Publications by authors named "Ellis J Neufeld"

117 Publications

Simoctocog Alfa (Nuwiq) in Previously Untreated Patients with Severe Haemophilia A: Final Results of the NuProtect Study.

Thromb Haemost 2021 Feb 13. Epub 2021 Feb 13.

St. Jude Children's Research Hospital, Memphis, Tennessee, United States.

Introduction:  FVIII inhibitor development is the most serious contemporary treatment complication in haemophilia A, particularly in previously untreated patients (PUPs). No inhibitors developed in clinical trials in previously treated patients treated with simoctocog alfa (Nuwiq), a fourth-generation recombinant FVIII produced in a human cell line.

Methods:  The NuProtect study investigated the immunogenicity of simoctocog alfa in PUPs. NuProtect was a prospective, multinational, open-label, non-controlled, phase III study. PUPs with severe haemophilia A (FVIII:C <1%) of any age and ethnicity were treated with simoctocog alfa for 100 exposure days or a maximum of 5 years. Patients were true PUPs without prior exposure to FVIII concentrates or blood components. Inhibitor titres were measured with the Nijmegen-modified Bethesda assay; cut-off for positivity was 0.6 BU mL (≥0.6 to <5 low-titre, ≥5 high titre).

Results:  A total of 108 PUPs with a median age at first treatment of 12.0 months (interquartile range: 8.0-23.5) were treated with simoctocog alfa. mutation type was known for 102 patients (94.4%) of whom 90 (88.2%) had null mutations and 12 (11.8%) had non-null mutations. Of 105 PUPs evaluable for inhibitor development, 28 (26.7%) developed inhibitors; 17 high titre (16.2%) and 11 low titre (10.5%). No PUPs with non-null mutations developed inhibitors.

Conclusion:  In the NuProtect study, the rate of inhibitor development in PUPs with severe haemophilia A treated with simoctocog alfa was lower than the rate reported for hamster-cell-derived recombinant factor VIII products in other recent clinical trials. No inhibitors were reported in PUPs with non-null mutations.
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http://dx.doi.org/10.1055/s-0040-1722623DOI Listing
February 2021

Comorbidities and complications in adults with pyruvate kinase deficiency.

Eur J Haematol 2020 Dec 28. Epub 2020 Dec 28.

Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Harvard Medical School, Boston, MA, USA.

Objectives: Pyruvate kinase (PK) deficiency is caused by PKLR gene mutations, leading to defective red blood cell glycolysis and hemolytic anemia. Rates of comorbidities and complications by transfusion history and relative to the general population remain poorly quantified.

Methods: Data for patients aged ≥ 18 years with two confirmed PKLR mutations were obtained from the PK deficiency Natural History Study (NCT02053480). Frequencies of select conditions were compared with an age- and sex-matched cohort from a general insured US population without PK deficiency.

Results: Compared with the matched population (n = 1220), patients with PK deficiency (n = 122) had significantly higher lifetime rates of osteoporosis, liver cirrhosis, and pulmonary hypertension; splenectomy and cholecystectomy rates were also significantly higher in the 8 years before the index date. Sixty-five (53.3%) patients with PK deficiency were classified as regularly transfused, 30 (24.6%) as occasionally transfused, and 27 (22.1%) as never transfused. Regularly transfused patients were significantly more likely than never transfused patients to have had splenectomy, cholecystectomy, and/or thrombosis. Liver iron overload was reported in 62% of patients and occurred regardless of transfusion cohort.

Conclusions: Even never transfused patients with PK deficiency had higher rates of select comorbidities and complications than individuals without PK deficiency.
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http://dx.doi.org/10.1111/ejh.13572DOI Listing
December 2020

A Phase 3 Trial of Luspatercept in Patients with Transfusion-Dependent β-Thalassemia.

N Engl J Med 2020 03;382(13):1219-1231

From the Department of Clinical Sciences and Community, University of Milan, IRCCS Ca' Granda Foundation Maggiore Policlinico Hospital, Milan (M.D.C.), Centro della Microcitemia e Anemie Congenite e del Dismetabolismo del Ferro, E.O. Ospedali Galliera, Genoa (G.L.F.), Ospedale Pediatrico Microcitemico A. Cao, Azienda Ospedaliera G. Brotzu, Cagliari (R.O.), Ematologia e Oncologia Pediatrica, Università della Campania L. Vanvitelli, Caserta (S.P.), and the Department of Clinical and Biological Sciences, University of Turin, Turin (A.P.) - all in Italy; Siriraj Hospital, Mahidol University, Bangkok (V.V.), and the Division of Hematology, Department of Internal Medicine, Chiang Mai University, Chiang Mai (A. Tantiworawit) - both in Thailand; the Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon (A.T.T.); St. George University Hospital for Active Treatment and Medical University of Plovdiv, Plovdiv (P. Georgiev), University Specialized Hospital for Active Treatment in Oncology, Sofia (P. Ganeva), and University Hospital St. Marina, Varna (L.G.) - all in Bulgaria; the Division of Medical Oncology and Hematology, Department of Medicine, University Health Network and Division of Hematology, Department of Medicine, University of Toronto, Toronto (K.H.M.K.); the Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles, and Keck School of Medicine of the University of Southern California, Los Angeles (T.C.), and the University of California San Francisco Benioff Children's Hospital, Oakland (A. Lal) - all in California; the Thalassemia and Sickle Cell Center, Laiko General Hospital (E. Voskaridou), and the First Department of Pediatrics, National and Kapodistrian University of Athens (A. Kattamis), Athens, and the Adult Thalassemia Unit, Hippokration Hospital, Thessaloniki (E. Vlachaki) - all in Greece; Hospital Sultanah Bahiyah, Alor Setar (H.K.L.), Hospital Umum, Sarawak, Kuching (L.P.C.), the University of Malaya Medical Center, Kuala Lumpur (P.C.B.), and Hospital Sultanah Aminah, Johor Bahru (S.M.L.) - all in Malaysia; the Comprehensive Center of Thalassemia, Rabin Medical Center, Beilinson Hospital, Petah Tikva, Israel (I.P.-K.); Farhat Hached University Hospital, Sousse (A. Khelif), and the National Bone Marrow Transplant Center and Faculty of Medicine, University of Tunis El Manar, Tunis (M.B.) - both in Tunisia; the Department of Pediatric Hematology and Oncology, Ege University Hospital, Izmir, Turkey (Y.A.); Royal Prince Alfred Hospital and the University of Sydney, Sydney (P.J.H.); National Taiwan University, Taipei, Taiwan (M.-Y. L.); the Department of Haematology, Whittington Health NHS Trust (F.S.), and the Department of Haematology, University College London and University College London Hospitals NHS Foundation Trust (J.P.) - all in London; St. Jude Children's Research Hospital, Memphis, TN (E.J.N.); Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago (A. Thompson); Celgene, Summit, NJ (A. Laadem, J. Zou, J. Zhang); Celgene, Boudry, Switzerland (J.K.S., D.M., T.Z.); Acceleron Pharma, Cambridge, MA (P.G.L., M.L.S.); and the Department of Hematology, Necker Hospital, Assistance Publique-Hôpitaux de Paris (O.H.), and Imagine Institute, INSERM Unité 1163, University of Paris (O.H.) - both in Paris.

Background: Patients with transfusion-dependent β-thalassemia need regular red-cell transfusions. Luspatercept, a recombinant fusion protein that binds to select transforming growth factor β superfamily ligands, may enhance erythroid maturation and reduce the transfusion burden (the total number of red-cell units transfused) in such patients.

Methods: In this randomized, double-blind, phase 3 trial, we assigned, in a 2:1 ratio, adults with transfusion-dependent β-thalassemia to receive best supportive care plus luspatercept (at a dose of 1.00 to 1.25 mg per kilogram of body weight) or placebo for at least 48 weeks. The primary end point was the percentage of patients who had a reduction in the transfusion burden of at least 33% from baseline during weeks 13 through 24 plus a reduction of at least 2 red-cell units over this 12-week interval. Other efficacy end points included reductions in the transfusion burden during any 12-week interval and results of iron studies.

Results: A total of 224 patients were assigned to the luspatercept group and 112 to the placebo group. Luspatercept or placebo was administered for a median of approximately 64 weeks in both groups. The percentage of patients who had a reduction in the transfusion burden of at least 33% from baseline during weeks 13 through 24 plus a reduction of at least 2 red-cell units over this 12-week interval was significantly greater in the luspatercept group than in the placebo group (21.4% vs. 4.5%, P<0.001). During any 12-week interval, the percentage of patients who had a reduction in transfusion burden of at least 33% was greater in the luspatercept group than in the placebo group (70.5% vs. 29.5%), as was the percentage of those who had a reduction of at least 50% (40.2% vs. 6.3%). The least-squares mean difference between the groups in serum ferritin levels at week 48 was -348 μg per liter (95% confidence interval, -517 to -179) in favor of luspatercept. Adverse events of transient bone pain, arthralgia, dizziness, hypertension, and hyperuricemia were more common with luspatercept than placebo.

Conclusions: The percentage of patients with transfusion-dependent β-thalassemia who had a reduction in transfusion burden was significantly greater in the luspatercept group than in the placebo group, and few adverse events led to the discontinuation of treatment. (Funded by Celgene and Acceleron Pharma; BELIEVE ClinicalTrials.gov number, NCT02604433; EudraCT number, 2015-003224-31.).
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http://dx.doi.org/10.1056/NEJMoa1910182DOI Listing
March 2020

Bioengineering hemophilia A-specific microvascular grafts for delivery of full-length factor VIII into the bloodstream.

Blood Adv 2019 12;3(24):4166-4176

Department of Cardiac Surgery, Boston Children's Hospital, Boston, MA.

Hemophilia A (HA) is a bleeding disorder caused by mutations in the F8 gene encoding coagulation factor VIII (FVIII). Current treatments are based on regular infusions of FVIII concentrates throughout a patient's life. Alternatively, viral gene therapies that directly deliver F8 in vivo have shown preliminary successes. However, hurdles remain, including lack of infection specificity and the inability to deliver the full-length version of F8 due to restricted viral cargo sizes. Here, we developed an alternative nonviral ex vivo gene-therapy approach that enables the overexpression of full-length F8 in patients' endothelial cells (ECs). We first generated HA patient-specific induced pluripotent stem cells (HA-iPSCs) from urine epithelial cells and genetically modified them using a piggyBac DNA transposon system to insert multiple copies of full-length F8. We subsequently differentiated the modified HA-iPSCs into competent ECs with high efficiency, and demonstrated that the cells (termed HA-FLF8-iECs) were capable of producing high levels of FVIII. Importantly, following subcutaneous implantation into immunodeficient hemophilic (SCID-f8ko) mice, we demonstrated that HA-FLF8-iECs were able to self-assemble into vascular networks, and that the newly formed microvessels had the capacity to deliver functional FVIII directly into the bloodstream of the mice, effectively correcting the clotting deficiency. Moreover, our implant maintains cellular confinement, which reduces potential safety concerns and allows effective monitoring and reversibility. We envision that this proof-of-concept study could become the basis for a novel autologous ex vivo gene-therapy approach to treat HA.
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http://dx.doi.org/10.1182/bloodadvances.2019000848DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6929393PMC
December 2019

Regional variation and cost implications of prescribed extended half-life factor concentrates among U.S. Haemophilia Treatment Centres for patients with moderate and severe haemophilia.

Haemophilia 2019 Jul 17;25(4):668-675. Epub 2019 Apr 17.

St. Jude Children's Research Hospital, Memphis, Tennessee.

Background: Extended half-life (EHL) factor VIII (FVIII) and IX (FIX) products are intended to decrease the burden of prophylaxis for patients with haemophilia A or B. Whether these newer concentrates have led to meaningful clinical practice change remains vague.

Aim: To characterize the longitudinal use of standard (SHL) and EHL factor concentrates at haemophilia treatment centres (HTCs), using the ATHNdataset, a US database of 138 ATHN-affiliated HTCs.

Methods: Factor concentrate use among moderate and severe haemophilia A and B patients without inhibitors was analysed at three time points over 18 months.

Results: Use of EHL concentrates rose from 10% of patients to 22% during this study. EHL FVIII prophylaxis is prescribed to the minority of patients, 28%; EHL FIX now predominates for prophylaxis, 52%. Rates of prescribed EHL products varied significantly by age group and HTC region. Median prescribed prophylaxis for SHL compared to EHL products was FVIII 6240 and 5200 and FIX 6968 and FIX 3900 IU/kg/y, respectively. On-demand EHL use has grown but has minimal contribution to overall usage (2%).

Conclusion: Haemophilia treatment centre region and patient age impact the rate of adoption of EHL products; however, EHL prescribing continues to rise nationally, particularly for EHL FIX. Careful attention to annual cost of prophylaxis is imperative as the decrease in median EHL prophylaxis consumption is not offset by the higher unit cost of these products. It is unclear how further growth in use of EHLs will be impacted by emerging non-factor replacement and gene therapies.
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http://dx.doi.org/10.1111/hae.13758DOI Listing
July 2019

Second-line treatments in children with immune thrombocytopenia: Effect on platelet count and patient-centered outcomes.

Am J Hematol 2019 07 29;94(7):741-750. Epub 2019 Apr 29.

Department of Pediatrics, Hematology/Oncology Section, Baylor College of Medicine, Houston, Texas.

Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder with isolated thrombocytopenia and hemorrhagic risk. While many children with ITP can be safely observed, treatments are often needed for various reasons, including to decrease bleeding, or to improve health related quality of life (HRQoL). There are a number of available second-line treatments, including rituximab, thrombopoietin-receptor agonists, oral immunosuppressive agents, and splenectomy, but data comparing treatment outcomes are lacking. ICON1 is a prospective, multi-center, observational study of 120 children starting second-line treatments for ITP designed to compare treatment outcomes including platelet count, bleeding, and HRQoL utilizing the Kids ITP Tool (KIT). While all treatments resulted in increased platelet counts, romiplostim had the most pronounced effect at 6 months (P = .04). Only patients on romiplostim and rituximab had a significant reduction in both skin-related (84% to 48%, P = .01 and 81% to 43%, P = .004) and non-skin-related bleeding symptoms (58% to 14%, P = .0001 and 54% to 17%, P = .0006) after 1 month of treatment. HRQoL significantly improved on all treatments. However, only patients treated with eltrombopag had a median improvement in KIT scores at 1 month that met the minimal important difference (MID). Bleeding, platelet count, and HRQoL improved in each treatment group, but the extent and timing of the effect varied among treatments. These results are hypothesis generating and help to improve our understanding of the effect of each treatment on specific patient outcomes. Combined with future randomized trials, these findings will help clinicians select the optimal second-line treatment for an individual child with ITP.
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http://dx.doi.org/10.1002/ajh.25479DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6527349PMC
July 2019

Focusing in on use of pharmacokinetic profiles in routine hemophilia care.

Res Pract Thromb Haemost 2018 Jul 27;2(3):607-614. Epub 2018 May 27.

Department of Health Research Methods, Evidence, and Impact McMaster University Hamilton ON Canada.

Background: Emergence of population pharmacokinetic models for prediction of individual pharmacokinetic (PK) profiles facilitates individualization of prescribed prophylactic therapy for patients with hemophilia A and B and may have a favorable impact on clinical outcomes and annual factor utilization. How providers approach the integration and application of these data into routine clinical practice is not clear.

Objective: To explore the potential application of and barriers to incorporating PK profiles into current hemophilia prophylaxis decision making.

Methods: A facilitated group discussion of hematologists practicing within the federally-supported United States Hemophilia Treatment Center Network was conducted. Separately, a group of parents of patients with severe hemophilia less than 18 years of age participated in a focus group on individualizing prophylactic factor regimens with the use of PK data.

Results: Physician participants constructed a conceptual model for factors that determined their selection of hemophilia prophylaxis. These factors clustered in five groupings. When charged with creating a prophylaxis regimen for a specific clinical case including PK data, eight of nine providers generated a unique regimen. Parent focus group supported PK data use as they preferred data driven treatment decisions.

Conclusions: Clinician application of PK data for prophylaxis decision making is heterogeneous. Prospective evaluation of the use of PK-tailored prophylaxis in routine care and its impact on patient outcomes is needed. Parents perceived that, while obtaining blood draws could be challenging, images of factor activity decay informed their decisions about physical activity timing and provided an opportunity for partnership and shared decision making with their provider.
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http://dx.doi.org/10.1002/rth2.12118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6046597PMC
July 2018

Performing and interpreting individual pharmacokinetic profiles in patients with Hemophilia A or B: Rationale and general considerations.

Res Pract Thromb Haemost 2018 Jul 20;2(3):535-548. Epub 2018 May 20.

Grifols Durham NC USA.

Objectives: In a separate document, we have provided specific guidance on performing individual pharmacokinetic (PK) studies using limited samples in persons with hemophilia with the goal to optimize prophylaxis with clotting factor concentrates. This paper, intended for clinicians, aims to describe how to interpret and apply PK properties obtained in persons with hemophilia.

Methods: The members of the Working Party on population PK (PopPK) of the ISTH SSC Subcommittee on Factor VIII and IX and rare bleeding disorders, together with additional hemophilia and PK experts, completed a survey and ranking exercise whereby key areas of interest in the field were identified. The group had regular web conferences to refine the manuscript's scope and structure, taking into account comments from the external feedback to the earlier document.

Results: Many clinical decisions in hemophilia are based on some form of explicit or implicit PK assessment. Individual patient PK profiles can be analyzed through traditional or PopPK methods, with the latter providing the advantage of fewer samples needing to be collected on any prophylaxis regimen, and without the need the for a washout period. The most useful presentation of PK results for clinical decision making are a curve of the factor activity level over time, the time to achieve a certain activity level, or related parameters like half-life or exposure (AUC). Software platforms have been developed to deliver this information to clinicians at the point of care. Key characteristics of studies measuring average PK parameters were reviewed, outlining what makes a credible head-to-head comparison among different concentrates. Large data collections of PK and treatment outcomes currently ongoing will advance care in the future.

Conclusions: Traditionally used to compare different concentrates, PK can support tailoring of hemophilia treatment by individual profiling, which is greatly simplified by adopting a PopPK/Bayesian method and limited sampling protocol.
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http://dx.doi.org/10.1002/rth2.12106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6046594PMC
July 2018

Cost analysis of plasma-derived factor VIII/von Willebrand factor versus recombinant factor VIII for treatment of previously untreated patients with severe hemophilia A in the United States.

J Med Econ 2018 Aug 6;21(8):762-769. Epub 2018 Jun 6.

d Grifols , Research Triangle Park , NC , USA.

Background: Inhibitor development to factor VIII (FVIII) hemophilia therapy results in increased complications and substantial economic costs. The SIPPET study, the first randomized controlled trial to compare the immunogenicity of plasma-derived FVIII (pdFVIII)/von Willebrand factor (VWF) and recombinant-DNA-derived FVIII (rFVIII), demonstrated higher inhibitor rates in previously untreated patients (PUPs) treated with rFVIII than in PUPs treated with pdFVIII/VWF.

Objective: To quantify the economic impact of treating PUPs with pdFVIII/VWF vs rFVIII.

Methods: An Excel-based clinical and economic model was developed from a US healthcare payer perspective and run over a 5-year period. The analysis utilized a cohort approach to model patient treatment and outcomes over a monthly cycle to quantify differences in costs of FVIII, bypassing agents, and hospitalizations for serious bleeds. Rates of high-titer inhibitor development were obtained from the SIPPET study. Patients developing high-titer inhibitors were treated with immune tolerance induction (ITI). Patients who developed low-titer inhibitors and those who did not develop inhibitors continued their usual FVIII treatment. Patients who were successfully treated with ITI returned to FVIII treatment, while unsuccessfully treated patients received bypassing agents. Total costs per treated patient were estimated and a one-way sensitivity analysis was conducted to quantify the impact of parameter uncertainty on the model outcomes.

Results: Total cumulative costs per patient over 5 years were $834,621 for pdFVIII/VWF patients and $1,237,163 for rFVIII patients, representing a total saving of $402,542 per patient over the 5-year period, for an average annual saving of $80,508 per patient.

Conclusions: Based on data from the SIPPET study, this analysis found that initiating FVIII treatment in severe hemophilia A PUPs with pdFVIII/VWF has the potential to offer substantial cost savings to healthcare payers, amounting to a one-third reduction in costs.
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http://dx.doi.org/10.1080/13696998.2018.1468335DOI Listing
August 2018

Physician decision making in selection of second-line treatments in immune thrombocytopenia in children.

Am J Hematol 2018 07 6;93(7):882-888. Epub 2018 May 6.

Division of Hematology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.

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.
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http://dx.doi.org/10.1002/ajh.25110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6037544PMC
July 2018

Clinical spectrum of pyruvate kinase deficiency: data from the Pyruvate Kinase Deficiency Natural History Study.

Blood 2018 05 16;131(20):2183-2192. Epub 2018 Mar 16.

Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.

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 ( = .007), lower indirect bilirubin ( = .005), and missense mutations ( = .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.
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http://dx.doi.org/10.1182/blood-2017-10-810796DOI Listing
May 2018

Safety and pharmacokinetics of the oral iron chelator SP-420 in β-thalassemia.

Am J Hematol 2017 Dec 31;92(12):1356-1361. Epub 2017 Oct 31.

Department of Pediatrics & Thalassemia Center, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.

Our phase I, open-label, multi-center, dose-escalation study evaluated the pharmacokinetics (PK) of SP-420, a tridentate oral iron chelating agent of the desferrithiocin class, in patients with transfusion dependent β-thalassemia. SP-420 was administered as a single dose of 1.5 (n = 3), 3 (n = 3), 6 (n = 3), 12 (n = 3), and 24 (n = 6) mg/kg or as a twice-daily dose of 9 mg/kg (n = 6) over 14-28 days. There was a near dose-linear increase in the mean plasma SP-420 concentrations and in the mean values for C and AUC over the dose range evaluated. The median t ranged from 0.5 to 2.25 h and was not dose dependent. The study was prematurely terminated by the sponsor due to renal adverse events (AE) including proteinuria, increase in serum creatinine, and one case of Fanconi syndrome. Other adverse effects included hypersensitivity reactions and gastrointestinal disturbances. Based on current dose administration, the renal AE observed outweighed the possible benefits from chelation therapy. However, additional studies assessing efficacy and safety of lower doses or less frequent dosing of SP-420 over longer durations with close monitoring would be necessary to better explain the findings of our study and characterize the safety of the study drug.
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http://dx.doi.org/10.1002/ajh.24914DOI Listing
December 2017

Risk of post-procedural bleeding in children on intravenous fish oil.

Am J Surg 2017 Oct 1;214(4):733-737. Epub 2016 Dec 1.

Vascular Biology Program and the Department of Surgery, Boston Children's Hospital, Boston, MA, USA. Electronic address:

Background: Intestinal failure-associated liver disease (IFALD) can be treated with parenteral fish oil (FO) monotherapy, but practitioners have raised concerns about a potential bleeding risk. This study aims to describe the incidence of clinically significant post-procedural bleeding (CSPPB) in children receiving FO monotherapy.

Methods: A retrospective chart review was performed on patients at our institution treated with intravenous FO for IFALD. CSPPB was defined as bleeding leading to re-operation, transfer to the intensive care unit, re-admission, or death, up to one month after any invasive procedure.

Results: From 244 patients reviewed, 183 underwent ≥1 invasive procedure(s) (n = 732). Five (0.68%, 95% CI 0.22-1.59%) procedures resulted in CSPPB. FO therapy was never interrupted. No deaths due to bleeding occurred.

Conclusions: Findings suggest that FO therapy is safe, with a CSPPB risk no greater than that reported in the general population. O3FA should not be held in preparation for procedures or in the event of bleeding.
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http://dx.doi.org/10.1016/j.amjsurg.2016.10.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5464992PMC
October 2017

Ringed sideroblasts in β-thalassemia.

Pediatr Blood Cancer 2017 05 3;64(5). Epub 2016 Nov 3.

Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston Children's Hospital, Boston, Massachusetts.

Symptomatic β-thalassemia is one of the globally most common inherited disorders. The initial clinical presentation is variable. Although common hematological analyses are typically sufficient to diagnose the disease, sometimes the diagnosis can be more challenging. We describe a series of patients with β-thalassemia whose diagnosis was delayed, required bone marrow examination in one affected member of each family, and revealed ringed sideroblasts, highlighting the association of this morphological finding with these disorders. Thus, in the absence of characteristic congenital sideroblastic mutations or causes of acquired sideroblastic anemia, the presence of ringed sideroblasts should raise the suspicion of β-thalassemia.
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http://dx.doi.org/10.1002/pbc.26324DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5697724PMC
May 2017

Increasing observation rates in low-risk pediatric immune thrombocytopenia using a standardized clinical assessment and management plan (SCAMP ).

Pediatr Blood Cancer 2017 05 26;64(5). Epub 2016 Oct 26.

Pediatric Hematology/Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, Massachusetts.

An observational approach is recommended in newly diagnosed children with immune thrombocytopenia (ITP) at low risk of bleeding; however, there is no standard definition of risk. A standardized clinical assessment and management plan (SCAMP ), a modifiable practice guideline, was implemented and revised (SCAMP-1 and SCAMP-2) and applied to 71 newly diagnosed patients with ITP. The Buchanan and Adix bleeding score guided treatment and was modified by stratifying by low- and high-risk grade 3 bleeding in SCAMP-2. Observation rates increased from 40% to 74% from SCAMP-1 to SCAMP-2 (P < 0.05) with no bleeding complications. We propose a modified bleeding score that increased observation rates in low-risk patients with ITP.
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http://dx.doi.org/10.1002/pbc.26303DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5366076PMC
May 2017

Skin testing, graded challenge, and desensitization to von Willebrand factor (VWF) products in type III von Willebrand disease (VWD).

J Allergy Clin Immunol Pract 2016 Sep-Oct;4(5):1006-8. Epub 2016 Jul 9.

Division of Immunology, Boston Children's Hospital, Boston, Mass. Electronic address:

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http://dx.doi.org/10.1016/j.jaip.2016.05.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5802411PMC
November 2018

Safety and efficacy of recombinant factor VIIa by pediatric age cohort: reassessment of compassionate use and trial data supporting US label.

Pediatr Blood Cancer 2016 10 27;63(10):1822-8. Epub 2016 May 27.

Clinical, Medical and Regulatory Affairs, Novo Nordisk Inc, Plainsboro, New Jersey.

Background: The relative safety and efficacy of recombinant activated coagulation factor VII (rFVIIa, NovoSeven® RT) across pediatric age cohorts is poorly defined. The objective of this analysis was to assess the safety and efficacy of rFVIIa in pediatric patients with congenital hemophilia with inhibitors (CHwI) in the clinical studies supporting the U.S. labeling.

Procedure: Pediatric data were derived from seven studies (five acute and two perioperative treatments) and pooled. All data were stratified by age (<2, 2 to <6, 6 to <12, and 12-16 years) and study category (acute treatment of bleeding episodes or surgery).

Results: The pediatric dataset included 172 patients; 144 received rFVIIa for the treatment of bleeding episodes and 28 for the control of bleeding perioperatively. Recombinant FVIIa was effective for 95.4% (1,026/1,076) of the evaluable bleeding episodes and had similar treatment effectiveness across pediatric age groups (range, 94.1-97.2%). The majority received doses of 90 mcg/kg. rFVIIa was effective in achieving perioperative hemostasis across pediatric age groups (range, 91-100%), with greater efficacy observed with the recommended (90 mcg/kg) versus lower dose (35 mcg/kg). A total of 88 pediatric patients experienced a total of 285 adverse drug reactions, similar in type to those reported among adult patients. A total of seven thrombotic events were recorded in seven pediatric patients; only one was confirmed related to rFVIIa upon individual case review.

Conclusions: rFVIIa is safe and effective in the treatment of bleeding episodes and prevention of periprocedure bleeding in CHwI with no apparent differences observed among pediatric age groups.
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http://dx.doi.org/10.1002/pbc.26082DOI Listing
October 2016

A Budget Impact Model of Hemophilia Bypassing Agent Prophylaxis Relative to Recombinant Factor VIIa On-Demand.

J Manag Care Spec Pharm 2016 Feb;22(2):149-57

6 Professor, Pharmaceutical Economics and Policy, and Professor, Health Policy and Economics, University of Southern California, Los Angeles.

Background: Hemophilia patients use factor-clotting concentrates (factor VIII for hemophilia A and factor IX for hemophilia B) for improved blood clotting. These products are used to prevent or stop bleeding episodes. However, some hemophilia patients develop inhibitors (i.e., the patient's immune system develops antibodies against these factor concentrates). Hence, these patients do not respond well to the factor concentrates. A majority of hemophilia patients with inhibitors are managed on-demand with the following bypassing agents: recombinant factor VIIa (rFVIIa) and activated prothrombin complex concentrate (aPCC). The recently published U.S. registries Dosing Observational Study in Hemophilia (DOSE) and Hemostasis and Thrombosis Research Society (HTRS) reported higher rFVIIa on-demand use for bleed management than previously described.

Objective: To estimate aPCC and rFVIIa prophylaxis costs relative to rFVIIa on-demand treatment cost based on rFVIIa doses reported in U.S. registries.

Methods: A literature-based cost model was developed assuming a base case on-demand annual bleed rate (ABR) of 28.7 per inhibitor patient, which was taken from a randomized phase 3 clinical trial. The doses for rFVIIa on-demand were taken from the median dose per bleed reported by the DOSE and HTRS registries. Model inputs for aPCC and rFVIIa prophylaxis (i.e., dosing and efficacy) were derived from respective randomized clinical trials. Cost analysis was from the U.S. payer perspective, and only direct drug costs were considered. The drug cost was based on the Medicare Part B 2014 average sale price (ASP). Two-way sensitivity and threshold analyses were performed by simultaneously varying on-demand ABR, prophylaxis efficacy, and unit drug cost. In addition to studying relative costs associated with on-demand and prophylaxis treatments, relative cost per bleeding episode avoided were also calculated for aPCC and rFVIIa prophylaxis treatments. The prophylaxis efficacy reported in the trials were used to determine the number of bleeding episodes avoided.

Results: Based on the median on-demand dose of 695 mcg per kg per bleed, reported by the DOSE registry, the annual rFVIIa on-demand cost was $34,009 per kg of body weight. The annual rFVIIa on-demand cost was $22,020 per kg of body weight when the median dose of 450 mcg per kg per bleed reported by the HTRS registry was considered. The annual cost rose to $38,461 per kg of body weight when the rFVIIa on-demand dose of 786 mcg per kg per bleed among patients infusing an initial dose ≥ 250 mcg per kg was considered. The aPCC (85 units per kg per every other day) and rFVIIa (90 mcg per kg per every day) annual prophylaxis costs were $26,536 and $60,700, respectively. Also, aPCC and rFVIIa prophyaxis treatments were estimated to prevent a total of 20.8 and 12.9 annual bleeding episodes, respectively. When compared with the on-demand dose of 695 mcg per kg per bleed (DOSE registry), the annual aPCC and rFVIIa prophylaxis costs were 21.9% lower and 78.4% higher, respectively. Additionally, aPCC prophylaxis saved $360 per kg for each bleeding episode avoided. rFVIIa prophylaxis cost $2,066 per kg for each bleeding episode avoided. Compared with the on-demand dose of 450 mcg per kg per bleed (HTRS registry), aPCC and rFVIIa prophylaxis costs were 20.5% and 174.9% higher, respectively. In this case, aPCC and rFVIIa prophylaxis treatment costs were $217 per kg and $2,995 per kg, respectively, for each bleeding episode avoided. aPCC and rFVIIa prophylaxis costs were 31.0% lower and 57.8% higher, respectively, when compared with the rFVIIa on-demand dose of 786 mcg per kg per bleed, among patients infusing an initial dose ≥ 250 mcg per kg (HTRS registry). In this case, aPCC prophylaxis saved $573 per kg for each bleeding episode avoided, while rFVIIa prophylaxis costs $1,724 per kg for each bleeding episode avoided. Results of the 2-way sensitivity analyses were robust in the majority of the scenarios considered.

Conclusions: aPCC prophylaxis may be cost saving for managing hemophilia patients with inhibitors who bleed frequently and infuse significant quantities of rFVIIa on-demand.
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http://dx.doi.org/10.18553/jmcp.2016.22.2.149DOI Listing
February 2016

Center-Based Quality Initiative Targets Youth Preparedness for Medical Independence: HEMO-Milestones Tool in a Comprehensive Hemophilia Clinic Setting.

Pediatr Blood Cancer 2016 Mar 23;63(3):499-503. Epub 2015 Oct 23.

Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston Hemophilia Center, Harvard Medical School, Boston, Massachusetts.

Background: Patient transition readiness self-assessment tools and investigation into patient and parent perceptions of the transition process from pediatric to adult care models have informed recognition of gaps in care, particularly for those with chronic disease. Implementation of a longitudinal transition process with patient tracking provides the opportunity for individualized education and skill building and fosters a patient-centered model.

Procedure: Quality improvement intervention was used to assess and improve our transition process at annual comprehensive clinic visits for patients with bleeding disorders at our tertiary care pediatric center.

Results: Thirty-one patients with rare bleeding disorders received an introduction to the transition process using the HEMO-milestones tool in our hemophilia comprehensive clinic from September to December 2014. The percentage of patients with documented, age-specific hemophilia knowledge/skill assessment increased from 21% to 97%. The percentage of patients with documented skill building or adult care transfer plan increased from 55% to 93%. Designated postclinic team debriefings facilitated the creation of collaborative documentation summarizing each patient's transition readiness and plan for continued skill building.

Conclusions: The HEMO-milestones tool promotes a standardized approach to evaluation of self-management competency. When combined with a collaborative multidisciplinary effort, it increases plans for skill building in patients with hemophilia. This tool is easily modifiable for alternate subspecialty use and does not require extensive training for implementation.
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http://dx.doi.org/10.1002/pbc.25807DOI Listing
March 2016

Guidelines for the Standard Monitoring of Patients With Thalassemia: Report of the Thalassemia Longitudinal Cohort.

J Pediatr Hematol Oncol 2015 Apr;37(3):e162-9

*Boston Children's Hospital, Boston, MA †Children's Hospital & Research Center Oakland, Oakland, CA ‡Weill Medical College of Cornell, New York, NY §Children's Memorial Hospital, Chicago, IL ∥University of Texas Southwestern Medical Center, Dallas, TX ¶Children's Hospital of Philadelphia, Philadelphia, PA.

Chronic transfusion therapy has played a central role in extending life expectancy for patients with hemoglobinopathies such as thalassemia. However, this life-saving therapy is associated with numerous complications that now comprise the bulk of management considerations for patients with thalassemia. This review reports on the experience of the Thalassemia Longitudinal Cohort and reviews available literature to establish guidelines for the management of patients with thalassemia.
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http://dx.doi.org/10.1097/MPH.0000000000000307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4511957PMC
April 2015

Sports Participation in Children and Adolescents with Immune Thrombocytopenia (ITP).

Pediatr Blood Cancer 2015 Dec 14;62(12):2223-5. Epub 2015 Jul 14.

Department of Pediatrics, Children's Hospital of Eastern Ontario, Ottawa, Canada.

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.
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http://dx.doi.org/10.1002/pbc.25644DOI Listing
December 2015

Platelet function tests, independent of platelet count, are associated with bleeding severity in ITP.

Blood 2015 Aug 2;126(7):873-9. Epub 2015 Jul 2.

Center for Platelet Research Studies, and Division of Hematology/Oncology, Boston Children's Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.

Immune thrombocytopenia (ITP) patients with similarly low platelet counts differ in their tendency to bleed. To determine if differences in platelet function in ITP patients account for this variation in bleeding tendency, we conducted a single-center, cross-sectional study of pediatric patients with ITP. Bleeding severity (assessed by standardized bleeding score) and platelet function (assessed by whole blood flow cytometry) with and without agonist stimulation was evaluated in 57 ITP patients (median age, 9.9 years). After adjustment for platelet count, higher levels of thrombin receptor activating peptide (TRAP)-stimulated percent P-selectin- and activated glycoprotein (GP)IIb-IIIa-positive platelets were significantly associated with a lower bleeding score, whereas higher levels of immature platelet fraction (IPF), TRAP-stimulated platelet surface CD42b, unstimulated platelet surface P-selectin, and platelet forward light scatter (FSC) were associated with a higher bleeding score. Thus, platelet function tests related to platelet age (IPF, FSC) and activation through the protease activated receptor 1 (PAR1) thrombin receptor (TRAP-stimulated P-selectin, activated GPIIb-IIIa, and CD42b), independent of platelet count, are associated with concurrent bleeding severity in ITP. These tests may be useful markers of future bleeding risk in ITP.
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http://dx.doi.org/10.1182/blood-2015-02-628461DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4536541PMC
August 2015

Erythrocyte pyruvate kinase deficiency: 2015 status report.

Am J Hematol 2015 Sep 14;90(9):825-30. Epub 2015 Aug 14.

Department, of Pediatrics and Pathology, Stanford University, Lucile Packard Children's Hospital, Palo Alto, California.

Over the last several decades, our understanding of the genetic variation, pathophysiology, and complications of the hemolytic anemia associated with red cell pyruvate kinase deficiency (PKD) has expanded. Nonetheless, there remain significant gaps in our knowledge with regard to clinical care and monitoring. Treatment remains supportive with phototherapy and/or exchange transfusion in the newborn period, regular or intermittent red cell transfusions in children and adults, and splenectomy to decrease transfusion requirements and/or anemia related symptoms. In this article, we review the clinical diversity of PKD, the current standard of treatment and for supportive care, the complications observed, and future treatment directions.
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http://dx.doi.org/10.1002/ajh.24088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5053227PMC
September 2015

Safety update on the use of recombinant activated factor VII in approved indications.

Blood Rev 2015 Jun;29 Suppl 1:S34-41

Novo Nordisk Inc., Princeton, NJ, USA.

This updated safety review summarises the large body of safety data available on the use of recombinant activated factor VII (rFVIIa) in approved indications: haemophilia with inhibitors, congenital factor VII (FVII) deficiency, acquired haemophilia and Glanzmann's thrombasthenia. Accumulated data up to 31 December 2013 from clinical trials as well as post-marketing data (registries, literature reports and spontaneous reports) were included. Overall, rFVIIa has shown a consistently favourable safety profile, with no unexpected safety concerns, in all approved indications. No confirmed cases of neutralising antibodies against rFVIIa have been reported in patients with congenital haemophilia, acquired haemophilia or Glanzmann's thrombasthenia. The favourable safety profile of rFVIIa can be attributed to the recombinant nature of rFVIIa and its localised mechanism of action at the site of vascular injury. Recombinant FVIIa activates factor X directly on the surface of activated platelets, which are present only at the site of injury, meaning that systemic activation of coagulation is avoided and the risk of thrombotic events (TEs) thus reduced. Nonetheless, close monitoring for signs and symptoms of TE is warranted in all patients treated with any pro-haemostatic agent, including rFVIIa, especially the elderly and any other patients with concomitant conditions and/or predisposing risk factors to thrombosis.
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http://dx.doi.org/10.1016/S0268-960X(15)30006-0DOI Listing
June 2015

Dysregulated arginine metabolism and cardiopulmonary dysfunction in patients with thalassaemia.

Br J Haematol 2015 Jun 24;169(6):887-98. Epub 2015 Apr 24.

Children's Hospital Oakland Research Institute, Oakland, CA, USA.

Pulmonary hypertension (PH) commonly develops in thalassaemia syndromes, but is poorly characterized. The goal of this study was to provide a comprehensive description of the cardiopulmonary and biological profile of patients with thalassaemia at risk for PH. A case-control study of thalassaemia patients at high versus low PH-risk was performed. A single cross-sectional measurement for variables reflecting cardiopulmonary status and biological pathophysiology were obtained, including Doppler-echocardiography, 6-min-walk-test, Borg Dyspnoea Score, New York Heart Association functional class, cardiac magnetic resonance imaging (MRI), chest-computerized tomography, pulmonary function testing and laboratory analyses targeting mechanisms of coagulation, inflammation, haemolysis, adhesion and the arginine-nitric oxide pathway. Twenty-seven thalassaemia patients were evaluated, 14 with an elevated tricuspid-regurgitant-jet-velocity (TRV) ≥ 2·5 m/s. Patients with increased TRV had a higher frequency of splenectomy, and significantly larger right atrial size, left atrial volume and left septal-wall thickness on echocardiography and/or MRI, with elevated biomarkers of abnormal coagulation, lactate dehydrogenase (LDH) levels and arginase concentration, and lower arginine-bioavailability compared to low-risk patients. Arginase concentration correlated significantly to several echocardiography/MRI parameters of cardiovascular function in addition to global-arginine-bioavailability and biomarkers of haemolytic rate, including LDH, haemoglobin and bilirubin. Thalassaemia patients with a TRV ≥ 2·5 m/s have additional echocardiography and cardiac-MRI parameters suggestive of right and left-sided cardiac dysfunction. In addition, low arginine bioavailability may contribute to cardiopulmonary dysfunction in β-thalassaemia.
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http://dx.doi.org/10.1111/bjh.13452DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4452408PMC
June 2015

Liver MRI is more precise than liver biopsy for assessing total body iron balance: a comparison of MRI relaxometry with simulated liver biopsy results.

Magn Reson Imaging 2015 Jul 20;33(6):761-7. Epub 2015 Feb 20.

Boston Children's Hospital and Harvard Medical School, Boston, MA.

Purpose: Liver biopsy was long considered the reference standard for measuring liver iron concentration. However, its high sampling variability and invasive nature make it poorly suited for serial analyses. To demonstrate the fallibility of liver biopsy, we use serial estimates of iron chelation efficiency (ICE) calculated by R2 and R2* MRI liver iron concentration (LIC) estimates as well as by simulated liver biopsy (over all physically reasonable sampling variability) to compare the robustness of these three techniques.

Materials And Methods: R2, R2*, transfusional volume, and chelator compliance were obtained from 49 participants in a phase II clinical trial of deferitazole over two years. Liver biopsy LIC results were simulated using sampling errors of 0%, 10%, 20%, 30%, 40% and iron assay variability of 12%. LIC estimates by R2, R2*, and simulated biopsy were used to calculate ICE over time. Bland-Altman limits of agreement were compared across observation intervals of 12, 24, and 48 weeks.

Results: At 48 week intervals, LIC estimates by R2, R2* and "perfect" liver biopsy had comparable accuracy in predicting ICE; both MRI methods were superior to any physically realizable liver biopsy (sampling error 10% or higher). LIC by R2* demonstrated the most robust ICE estimates at monitoring intervals of 24 and 12 weeks, but this difference did not remain significant at 48 week intervals.

Conclusion: MRI relaxometry is superior to liver biopsy for serial LIC observations, such as used in the care of tranfusional siderosis patients, and should also be considered the new standard of LIC determination for regulatory purposes. Among relaxometry techniques, LIC estimates by R2* are more robust for tracking changes in iron balance over intermediate time scales (<=24 weeks).
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http://dx.doi.org/10.1016/j.mri.2015.02.016DOI Listing
July 2015

Treatment and outcomes of immune cytopenias following solid organ transplant in children.

Pediatr Blood Cancer 2015 02 12;62(2):214-218. Epub 2014 Oct 12.

Pediatric Hematology/Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorder Center, Boston, Massachusetts.

Background: Immune cytopenias are a recognized life-threatening complication following pediatric solid organ transplants (SOT), but treatment responses and overall outcome are not well described. The aim of this study was to evaluate the demographic characteristics, response to treatments, and outcomes of a cohort of patients who developed immune cytopenias following SOT.

Procedure: In this single center retrospective review, patients with immune cytopenias after SOT were identified by electronic medical record (EMR) search and transplant databases from 1995-2012.

Results: Of 764 SOT patients, 19 (2.4%) developed immune cytopenias. Incidence varied widely by transplant type from 1.2% (renal) to 23.5% (multivisceral). Autoimmune hemolytic anemia (AIHA) was the most common immune cytopenia. Overall median time from transplant to immune cytopenia was 8 m and varied by transplant type from 3 m (liver) to 74 m (heart). Standard therapies for immune cytopenias were often used and ineffective. The most effective therapy for the immune cytopenia was changing immunosuppression from tacrolimus to another agent. Three of 19 patients died; none directly attributed to the immune cytopenia.

Conclusions: Immune cytopenias are not rare after SOT, and patients usually do not respond well to traditional first line therapies. Provided that the risk of organ rejection is otherwise manageable, temporary cessation of tacrolimus could be more widely explored in this challenging clinical context. Pediatr Blood Cancer 2015;62:214-218. © 2014 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/pbc.25215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4394012PMC
February 2015

Pediatric heparin-induced thrombocytopenia: prevalence, thrombotic risk, and application of the 4Ts scoring system.

J Pediatr 2015 Jan 14;166(1):144-50. Epub 2014 Oct 14.

Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA; Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA. Electronic address:

Objective: To characterize heparin-induced thrombocytopenia (HIT) at a single pediatric center including the prevalence and the accuracy of the 4Ts scoring system as a predictor of HIT.

Study Design: In this retrospective cohort study, we identified 155 consecutive patients <21 years old with sufficient data for 4Ts scoring. The 4Ts scoring system is a validated pretest tool in adults that predicts the likelihood of HIT using clinical features. Hospital-wide exposure to unfractionated and low molecular weight heparin was determined by querying the hospital pharmacy database.

Results: The majority of patients with suspected HIT (61.2%) were on surgical services. Prediction of HIT risk using initial 4Ts scoring found 3 (2%) had high risk 4Ts scores, 114 (73%) had intermediate risk 4Ts scores, and the remaining 38 (25%) had low risk 4Ts scores. HIT was confirmed in 0/38 patients with low risk 4Ts scores, 2/114 patients with intermediate-risk 4Ts scores, and all 3 patients with high-risk 4Ts scores presented with HIT with thrombosis. Of 12 positive HIT screening tests, results were falsely positive in 66.6% of patients with intermediate risk 4Ts scores and 100% of patients with low risk 4Ts scores. The prevalence of HIT was 0.058% and HIT with thrombosis was 0.046% in pediatric patients on unfractionated heparin.

Conclusions: The prevalence of HIT appears significantly lower in pediatric patients compared with adults. Application of the 4Ts system as a pretest tool may reduce laboratory evaluation for HIT in heparin-exposed children with low risk 4Ts scores, decreasing unnecessary further testing, intervention, and cost.
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http://dx.doi.org/10.1016/j.jpeds.2014.09.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4274245PMC
January 2015

Impact of acute bleeding on daily activities of patients with congenital hemophilia with inhibitors and their caregivers and families: observations from the Dosing Observational Study in Hemophilia (DOSE).

Value Health 2014 Sep 14;17(6):744-8. Epub 2014 Aug 14.

Novo Nordisk Inc., Princeton, NJ, USA.

Objectives: There is limited understanding of the effects of bleeding episodes on the daily lives of patients with congenital hemophilia with inhibitors and their caregivers. This analysis of the Dosing Observational Study in Hemophilia examined the impact of acute bleeding episodes on work, school, and family activities.

Methods: Patients and caregivers participated in a diary study for 90 or more days or until patients experienced four bleeding episodes. All bleed treatments, interference with daily activities, and quality-of-life assessments were captured in daily records. Patients and caregivers reported planned workdays or school days eligible to be "lost" so as to differentiate from days lost because of disability or nonworking status, weekends, and vacations.

Results: Diaries were completed for 39 patients (18 adults and 21 children). Bleeding episodes that continued for 3 or more days (16.4%) accounted for most of the major changes to family plans. For the 38 patients with bleeding episodes, 47% of 491 bleed days fell on planned workdays or school days; the remainder fell on weekends, holidays, or nonworkdays or non-school days and therefore did not count as "lost days." Patients reported a loss of productivity on a greater percentage of eligible bleed days than did caregivers (3.9% vs. 0.8%, respectively). Patients and caregivers reported 13.5%/9.3% fully missed and 3.5%/7.6% partially missed days.

Conclusions: This study demonstrated that in hemophilia with inhibitors, bleeding episodes interfere with the daily activities of patients and their caregivers. Furthermore, documenting only lost days underestimated the impact of bleeding episodes because of the high percentage of days without planned work or school.
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http://dx.doi.org/10.1016/j.jval.2014.07.003DOI Listing
September 2014