Publications by authors named "Matthew M Heeney"

75 Publications

Belzutifan, a Potent HIF2α Inhibitor, in the Pacak-Zhuang Syndrome.

N Engl J Med 2021 11;385(22):2059-2065

From the Departments of Pediatric Oncology (J.K., K.V.H., J.A.P., C.M.C., A.I., C.B.W., K.A.J., S.G.D.) and Medical Oncology (W.G.K.), Dana-Farber Cancer Institute, Harvard Medical School, the Divisions of Hematology and Oncology (J.K., J.A.P., M.M.H., K.A.J., S.G.D.) and Endocrinology (A.J.W.) and the Departments of Surgery (B.R.W.), Pathology (S.O.V.), and Radiology (S.D.V.), Boston Children's Hospital, Harvard Medical School, and the Manton Center for Orphan Disease Research and the Division of Genetics and Genomics, Boston Children's Hospital (J.A.M., J.L.) - all in Boston; Howard Hughes Medical Institute, Chevy Chase, MD (W.G.K.); and Merck, Kenilworth, NJ (R.F.P., N.J.Z.).

The integration of genomic testing into clinical care enables the use of individualized approaches to the management of rare diseases. We describe the use of belzutifan, a potent and selective small-molecule inhibitor of the protein hypoxia-inducible factor 2α (HIF2α), in a patient with polycythemia and multiple paragangliomas (the Pacak-Zhuang syndrome). The syndrome was caused in this patient by somatic mosaicism for an activating mutation in . Treatment with belzutifan led to a rapid and sustained tumor response along with resolution of hypertension, headaches, and long-standing polycythemia. This case shows the application of a targeted therapy for the treatment of a patient with a rare tumor-predisposition syndrome. (Funded by the Morin Family Fund for Pediatric Cancer and Alex's Lemonade Stand Foundation.).
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http://dx.doi.org/10.1056/NEJMoa2110051DOI Listing
November 2021

Prevalence and Predictors of Iron Deficiency in Adolescent and Young Adult Outpatients: Implications for Screening.

Clin Pediatr (Phila) 2021 Nov 19:99228211059647. Epub 2021 Nov 19.

Boston Children's Hospital, Boston, MA, USA.

Current screening guidelines may not be adequate to identify iron deficiency (ID) and iron deficiency anemia (IDA) in adolescent and young adults. Adolescent and young adult outpatients from 4 hospital-based clinics (N = 493) reported on diet, health, and bleeding, and had phlebotomy for iron and hematologic tests. We examined sex-specific factors associated with ID and IDA and ability of universal and risk factor-based screening using hemoglobin and hemoglobin plus ferritin to detect ID and IDA. Among females (n = 350), 34.6% had ID and 6.3% had IDA. Nearly 1 in 3 females with ID had no risk factors. Among males, 12.6% had ID; none had IDA. More than 1 in 3 males with ID did not have risk factors. Current screening approaches would have missed ID in 47% to 82% of females and 95% to 100% of males. ID was prevalent in both male and female adolescents and young adult outpatients. New approaches to screening for ID are needed to accurately evaluate iron status in this population.
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http://dx.doi.org/10.1177/00099228211059647DOI Listing
November 2021

SLC25A38 congenital sideroblastic anemia: Phenotypes and genotypes of 31 individuals from 24 families, including 11 novel mutations, and a review of the literature.

Hum Mutat 2021 Nov 5;42(11):1367-1383. Epub 2021 Aug 5.

Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, USA.

The congenital sideroblastic anemias (CSAs) are a heterogeneous group of inherited disorders of erythropoiesis characterized by pathologic deposits of iron in the mitochondria of developing erythroblasts. Mutations in the mitochondrial glycine carrier SLC25A38 cause the most common recessive form of CSA. Nonetheless, the disease is still rare, there being fewer than 70 reported families. Here we describe the clinical phenotype and genotypes of 31 individuals from 24 families, including 11 novel mutations. We also review the spectrum of reported mutations and genotypes associated with the disease, describe the unique localization of missense mutations in transmembrane domains and account for the presence of several alleles in different populations.
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http://dx.doi.org/10.1002/humu.24267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8511274PMC
November 2021

A systematic review of ketamine for the management of vaso-occlusive pain in sickle cell disease.

Pediatr Blood Cancer 2021 07 31;68(7):e28989. Epub 2021 Mar 31.

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

Vaso-occlusive episodes (VOEs) are a common complication of sickle cell disease (SCD) and a significant cause of morbidity. Managing VOE pain can be difficult and complex. Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, has been used to manage VOE pain. This systematic literature review synthesizes research published from 2010 to 2020 on the use of ketamine infusion to decrease VOE pain. The review demonstrates that ketamine, a safe and effective treatment for VOE pain, could be considered more widely. However, the significant variability among published clinical studies with regard to dosing, timing of initiation, duration of infusion, and timing of discontinuation highlights the need for standardized ketamine infusion protocols for the management of VOE pain. We conclude with a brief discussion of key components of a potential standardized protocol supported by the literature reviewed as well as areas for future investigation.
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http://dx.doi.org/10.1002/pbc.28989DOI Listing
July 2021

Post-Transcriptional Genetic Silencing of to Treat Sickle Cell Disease.

N Engl J Med 2021 01 5;384(3):205-215. Epub 2020 Dec 5.

From the Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Harvard Medical School (E.B.E., L.E.L., A.B., C.B., M.F.C., B.M., K.B., S.-Y.P., W.B.L., C.D., M.M.H., D.A.W.), the Harvard Stem Cell Institute, Harvard Medical School (A.B., C.B.), the Gene Therapy Program, Dana-Farber/Boston Children's Cancer and Blood Disorders Center (A.B., M.F.C., B.M., E.M., A.F., S.-Y.P., C.D., D.A.W.), the Division of Hematology, Brigham and Women's Hospital, Harvard Medical School (M. Achebe), the Connell and O'Reilly Families Cell Manipulation Core Facility, Dana-Farber Cancer Institute (H.D., R.K., K.S., H.N., S.N., J.R.), the TransLab, Boston Children's Hospital (D.A., M. Armant), and the Department of Laboratory Medicine, Boston Children's Hospital, Harvard Medical School (J.P.M.) - all in Boston; and Bluebird Bio, Cambridge, MA (O.N.).

Background: Sickle cell disease is characterized by hemolytic anemia, pain, and progressive organ damage. A high level of erythrocyte fetal hemoglobin (HbF) comprising α- and γ-globins may ameliorate these manifestations by mitigating sickle hemoglobin polymerization and erythrocyte sickling. is a repressor of γ-globin expression and HbF production in adult erythrocytes. Its down-regulation is a promising therapeutic strategy for induction of HbF.

Methods: We enrolled patients with sickle cell disease in a single-center, open-label pilot study. The investigational therapy involved infusion of autologous CD34+ cells transduced with the BCH-BB694 lentiviral vector, which encodes a short hairpin RNA (shRNA) targeting mRNA embedded in a microRNA (shmiR), allowing erythroid lineage-specific knockdown. Patients were assessed for primary end points of engraftment and safety and for hematologic and clinical responses to treatment.

Results: As of October 2020, six patients had been followed for at least 6 months after receiving BCH-BB694 gene therapy; median follow-up was 18 months (range, 7 to 29). All patients had engraftment, and adverse events were consistent with effects of the preparative chemotherapy. All the patients who could be fully evaluated achieved robust and stable HbF induction (percentage HbF/(F+S) at most recent follow-up, 20.4 to 41.3%), with HbF broadly distributed in red cells (F-cells 58.9 to 93.6% of untransfused red cells) and HbF per F-cell of 9.0 to 18.6 pg per cell. Clinical manifestations of sickle cell disease were reduced or absent during the follow-up period.

Conclusions: This study validates BCL11A inhibition as an effective target for HbF induction and provides preliminary evidence that shmiR-based gene knockdown offers a favorable risk-benefit profile in sickle cell disease. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT03282656).
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http://dx.doi.org/10.1056/NEJMoa2029392DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7962145PMC
January 2021

Hydroxyurea Optimization through Precision Study (HOPS): study protocol for a randomized, multicenter trial in children with sickle cell anemia.

Trials 2020 Nov 27;21(1):983. Epub 2020 Nov 27.

University of Cincinnati College of Medicine, Cincinnati, OH, USA.

Background: Sickle cell disease (SCD) is a severe and devastating hematological disorder that affects over 100,000 persons in the USA and millions worldwide. Hydroxyurea is the primary disease-modifying therapy for the SCD, with proven benefits to reduce both short-term and long-term complications. Despite the well-described inter-patient variability in pharmacokinetics (PK), pharmacodynamics, and optimal dose, hydroxyurea is traditionally initiated at a weight-based dose with a subsequent conservative dose escalation strategy to avoid myelosuppression. Because the dose escalation process is time consuming and requires frequent laboratory checks, many providers default to a fixed dose, resulting in inadequate hydroxyurea exposure and suboptimal benefits for many patients. Results from a single-center trial of individualized, PK-guided dosing of hydroxyurea for children with SCD suggest that individualized dosing achieves the optimal dose more rapidly and provides superior clinical and laboratory benefits than traditional dosing strategies. However, it is not clear whether these results were due to individualized dosing, the young age that hydroxyurea treatment was initiated in the study, or both. The Hydroxyurea Optimization through Precision Study (HOPS) aims to validate the feasibility and benefits of this PK-guided dosing approach in a multi-center trial.

Methods: HOPS is a randomized, multicenter trial comparing standard vs. PK-guided dosing for children with SCD as they initiate hydroxyurea therapy. Participants (ages 6 months through 21 years), recruited from 11 pediatric sickle cell centers across the USA, are randomized to receive hydroxyurea either using a starting dose of 20 mg/kg/day (Standard Arm) or a PK-guided dose (Alternative Arm). PK data will be collected using a novel sparse microsampling approach requiring only 10 μL of blood collected at 3 time-points over 3 h. A protocol-guided strategy more aggressive protocols is then used to guide dose escalations and reductions in both arms following initiation of hydroxyurea. The primary endpoint is the mean %HbF after 6 months of hydroxyurea.

Discussion: HOPS will answer important questions about the clinical feasibility, benefits, and safety of PK-guided dosing of hydroxyurea for children with SCD with potential to change the treatment paradigm from a standard weight-based approach to one that safely and effectively optimize the laboratory and clinical response.

Trial Registration: ClinicalTrials.gov NCT03789591 . Registered on 28 December 2018.
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http://dx.doi.org/10.1186/s13063-020-04912-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7691962PMC
November 2020

Biochemical and therapeutic effects of Omega-3 fatty acids in sickle cell disease.

Complement Ther Med 2020 Aug 9;52:102482. Epub 2020 Jun 9.

Dana-Farber / Boston Children's Cancer and Blood Disorders Center, Harvard Medical School, Boston, MA, United States. Electronic address:

Sickle cell disease (SCD) is a hematologic disorder with complex pathophysiology that includes chronic hemolysis, vaso-occlusion and inflammation. Increased leukocyte-erythrocyte-endothelial interactions, due to upregulated expression of adhesion molecules and activated endothelium, are thought to play a primary role in initiation and progression of SCD vaso-occlusive crisis and end-organ damage. Several new pathophysiology-based therapeutic options for SCD are being developed, chiefly targeting the inflammatory pathways. Omega-3 fatty acids are polyunsaturated fatty acids that are known to have effects on diverse physiological processes. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are the principal biologically active omega-3 fatty acids. The therapeutic effects of DHA and EPA on chronic inflammatory disorders and cardiovascular diseases are well recognized. The therapeutic effects of omega-3 fatty acids are attributed to their anti-inflammatory and anti-thrombotic eicosanoids, and the novel class of EPA and DHA derived lipid mediators: resolvins, protectins and maresins. Blood cell membranes of patients with SCD have abnormal fatty acids composition characterized by high ratio of pro-inflammatory arachidonic acid (AA) to anti-inflammatory DHA and EPA (high omega-6/omega-3 ratio). In addition, experimental and clinical studies provide evidence that treatment with DHA does confer improvement in rheological properties of sickle RBC, inflammation and hemolysis. The clinical studies have shown improvements in VOC rate, markers of inflammation, adhesion, and hemolysis. In toto, the results of studies on the therapeutic effects of omega-3 fatty acids in SCD provide good body of evidence that omega-3 fatty acids could be a safe and effective treatment for SCD.
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http://dx.doi.org/10.1016/j.ctim.2020.102482DOI Listing
August 2020

Mutations in the iron-sulfur cluster biogenesis protein HSCB cause congenital sideroblastic anemia.

J Clin Invest 2020 10;130(10):5245-5256

Department of Pathology, Boston Children's Hospital, Boston, Massachusetts, USA.

The congenital sideroblastic anemias (CSAs) can be caused by primary defects in mitochondrial iron-sulfur (Fe-S) cluster biogenesis. HSCB (heat shock cognate B), which encodes a mitochondrial cochaperone, also known as HSC20 (heat shock cognate protein 20), is the partner of mitochondrial heat shock protein A9 (HSPA9). Together with glutaredoxin 5 (GLRX5), HSCB and HSPA9 facilitate the transfer of nascent 2-iron, 2-sulfur clusters to recipient mitochondrial proteins. Mutations in both HSPA9 and GLRX5 have previously been associated with CSA. Therefore, we hypothesized that mutations in HSCB could also cause CSA. We screened patients with genetically undefined CSA and identified a frameshift mutation and a rare promoter variant in HSCB in a female patient with non-syndromic CSA. We found that HSCB expression was decreased in patient-derived fibroblasts and K562 erythroleukemia cells engineered to have the patient-specific promoter variant. Furthermore, gene knockdown and deletion experiments performed in K562 cells, zebrafish, and mice demonstrate that loss of HSCB results in impaired Fe-S cluster biogenesis, a defect in RBC hemoglobinization, and the development of siderocytes and more broadly perturbs hematopoiesis in vivo. These results further affirm the involvement of Fe-S cluster biogenesis in erythropoiesis and hematopoiesis and define HSCB as a CSA gene.
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http://dx.doi.org/10.1172/JCI135479DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524500PMC
October 2020

An emerging role for endothelial barrier support therapy for congenital disorders of glycosylation.

J Inherit Metab Dis 2020 07 27;43(4):880-890. Epub 2020 Feb 27.

Division of Genetics and Genomics, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts.

Congenital disorders of glycosylation (CDGs) are clinically heterogeneous disorders defined by a decreased ability to modify biomolecules with oligosaccharides. Critical disruptions in protein recognition, interaction, binding, and anchoring lead to broad physiological effects. Patients present with endocrinopathy, immunodeficiency, hepatopathy, coagulopathy, and neurodevelopmental impairment. Patients may experience mortality/morbidity associated with shock physiology that is frequently culture negative and poorly responsive to standard care. Oedema, pleural and pericardial effusions, ascites, proteinuria, and protein-losing enteropathy are observed with an exaggerated inflammatory response. The negative serum protein steady state results from several mechanisms including reduced hepatic synthesis and secretion, increased consumption, and extravasation. Disruption of the glycocalyx, a layer of glycosylated proteins that lines the endothelium preventing thrombosis and extravasation, is a suspected cause of endothelial dysfunction in CDG patients. We performed a retrospective review of CDG patients admitted to our institution with acute illness over the past 2 years. Longitudinal clinical and laboratory data collected during the sick and well states were assessed for biomarkers of inflammation and efficacy of interventions. Six patients representing 4 CDG subtypes and 14 hospitalisations were identified. Acute D-dimer elevation, proteinuria, decreased serum total protein levels, coagulation proteins, and albumin were observed with acute illness. Infusion of fresh frozen plasma, and in some cases protein C concentrate, was associated with clinical and biomarker improvement. This was notable with intra-patient comparison of treated vs untreated courses. Use of endothelial barrier support therapy may reduce endothelial permeability by restoring both regulatory serum protein homeostasis and supporting the glycocalyx and is likely a critical component of care for this population.
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http://dx.doi.org/10.1002/jimd.12225DOI Listing
July 2020

Geographic Differences in Phenotype and Treatment of Children with Sickle Cell Anemia from the Multinational DOVE Study.

J Clin Med 2019 Nov 17;8(11). Epub 2019 Nov 17.

Department of Pediatrics and Adolescent Medicine, American University of Beirut, Beirut 11-0236, Lebanon.

Background: DOVE (Determining Effects of Platelet Inhibition on Vaso-Occlusive Events) was a Phase 3, randomized, double-blind, placebo-controlled study conducted in children with sickle cell anemia at 51 sites in 13 countries across four continents.

Procedure: Data from DOVE were assessed for regional differences in subject phenotype and treatment. Demographics, baseline clinical and laboratory data, hydroxyurea (HU) use, vaso-occlusive crisis (VOCs; composite endpoint of painful crisis or acute chest syndrome (ACS, Beijing, China)), serious adverse events (SAEs, Florence, Italy), hospitalization, and treatments were compared across the Americas, Europe, North Africa/Middle East, and Sub-Saharan Africa (SSA).

Results: Race, body mass index, and blood pressures differed by region. Pre-enrollment VOCs were highest in the Americas. For subjects not on HU, baseline hemoglobin was lowest in SSA; reticulocyte count was lowest in the Americas. Within SSA, Kenya subjects presented higher baseline hemolysis. Painful crisis was the most common SAE, followed by ACS in the Americas and infections in other regions. VOC rate and percentage of VOC hospitalizations were highest in Europe. Regardless of region, most VOCs were treated with analgesics; approximately half were treated with intravenous fluids. The proportion of VOC-related transfusions was greatest in Europe. Lengths of hospital stay were similar across regions.

Conclusions: Overall differences in SAEs and hospitalization for VOCs may be due to cultural diversities, resource utilization, disease severity, or a combination of factors. These data are of importance for the planning of future trials in SCA in a multinational setting.
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http://dx.doi.org/10.3390/jcm8112009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6912763PMC
November 2019

Ticagrelor versus placebo for the reduction of vaso-occlusive crises in pediatric sickle cell disease: Rationale and design of a randomized, double-blind, parallel-group, multicenter phase 3 study (HESTIA3).

Contemp Clin Trials 2019 10 22;85:105835. Epub 2019 Aug 22.

BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Pepparedsleden 1, Mölndal 431 83, Sweden. Electronic address:

Background: An unmet need for therapies exists to reduce sickle cell disease (SCD) complications in pediatric patients. Activated platelets contribute to the formation of cellular aggregates during sickling and vaso-occlusive crises (VOCs). Ticagrelor is an oral, direct-acting, and reversible adenosine diphosphate P2Y receptor antagonist that inhibits platelet activation and aggregation. Although ticagrelor was well tolerated in two phase 2 studies in children and young adults with SCD, larger and longer-term treatment studies are needed to assess ticagrelor's efficacy to reduce VOCs. HESTIA3 will evaluate the efficacy, safety, and tolerability of ticagrelor versus placebo over a minimum of 1 year (maximum 2 years) in pediatric patients with SCD.

Methods: Approximately 180 patients (aged ≥ 2 to <18 years) with SCD (≥ 2 VOCs in the prior year) from 18 countries will be randomized 1:1 to ticagrelor or placebo. Primary endpoint: number of VOCs (a composite endpoint of painful crises and/or acute chest syndrome); key secondary endpoints: hospitalizations, pain intensity and analgesic use during VOCs, acceptability of formulation, and health-related quality of life. The weight-based doses of ticagrelor are set by modeling and simulation. Platelet inhibition data, measured by the vasodilator-stimulated phosphoprotein assay, will be collected for exploratory purposes.

Conclusions: HESTIA3 aims to demonstrate that using greater target platelet inhibition than previous studies on SCD, ticagrelor will decrease the frequency of VOC in pediatric patients. Trial Identifier: NCT03615924; EudraCT2017-002421-38.
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http://dx.doi.org/10.1016/j.cct.2019.105835DOI Listing
October 2019

Clinical and laboratory outcomes following total or partial splenectomy in patients with hereditary spherocytosis.

Pediatr Hematol Oncol 2019 Sep 26;36(6):382-389. Epub 2019 Jul 26.

Harvard Medical School , Boston , Massachusetts , USA.

This study compared outcomes following total (TS) or partial splenectomy (PS) among patients with hereditary spherocytosis. Seventy-nine patients (TS = 33, PS = 46) were identified. The follow-up period was longer after PS (59.6 vs. 24.9 months,  < .001). Long-term adverse events occurred more frequently following PS (50% vs. 29%,  = .001). Anemia, jaundice, and fatigue recurred in six patients with PS, leading to five completion splenectomies. Hemoglobin was not different between PS and TS by 5 years post-procedure (12.3 vs. 13.4 g/dL,  = .25). Both PS and TS ameliorate symptoms and improve hematologic parameters. The rate of secondary surgery following PS should be considered when planning the initial surgical procedure.
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http://dx.doi.org/10.1080/08880018.2019.1637983DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6752974PMC
September 2019

Patient- and Nurse-Controlled Analgesia: 22-Year Experience in a Pediatric Hospital.

Hosp Pediatr 2019 02 17;9(2):129-133. Epub 2019 Jan 17.

Departments of Anesthesiology, Critical Care, Pain Medicine,

Objectives: Pediatric pain management has rapidly changed over the last 2 decades. In this study, we describe the changing practices and adverse events (AEs) related to patient-controlled analgesia (PCA) and/or nurse-controlled analgesia (NCA) over a 22-year period.

Methods: After institutional review board approval, retrospective data from a single tertiary-care pediatric hospital were collected between 1994 and 2016. Subgroup analyses were done for surgical and medical case patients. We reported the number of times that PCA and/or NCA was ordered annually, the median and interquartile ranges for age, PCA and/or NCA duration and length of stay, and AE frequencies.

Results: Over 22 years, 32 338 PCAs and/or NCAs were ordered in this institution. Morphine and hydromorphone were used most commonly. Between 1994 and 2006, initial orders for PCA and/or NCA increased 2.5-fold. After 2007, initial orders for PCA and/or NCA rapidly decreased; after 2013, the decrease continued at a slower rate, with a total of 1007 orders in 2016. This decrease occurred despite increased hospital admissions and surgeries. Between 2007 and 2012, peripheral nerve blocks rapidly increased (10-fold). After 2002, 146 AEs were reported (1.0%). Of those, 50.5% were nonintercepted, and 20.6% were intercepted AEs; 5.5% and 6.2% were preventable and nonpreventable AEs, respectively.

Conclusions: PCA and/or NCA usage continues to be common in pediatric patients, although usage has declined and stabilized in the setting of other emerging methods of analgesia and increases in the number of minimally invasive surgical procedures. The overall rate of AEs was extremely low. However, improvements to eliminate all errors are needed, especially with medications with a great risk of harm (such as opioids).
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http://dx.doi.org/10.1542/hpeds.2018-0179DOI Listing
February 2019

Successful hematopoietic stem cell mobilization and apheresis collection using plerixafor alone in sickle cell patients.

Blood Adv 2018 10;2(19):2505-2512

Division of Hematology/Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA.

Novel therapies for sickle cell disease (SCD) based on genetically engineered autologous hematopoietic stem and progenitor cells (HSPCs) are critically dependent on a safe and effective strategy for cell procurement. We sought to assess the safety and efficacy of plerixafor when used in transfused patients with SCD for HSC mobilization. Six adult patients with SCD were recruited to receive a single dose of plerixafor, tested at lower than standard (180 µg/kg) and standard (240 µg/kg) doses, followed by CD34 cell monitoring in peripheral blood and apheresis collection. The procedures were safe and well-tolerated. Mobilization was successful, with higher peripheral CD34 cell counts in the standard vs the low-dose group. Among our 6 donors, we improved apheresis cell collection results by using a deep collection interface and starting apheresis within 4 hours after plerixafor administration. In the subjects who received a single standard dose of plerixafor and followed the optimized collection protocol, yields of up to 24.5 × 10 CD34 cells/kg were achieved. Interestingly, the collected CD34 cells were enriched in immunophenotypically defined long-term HSCs and early progenitors. Thus, we demonstrate that plerixafor can be employed safely in patients with SCD to obtain sufficient HSCs for potential use in gene therapy.
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http://dx.doi.org/10.1182/bloodadvances.2018016725DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6177648PMC
October 2018

Bronchodilator Use for Acute Chest Syndrome Among Large Pediatric Hospitals in North America.

Clin Pediatr (Phila) 2018 12 3;57(14):1630-1637. Epub 2018 Sep 3.

3 Boston Children's Hospital, Boston, MA, USA.

The utility of bronchodilators to treat acute chest syndrome (ACS) in patients with sickle cell disease is unknown. Our objectives were to examine the variability in bronchodilator use for ACS among pediatric hospitals contributing to a large database and to examine the relationship between bronchodilator use and length of stay (LOS) and mortality. Between 2005 and 2011, bronchodilators were used during 6812/11 328 hospitalizations (60.1%) and use varied from 0.0% to 97.0% (median = 46.0%, interquartile range = 37.0% to 74.0%). Median LOS was 4 days, and interquartile range was 2 to 6 days. Bronchodilator use was associated with a 13.2% increase in LOS (95% confidence interval = 9.2% to 17.3%, P < .001). However, in the subgroup with asthma, bronchodilator use was associated with a 17.9% decrease in LOS (95% confidence interval = 1.7% to 31.4%, P = .03). There is wide variability in bronchodilator use for ACS, and it has variable association with LOS, depending on comorbid asthma. Prospective trials are needed to evaluate bronchodilators for ACS.
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http://dx.doi.org/10.1177/0009922818796661DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6505689PMC
December 2018

Double-blind, randomized, multicenter phase 2 study of SC411 in children with sickle cell disease (SCOT trial).

Blood Adv 2018 08;2(15):1969-1979

Division of Hematology/Oncology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA.

Blood cell membranes in sickle cell disease (SCD) have low docosahexaenoic acid (DHA). DHA treatment reduces sickle cell crisis (SCC) rate and ameliorates the inflammation, oxidative stress, and hypercoagulable state of SCD. SC411 is a novel DHA ethyl ester formulation with a proprietary delivery platform (Advanced Lipid Technology) that enhances DHA bioavailability. The SCOT trial investigated the effect of 3 different doses of SC411 on clinical and biochemical endpoints in 67 children with SCD (5-17 years old). Seventy-six percent of subjects were also receiving hydroxyurea. After 4 weeks of treatment with SC411 at 20, 36, and 60 mg DHA/kg per day or placebo a statistically significant ( < .001) mean percentage increase of blood cell membrane DHA and eicosapentaenoic acid was seen vs baseline: 109.0% (confidence interval [CI], 46.7-171.3), 163.8% (CI, 108.3-219.2), 170.8% (CI, 90.2-251.4), and 28.6% (CI, 250.1 to 107.3), respectively. After 8 weeks of treatment, statistically significant changes vs placebo were also observed in D-dimer ( = .025) and soluble E-selectin ( = .0219) in subjects exposed to 36 mg/kg. A significant increase in hemoglobin was observed against placebo in subjects receiving 20 mg DHA/kg per day ( = .039). SC411 significantly reduced electronic diary recorded SCC, analgesic use at home, and days absent from school because of sickle cell pain. The lower rate of clinical SCC observed in the pooled active groups vs placebo did not reach statistical significance (rate ratio, 0.47; 95% CI, 0.20-1.11; = .07). All tested doses were safe and well tolerated. This trial was registered at www.clinicaltrials.gov as #NCT02973360.
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http://dx.doi.org/10.1182/bloodadvances.2018021444DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6093734PMC
August 2018

The phenotypic spectrum of germline variants: from isolated sideroblastic anemia to mitochondrial myopathy, lactic acidosis and sideroblastic anemia 2.

Haematologica 2018 12 19;103(12):2008-2015. Epub 2018 Jul 19.

Dana Farber-Boston Children's Center for Cancer and Blood Disorders, Boston, MA, USA.

variants have previously been described in patients with myopathy, lactic acidosis and sideroblastic anemia 2 (MLASA2). encodes the mitochondrial tyrosyl-tRNA synthetase, which is responsible for conjugating tyrosine to its cognate mt-tRNA for mitochondrial protein synthesis. Here we describe 14 individuals from 11 families presenting with sideroblastic anemia and variants that we identified using a sideroblastic anemia gene panel or exome sequencing. The phenotype of these patients ranged from MLASA to isolated congenital sideroblastic anemia. As in previous cases, inter- and intra-familial phenotypic variability was observed, however, this report includes the first cases with isolated sideroblastic anemia and patients with biallelic variants that have no clinically ascertainable phenotype. We identified ten novel variants and three previously reported variants. amino-acylation assays of five novel missense variants showed that three had less effect on the catalytic activity of YARS2 than the most commonly reported variant, p.(Phe52Leu), associated with MLASA2, which may explain the milder phenotypes in patients with these variants. However, the other two missense variants had a more severe effect on YARS2 catalytic efficiency. Several patients carried the common c.572 G>T, p.(Gly191Val) variant (minor allele frequency =0.1259) in with a rare deleterious variant. We have previously shown that the p.(Gly191Val) variant reduces YARS2 catalytic activity. Consequently, we suggest that biallelic variants, including severe loss-of-function alleles in of the common p.(Gly191Val) variant, should be considered as a cause of isolated congenital sideroblastic anemia, as well as the MLASA syndromic phenotype.
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http://dx.doi.org/10.3324/haematol.2017.182659DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6269294PMC
December 2018

A Scientific Renaissance: Novel Drugs in Sickle Cell Disease.

Pediatr Clin North Am 2018 06;65(3):445-464

Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.

We have entered an era of exploding interest in therapeutics for sickle cell disease. The expansion in our understanding of sickle cell disease pathophysiology has enhanced the range of potential therapeutic targets. From induction of fetal hemoglobin to antiadhesion molecules, we are potentially on the cusp of making life-altering modifications for individuals with sickle cell disease. This disease population cannot afford to let the current momentum wane. Studies exploring combinations of therapies affecting multiple steps in the pathophysiology and exploring novel and clinically relevant outcomes are incumbent.
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http://dx.doi.org/10.1016/j.pcl.2018.01.006DOI Listing
June 2018

The effect of iron chelation therapy on overall survival in sickle cell disease and β-thalassemia: A systematic review.

Am J Hematol 2018 07 28;93(7):943-952. Epub 2018 Apr 28.

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

Red blood cell transfusions have become standard of care for the prevention of life-threatening anemia in patients with β-thalassemia and sickle cell disease (SCD). However, frequent transfusions can lead to accumulation of iron that can result in liver cirrhosis, diabetes mellitus, arthritis, arrhythmias, cardiomyopathy, heart failure, and hypogonadotropic hypogonadism. Iron chelation therapy has been shown to reduce serum ferritin levels and liver iron content, but limitations of trial design have prevented any demonstration of improved survival. The objective of this systematic review was to investigate the impact of iron chelation therapy on overall and event-free survival in patients with β-thalassemia and SCD. Eighteen articles discussing survival in β-thalassemia and 3 in SCD were identified. Overall iron chelation therapy resulted in better overall survival, especially if it is instituted early and compliance is maintained. Comparative studies did not show any significant differences between available iron chelation agents, although there is evidence that deferiprone is better tolerated than deferoxamine and that compliance is more readily maintained with the newer oral drugs, deferiprone and deferasirox. Iron chelation therapy, particularly the second-generation oral agents, appears to be associated with improved overall and event-free survival in transfusion-dependent patients with β-thalassemia and patients with SCD.
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http://dx.doi.org/10.1002/ajh.25103DOI Listing
July 2018

Randomized phase 2 trial of regadenoson for treatment of acute vaso-occlusive crises in sickle cell disease.

Blood Adv 2017 Sep 28;1(20):1645-1649. Epub 2017 Aug 28.

Department of Pediatrics, Boston Children's Hospital, Boston, MA.

Adenosine A receptor (AR) agonists have been shown to decrease tissue inflammation induced by hypoxia/reoxygenation in mice with sickle cell disease (SCD). The key mediator of the AR agonist's anti-inflammatory effects is a minor lymphocyte subset, invariant natural killer T (iNKT) cells. We tested the hypothesis that administration of an AR agonist in patients with SCD would decrease iNKT cell activation and dampen the severity of vaso-occlusive (VO) crises. In a phase 2, randomized, placebo-controlled trial, we administered a 48-hour infusion of the AR agonist regadenoson (1.44 μg/kg per hour) to patients with SCD during VO crises to produce a plasma concentration of ∼5 nM, a concentration known from prior studies to suppress iNKT cell activation in SCD. The primary outcome measure was a >30% reduction in the percentage of activated iNKT cells. Ninety-two patients with SCD were randomized to receive a 48-hour infusion of regadenoson or placebo, in addition to standard-of-care treatment, during hospital admission for a VO crisis and had analyzable iNKT cell samples. The proportion of subjects who demonstrated a reduction of >30% in activated iNKT cells was not significantly different between the regadenoson and placebo arms (43% vs 23%; = .07). There were also no differences between regadenoson and placebo groups in length of hospital stay, mean total opioid use, or pain scores. These data demonstrate that a low-dose infusion of regadenoson intended to reduce the activity of iNKT cells is not sufficient to produce a statistically significant reduction in such activation or in measures of clinical efficacy. This trial was registered at www.clinicaltrials.gov as #NCT01788631.
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http://dx.doi.org/10.1182/bloodadvances.2017009613DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5728341PMC
September 2017

Alu element insertion in PKLR gene as a novel cause of pyruvate kinase deficiency in Middle Eastern patients.

Hum Mutat 2018 03 11;39(3):389-393. Epub 2018 Jan 11.

Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio.

Pyruvate kinase deficiency (PKD) is the most frequent red blood cell enzyme abnormality of the glycolytic pathway and the most common cause of hereditary nonspherocytic hemolytic anemia. Over 250 PKLR-gene mutations have been described, including missense/nonsense, splicing and regulatory mutations, small insertions, small and gross deletions, causing PKD and hemolytic anemia of variable severity. Alu retrotransposons are the most abundant mobile DNA sequences in the human genome, contributing to almost 11% of its mass. Alu insertions have been associated with a number of human diseases either by disrupting a coding region or a splice signal. Here, we report on two unrelated Middle Eastern patients, both born from consanguineous parents, with transfusion-dependent hemolytic anemia, where sequence analysis revealed a homozygous insertion of AluYb9 within exon 6 of the PKLR gene, causing precipitous decrease of PKLR RNA levels. This Alu element insertion consists a previously unrecognized mechanism underlying pathogenesis of PKD.
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http://dx.doi.org/10.1002/humu.23392DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5805577PMC
March 2018

Successful utilization of an electronic pain diary in a multinational phase 3 interventional study of pediatric sickle cell anemia.

Clin Trials 2017 Dec 26;14(6):563-571. Epub 2017 Jul 26.

8 Emory University School of Medicine and AFLAC Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Atlanta, GA, USA.

Background/aims: Patients with sickle cell anemia can experience recurrent pain episodes, which affect quality of life. The reported prevalence of pain is higher in studies using patient diaries than in healthcare facility utilization data. Determining Effects of Platelet Inhibition on Vaso-Occlusive Events was a multinational study that assessed the efficacy and safety of prasugrel in reducing the rate of vaso-occlusive events in children with sickle cell anemia (NCT01794000) and included an electronic patient-reported outcome diary to record pain occurrence. We aimed to capture diary completion rates and compliance in children who used the electronic patient-reported outcome diary during the Determining Effects of Platelet Inhibition on Vaso-Occlusive Events study and examine factors contributing to diary completion rates and compliance.

Methods: Daily electronic patient-reported outcome diary data were collected for up to 9 months in Determining Effects of Platelet Inhibition on Vaso-Occlusive Events participants aged 4 to <18 years in Africa, the Americas, Europe, and the Middle East. The questionnaires were available in 11 languages/dialects for collecting subjective (pain intensity, activity interference) and objective (study drug use, analgesic use, school attendance) data. Pain intensity was measured using the Faces Pain Scale-Revised. Data were entered by participants or caregivers and transferred wirelessly each day to a central database. Diary completion rates were the number of daily diary entries divided by the total number of expected daily diary entries. Percentages of participants who were compliant with the diary (≥80% diary completion) were calculated.

Results: A total of 311 participants received a diary; 268 provided diary data through Month 9. Diary completion rates and compliance were high throughout the collection period and across all groups and regions, despite no games being included on the device. For subjective data, the overall completion rate was 94.4%, and 92.6% of participants were compliant. For objective data, the overall completion rate was 93.3%, and 89.7% of participants were compliant. Completion rates and compliance differed significantly by age and region and were higher for 4 to <12 year olds and very much higher for participants from Africa and the Middle East. Caregivers almost always entered data for participants <6 years and rarely entered data for participants ≥12 years. Comparing participant-entered and caregiver-entered data, pain intensity score data were more consistent for 4 to <12 year olds than older children, but pain intensity scores for older children were higher when entered by caregivers.

Conclusion: With appropriate design, participant training, and sufficient monitoring, an electronic patient-reported outcome diary can capture daily sickle cell-related pain data in large multinational studies. Providing a mechanism for caregiver reporting is particularly valuable for participants <6 years and may also facilitate compliance in older children who experience high levels of pain.
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http://dx.doi.org/10.1177/1740774517723307DOI Listing
December 2017

Neonatal anemia: Revisiting the enigmatic pyknocyte.

Am J Hematol 2017 Jul 26;92(7):717-721. Epub 2017 May 26.

Department of Pediatrics, Section of Hematology/Oncology/Stem Cell Transplantation, University of Chicago, Comer Children's Hospital, Chicago, Illinois, USA.

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http://dx.doi.org/10.1002/ajh.24731DOI Listing
July 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

Lineage-specific BCL11A knockdown circumvents toxicities and reverses sickle phenotype.

J Clin Invest 2016 10 6;126(10):3868-3878. Epub 2016 Sep 6.

Reducing expression of the fetal hemoglobin (HbF) repressor BCL11A leads to a simultaneous increase in γ-globin expression and reduction in β-globin expression. Thus, there is interest in targeting BCL11A as a treatment for β-hemoglobinopathies, including sickle cell disease (SCD) and β-thalassemia. Here, we found that using optimized shRNAs embedded within an miRNA (shRNAmiR) architecture to achieve ubiquitous knockdown of BCL11A profoundly impaired long-term engraftment of both human and mouse hematopoietic stem cells (HSCs) despite a reduction in nonspecific cellular toxicities. BCL11A knockdown was associated with a substantial increase in S/G2-phase human HSCs after engraftment into immunodeficient (NSG) mice, a phenotype that is associated with HSC exhaustion. Lineage-specific, shRNAmiR-mediated suppression of BCL11A in erythroid cells led to stable long-term engraftment of gene-modified cells. Transduced primary normal or SCD human HSCs expressing the lineage-specific BCL11A shRNAmiR gave rise to erythroid cells with up to 90% reduction of BCL11A protein. These erythrocytes demonstrated 60%-70% γ-chain expression (vs. < 10% for negative control) and a corresponding increase in HbF. Transplantation of gene-modified murine HSCs from Berkeley sickle cell mice led to a substantial improvement of sickle-associated hemolytic anemia and reticulocytosis, key pathophysiological biomarkers of SCD. These data form the basis for a clinical trial application for treating sickle cell disease.
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http://dx.doi.org/10.1172/JCI87885DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5096824PMC
October 2016

A recurring mutation in the respiratory complex 1 protein NDUFB11 is responsible for a novel form of X-linked sideroblastic anemia.

Blood 2016 10 3;128(15):1913-1917. Epub 2016 Aug 3.

Department of Pathology and.

The congenital sideroblastic anemias (CSAs) are a heterogeneous group of inherited blood disorders characterized by pathological mitochondrial iron deposition in erythroid precursors. Each known cause has been attributed to a mutation in a protein associated with heme biosynthesis, iron-sulfur cluster biogenesis, mitochondrial translation, or a component of the mitochondrial respiratory chain. Here, we describe a recurring mutation, c.276_278del, p.F93del, in NDUFB11, a mitochondrial respiratory complex I-associated protein encoded on the X chromosome, in 5 males with a variably syndromic, normocytic CSA. The p.F93del mutation results in respiratory insufficiency and loss of complex I stability and activity in patient-derived fibroblasts. Targeted introduction of this allele into K562 erythroleukemia cells results in a proliferation defect with minimal effect on erythroid differentiation potential, suggesting the mechanism of anemia in this disorder.
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http://dx.doi.org/10.1182/blood-2016-05-719062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5064715PMC
October 2016

Newborn Screening for Sickle Cell Disease in Liberia: A Pilot Study.

Pediatr Blood Cancer 2016 Apr 6;63(4):671-6. Epub 2016 Jan 6.

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

Background: In malaria-endemic countries in West Africa, sickle cell disease (SCD) contributes to childhood mortality. Historically, Liberia had regions wherein hemoglobin S and beta-thalassemia trait were mutually exclusive. Data on hemoglobinopathies in the Monrovia, the capital, are outdated and do not reflect urban migration. Updating the epidemiology of SCD is necessary to plan a public health and clinical agenda. Neither newborn screening (NBS) nor screening tools were available in country. This pilot study aimed to determine the feasibility of NBS using a South-South partnership and define the incidence of sickle cell trait (SCT) and SCD in Monrovia.

Procedure: This descriptive epidemiologic feasibility study collected dried blood spots from 2,785 consecutive newborns delivered at a hospital in Monrovia. Samples were analyzed by isoelectric focusing at a regional reference laboratory. Infants with SCD were referred for preventive care.

Results: SCT occurred in 10.31% of infants screened. SCD occurred in 33 infants screened [1.19% (95% confidence interval [CI]: 0.79-1.59%)] (FS: 28/33, FSB: 2/33, FSA: 2/33, FSX: 1/33). There were no infants with FSC phenotype observed. Nonsickling hemoglobin phenotypes "FC" and "F" were each present in three infants screened. Seventy-six percent of infants with SCD were brought to care, demonstrating the feasibility of our approach.

Conclusions: The incidence of SCD and other hemoglobinopathies remains high in Liberia. Additional studies are needed to clarify sickle genotypes and identify the contribution of silent beta-thalassemia alleles. By developing regional partnerships, countries similar to Liberia can acquire current data to inform NBS as an important public health initiative toward improving child health.
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http://dx.doi.org/10.1002/pbc.25875DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4755789PMC
April 2016
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