with ALL. Methods: We identified all children Results: Of 801 children with ALL, 751 (93.8%) had an identified PCP at the time of diagnosis. Excluding a further 8 (1.0%) patients who did not have treatment information available resulted in 743 cases and 3,112 controls. The median age of children with ALL was 4.0 years [interquartile range (IQR) 3.0-8.0], 409 (55%) of whom were male. Nearly half of patients (361, 48.6%) did not visit their PCP during treatment. The rate of PCP visits during treatment was 0.64 per person per year (PPPY) compared to 1.4 PPPY among controls. Adjusting for age, sex, and socioeconomic status resulted in an adjusted rate ratio (aRR) of 0.47 [95th confidence interval (95CI) 0.40-0.54; p Excluding 32 (4.3%) patients who relapsed, died, or underwent stem cell transplant prior to completing frontline therapy yielded 711 cases (survivors) and 2,973 controls available for analyses of post-treatment PCP visits. The median time of follow up after the end of treatment among survivors was 6.0 years (IQR 4.0-8.5). Though 287 (40.4%) of survivors did not visit their PCP during the post-treatment period, survivors overall still experienced greater post-treatment PCP visit rates compared to controls (aRR 1.4, 95CI 1.2-1.6; p Conclusions: Only a portion of children with ALL see their PCPs during treatment and return to PCP care following the completion of leukemia treatment, indicating that PCP-led survivorship care is feasible only for a subset of this population. The rate of PCP visits among survivors however continues to increase relative to general-population controls beyond 10 years after end of treatment. Post-treatment engagement with PCPs may be improved by PCP involvement during treatment, as well as in some cases the involvement of community pediatricians. Disclosures Gupta: Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Introduction: Though cure rates for childhood acute lymphoblastic leukemia (ALL) have improved significantly, outcomes for children with relapsed ALL remain poor. Novel immunotherapies have proved effective in relapsed disease. Blinatumomab, a bispecific T-cell engager targeting CD19, was recently shown to improve disease-free and overall survival among children with high-risk relapsed disease (Brown et al, 2021) prior to proceeding to stem cell transplant. Blinatumomab however also represents a significant cost burden to institutions and healthcare systems. Our objective was thus to determine the cost-effectiveness of blinatumomab vs. standard of care therapy among children with high-risk relapsed ALL. Methods: We used a childhood ALL-specific policy simulation model previously developed using real world clinical, healthcare utilization, and cost population-based data from Ontario, Canada, and restricted it to children with B-lineage ALL who relapsed with 18 months of their original diagnosis to capture a population of patients with high-risk relapse who survived their original month of re-induction chemotherapy. This model was combined with published data from the Children's Oncology Group randomized control study AALL1331 to estimate the long-term survival, healthcare costs and quality adjusted life years associated with two courses of blinatumomab vs. two courses of standard intensive chemotherapy, followed by stem cell transplant. Combining these two sources allowed for the creation of a multi-state survival model and the estimation of the impact of blinatumomab upon relapse and survival. Healthcare costs for the administration of blinatumomab or chemotherapy were sourced from administrative data, provincial formularies, and published sources. Lifetime costs and quality-adjusted life years were calculated while Monte Carlo simulation was used to propagate parameter uncertainty in the cost-effectiveness outcomes. All costs were calculated in Canadian dollars (CAD). Results: Blinatumomab was associated with on average higher life expectancy (43.4 years vs. 36.8 years) and a higher number of quality adjust life years [2.75 QALYs gained, 95 th confidence interval (95CI) -0.44 to 5.99] but higher costs (60,420 CAD, 95CI 26,794 - 94,047) compared to standard intensive chemotherapy. The incremental cost effectiveness ratio (ICER) associated with blinatumomab was 21,970 CAD/QALY gained. However, substantial uncertainty around model parameters resulted in wide confidence intervals around cost-effectiveness outcomes. Discussion: Initial evidence indicates that the use of blinatumomab in high-risk relapse of childhood ALL as compared to standard chemotherapy is associated with a cost-effectiveness ratio that is comparable to or lower than that associated with other interventions recently introduced in pediatric ALL, and represents a cost-effective intervention for this population. However, estimates are based on limited evidence; further research is necessary to better inform several model parameters and thereby decrease uncertainty in cost-effectiveness outcomes. Disclosures Gupta: Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Purpose Consumption of medical opium for pain relief in India is low, despite the country being one of the main world producers of the substance. We investigated obstacles to opioid use and physician perceptions about optimal pain management in pediatric oncology patients in India. Methods Semistructured interviews were conducted with oncologists who work in pediatric oncology settings. A mixed sampling strategy was used, including maximum variation and confirmation and disconfirmation of cases, as well as snowball sampling. Key informants were identified. Interviews were audio recorded, transcribed verbatim, and analyzed by thematic analysis methodology. Results Twenty-three interviews were performed across 20 Indian institutions. The main obstacles identified were lack of financial resources, inadequate education of health care providers on pain management, insufficient human resources (particularly lack of dedicated trained oncology nurses), poor access to opioids, and cultural perceptions about pain. Children from rural areas, treated in public hospitals, and from lower socioeconomic classes appear disadvantaged. A significant equality gap exists between public institutions and private institutions, which provide state-of-the-art treatment. Conclusion The study illuminates the complexity of pain management in pediatric oncology in India, where financial constraints, lack of education, and poor access to opioids play a dominant role, but lack of awareness and cultural perceptions about pain management among health care providers and parents emerged as important contributing factors. Urgent interventions are needed to optimize care in this vulnerable population.

BACKGROUND: Though cooperative trial groups use different treatment protocols for newly diagnosed childhood acute lymphoblastic leukemia (ALL), all achieve high cure rates. The healthcare utilization and costs associated with different treatment strategies have not been rigorously compared. Minimizing utilization and costs may increase quality of life and decrease health system burden. We compared Children's Oncology Group (COG) and Dana-Farber Cancer Institute (DFCI)-based treatment. METHODS: We identified all children diagnosed with ALL in pediatric cancer centers in Ontario, Canada between 2002 and 2012 through the Pediatric Oncology Group of Ontario Networked Information System (POGONIS), a provincial pediatric cancer registry. Detailed data on demographics, disease risk factors (e.g. cytogenetics, minimal residual disease), treatment (e.g. treatment protocol, start and end date of each therapy phase) and events (relapse/progression, death, second cancer) were captured via chart abstraction. Treatment protocols were categorized as either based on COG or DFCI trials. Linkage to population-based health services databases identified all outpatient and emergency department (ED) visits, hospitalizations, and physician billings. Healthcare utilization-associated costs were determined through validated costing algorithms. Chemotherapy-associated costs were calculated separately using local prices. All administered doses of asparaginase (ASNase), including E. Coli, PEG-ASNase, and Erwinia ASNase were recorded. Event-free survival (EFS), overall survival (OS), healthcare utilization rates, and costs were compared between COG and DFCI-treated patients while adjusting for demographics and disease-factors using appropriate regression models. Healthcare-associated costs, ASNase costs, and total chemotherapy costs (2018 Canadian dollars) were compared. RESULTS: The study cohort included 802 patients, 146 (18.2%) of whom were treated on DFCI-based protocols. Median follow-up did not differ between between COG and DFCI patients; nor did EFS or OS. When adjusted for all demographic and disease-related variables, COG patients experienced significantly higher rates of ED visits [rate ratio (RR) 1.3, 95% confidence interval (95CI) 1.1-1.5; p=0.01]. Neither hospitalization rates nor rates of inpatient days differed between the two groups of patients. However, rates of outpatient visits were 60% higher among DFCI patients (RR 1.6, 95CI 1.5-1.7; p The median healthcare-associated cost in the first 5 years following initial diagnosis was $193,700 among COG patients [interquartile range (IQR) 149,200-272,700] compared to $288,000 among DFCI patients (IQR 233,300-407,300; p The median ASNase-related cost was similar between COG and DFCI patients [$21,100, IQR 14,800-35,400 vs. $19,900, IQR 15,600-39,900; p=0.91]. The median total chemotherapy cost was higher among COG patients ($29,100, IQR 20,300-50,300 vs. $22,400, IQR 17,300-42,600; p CONCLUSIONS: Though COG and DFCI protocols are associated with equivalent EFS and OS, patterns of healthcare utilization differ with the former associated with a 30% increase in the rate of ED visits and the latter associated with a 60% increase in the rate of outpatient visits. Overall, healthcare utilization-associated costs were increased in DFCI-treated patients. Though ASNase costs historically did not differ, the shift to PEG-ASNase is associated with higher ASNase and total chemotherapy costs on DFCI protocols. Decreases in PEG-ASNase cost and the ability to administer intravenous or intramuscular chemotherapy at home would decrease overall healthcare utilization and costs, and mitigate differences between COG and DFCI protocols. These results can inform efforts to decrease burden on both families and health systems. Disclosures No relevant conflicts of interest to declare.

Pyruvate kinase (PK) deficiency is the most common red cell glycolytic enzyme defect causing hereditary non-spherocytic hemolytic anemia. Current treatments are mainly supportive and include red cell transfusions and splenectomy.[1][1] Regular red cell transfusions are known to result in iron

7031 Background: Outcomes in pediatric acute lymphoblastic leukemia (ALL) have shown remarkable improvements in large part due to sequential clinical trials. Concerns however persist around whether access to clinical trials is equitable. It is also unclear whether patient outcomes are improved simply by enrolling on a clinical trial. Our objective was to therefore determine which patient and disease-related factors are associated with enrollment, and whether enrollment was associated with clinical outcomes among children and adolescents with ALL in a single-payer health system in Ontario, Canada. Methods: We included all Ontario patients diagnosed with ALL between 0-18 years of age from 2002-2012 treated at a pediatric center, identified through a provincial pediatric cancer registry. Clinical trial availability was determined by whether each patient’s primary institution had an open frontline trial for which the patient was eligible at the time of their diagnosis, considering individual disease characteristics such as lineage, central nervous system (CNS) status and risk group. Demographic, disease, trial enrolment, and outcome data were obtained through chart abstraction. Logistic regression models determined factors associated with trial enrolment, while Cox proportional hazard models determined factors associated with event-free and overall survival (EFS, OS). Results: Of 858 patients, 693 (81%) were eligible for an open clinical trial at their time of diagnosis. 476 (69%) enrolled on a trial. In adjusted analyses, age > 15 years (odds ratio 0.4 vs. age 5-9, 95th confidence interval (95CI) 0.2-0.8; p = 0.01) and CNS3 disease (OR 0.38 vs. CNS1, 95CI 0.17-0.83; p = 0.01) were significantly associated with decreased likelihood of enrolment, while sex and neighborhood income quintile were not associated with enrolment. Adjusted for disease and demographic factors, clinical trial enrolment was not significantly associated with either EFS (hazard ratio (HR) 1.1, 95CI 0.7-1.7; p = 0.83) or OS (HR 1.3, 95CI 0.7-2.5; p = 0.44). Conclusions: The majority of patients with ALL eligible for available clinical trials at their time of diagnosis were enrolled. While no disparities in enrolment by income status were noted, adolescents were substantially less likely to participate in trials even within pediatric centers. Studies of mechanisms underlying this disparity are warranted in order to design and implement effective interventions targeting increased enrolment rates in this patient population. Our results however also suggest that clinical trial enrolment on its own is not associated with improved outcomes in the context of a single payer health system.

Acute neurological changes in sickle cell disease (SCD) patients often raise the suspicion for stroke. Posterior reversible encephalopathy syndrome (PRES) can mimic stroke in its clinical presentation. We aimed to (i) review the PRES literature in SCD patients including clinical presentation, risk factors, pathophysiology, and management and (ii) elucidate the distinction between PRES and stroke in SCD. The exact pathophysiology of PRES in SCD remains elusive but is likely multifactorial and related to sickling, ischemia, and chronic anemia predisposing to vasogenic edema. PRES and stroke in SCD are distinguishable conditions. Our review may help elucidate a clinical approach to this distinction.

BACKGROUND Neonatal alloimmune thrombocytopenia (NAIT) has been reported only rarely in twins and not at all, to our knowledge, in triplets. CASE REPORT Nonidentical triplets were born with severe thrombocytopenia. Nadir platelet (PLT) counts were 17 × 109, 12 × 109, and 10 × 109/L. NAIT was confirmed by an incompatibility for human PLT antigen (HPA)−1a and the presence of maternal anti-HPA-1a. The maternal genotype was HPA-1bb and the paternal genotype was HPA-1aa; thus, all children were affected. RESULTS PLT counts for each infant improved with the administration of random-donor PLT transfusions. All three infants also received intravenous immunoglobulin. None had major bleeding. A small isolated subependymal hemorrhage was found incidentally in one infant; this remained stable on repeat imaging. CONCLUSIONS This is the first report of triplets with NAIT. Anti-HPA-1a is sufficiently potent to affect three infants simultaneously. Random-donor PLTs were effective in improving PLT counts in all three infants.

Background Accessible self-management interventions are critical for adolescents with sickle cell disease to better cope with their disease, improve health outcomes and health-related quality of life, and promote successful transition to adult health care services. However, very few comprehensive self-management and transitional care programs have been developed and tested in this population. Internet and mobile phone technologies can improve accessibility and acceptability of interventions to promote disease self-management in adolescents with sickle cell disease. Objective The aim of this study was to qualitatively explore the following from the perspectives of adolescents, parents, and their health care providers: (1) the impact of sickle cell disease on adolescents to identify challenges to their self-management and transitional care and (2) determine the essential components of a digital self-management and transitional care program as the first phase to inform its development. Methods A qualitative descriptive design utilizing audio-recorded, semistructured interviews was used. Adolescents (n=19, aged 12-19 years) and parents (n=2) participated in individual interviews, and health care providers (n=17) participated in focus group discussions and were recruited from an urban tertiary care pediatric hospital. Audio-recorded data were transcribed verbatim and organized into categories inductively, reflecting emerging themes using simple content analysis. Results Data were categorized into 4 major themes: (1) impact of sickle cell disease, (2) experiences and challenges of self-management, (3) recommendations for self-management and transitional care, and (4) perceptions about a digital self-management program. Themes included subcategories and the perspectives of adolescents, parents, and health care providers. Adolescents discussed more issues related to self-management, whereas health care providers and parents discussed issues related to transition to adult health services. Conclusions Adolescents, parents, and health care providers described the continued challenges youth with sickle cell disease face in terms of psychosocial impacts and stigmatization. Participants perceived a benefit to alleviating some of these challenges through a digital self-management tool. They recommended that an effective digital self-management program should provide appropriate sickle cell disease–related education; guidance on developing self-advocacy and communication skills; empower adolescents with information for planning for their future; provide options for social support; and be designed to be engaging for both adolescents and parents to use. A digital platform to deliver these elements is an accessible and acceptable way to address the self-management and transitional care needs of adolescents.

An international, multicenter registry was established to collect retrospective and prospective clinical data on patients with pyruvate kinase (PK) deficiency, the most common glycolytic defect causing congenital nonspherocytic hemolytic anemia. Medical history and laboratory and radiologic data were retrospectively collected at enrollment for 254 patients with molecularly confirmed PK deficiency. Perinatal complications were common, including anemia that required transfusions, hyperbilirubinemia, hydrops, and prematurity. Nearly all newborns were treated with phototherapy (93%), and many were treated with exchange transfusions (46%). Children age 5 years and younger were often transfused until splenectomy. Splenectomy (150 [59%] of 254 patients) was associated with a median increase in hemoglobin of 1.6 g/dL and a decreased transfusion burden in 90% of patients. Predictors of a response to splenectomy included higher presplenectomy hemoglobin (P 5 .007), lower indirect bilirubin (P 5 .005), and missense PKLR mutations (P 5 .0017). Postsplenectomy thrombosis was reported in 11% of patients. The most frequent complications included iron overload (48%) and gallstones (45%), but other complications such as aplastic crises, osteopenia/bone fragility, extramedullary hematopoiesis, postsplenectomy sepsis, pulmonary hypertension, and leg ulcers were not uncommon. Overall, 87 (34%) of 254 patients had both a splenectomy and cholecystectomy. In those who had a splenectomy without simultaneous cholecystectomy, 48% later required a cholecystectomy. Although the risk of complications increases with severity of anemia and a genotype-phenotype relationship was observed, complications were common in all patients with PK deficiency. Diagnostic testing for PK deficiency should be considered in patients with apparent congenital hemolytic anemia and close monitoring for iron overload, gallstones, and other complications is needed regardless of baseline hemoglobin. This trial was registered at www.clinicaltrials.gov as #NCT02053480.

Immune thrombocytopenia (ITP) often presents clinically as petechiae, bruising, and/or mucocutaneous bleeding with an acute onset. Severe bleeding at the time of presentation is rare but can be life threatening. A detailed clinical history, including a review of the patient’s family history, is important to assess for possible inherited and/or secondary causes of thrombocytopenia (see Chap. 1). The physical examination reveals an otherwise healthy individual with skin bruising, purpura, and/or petechial rash in the absence of other findings, specifically lymphadenopathy or hepatosplenomegaly, or other systemic signs/symptoms such as fever, fatigue, weight loss, malaise, and/or pain. The diagnosis of primary ITP is one of exclusion and relies on ruling out other causes of thrombocytopenia in addition to a careful review for conditions associated with secondary ITP. The initial investigations often show severe thrombocytopenia, with variable to high mean platelet volume (MPV). In otherwise typical presentations, no additional testing is needed. The role of bone marrow testing remains controversial and is generally reserved for patients with an uncertain diagnosis or an atypical course.

Introduction It is unclear which outcome indicators should be used to measure the success of haemophilia transition programs, and what are key elements of a haemophilia transition program to ensure success. Aim To establish by expert consensus a list of important and feasible outcome indicators of successful haemophilia transition, and a list of key elements of transition planning. Methods A modified two-stage Delphi survey was developed and disseminated among a panel of Canadian interdisciplinary haemophilia care providers. Participants were asked to rate the importance and feasibility of outcome indicators of effective haemophilia transition and elements of haemophilia transition program. In the second round, participants were asked to choose the top five outcomes suitable for inclusion in a core outcome set of transition effectiveness, and the top five elements that are important and feasible for implementation within the next 5 years. Results In total, 34/73 (47%) of participants completed the first round and 33 completed the second round, representing a variety of disciplines. Top outcome indicators recommended for a core outcome set include measurement of adherence, change in bleeding rate, self-efficacy skills, haemophilia knowledge, patient and caregiver satisfaction, time gap between last paediatric and first adult clinic, and number of emergency room or hospital admissions. Fourteen elements of transition achieved consensus in importance ratings, while eight were felt to be feasible for implementation within next 5 years. Conclusions Results will contribute towards the development of a haemophilia transition outcome instrument and provide guidance for future studies of the effectiveness of transition programs.

Background Pediatric patients with chronic and/or refractory autoimmune multi-lineage cytopenias present challenges in both diagnosis and management. Increasing availability of diagnostic testing has revealed an underlying immune dysfunction in patients previously diagnosed with Evans Syndrome. However, the data are sparse and the majority of patients are adults. Procedure We performed a retrospective chart review to document the natural history of 23 pediatric patients with autoimmune multi-lineage cytopenias followed at three tertiary care pediatric hematology clinics. Results Investigations revealed seven patients (30.4%) with an autoimmune lymphoproliferative-like syndrome and six patients (26.1%) with other primary immunodeficiencies. Only one (4.3%) patient was suspected to have systemic lupus erythematosus and six patients (26.1%) had other types of autoimmunity. Treatment consisted of immunosuppressive therapy, intravenous gammaglobulin, and splenectomy. Supportive care included granulocyte-colony stimulating factor, and blood product transfusions. Two patients (8.7%) died. Complete remission was achieved in 3 patients (13.0%); of the remaining, 14 patients (60.9%) had chronic immune thrombocytopenic purpura, 10 patients (43.5%) chronic autoimmune neutropenia, and 4 patients (17.4%) chronic autoimmune hemolytic anemia with a median follow up of 5 years (2 months–12 years). Conclusions These data suggest that pediatric patients presenting with autoimmune multi-lineage cytopenias should undergo investigation for underlying immune dysregulation, including autoimmune lymphoproliferative syndrome, other primary immunodeficiencies and autoimmune disorders. The development of an international registry for such patients is imperative to improve the understanding of their complex natural history. Pediatr Blood Cancer © 2015 Wiley Periodicals, Inc.

Background Phenotypic overlap among the inherited bone marrow failure syndromes (IBMFSs) frequently limits the ability to establish a diagnosis based solely on clinical features. >70 IBMFS genes have been identified, which often renders genetic testing prolonged and costly. Since correct diagnosis, treatment and cancer surveillance often depend on identifying the mutated gene, strategies that enable timely genotyping are essential. Methods To overcome these challenges, we developed a next-generation sequencing assay to analyse a panel of 72 known IBMFS genes. Cases fulfilling the clinical diagnostic criteria of an IBMFS but without identified causal genotypes were included. Results The assay was validated by detecting 52 variants previously found by Sanger sequencing. A total of 158 patients with unknown mutations were studied. Of 75 patients with known IBMFS categories (eg, Fanconi anaemia), 59% had causal mutations. Among 83 patients with unclassified IBMFSs, we found causal mutations and established the diagnosis in 18% of the patients. The assay detected mutant genes that had not previously been reported to be associated with the patient phenotypes. In other cases, the assay led to amendments of diagnoses. In 20% of genotype cases, the results indicated a cancer surveillance programme. Conclusions The novel assay is efficient, accurate and has a major impact on patient care.

Adolescents with haemophilia must assume responsibility for their health and management of their disease. An online self-management program was developed to support adolescents during this transition. To determine the feasibility of the program using a randomized control trial (RCT) design in terms of accrual/attrition rates, willingness to be randomized, compliance with the program/outcome measures and satisfaction. Adolescents, ages 13-18, were enrolled in a pilot RCT (NCT01477437) and randomized to either the intervention (8-week program with telephone coaching) or the control arm (no access to the website, weekly telephone call as attention-strategy). All participants completed pre/post-outcome measures. Twenty-nine teens participated (intervention n = 16, control n = 13). Participants in the intervention arm spent an average of 50 min on the website per week and completed the modules in an average of 14 weeks (SD = 4.9). Attrition was higher in the control group compared to the intervention group (54% vs. 25%). 17/18 (94%) who completed the program also completed the poststudy measures. Teens on the intervention arm showed significant improvement in disease-specific knowledge (P = 0.004), self-efficacy (P = 0.007) and transition preparedness (P = 0.046). There was a statistically significant improvement in knowledge in the intervention group when compared to the control group (P = 0.01). Overall, the teens found the website to be informative, comprehensive and easy to use and were satisfied with the program. This pilot RCT study suggests benefit to the program and indicates an RCT design to be feasible with minor adjustments to the protocol.

BACKGROUND Cannabis use for medical purposes has gathered growing interest from the public through its purported benefits. Since 2001, Health Canada has authorized availability from health practitioners, even for paediatric patients, despite concerns regarding efficacy and adverse effects among children and adolescents. It is likely that a lack of knowledge regarding the substance and indications for use, tempered by known and unknown side effects, dictate paediatricians’ practice toward cannabis. OBJECTIVES This study examines the views and knowledge of Canadian paediatricians regarding the use of cannabis for medical purposes among children and adolescents. Differences between general paediatricians and sub-specialists were explored. DESIGN/METHODS Data was collected using a Canadian Paediatric Surveillance Program (CPSP) one-time survey performed in 2017. A total of 864 paediatric physicians (33% participation rate) were asked about medical use of cannabis. They were also asked personal and professional characteristics. Descriptive statistics regarding their views and knowledge towards cannabis use for medical purposes are reported, as well as significant differences (p RESULTS General paediatricians represented 55.4% of the analyzed sample, with 36.7% having ≥ 20 years of practice. Half (50.4%) of all surveyed paediatricians had encountered in the past year patients who used cannabis for medical purposes (authorized or not). Half (50.6%) were also aware that Canadian physicians could authorize cannabis to children for medical purposes. More (61.3%) knew they could authorize it to adolescents (significantly more among sub-specialists, p=0.03). Nearly half (46.5%) believed that there are appropriate indications to support the authorization of cannabis for medical reasons to the paediatric population (significantly more among sub-specialists, p CONCLUSION Cannabis use for medical purposes is a situation frequently encountered by paediatricians. While they are generally supportive of certain medical indications for its authorization, most have minimal knowledge on its use and, report concerns about efficacy and safety. Differences between general paediatricians and sub-specialists probably emerge from conditions treated by these two groups. Our study highlights the need for timely continuing education for all paediatricians on this topic.

Introduction: Pyruvate kinase (PK) deficiency causes a defect in the glycolytic pathway, leading to a hereditary hemolytic anemia. Management is supportive and consists of splenectomy, transfusions, and chelation therapy. Aim: To better understand the comorbidity and complication profile of adults with PK deficiency, and the extent to which transfusion frequency contributes, the objectives of this study were to (1) quantify the prevalence of comorbidities and complications according to transfusion history and (2) compare the types and rates of select comorbidities and complications with the general population. Methods: Data were obtained from the enrollment survey of the PK Deficiency Natural History Study (NHS), a longitudinal, retrospective and prospective cohort study in which clinical, laboratory, transfusion, and radiologic data were collected; all participants were confirmed to have 2 mutations in the PKLR gene. Patients (n=122) were eligible for this analysis if they were ≥18 years of age and had sufficient data on transfusion history to enable classification into 1 of 3 cohorts: "Ever Regularly Transfused" (ERT, defined as ≥6 transfusions in any 12-month period), "Never Regularly Transfused" (NRT, defined as having ≥1 lifetime transfusion but never having >4 transfusions in any 12-month period), or "Never Transfused" (NT). To contextualize the findings, the frequencies of select conditions were compared with an age- and gender-matched cohort of individuals from the insured, general US population who did not have any hemolytic anemia diagnoses and had ≥5 years of continuous enrollment in the Truven MarketScan administrative claims database. The NHS reported lifetime prevalence rates, whereas rates obtained from the MarketScan data were based on diagnosis and procedure codes over varying look-back periods; therefore, to minimize bias, we limited PK deficiency vs. general population comparisons to (1) chronic conditions that require lifetime management and would thus still be recorded in claims data years after initial diagnosis, and/or (2) conditions for which a diagnosis/procedure date was available in the NHS and could be matched in time to the average 8-year look-back period for the general population. Frequencies were compared across mutually exclusive cohorts using Fisher's exact 2-tailed tests of significance. Results: ERT (n=65), NRT (n=30), and NT patients (n=27) had a mean age of 34.2, 39.5, and 37.2 years at enrollment, respectively (not significant [ns]), with 46.2%, 56.7%, and 59.3%, respectively, being male (ns). ERT patients trended toward being more likely than NT patients to be Amish and have the homozygous R479H splice variant (30.8% vs 11.1% [p=0.064]) but were significantly less likely to have a missense/missense PKLR genotype (32.3% vs 70.4% [p=0.001]). Compared with the general population, patients with PK deficiency had significantly higher rates of splenectomy, cholecystectomy, osteoporosis, liver cirrhosis, pulmonary hypertension, and current prophylactic antibiotic and anticoagulant use (Table). Rates of splenectomy, cholecystectomy, and osteoporosis were significantly higher in patients with PK deficiency, regardless of transfusion cohort, and both ERT and NRT patients had significantly higher rates of liver cirrhosis than individuals from the general population. A gradient was seen across transfusion cohorts for other conditions. Notably, 83.1% of ERT patients, 50.0% of NRT patients, and 25.9% of NT patients had a history of liver iron overload. ERT patients were also significantly more likely than NRT and NT patients to have had a splenectomy, cholecystectomy, and/or thrombosis, and to currently use prophylactic antibiotics. Findings were consistent when the analysis was restricted to non-Amish patients with PK deficiency. Conclusions: Patients with PK deficiency have higher rates of select comorbidities and complications than age- and gender-matched individuals who do not have PK deficiency. Even patients with PK deficiency who have never been transfused are at increased risk of complications of the disease and its treatment. Disclosures Boscoe: Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Yan:Agios Pharmaceuticals, Inc.: Consultancy. Hedgeman:IBM Watson Health: Employment. van Beers:Agios Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Research Funding; RR Mechatronics: Research Funding. Al-Samkari:Agios: Consultancy, Research Funding; Dova: Consultancy, Research Funding; Moderna: Consultancy. Barcellini:Incyte: Consultancy; Alexion: Consultancy, Speakers Bureau; Agios Pharmaceuticals, Inc.: Consultancy; Novartis: Speakers Bureau; Apellis: Consultancy; bioverativ: Consultancy. Eber:Agios Pharmaceuticals, Inc.: Consultancy. Glader:Agios Pharmaceuticals, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Chonat:Alexion: Other: advisory board; Agios Pharmaceuticals, Inc.: Other: advisory board. Rothman:Agios: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding. Kuo:Agios: Consultancy; Alexion: Consultancy, Honoraria; Apellis: Consultancy; Bioverativ: Other: Data Safety Monitoring Board; Bluebird Bio: Consultancy; Celgene: Consultancy; Novartis: Consultancy, Honoraria; Pfizer: Consultancy. Kwiatkowski:Agios: Consultancy; bluebird bio, Inc.: Consultancy, Research Funding; Imara: Consultancy; Apopharma: Research Funding; Novartis: Research Funding; Celgene: Consultancy; Terumo: Research Funding. Ravindranath:Agios Pharmaceuticals, Inc.: Other: I am site PI on several Agios-sponsored studies, Research Funding. Neufeld:Octapharma, Shire Pharmaceuticals (Baxalta), Novo Nordisk, Celgene, NHLBI/NIH: Research Funding; Octapharma, Agios, Acceleron, Grifols, Pfizer, CSL Behring, Shire Pharmaceuticals (Baxalta), Novo Nordisk, ApoPharma, Genentech, Novartis, Bayer Healthcare: Consultancy; Octapharma: Other: study investigator, NuProtect study (Octapharma-sponsored). Holzhauer:Agios Pharmaceuticals, Inc.: Consultancy. Verhovsek:Sickle Cell Disease Association of Canada: Membership on an entity's Board of Directors or advisory committees, Research Funding; Canadian Haemoglobinopathy Association: Membership on an entity's Board of Directors or advisory committees; Vertex: Consultancy; Sickle Cell Awareness Group of Ontario: Membership on an entity's Board of Directors or advisory committees. Kunz:Novartis: Membership on an entity's Board of Directors or advisory committees. Sheth:Apopharma: Other: Clinical trial DSMB; Celgene: Consultancy; CRSPR/Vertex: Other: Clinical Trial Steering committee. Despotovic:Novartis: Research Funding; Dova: Honoraria. Grace:Agios Pharmaceuticals, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding.

Background: Pyruvate kinase deficiency (PKD) is the most common cause of chronic hereditary non-spherocytic hemolytic anemia. The spectrum of disease in PKD is broad, ranging from an incidentally discovered mild anemia to a severe transfusion-dependent anemia. Splenectomy partially ameliorates the anemia and reduces the transfusion burden in the majority of patients. Because hemoglobin poorly correlates with symptoms in PKD, transfusion requirements are typically used clinically to classify disease severity with those who are regularly transfused despite splenectomy recognized as the most severely affected subgroup. Aim: To compare demographics, complications, and laboratory results between the most severely-affected PKD patients (those that are splenectomized and regularly transfused) with non-regularly transfused splenectomized PKD patients. Methods: After ethics committee approval, patients were enrolled on the PKD Natural History Study, a prospective 30 site international study. All patients had molecularly confirmed PKD. Only splenectomized patients were included in the analysis. Transfusion frequency was observed over a 3-year period. Patients were divided into two groups based on transfusion frequency: the severe phenotype group was defined as those who receive regular transfusions (≥6 discrete red cell transfusion episodes per year) and the control group did not receive regular transfusions. Phenotype stability over the 3-year period was also assessed. Results: 154 splenectomized patients with PKD were included: 30 patients in the severe PKD phenotype group and 124 patients in the comparison PKD group. Results of the analysis comparing the two groups are described in the Table. Severely affected patients were more likely to be female (77% versus 51%, p=0.013), older at the time of splenectomy (median age: 5 versus 3.6, p=0.011), have iron overload (93% vs. 51%, p Conclusions: Patients with PKD who are regularly transfused despite splenectomy appeared to have similar rates of PKD-associated complications (except for iron overload) and similar relevant laboratory values and genotypes when compared to those who are not regularly transfused after splenectomy. The similarity observed between severe phenotype patients and comparison patients with PKD may result from a protective effect of transfusion (e.g. reduction of bone fractures and extramedullary hematopoiesis) or could suggest transfusion-dependence is an artificial signifier of disease severity, reflective of provider practices and patient symptoms rather than an actual distinct phenotype. Transfusion requirements in severe PKD appear to fluctuate significantly over time. Disclosures Al-Samkari: Dova: Consultancy, Research Funding; Agios: Consultancy, Research Funding; Moderna: Consultancy. van Beers:RR Mechatronics: Research Funding; Agios Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Research Funding. Barcellini:Agios: Consultancy, Other: Advisory board; Apellis: Consultancy; Incyte: Consultancy, Other: Advisory board; Bioverativ: Consultancy, Other: Advisory board; Novartis: Research Funding, Speakers Bureau; Alexion: Consultancy, Research Funding, Speakers Bureau. Eber:Agios Pharmaceuticals, Inc.: Consultancy. Glader:Agios Pharmaceuticals, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Chonat:Alexion: Other: advisory board; Agios Pharmaceuticals, Inc.: Other: advisory board. Kuo:Pfizer: Consultancy; Novartis: Consultancy, Honoraria; Celgene: Consultancy; Agios: Consultancy; Alexion: Consultancy, Honoraria; Apellis: Consultancy; Bioverativ: Other: Data Safety Monitoring Board; Bluebird Bio: Consultancy. Despotovic:Dova: Honoraria; Novartis: Research Funding; Amgen: Research Funding. Kwiatkowski:Celgene: Consultancy; Terumo: Research Funding; Apopharma: Research Funding; bluebird bio, Inc.: Consultancy, Research Funding; Agios: Consultancy; Imara: Consultancy; Novartis: Research Funding. Thompson:Baxalta: Research Funding; Novartis: Consultancy, Research Funding; bluebird bio, Inc.: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Ravindranath:Agios Pharmaceuticals, Inc.: Other: I am site PI on several Agios-sponsored studies, Research Funding. Rothman:Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Agios: Honoraria, Research Funding. Verhovsek:Sickle Cell Awareness Group of Ontario: Membership on an entity's Board of Directors or advisory committees; Sickle Cell Disease Association of Canada: Membership on an entity's Board of Directors or advisory committees, Research Funding; Canadian Haemoglobinopathy Association: Membership on an entity's Board of Directors or advisory committees; Vertex: Consultancy. Kunz:Novartis: Membership on an entity's Board of Directors or advisory committees. Sheth:CRSPR/Vertex: Other: Clinical Trial Steering committee; Apopharma: Other: Clinical trial DSMB; Celgene: Consultancy. London:United Therapeutics: Consultancy; ArQule, Inc: Consultancy. Grace:Novartis: Research Funding; Agios Pharmaceuticals, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Introduction Inherited bone marrow failure syndromes (IBMFSs) are rare genetic disorders characterized by abnormal hematopoiesis resulting in cytopenias and increased risk of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Once patients develop MDS the only curative therapy is hematopoietic stem cell transplant (HSCT). The rate of progression from early MDS to advanced MDS and AML is variable and risk factors for progression in IBMFS patients are poorly defined. We hypothesized that certain variables could predict the likelihood of progression from early stages of IBMFS-associated MDS/clonal hematopoiesis to advanced MDS or AML, and that the type of disease progression may impact overall survival (OS). Methods Data were collected from patients prospectively enrolled in the Canadian Inherited Marrow Failure Registry (CIMFR), a collaboration of 1 adult and 16 pediatric hospitals in Canada that care for >95% of pediatric IBMFS patients. IBMFS patients were diagnosed as having a specific syndrome or unclassified IBMFS (UCIBMFS) based on published criteria from our lab and others'. Diagnostic criteria for pediatric MDS defined by Hasle et al. were used. Progression of MDS was defined as 1 or more of: (1) a new cytogenetic abnormality, (2) progression in cytopathology from refractory cytopenia (RC) or refractory cytopenia with ringed sideroblasts (RCRS) to refractory cytopenia with dysplasia (RCD), refractory cytopenia with excess blasts (RCEB) or AML, or (3) increased degree of cytopenia severity. Time to progression was described by Kaplan-Meier analysis and risk factors were evaluated using the Cox proportional hazards model. Results Of 601 patients enrolled in CIMFR, 59 (9.8%) developed cytogenetic clones/MDS. Thirteen (22%) had Fanconi Anemia (FA), 13 (22%) had Shwachman-Diamond Syndrome (SDS), 10 (16.9%) had UCIBMFS, and 23 (39%) had other marrow failure syndromes (i.e. Dyskeratosis Congenita, Severe Congenital Neutropenia, Diamond Blackfan Anemia, GATA2-related disorders). The majority presented with cytogenetic clones/RC (n=45, 76%), 9 (15%) had RCEB, 3 (5%) RCD and 1 (1.7%) RCRS. The most common cytogenetic abnormalities at presentation were -7/-7q (n=18, 30%) and isochromosome 7q10 (n=7, 12%). Four patients had complex cytogenetics (6.8%). Of the patients who developed MDS, 32 (54%) went to HSCT. Patients who developed MDS had significantly worse OS (HR 3, 95% CI 2 to 6, p Twenty four MDS patients (40%) had disease progression, with a median time to progression of 4.7 months (1.14-131). Nine patients (38%) with disease progression had FA, 5 (21%) had SDS, 4 (17%) had UC, and 6 (25%) had other marrow failure syndromes. Ten patients (42%) developed more advanced cytopathology, 10 (42%) a new cytogenetic abnormality, and 5 (20%) worsening cytopenias. Eight patients progressed from RC to RCEB, with a median time to progression of 5.7 months (1.14 to 113). Progression to more advanced cytopathology was associated with lower OS (HR 2.7, 95% CI 1.0 to 7.4, p=0.046). Median time to progression of cytogenetics was 4.13 months (1.14 to 131), which was not predictive of worse OS (p=0.22). Notably, there was no difference in OS or risk of progression between the -7/-7q and isochromosome 7q groups (p=0.644). Finally, patients who progressed due to worsening cytopenias had significantly lower OS compared to those who did not (p=0.011), but numbers were small. Seventeen (71%) of the MDS patients who progressed underwent HSCT. Conclusion Development of MDS has a significant adverse impact on the OS of IBMFS patients, with disease progression occurring 4.7 months from MDS diagnosis. Progression to advanced cytopathology is associated with decreased survival, while worsening cytogenetic clones and cytopenias may not carry the same risk. Importantly, isochromosome 7q10 is also associated with a risk of progression to more severe hematological disease, and may have an impact on survival. Further analysis of additional variables (i.e. HSCT) will provide insight into the important predictors of survival and disease progression, and help to guide treatment decisions for this high-risk patient population. Disclosures No relevant conflicts of interest to declare.

Background: Over the last decade major progress has been made in developing new diagnostic methods and in phenotypic and molecular classification of inherited bone marrow failure syndromes (IBMFSs). Nevertheless, data from the Canadian Inherited Marrow Failure Registry (CIMFR) indicates that 28% of patients with inherited bone marrow failure syndromes (IBMFS) cannot be assigned a specific syndromic diagnosis. These unclassified IBMFS (UIBMFS) cases may represent either novel syndromes or atypical presentations of previously described disorders. Hematopoietic stem cell transplantation (HSCT) is the only curative option for bone marrow failure and malignant myeloid transformation in IBMFSs. However, it is unknown whether the application of this treatment to UIBMFS patients without an ability to modify the procedure according to the underlying genetic and syndromic diagnosis affects outcome. To our knowledge, there are no published transplant data on cohorts of patients with UIBMFSs. The aims of this study were to evaluate the outcome and prognostic factors of HSCT in a cohort of patients with UIBMFSs and to determine whether the knowledge of the syndromic/genetic diagnosis before HSCT has an impact on transplant outcome. Methods: Patients were enrolled on the CIMFR if they were diagnosed with a specific IBMFSs (e.g. Fanconi anemia), and/or they had bone marrow failure and either a family history of bone marrow, or physical malformations or a diagnosis before the age of one year. Patients were considered as having an UIBMFS if they fulfilled the above criteria, but could not be assigned a specific syndromic diagnosis since they did not meet the diagnostic criteria for any known IBMFS. HSCT data were extracted from the CIMFR database and analyzed. Descriptive statistics were used to compare between groups. Cox proportional hazards model was used for univariate analysis to identify risk factors for worse overall survival post HSCT in patients with UIBMFSs. Results: Among the patients enrolled in the CIMFR, 22 with UIBMFSs and 68 with classified IBMFSs (CIBMFSs) underwent HSCT between January 2001 and December 31, 2017. Transplanted patients with UIBMFSs were hematologically characterized by multilineage cytopenia (n=13), single-lineage cytopenia (n=1), myelodysplastic syndrome (MDS) (n=5) or acute myeloid leukemia (AML) (n=3). Patients with CIBMFSs had Fanconi anemia (n=30), dyskeratosis congenita (n=7), Shwachman-Diamond syndrome (n=9), Kostmann syndrome (n=6), Diamond-Blackfan anemia (n=4) or others (n= 11). Median age at diagnosis of patients with UIBMFSs was 4.18 years (range; 0 to 32.0 years) and median age at HSCT for UIBMFSs was 5.74 years (range; 0.17-66.67 years). Median time between diagnosis of UIBMFS and HSCT was 0.48 years (range; 0.12 - 34.67), this was significantly shorter than that of CIBMFS (1.77 years, range; 0.17 - 15 years, P=0.014). Six patients (27.3%) of UIBMFS and 9 patients (19.7%) with CIBMFS underwent HSCT for MDS-RCEB or AML (P=0.15). The overall 5-year survival of UIBMFS patients was significantly inferior to that of CIBMFS patients: 56±11.4% vs. 76±5.5%, respectively (P=0.047). 5-year overall survival of patients with UIBMFSs was significantly worse among those whose stem cell source was cord blood (15±13.3%) vs. those who received other stem cell sources (91±8.7%, P=0.04), while stem cell source did not affect prognosis of patients with CIBMFSs. Engraftment failure among UIBMFS patients who received cord blood was significantly higher than engraftment failure among those who received bone marrow (55.6% vs. 9.1%, P=0.024). No other factors reached statistical significance when the impact of stem cell source on overall survival was analyzed, including transfusion load, transplant indications, intensity of conditioning regimens, related/non-related donor, degree of human leukocyte antigen (HLA) matching or identifying a diagnosis after HSCT. Conclusion: Identifying the syndromic diagnosis of IBMFSs is critically important when considering HSCT. The worse HSCT outcome of UIBMFSs in this study might be related to an inability to tailor the transplant approach to the patient specific phenotype and genotype. Our data suggest that cord blood should be avoided as a stem cell source in patients with UIBMFSs. Disclosures No relevant conflicts of interest to declare.

We surveyed 278 pediatric hematologists/oncologists regarding how children with immune thrombocytopenia (ITP) are counseled for participation in sports. Results show substantial variation in physician perception of contact risk for different sports, and the advice offered about restriction of sport activities of affected children. Many physicians recommend restriction of sports when platelet counts are under 50 × 10(9) /L. Such restriction may affect the child's quality of life despite their having an overall benign disease.

Objectives To assess the quality and content of Internet information about cancer from the perspectives of adolescents with cancer (AWC), their parents and healthcare professionals (HCP). Methods Key words relevant to pediatric cancer were searched across 6 search engines. Quality of information was appraised using the DISCERN tool. Website content completeness, accuracy, readability, cultural sensitivity, and desirability were assessed. Results Only 29 websites had DISCERN scores above 50 (indicating fair quality; mean 55.76 ± 8.23, range 42.50–70.5). The majority of sites targeted parents and only four (14%) were specific to AWC. Overall completeness of the sites was rated 11.46 out of 20 (±3.60; range 4–17.5) and accuracy was rated 4/4, indicating high accuracy with moderate completeness. The average SMOG score was 11.87 (±2.51, range 7.7–18.67) and the Flesch Reading Ease score was 57.44 (±16.94, range 9.1–92.4) indicating that the material was too difficult to read. The average cultural sensitivity scores for the Format, Written message and Visual material scales were 3.08/4 (±0.53, range 2–4), 3.48/4 (±0.41, range 2.6–4) and 2.84/4 (±1.03, range 0–4) indicating the websites were adequately culturally sensitive. On Average, websites had 4/21 features from the desirability checklist, indicating the sites had low desirability. Conclusion Given the paucity of high quality Internet health information at an appropriate reading level for AWC there is a critical need for HCP's to develop Internet programs to meet their unique needs. Pediatr Blood Cancer 2011;57:97–104. © 2011 Wiley-Liss, Inc.

Background: Pyruvate Kinase (PK) deficiency is the most common enzyme defect of the glycolytic pathway causing hereditary non-spherocytic hemolytic anemia. Patients have a broad phenotypic spectrum, ranging from mild anemia to transfusion dependence, and there is wide variation in transfusion practices and decisions about splenectomy. No prior studies have reported on the use of validated health related quality of life (HRQoL) measures in this population. Aim: To describe patient reported outcomes including general HRQoL and fatigue in adults with PK deficiency and the correlation with clinical and laboratory features. Methods: Patients were enrolled on the PK Deficiency Natural History Study, a prospective 30 site international study. All patients had molecularly confirmed PK deficiency. Adults (n=132), ages ≥18 years, completed the EuroQol-5D (high index equivalent to better QoL), PROMIS Fatigue Short Form 7a (high scores equivalent to higher fatigue), and the Functional Assessment of Cancer Therapy-Anemia (FACT-An, high scores equivalent to less fatigue) surveys at enrollment and annually. Timing of administration was convenience based. Survey data were analyzed according to proprietary scoring guidelines. Tests of association were performed using Fisher's exact test (categorical) and Wilcoxon rank sum test (continuous). Regular transfusions were defined as ≥6 transfusions in 12 months. Genotypes were grouped as two missense mutations (M/M), one missense/one non-missense (M/NM), or two non-missense mutations (NM/NM)); non-missense included deletions or other drastic variants. The minimal important difference (MID) for the FACT-An has been reported as 7 points (Cella et al, J Pain Symptom Manage 2002). P-values Results: At enrollment, 128 adults completed the FACT-An with a median total score of 156 (IQR 122-190). Patients receiving regular transfusions reported significantly lower FACT-An scores than those who were not regularly transfused (median 129 vs 156, p=0.004) with significantly lower scores for physical, emotional, and functional well-being and anemia sub-scores (Table). This difference also surpassed the MID. However, non- regularly transfused patients with hemoglobin (Hb) 1000 ng/dL or chelation), higher number of lifetime transfusions, and two missense mutations. Females reported significantly lower scores than males (median 143 vs. 160, p=0.006) with significantly lower anemia sub-scores (p=0.0009). FACT-An surveys completed at the one year follow-up time point validated these findings. EuroQol-5D scores (n=124) at enrollment were similar to the healthy population (median PK deficiency index score 0.88; healthy population index mean 0.88, Shaw et al, Medical Care 2005). No significant differences were found by Hb level, splenectomy status, transfusion status, or genotype group. The median PROMIS fatigue T score (n=66) was 52.1 (IQR 40.5-63.7). Similar to the FACT-An survey data, PROMIS fatigue scores were significantly worse in patients who were regularly transfused (67.0 vs 52.4, p=0.02). PROMIS fatigue scores were also significantly worse in patients ≥40 years old (p=0.05) and females (p=0.01). Conclusions: Using the FACT-An and PROMIS Fatigue measures, patients with PK deficiency who are regularly transfused report significantly more fatigue and worse HRQoL compared with those who are not transfused. Important differences were also seen by iron status and mutation group using the FACT-An. Patients report similar fatigue levels regardless of Hb level, which suggests that symptoms, rather than Hb value alone, should be factored into clinical decision making. In contrast to anemia related HRQoL scores, overall HRQoL scores using validated generic measures in patients with PK deficiency show no differences compared with the healthy population, suggesting that disease-specific measures may better detect the effects of PK deficiency on HRQoL. Disclosures Van Beers: Agios Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Glader:Agios Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Chonat:Agios Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Despotovic:AmGen: Research Funding; Novartis: Research Funding; Sanofi: Consultancy. Kwiatkowski:bluebird bio: Consultancy, Honoraria, Research Funding; Agios Pharmaceuticals: Consultancy, Research Funding; Novartis: Research Funding; Apopharma: Research Funding; Terumo: Research Funding. Thompson:La Jolla Pharmaceutical: Research Funding; Baxalta/Shire: Research Funding; Novartis: Research Funding; Celgene: Research Funding; bluebird bio: Consultancy, Research Funding; Biomarin: Research Funding; Amgen: Research Funding. Newburger:TransCytos LLC: Consultancy; Janssen Research & Development, LLC: Consultancy, Honoraria; X4 Pharmaceutics: Consultancy, Honoraria. Ravindranath:AGIOS: Other: Site Investigator for Pyruvate Kinase Deficiency. Sheth:Terumo Corporation: Research Funding; Novartis: Research Funding; La Jolla Pharmaceutical Company: Research Funding; Celgene Corporation: Consultancy, Research Funding; Bluebird Bio: Consultancy. Grace:Agios Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Research Funding; Agios Pharmaceuticals: Consultancy.

Summary. In the last two decades, the transition from paediatric to adult care has received increasing attention. Health care professionals have become more aware of the unique needs of adolescents and young adults with chronic illnesses and efforts have been made to support youth through this challenging time of change. For patients with haemophilia and their families, there is little evidence regarding best practice for transition of care. We reviewed the transition literature and current guidelines for transition for patients with haemophilia. We advocate that comprehensive haemophilia care includes a conscientious approach to transition of care that should start in early adolescence and be developmentally sensitive. In considering the needs of patients and parents, we must engage both paediatric and adult health care providers to make the transfer smooth and ensure the best care possible during this time.

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.

Inherited bone marrow failure syndromes are a group of rare, heterogeneous genetic disorders with a risk of clonal and malignant myeloid transformation including clonal marrow cytogenetic abnormalities, myelodysplastic syndrome and acute myeloid leukemia. The clinical characteristics, risk classification, prognostic factors and outcome of clonal and malignant myeloid transformation associated with inherited bone marrow failure syndromes are largely unknown. The aims of this study were to determine the impact of category, cytopathology and cytogenetics, the three components of the “Category Cytology Cytogenetics” classification of pediatric myelodysplastic syndrome, on the outcome of clonal and malignant myeloid transformation associated with inherited bone marrow failure. We used data from the Canadian Inherited Marrow Failure Registry. Among 327 patients with inherited bone marrow failure syndrome enrolled in the registry, the estimated risk of clonal and malignant myeloid transformation by the age of 18 years was 37%. The risk of clonal and malignant myeloid transformation varied according to the type of inherited bone marrow failure syndrome but was highest in Fanconi anemia. The development of clonal and malignant myeloid transformation significantly affected overall survival. Mortality varied based on cytopathological group. The largest group of patients had refractory cytopenia. Clonal marrow cytogenetic abnormalities were identified in 87% of patients with clonal and malignant myeloid transformation, and different cytogenetic groups had different impacts on disease progression. We conclude that category, cytopathology and cytogenetics in cases of clonal and malignant myeloid transformation associated with inherited bone marrow failure syndromes have an important impact on outcome and that the classification of such cases should incorporate these factors.

This study aimed to examine the treatment decision-making process for children hospitalized with newly diagnosed immune thrombocytopenia (ITP). Using focus groups, we studied children with ITP, parents of children with ITP, and health care professionals, inquiring about participants' experience with decision support and decision making in newly diagnosed ITP. Data were examined using thematic analysis. Themes that emerged from children were feelings of "anxiety, fear, and confusion"; the need to "understand information"; and "treatment choice," the experience of which was age dependent. For parents, "anxiety, fear, and confusion" was a dominant theme; "treatment choice" revealed that participants felt directed toward intravenous immune globulin (IVIG) for initial treatment. For health care professionals, "comfort level" highlighted factors contributing to professionals' comfort with offering options; "assumptions" were made about parental desire for participation in shared decision making (SDM) and parental acceptance of treatment options; "providing information" was informative regarding modes of facilitating SDM; and "treatment choice" revealed a discrepancy between current practice (directed toward IVIG) and the ideal of SDM. At our center, families of children with newly diagnosed ITP are not experiencing SDM. Our findings support the implementation of SDM to facilitate patient-centered care for the management of pediatric ITP.

Factor XIII (FXIII) deficiency is a rare congenital bleeding disorder estimated to affect 1 in 2 million live births. Treatment often involves prophylaxis with FXIII concentrate and is especially important in preventing intracranial hemorrhage (ICH) and maintaining pregnancy in women of childbearing age. The rarity of this condition and lack of good quality evidence has resulted in a literature largely based on case reports/case series. A review of the literature was conducted in order to provide information about the optimal management of FXIII deficiency. Articles were identified by searching MEDLINE from 1961 to June 2012. Eligible studies included details on patients with FXIII deficiency that received treatment. Information collected included dose, frequency, duration, hemostatic efficacy and adverse events. Of 606 abstracts reviewed, 43 articles, including a total of 328 patients met the selection criteria. Common bleeding manifestations included umbilical cord bleeding, ICH and hematomas. Patients were generally placed on prophylactic factor replacement therapy upon diagnosis of severe or symptomatic FXIII deficiency, which decreased and/or prevented bleeding episodes. Patients with FXIII deficiency that received prophylactic treatment successfully maintained pregnancies. Alternative treatments included the use of cryoprecipitate or frozen plasma when FXIII concentrate was not available or affordable. Recent studies of a new recombinant FXIII concentrate show promising results in regards to safety and efficacy. There are limited data to guide the optimal treatment of FXIII deficiency. Larger patient registries and international collaborations are needed to improve the evidence and enhance clinical outcomes in this rare bleeding disorder.

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.

Introduction: In North America, there are a growing number of patients with hemoglobinopathies, including sickle cell disease and thalassemia. As previously identified in needs assessment surveys of Canadian hematology training program directors and fellows (Verhovsek et. al. 2014 - https://ash.confex.com/ash/2014/webprogram/Paper71742.html), hemoglobinopathy learning constitutes an integral component of the hematology residency curriculum, however there are significant differences in volume and case-mix of hemoglobinopathy exposure among training programs. Fellows and program directors expressed strong interest in online e-learning modules to address gaps in clinical and laboratory learning. As such, we developed a set of e-learning modules for hemoglobinopathies that were implemented as a pilot study. We hypothesized that the e-learning-based curriculum would enhance education and standardize curricular exposure between Canadian hematology programs. Methods: Based on the National Hemoglobinopathy Learning Objectives, a curriculum of 12 case-based modules was developed. Modules were implemented as a pilot study in four Canadian hematology training programs using a distributed practice model - two modules every two months over the 12-month academic year. Training programs were selected based on baseline hemoglobinopathy exposure in their curriculum (two programs with high baseline exposure and two programs with low baseline exposure). Fellows completed the modules independently. Learning was supplemented with bimonthly module review sessions facilitated by expert faculty. In programs where the program directors did not identify a local faculty member with content expertise, review sessions were run by web conference. Data were collected regarding the efficacy of the intervention through three main formats: in-person fellow focus groups, online fellow questionnaires, and sets of designated hemoglobinopathy-related questions at the annual National Hematology Online Practice Exam for all Canadian Hematology fellows. Results: From online graded survey responses (1 to 5, "strongly disagree" to "strongly agree"), 97% of respondents indicated the modules were relevant to their particular learning needs (Mean 4.39, SD = 0.55). All survey respondents indicated the case scenarios were realistic, and 95% felt that the e-learning software was easy to use, engaging and offered flexibility of computer-based learning. Responses in focus group feedback sessions mirrored the survey findings: modules were described as "very useful", "realistic", and of high production quality, with participants indicating they felt the issue of variability in case mix could be addressed with online cases. With respect to the expert-led case review sessions, the majority of focus group responses indicated they were valuable and enhanced the learning obtained from online modules, with review sessions being increasingly useful with later modules that were more challenging. In addition, both online survey responses and focus group feedback identified that participants would strongly recommend the modules to their colleagues (97% of survey responses, Mean 4.43, SD = 0.56). Finally, comparing results of the annual National Hematology Online Practice exam, programs that participated in the online hemoglobinopathy modules saw their fellows achieve a higher incremental change in their score from 2015 to 2016, as compared to their counterparts who did not participate in the online modules (increase of 18.5% vs. 14.8%). Conclusion/Implications: In this pilot implementation study, online hemoglobinopathy modules were shown to have high usability and user satisfaction with content. Fellows agreed that the e-learning modules addressed current gaps in curricula and variability in case-mix exposure. Among fellows who have completed the annual National Hematology Online Practice Exam, comparison of the 2015 and 2016 exam scores in participating and non-participating programs indicated improved performance on hemoglobinopathy-related questions. Taken together, our study has shown that our proposed e-learning-based curriculum has been a successful intervention in promoting, standardizing and enhancing education in hemoglobinopathies among Canadian hematology programs. Disclosures Bates: Eli Lilly Canada: Other: Partial salary support through Eli Lilly Canada/May Cohen Chair in Women's Health.

Background: PKD causes a defect in glycolysis resulting in a hereditary non-spherocytic hemolytic anemia. The prevalence of iron overload is not well described for PKD. Aim: We aim to describe the demographic features and prevalence of iron overload in transfusion dependent and transfusion independent patients with PKD. Methods: Between March 2014 and April 2016, 203 patients enrolled on the PKD Natural History Study at 29 IRB approved sites. All patients were confirmed to have two compound heterozygous or homozygous mutations in the PKLR gene. Children < 1 year of age (n=9) were excluded from this analysis, because elevated ferritin levels are less reliably related to iron overload. Patients were designated with iron overload at the time of enrollment if the plasma ferritin was >1000 ng/mL or the patient was on chelation therapy at any time during the prior 12 months. Patients were designated with having had iron overload if a MRI ever showed liver iron content (LIC) >3 mg/g dry weight or if they had ever received chelation therapy. Tests of association were performed using Fisher's exact test (categorical) and Wilcoxon rank sum test (continuous). Linear associations between variables were measured by Pearson correlation coefficient. P-values Results: Of the 194 patients, 111 (57%) were adults ≥18 years and 83 (43%) were children. The median age of enrollment was 20.6 y (range: 1.3-69.9). Splenectomy had been performed in 65% (126/194). Screening ferritin levels were available for 72% (140/194) and LIC for 32% (62/194). At enrollment, 48% (70/147) had iron overload as defined by ferritin and/or current chelation. Using the LIC criterion, iron overload had been present at some point in 86% (95/110) of patients. Ferritin positively correlated with LIC (n=45); r=0.62, p3 mg/g DW. Baseline characteristics in patients with and without iron overload are shown in the Table. Notably, even in patients that were never regularly transfused and had a hemoglobin (Hb) >8.7 g/dl, the prevalence of iron overload was 26% (8/31). The frequency of iron overload was significantly higher in patients who had a prior splenectomy (p Data on cardiac iron status was available for 66 patients.Only 2 had cardiac iron overload (defined as T2* Of the 194 patients, 52 (27%) were from the Pennsylvania Amish community. These patients were managed differently than the non-Amish, in that only 2% of the Amish patients were on iron chelation therapy in the 12 months prior to enrollment compared with 43% among the non-Amish cohort. In addition, the Amish had a significant higher prevalence of splenectomy (96% vs 52%, p Conclusion: Iron overload is a common, serious complication in PKD, regardless of age, disease severity, or transfusion status. Although ferritin correlates with LIC for the PKD population overall, at the individual patient level, ferritin is not a good predictor of LIC and a ferritin Disclosures Barcellini: Agios: Consultancy. Neufeld:Novartis: Consultancy. Morton:Agios Pharmaceuticals: Research Funding. Yaish:Octapharma: Other: Study investigator. Kuo:Agios Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Alexion: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Apotex: Other: unrestricted educational grant; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Thompson:bluebird bio: Consultancy, Research Funding; Eli Lily: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mast: Research Funding; Baxalta (now part of Shire): Research Funding; ApoPharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Amgen: Research Funding. Grace:Agios Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding.