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MRI-based R2* mapping enabled reproducible quantification of liver iron overload across four centers, three vendors, and three field strengths (1.5 T, 2.89 T, and 3.0 T).

Introduction:Excessive accumulation of iron is caused by a variety of conditions, including hereditary hemochromatosis and transfusional hemosiderosis. If untreated, iron overload can lead to damage in those organs where iron accumulates. Therefore, accurate and reproducible evaluation of body iron stores is needed to guide diagnosis, grading, and treatment monitoring of iron overload. While serum ferritin is the simplest means to assess body iron, it is also an acute phase reactant and therefore is not a reliable biomarker of body iron. Liver iron concentration (LIC) is directly and linearly related to total body iron stores. As such, LIC is widely recognized as a useful surrogate biomarker for the evaluation of iron overload. Liver biopsy is limited by its invasive nature and is contraindicated in many patients (eg. thrombocytopenia) due to bleeding risk. Magnetic resonance imaging (MRI) is a standard of care tool to measure LIC. Arguably the most practical method is R2* MRI due to its speed and ease of use, but the cross-vendor reproducibility of R2*-based LIC estimation remains unknown. Therefore, we evaluated the reproducibility and calibration of R2*-based LIC measurement via a single-breath-hold, confounder-corrected R2*-MRI at both 1.5T and 3T, through a multi-center, multi-vendor study.

Background:

Background. Platelet transfusion is a critical therapy for hematology-oncology patients at risk of transfusion-transmitted infection (TTI) and pulmonary injury. Amotosalen-UVA pathogen reduction (PR) treatment of apheresis platelet components (PC) in plasma or additive solution (INTERCEPT Blood System for Platelets, Cerus, Concord, CA) is FDA approved to reduce risk of TTI and transfusion associated graft vs. host disease (TA-GVHD). PRPC meet the FDA bacteria risk reduction guidance, and approximately 50% of U.S. PC are PRPC. Amotosalen-UVA PR replaces bacteria screening, gamma irradiation, and CMV serology. PR is performed within 24 hours of collection enabling early release of PRPC with 5-day storage. We tested the hypothesis that PRPC were not inferior to conventional PC(CPC) for the incidence of pulmonary injury. Methods. An open-label sequential cohort study in platelet transfusion dependent hematology-oncology patients was conducted under routine practice conditions in 15 clinical centers. Each site enrolled a CPC cohort followed by a PRPC cohort using 4 primary therapy strata matched ± 10%: chemotherapy without hematopoietic cell transplant (HCT), HCT with myeloablation, HCT with non-myeloablative conditioning, and HCT with reduced intensity conditioning (RIC). Patients were supported with the assigned PC type for up to 21 days with 7 days of surveillance after the last PC exposure. Patients participated in only one cohort. The primary endpoint was treatment emergent assisted mechanical ventilation (TEAMV) by intubation or tight mask with positive end expiration pressure (5cm H 2O) after initiation of study PC. All endpoint patients were adjudicated by a blinded pulmonary expert panel (PEP) for diagnosis of acute respiratory distress syndrome (ARDS) by the Berlin Criteria. Secondary endpoints included: time to initiation of TEAMV, clinically significant pulmonary adverse events (CSPAE, CTCAE ≥ Grade 2), transfusion reactions, and mortality. The incidence of TEAMV by non-inferiority (margin = 2.3%), and secondary endpoints were analyzed by modified intention to treat (mITT) and per protocol (PP). Sensitivity analyses with propensity score matching for key variables were conducted for the primary endpoint. The associations between PC and categorical variables were tested by stratified Cochran-Mantel-Haenszel and continuous variables by ANOVA for two-sided significance p = 0.05. results. A total of 2291 pediatric and adult patients (1068 PRPC and 1223 CPC) were enrolled in the respective cohorts with transfusion of 5,277 PRPC and 5,491 CPC. PC assignment compliance and study completion were > 94%. For the mITT data set, the cumulative incidence of TEAMV was lower for the PRPC cohort (log rank p = 0.039) than the CPC cohort (2.9% versus 4.6%, HR = 0.633: 95% CI 0.408-0.982). PRPC by mITT were non-inferior to CPC for the incidence of TEAMV due to all indications, and for TEAMV with pulmonary dysfunction (PD) by PEP (Table). PP analyses were consistent with mITT. Relative risk (RR) of TEAMV showed significantly (p<0.05) decreased RR of PRPC respectively for baseline covariates: age < 65 (0.53), male (0.54), non-white (0.32), chemotherapy (0.40), prior pulmonary disease (0.55), and prior cardiac disease (0.58). Least squares (LS) mean days to initiation of TEAMV for patients with PD were longer for PRPC recipients. PEP adjudicated incidence of ARDS was not significantly different between cohorts (Table). Total and serious CSPAE were not different between the cohorts. There were no significant differences between cohorts in Respiratory, Thoracic, and Mediastinal Disorders, the most frequent system organ class event. Mortality was not different between cohorts. Multivariate analysis (mITT) for the probability of CSPAE or transfusion associated cardiac overload (TACO) showed PC type had no effect. The odds ratio (OR) of CSPAE or TACO during PC support was significantly increased (p< 0.05) in both cohorts for history of cardiac disease (1.35), history of pulmonary disease (2.57), diagnosis of Myelodysplasia (1.88), and diagnosis of Myelodysplasia/Myeloproliferative disease (2.27). There was a significant treatment interaction (p= 0.043) between PC type and acute myelogenous leukemia (AML), increased OR = 1.49 for CPC versus PRPC. Conclusions.PRPC did not potentiate pulmonary injury during PC support; and their use may decrease TEAMV risk with benefit of reduced TTI risk.

No relevant conflicts of interest to declare.

Hernando: Calimetrix: Current holder of individual stocks in a privately-held company. Pedrosa: Merck: Honoraria; Bayer Healthcare: Honoraria; Health Tech International: Current holder of stock options in a privately-held company. Vasanawala: HeartVista: Current holder of individual stocks in a privately-held company; InkSpace: Current holder of individual stocks in a privately-held company; Arterys: Current holder of individual stocks in a privately-held company. Reeder: Bayer: Research Funding; Pfizer: Research Funding; Calimetrix, LLC: Current holder of individual stocks in a privately-held company; Reveal Pharmaceuticals: Current holder of individual stocks in a privately-held company; Elucent Medical: Current holder of individual stocks in a privately-held company; Cellectar Biosciences: Current holder of individual stocks in a privately-held company; HeartVista: Current holder of individual stocks in a privately-held company.

Wheeler: Novo Nordisk A/S: Consultancy; Bayer: Consultancy; BioMarin: Consultancy; HEMA Biologics: Consultancy; Spark: Consultancy; Takeda: Consultancy; UniQure: Consultancy. Nooka: Janssen Oncology: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Sanofi: Consultancy; Oncopeptides: Consultancy; Amgen: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy; Adaptive technologies: Consultancy; GlaxoSmithKline: Consultancy, Other: Travel expenses; Karyopharm Therapeutics: Consultancy. Uhl: UpToDate: Patents & Royalties; Abbott: Consultancy, Speakers Bureau; Grifols: Consultancy, Speakers Bureau. Spinella: Secure Transfusion Services: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; Cerus Corporation: Consultancy, Research Funding. Liu: Cerus Corporation: Current Employment, Current equity holder in publicly-traded company. Benjamin: Cerus Corporation: Current Employment, Current equity holder in publicly-traded company. Corash: Cerus Corporation: Current Employment, Current equity holder in publicly-traded company.

Hepatic sequestration is an uncommon complication in patients with homozygous sickle cell disease. Although transfusion therapy has been effective for the acute condition, no definitive treatment of chronic hepatic sequestration has been identified. We describe a 17-year-old male patient with hemoglobin SS and chronic hepatic sequestration who was treated with long-term (60 months) hydroxyurea. After 36 months of HU therapy, the patient had both an excellent hematologic response and a resolution of hepatic sequestration, as evidenced by disappearance of clinical hepatomegaly, normalization of liver volume on serial computed tomography scans, as well as decreased sinusoidal dilatation and congestion and red blood cell sickling on liver biopsy. The findings in this case suggest that hydroxyurea may benefit patients who have unusual complications of sickle cell disease, such as chronic erythrocyte sickling in the liver.

A 13-year-old boy and a 16-year-old girl both presented with headaches and nausea after they were diagnosed with severe acquired aplastic anemia. Both patients had symptoms and signs consistent with the clinical syndrome of pseudotumor cerebri including headaches, nausea, papilledema, and elevated intracranial pressure. Both patients were treated with therapeutic lumbar puncture and acetazolamide, which relieved their symptoms. Acetazolamide dosage was given while the patients underwent an immunosuppressive regimen. We hypothesize that the pseudotumor cerebri in these two pediatric patients was the result of an increased production of cerebrospinal fluid in response to anemia and that the removal of fluid and treatment with acetazolamide appear to be helpful in such cases.

Introduction:Langerhans cell histiocytosis (LCH) is a myeloid neoplasia characterized by inflammatory lesions with pathologic CD207+ myeloid dendritic cells (DC). Activation of ERKoccurs in all patients with the most common somatic driver mutation being BRAF-V600Ebeing found in up to 60% of patients.Mononuclear cells harboring the BRAF-V600Emutation have been found in peripheral blood of patients with involvement of the liver, spleen, or bone marrow, known as high risk organs. LCH involvement of the brain may include mass lesions in 25% of patients, most commonly the pituitary gland, or a progressive neurodegenerative syndrome (LCH-ND) that arises in approximately 5% of patients. LCH-ND may arise years after the initial LCH episode was presumed to have been cured and may lead to permanent neurologic deficits. The pathogenesis of LCH-ND is poorly understood, but is believed to be due to an autoimmune or paraneoplastic process. No standard approaches to surveillance or therapy exist. In order to define the etiology of LCH-ND, develop clinical tools for identifying patients at risk for LCH-ND, and to identify potential targets for novel therapies, we evaluated cerebral spinal fluid (CSF) proteins, extracellular BRAF- V600EDNA in CSF, and BRAF-V600E+ cells in peripheral blood and brain biopsies.

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.

Introduction:HLH in adults is a fulminant, often fatal hyperinflammatory disorder that often mimics sepsis and is associated with significant cytopenias, primary and secondary infections, immunosuppression, and bleeding. The etiologies in adults are typically autoimmune disease or lymphoma. As a result, HLH patients are immunocompromised hosts who represent a distinct group of high blood product users. Importantly, the need for adequate blood product support can obligate care in tertiary or quaternary settings. The literature lacks sufficient description of transfusion need patterns and the factors associated with blood product use in HLH. This IRB approved resource utilization study investigates this unique group of patients' transfusion needs and seeks to identify factors associated significant cytopenias that result in transfusion dependence.

HLH is a highly fatal hyperinflammatory disorder that mimics sepsis in adults. Diagnostic criteria have not been validated in adults and standards for therapy have not been established. As a result, delays in diagnosis are common. Elevations in temperature, ferritin, and soluble interleukin 2 receptor (SIL-2R) are associated with HLH. Based on the Agency for Healthcare Research and Quality (AHRQ) National Inpatient Sample data, the mean cost per hospitalization of adult patients with HLH in 2014 was $70,860 in 2017 US Dollars, with a mean length of stay (LOS) of 16.8 days. In contrast, mean cost per hospitalization in patients with severe sepsis was just $30,149, with a mean LOS of 8.1 days.

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.

Pediatric Immune Thrombocytopenia (ITP) has an incidence of 4–6/100,000 with 1/3 of cases becoming chronic. Treatment choice is arbitrary, because few studies are powered to identify predictors of therapy response. Increasingly, rituximab is becoming a treatment of choice in those refractory to other therapies (Neunert CE, et al. Pediatr Blood Cancer 2008; 51(4):513). Previous studies in ITP have not examined predictors of response to rituximab or whether response to prior treatments predicts response.To evaluate univariate and multivariable predictors of platelet count response to rituximab.After local IRB approval, 550 patients with chronic ITP enrolled in the longitudinal, North American Chronic ITP Registry (NACIR) between January 2004 and June 2010. Eligibility included: ages 6 months-18 years at ITP diagnosis, clinical diagnosis of ITP, and ITP duration >6 months. Primary ITP was defined as isolated thrombocytopenia without associated conditions. Secondary ITP included those patients with immune thrombocytopenia associated with other immune-mediated medical conditions, including Evans Syndrome. Treatment response was defined as a post-treatment platelet count ≥50,000/uL within 16 weeks of rituximab and within 14 days of steroids. Steroids were prescribed as 1–4 mg/kg prednisone or adult equivalent over 4–14 days with or without taper. The NACIR captured treatment responses both retrospectively prior to enrollment and then prospectively, and both periods were included in this analysis. The multivariable logistic regression modeling process utilized SAS 9.1 using binary variables which were either significant in the univariate analysis or clinically important. A backwards elimination procedure was used to select the final model.Seventy-six (13.8%) patients were treated with rituximab. Demographics of the patients treated with rituximab include: 42% male; 81% Caucasian, 17% Black, and 2% Asian. The mean age at diagnosis of ITP was 8.4 ± SD 5.1 years. The median platelet count at diagnosis of acute ITP was 10,000/uL (IQR 5,000-20,000/uL). 19 (25%) patients had secondary ITP or Evans syndrome. Treatment with rituximab had an overall response rate of 63.2% (48/76). Univariate predictors of response to rituximab are shown in Table I. The strongest univariate predictor of response to rituximab was response to steroids. Gender, ethnicity, and race were not predictive of response to rituximab. Furthermore, other variables which did not predict rituximab response include: history of a bleeding score ≥3 (Buchanan and Adix, J Pediatr 2002; 141: 683), symptoms ≥1 month prior to ITP diagnosis, older age (age >5 years), platelets ≥20,000/uL at acute ITP diagnosis, and a positive ANA. In multivariable analysis, response to steroids remained a strong predictor of response to rituximab with an OR 6.2 (95% CI 1.8–21.3, p=0.004). Secondary ITP also remained a strong a predictor of a positive response to rituximab with an OR 5.9 (95% CI 1.2–33.3, p=0.03).In the NACIR, response to steroids and secondary ITP were strong predictors of response to rituximab, a finding not previously reported in children or adults. Although this finding requires further validation, this result may provide evidence that rituximab should be most considered in patients previously responsive to steroids.Off Label Use: Rituximab for chronic ITP. Lambert:Cangene: Membership on an entity's Board of Directors or advisory committees. Klaassen:Novartis: Research Funding; Cangene: Research Funding. Neufeld:Novartis, Inc: Research Funding.

Chronic pediatric immune thrombocytopenia (ITP) has an incidence of 1–2/100,000. Due to its low incidence, large studies in pediatric chronic ITP are difficult. This registry includes patients from 16 sites in the US and Canada and represents one of the largest longitudinal datasets of children/adolescents with chronic ITP.To describe the North American Chronic ITP Registry (NACIR) study population and evaluate univariate predictors of platelet count response to therapies, including IVIG, anti-D globulin (anti-D), steroids (5–14 day course), and splenectomy.After local IRB approval, 550 patients with chronic ITP enrolled in the NACIR between January 2004 and June 2010. Eligibility included: ages 6 months-18 years at ITP diagnosis, clinical diagnosis of ITP, and ITP duration >6 months. Primary ITP was defined as isolated thrombocytopenia without associated conditions. Secondary ITP included those patients with immune thrombocytopenia associated with other immune-mediated medical conditions, including Evans Syndrome. Treatment response was defined as a post-treatment platelet count ≥50,000/uL within 7 days of IVIG, 10 days of anti-D, 14 days of steroids, and 30 days of splenectomy. 365 subjects had at least one 6 month follow-up report after enrollment; median duration of follow-up was 2.1 yrs. Demographics of participants include: 46% male; 84% Caucasian, 7% Black, and 7% Asian; and 20% Hispanic. Mean age at diagnosis of acute ITP was 8.7 ± SD 5.2 years. At the time of enrollment in NACIR, subjects had received a median of 2 prior treatments (range 0–7).The median platelet count at diagnosis of acute ITP was 11,000/uL (IQR 6,000–31,000/uL) and at chronic ITP was 35,000/uL (IQR 18,000–66,000/uL). 69 (12.5%) patients had secondary ITP or Evans syndrome. Of those tested, 25.6% (98/359) of patients had a positive ANA (titer > 1:40), and 75/337 (22.3%) had a positive direct anti-globulin test (DAT). 27.5% of patients had an antecedent viral illness. Of the 550 subjects, 2 (0.4%) experienced life-threatening bleeding. Patients were treated as follows: 259 (47.1%) with steroids, 253 (46%) with IVIG, 189 (34.4%) with anti-D, and 64 (11.6%) with splenectomy. Overall responses to therapy included: 69.1% response to steroids, 74.3% response to IVIG, 66.7% response to anti-D, and 85.9% response to splenectomy. Univariate predictors of response to treatments are shown in Table I. Higher platelet count at chronic ITP diagnosis and DAT positive predicted a platelet response to a short course of steroids in univariate analysis. This was confirmed in multivariable analysis of potential confounders, using logistic regression with a backwards elimination procedure. Response to one type of therapy was often strongly associated with a response to a second therapy. Gender, ethnicity, race, older age, and platelets ≥20,000/uL at acute ITP diagnosis were not associated with response to any single therapy.The demographics and laboratory findings of the large, well characterized NACIR population are consistent with other reports of young people with chronic ITP. The novel finding that DAT positivity predicts steroid response, even with multivariable adjustment for confounders, provides evidence that the NACIR is a robust and useful tool for trying to predict response to ITP treatment strategies.Klaassen: Novartis: Research Funding; Cangene: Research Funding. Lambert: Cangene: Membership on an entity's Board of Directors or advisory committees.

Abstract 3681

Abstract 2509