Neurocognitive outcome in children with sickle cell disease after myeloimmunoablative conditioning and haploidentical hematopoietic stem cell transplantation: a non-randomized clinical trial.

Background: Due to the risk of cerebral vascular injury, children and adolescents with high-risk sickle cell disease (SCD) experience neurocognitive decline over time. Haploidentical stem cell transplantation (HISCT) from human leukocyte antigen-matched sibling donors may slow or stop progression of neurocognitive changes. Objectives: The study is to determine if HISCT can ameliorate SCD-associated neurocognitive changes and prevent neurocognitive progression, determine which specific areas of neurocognitive functioning are particularly vulnerable to SCD, and determine if there are age-related differences in neurocognitive functioning over time. Methods: We performed neurocognitive and neuroimaging in SCD recipients following HISCT. Children and adolescents with high-risk SCD who received parental HISCT utilizing CD34+ enrichment and mononuclear cell (T-cell) addback following myeloimmunoablative conditioning received cognitive evaluations and neuroimaging at three time points: pre-transplant, 1 and 2 years post-transplant. Results: Nineteen participants (13.1 ± 1.2 years [3.3-20.0]) received HISCT. At 2 years post-transplant, neuroimaging and cognitive function were stable. Regarding age-related differences pre-transplantation, older children (≥13 years) had already experienced significant decreases in language functioning (p < 0.023), verbal intelligence quotient (p < 0.05), non-verbal intelligence quotient (p < 0.006), and processing speed (p < 0.05), but normalized post-HISCT in all categories. Conclusion: Thus, HISCT has the potential to ameliorate SCD-associated neurocognitive changes and prevent neurocognitive progression. Further studies are required to determine if neurocognitive performance remains stable beyond 2 years post-HISCT.Clinical trial registration: The study was conducted under an investigator IND (14359) (MSC) and registered at clinicaltrials.gov (NCT01461837).

COVID-19 Infection and Outcomes in Newborn Screening Cohorts of Sickle Cell Trait and Sickle Cell Disease in Michigan and Georgia.

The sickle cell mutation increases morbidity in those with sickle cell disease (SCD) and potentially sickle cell trait, impacting pulmonary, coagulation, renal, and other systems that are implicated in COVID-19 severity. There are no population-based registries for hemoglobinopathies, and they are not tracked in COVID-19 testing. We used COVID-19 test data from 2 states linked to newborn screening data to estimate COVID outcomes in people with SCD or trait compared with normal hemoglobin. We linked historical newborn screening data to COVID-19 tests, hospitalization, and mortality data and modeled the odds of hospitalization and mortality. Georgia's cohort aged 0 to 12 years; Michigan's, 0 to 33 years. Over 8% of those in Michigan were linked to positive COVID-19 results, and 4% in Georgia. Those with SCD showed significantly higher rates of COVID-19 hospitalization than the normal hemoglobin Black cohort, and Michigan had higher rates of mortality as well. Outcomes among those with the trait did not differ significantly from the normal hemoglobin Black group. People with SCD are at increased risk of COVID-19-related hospitalization and mortality and are encouraged to be vaccinated and avoid infection. Persons with the trait were not at higher risk of COVID-related severe outcomes.

The Clinical Phenotypes of Alpha Thalassemia.

Clinical manifestations of α-thalassemia range from no symptoms to severe transfusion-dependent anemia. Alpha thalassemia trait is deletion of 1 to 2 α-globin genes, whereas α-thalassemia major (ATM; Barts hydrops fetalis) is the deletion all 4 α genes. All other genotypes of intermediate severity are categorized as HbH disease, a vastly heterogenous group. Clinical spectrum is classified as mild, moderate, and severe by symptoms and need for intervention. Anemia in prenatal period may be fatal without intrauterine transfusions. New therapies to modify HbH disease or provide cure for ATM are under development.

Fertility and Pregnancy in Women with Transfusion-Dependent Thalassemia.

Because women with transfusion-dependent thalassemia are seeking pregnancy, ensuring the best outcomes for both mother and baby require concerted and collaborative efforts between the hematologist, obstetrician, cardiologist, hepatologist, and genetic counselor among others. Proactive counseling, early fertility evaluation, optimal management of iron overload and organ function, and application of advances in reproductive technology and prenatal screening are important in ensuring a healthy outcome. Many unanswered questions remain requiring further study, including fertility preservation, non-invasive prenatal diagnosis, chelation therapy during pregnancy, and indications and duration of anticoagulation.

Transitioning Adolescents With Sickle Cell Disease From Pediatric to Adult Care: Results From a New Survey of Health Care Professionals.

Transition from pediatric to adult care for adolescents and young adults (AYA) with sickle cell disease (SCD) comes at a time when a range of biopsychosocial issues occur simultaneously. A new survey sought information from physicians who treat AYA with SCD about their practices in how they transition pediatric patients to adult care. An online survey to physicians who treat SCD was conducted using SurveyMonkey between November 2019 and January 2020. Of 209 physicians who were contacted, 58 completed the survey; 62.1% treated primarily pediatric patients and 37.9% treated adults. Patient education on transition was regarded as "important" or "very important" by 94.2% of the physicians. Patients' knowledge about their disease and their ability to navigate the health care system were identified as 2 primary barriers to transition (mean 1.30 and 1.67 on a 3-point scale, respectively). Most physicians employ established models to facilitate the transition, including Got Transition (41.3%) and a biopsychosocial model (34.8%), with 34.8% using a mix of models and 23.9% not using an established model. Fewer than half (34.8%) rated their program as "very successful" or "successful." Transition protocols from pediatric to adult care should be re-examined to facilitate successful transition for AYA with SCD.

Time to rethink haemoglobin threshold guidelines in sickle cell disease.

Alleviating anaemia in patients with sickle cell disease (SCD) is crucial in managing acute complications, mitigating end-organ damage and preventing early mortality. Some disease-modifying and curative therapies have increased haemoglobin (Hb) levels to exceed 100 g/l, a threshold above which complications from red blood cell (RBC) transfusions have occurred, raising concern about whole-blood viscosity-related complications with these therapies. Here we discuss the rationale behind this limit, the effect of viscosity on blood flow and the applicability of this Hb threshold to therapies for SCD beyond RBC transfusions.

Stable to improved cardiac and pulmonary function in children with high-risk sickle cell disease following haploidentical stem cell transplantation.

Children with sickle cell disease (SCD) are at high-risk of progressive, chronic pulmonary and cardiac dysfunction. In this prospective multicenter Phase II trial of myeloimmunoablative conditioning followed by haploidentical stem cell transplantation in children with high-risk SCD, 19 patients, 2.0-21.0 years of age, were enrolled with one or more of the following: history of (1) overt stroke; (2) silent stroke; (3) elevated transcranial Doppler velocity; (4) multiple vaso-occlusive crises; and/or (5) two or more acute chest syndromes and received haploidentical transplants from 18 parental donors. Cardiac and pulmonary centralized cores were established. Pulmonary function results were expressed as percent of the median of healthy reference cohorts, matched for age, sex, height and race. At 2 years, pulmonary functions including forced expiratory volume (FEV), FEV1/ forced vital capacity (FVC), total lung capacity (TLC), diffusing capacity of lung for carbon monoxide (DLCO) were stable to improved compared to baseline values. Importantly, specific airway conductance was significantly improved at 2 years (p < 0.004). Left ventricular systolic function (fractional shortening) and tricuspid regurgitant velocity were stable at 2 years. These results demonstrate that haploidentical stem cell transplantation can stabilize or improve cardiopulmonary function in patients with SCD.

Pituitary iron and factors predictive of fertility status in transfusion dependent thalassemia.

Not available.

Influence of sickle cell disease on susceptibility to HIV infection.

People with sickle cell disease (SCD) are reported to have low rates of HIV infection, slower progression to AIDS and lower HIV-associated mortality compared to the general population. Mechanisms of potential resistance to HIV in SCD are incompletely understood. We retrospectively reviewed the Transfusion Safety Study to compare HIV status between people with SCD and other congenital anemias who were routinely exposed to blood products during the high-risk period before HIV screening implementation. Non-SCD congenital anemia diagnosis was associated with a higher risk of HIV acquisition compared to SCD (OR 13.1 95%CI 1.6-108.9). In addition, we prospectively enrolled 30 SCD cases and 30 non-SCD controls to investigate potential mechanisms of resistance to HIV in SCD. CCR5 and CCR7 expression was lower and CD4 expression was higher on CD4+ T cells from SCD cases compared to controls. Surface expression of CD4+ T cell CXCR4, CD38 and HLA-DR did not differ between the groups. SCD CD4+ T cells were not less susceptible to HIV infection than controls. Levels of multiple cytokines were elevated in the SCD plasma, but SCD plasma compared to control plasma did not inhibit HIV infection of target cells. In conclusion, our epidemiological data support people with SCD being resistant to HIV infection. Potential mechanisms include lower CD4+ T cell expression of CCR5 and CCR7, balanced by increased CD4 expression and cytokine levels, which did not result in in vitro resistance to HIV infection. Further study is needed to define the risk and pathophysiology of HIV in persons with SCD.

Evaluation of Mandible Fractures in Patients With Sickle Cell Anemia-A Nationwide Study.

PURPOSE: Sickle cell anemia is the most commonly inherited blood disorder in the United States. Despite its prevalence, clinicians know little about the extent of its impact on orofacial manifestations. MATERIALS AND METHODS: All patients with diagnoses of mandible fracture and sickle cell anemia admitted from 2004 through 2014 were identified using the National Inpatient Sample. Patient demographics, fracture regions, and complications were characterized by descriptive statistics. RESULTS: Fifty-one of 48,464 patients admitted for mandible fracture had sickle cell anemia. The mean age of the identified patients was 25 years (range, 4 to 58 yr). Of all admitted patients, mandible angle fracture was the most common (19%), followed by fracture of the body of the mandible. Seventy-five percent of cases reviewed were treated with open reduction and internal fixation. CONCLUSIONS: Most mandible fractures in patients with sickle cell anemia were located in the angle of the mandible. Complications were minimal and outcomes were satisfactory. Aseptic necrosis of the jaw was a frequent complication of mandible fracture in patients with sickle cell anemia. These results provide clinicians with a better understanding of the distribution and hospital course of patients with sickle cell anemia and facial fractures.

Epidemiologic and clinical characteristics of nontransfusion-dependent thalassemia in the United States.

BACKGROUND: Nontransfusion-dependent thalassemia (NTDT) refers to a diverse group of thalassemia mutations and clinical phenotypes that do not require chronic transfusions. It is increasingly prevalent in the United States. PROCEDURE: This study reviews the epidemiology and clinical characteristics of 138 patients with NTDT treated at four US thalassemia centers from 1997 to 2014. Data on laboratory results, transfusions, and clinical complications were collected from patient charts. RESULTS: Overall, 84 patients with α-thalassemia (62 deletional hemoglobin H; 22 nondeletional hemoglobin H), 39 with ß-thalassemia (26 with homozygous or double heterozygous ß mutations; 13 with single ß mutations with or without α triplication), and 15 with E/ß-thalassemia (12 E/ß0 ; three E/ß+ ) were identified. At study entry, the median age for patients with α-thalassemia was 2.3 years; 9.2 years for patients with ß-thalassemia and 2.2 years for patients with E/ß-thalassemia. Most patients with α-thalassemia were Asian. Patients with ß-thalassemia were predominantly Caucasian (46%) or of African descent (36%). Twenty percent of patients were born outside the United States and 5% were transfused before immigration. Complications varied by genotype and age. Individuals with nondeletional hemoglobin H were severely affected and, despite their young age, had many complications. Iron overload increased with age and was more common in patients who received transfusions. CONCLUSIONS: NTDT in the United States is a multi-ethnic disease with different genotypic mutations and phenotypic manifestations. A higher than expected proportion of patients was Black/African American. NTDT-related complications are common and increase with age, supporting a need for early diagnosis.

Gene Therapy in Patients with Transfusion-Dependent ß-Thalassemia.

BACKGROUND: Donor availability and transplantation-related risks limit the broad use of allogeneic hematopoietic-cell transplantation in patients with transfusion-dependent ß-thalassemia. After previously establishing that lentiviral transfer of a marked ß-globin (ßA-T87Q) gene could substitute for long-term red-cell transfusions in a patient with ß-thalassemia, we wanted to evaluate the safety and efficacy of such gene therapy in patients with transfusion-dependent ß-thalassemia. METHODS: In two phase 1-2 studies, we obtained mobilized autologous CD34+ cells from 22 patients (12 to 35 years of age) with transfusion-dependent ß-thalassemia and transduced the cells ex vivo with LentiGlobin BB305 vector, which encodes adult hemoglobin (HbA) with a T87Q amino acid substitution (HbAT87Q). The cells were then reinfused after the patients had undergone myeloablative busulfan conditioning. We subsequently monitored adverse events, vector integration, and levels of replication-competent lentivirus. Efficacy assessments included levels of total hemoglobin and HbAT87Q, transfusion requirements, and average vector copy number. RESULTS: At a median of 26 months (range, 15 to 42) after infusion of the gene-modified cells, all but 1 of the 13 patients who had a non-ß0/ß0 genotype had stopped receiving red-cell transfusions; the levels of HbAT87Q ranged from 3.4 to 10.0 g per deciliter, and the levels of total hemoglobin ranged from 8.2 to 13.7 g per deciliter. Correction of biologic markers of dyserythropoiesis was achieved in evaluated patients with hemoglobin levels near normal ranges. In 9 patients with a ß0/ß0 genotype or two copies of the IVS1-110 mutation, the median annualized transfusion volume was decreased by 73%, and red-cell transfusions were discontinued in 3 patients. Treatment-related adverse events were typical of those associated with autologous stem-cell transplantation. No clonal dominance related to vector integration was observed. CONCLUSIONS: Gene therapy with autologous CD34+ cells transduced with the BB305 vector reduced or eliminated the need for long-term red-cell transfusions in 22 patients with severe ß-thalassemia without serious adverse events related to the drug product. (Funded by Bluebird Bio and others; HGB-204 and HGB-205 ClinicalTrials.gov numbers, NCT01745120 and NCT02151526 .).

Sickle cell disease.

Sickle cell disease (SCD) is a group of inherited disorders caused by mutations in HBB, which encodes haemoglobin subunit ß. The incidence is estimated to be between 300,000 and 400,000 neonates globally each year, the majority in sub-Saharan Africa. Haemoglobin molecules that include mutant sickle ß-globin subunits can polymerize; erythrocytes that contain mostly haemoglobin polymers assume a sickled form and are prone to haemolysis. Other pathophysiological mechanisms that contribute to the SCD phenotype are vaso-occlusion and activation of the immune system. SCD is characterized by a remarkable phenotypic complexity. Common acute complications are acute pain events, acute chest syndrome and stroke; chronic complications (including chronic kidney disease) can damage all organs. Hydroxycarbamide, blood transfusions and haematopoietic stem cell transplantation can reduce the severity of the disease. Early diagnosis is crucial to improve survival, and universal newborn screening programmes have been implemented in some countries but are challenging in low-income, high-burden settings.

Fertility and Pregnancy in Women with Transfusion-Dependent Thalassemia.

As more women with transfusion-dependent thalassemia are seeking pregnancy, ensuring the best outcomes for both the mother and baby requires concerted, collaborative efforts between practitioners and the family. Proactive counseling, early fertility evaluation, recent developments in reproductive technology, and optimal management of iron overload, have resulted in more successful pregnancies and the birth of healthy newborns. With advances in technology for prenatal screening and increased awareness to perform screening for hemoglobinopathies, healthy pregnancy outcomes have become the expectation. Topics that require further study include management that allows fertility preservation, improved non-invasive prenatal diagnosis methods for affected fetuses, the use of chelation therapy during pregnancy, and indications for and duration of anticoagulation.

Dietary nonheme iron is equally bioavailable from ferritin or ferrous sulfate in thalassemia intermedia.

Transfusion-independent patients with thalassemia intermedia (TI) develop fatal iron overload from excessive iron absorption triggered by ineffective erythropoiesis. More information about iron pharmacokinetics and nonheme, dietary iron absorption in such patients is needed to optimize management. To obtain more information, different forms of supplemental nonheme iron sources (ferritin and ferrous sulfate) were compared in 4 TI (hemoglobin <9 g/dL) and 6 control (hemoglobin 12-16 g/dL) patients. Serial serum iron concentrations were measured during the 24 hours following consumption of 1 mg/kg of elemental iron as ferritin or ferrous sulfate. Serum iron concentrations were also measured for one TI patient and one control patient 2 hours after the ingestion of 2 mg/kg of dietary iron in ferritin or ferrous sulfate. Maximum serum iron concentrations were observed 4 hours after the consumption of either dietary iron source. However, the serum iron values were unchanged for either dietary iron source, even at the higher doses of consumed iron. Thus, the bioavailability of dietary iron, either as ferritin or ferrous sulfate, was equivalent in both groups of patients. The pilot data support ferritin as an alternative dietary iron supplement to ferrous sulfate. ABBREVIATIONS: CRP C-reactive protein; Hb hemoglobin; IDA iron-deficient anemia; ICP inductively coupled plasma; IE ineffective erythropoiesis; SCD sickle cell disease; sTf transferrin saturation; TI thalassemia intermedia; TIBC total iron binding capacity; TM thalassemia major; Tf transferrin.

Encephaloduroarteriosynangiosis (EDAS) in young patients with cerebrovascular complications of sickle cell disease: Single-institution experience.

Moyamoya syndrome occurs in sickle cell disease (SCD) as a secondary complication of large-artery stenosis. Moyamoya increases the risk of stroke, but its optimal management in SCD is not established. Encephaloduroarteriosynangiosis (EDAS) is a neurosurgical revascularization procedure for moyamoya whose use has been reported in SCD patients. We report the outcomes of 11 patients with SCD systematically evaluated for EDAS by a multidisciplinary team and compare the rate of stroke in patients who received EDAS to those who did not. Moyamoya syndrome was diagnosed by flow abnormalities on magnetic resonance angiography at median age of 8.2 years. Four patients deferred surgery. Seven patients underwent EDAS at median age of 19 years. There were no intraoperative complications, perioperative strokes, or deaths. Transient postoperative complications occurred in six cases (86%). On follow-up, three patients (43%) had no evidence of flow in their EDAS grafts, and one later developed a hemorrhagic stroke. Five EDAS patients (71%) had radiographically stable vasculopathy. Compared to the four patients who deferred surgery, the incidence of stroke in EDAS group was no different. The optimal use of EDAS in patients with SCD-associated moyamoya syndrome requires further investigation by a prospective, controlled clinical trial.

Simvastatin reduces vaso-occlusive pain in sickle cell anaemia: a pilot efficacy trial.

Sickle cell anaemia (SCA) is a progressive vascular disease characterized by episodic vaso-occlusive pain. Despite the broad impact of inflammation on acute and chronic clinical manifestations of SCA, no directed anti-inflammatory therapies currently exist. Statins are cholesterol-lowering agents shown to confer protection from vascular injury by suppressing inflammation. We previously documented a reduction in soluble biomarkers of inflammation in patients with sickle cell disease treated with simvastatin. To determine the potential clinical efficacy of simvastatin, we treated 19 SCA patients with single daily dose simvastatin for 3 months and assessed changes from baseline in the frequency and intensity of diary-reported pain and levels of circulating nitric oxide metabolites (NOx), high sensitivity C-reactive protein (hs-CRP), vascular cell adhesion molecule 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), ICAM-3, E-selectin, and vascular endothelial growth factor (VEGF). Treatment with simvastatin resulted in a significant reduction in the frequency of pain (P = 0·0003), oral analgesic use (P = 0·003) and circulating hs-CRP (P = 0·003), soluble (s)E-selectin (P = 0·01), sICAM-1 (P = 0·02), sICAM-3 (P = 0·02) and sVEGF (P = 0·01). Simvastatin had no effect on pain intensity or levels of NOx, sP-selectin and sVCAM-1. The observed reductions in pain rate and markers of inflammation were greatest in subjects receiving hydroxycarbamide (HC), suggesting a synergistic effect of simvastatin. These results provide preliminary clinical data to support a larger trial of simvastatin in SCA.