Background: Vaso-occlusive pain episodes (VOE) are the most common complication and reason for hospital admission in individuals with Sickle Cell Anemia (SCA). Recently our team demonstrated that in adults with SCA followed prospectively for approximately 5 years, a lower baseline Forced Expiratory Volume in 1 second percent predicted (FEV1%), which is associated with earlier mortality, but evidence of obstructive or restrictive lung function patterns is not (Blood 2015, in press). Based on the evidence that abnormal pulmonary function is associated with earlier mortality, we tested the hypothesis that baseline pulmonary function patterns were associated with SCA-related morbidity, including VOE and acute chest syndrome (ACS) events.Procedure: A prospective cohort of adults with SCA followed in the Cooperative Study for Sickle Cell Disease (CSSCD) was constructed based on a planned secondary analysis. Data from the first PFT record at age 21 and older were used for this study. Percent predicted values were determined for each participant based on their age, gender, height, and race for FEV1 and the ratio of FEV1 to forced vital capacity (FEV1/FVC) using the Global Lung Function 2012 equations (Eur Respir J, 2012; 40(6): 1324-1343). Assessment of lower airway obstruction was based on % predicted FEV1/FVC. Percent predicted total lung capacity (TLC), a measure of restrictive lung disease, was determined using published equations and corrected based on race. All PFT evaluations were checked for quality. Negative binomial regression models were used to determine the association between future VOE, ACS events, and spirometry measurements after adjusting for age, sex, hemoglobin, and fetal hemoglobin levels.Results: A total of 430 adults with SCA were evaluated. Ages of the study participants ranged from 21.7-66.4 years with a median age of 32.6 years at the time of first PFT and median follow-up was 5.5 years. Only FEV1/FVC% predicted as a continuous covariate was a significant predictor of future VOE. Lower FEV1/FVC% predicted was associated with higher future pain event rates with a rate ratio of 1.022 (95% CI 1.002 – 1.042; p=0.028). For every 10% decrease in FEV1/FVC% predicted there is a 23% increase in the rate ratio. TLC% predicted did not predict future VOE (p=0.762). FEV1/FVC% predicted or TLC% predicted did not predict future ACS events (p=0.618 and p=0.430 respectively). When FEV1/FVC% predicted and TLC% predicted < 5th percentile were used in the regression equation instead of continuous values, neither abnormal lung function parameter was associated with an increased incidence of VOE or ACS events.Conclusions: For the first time, we have demonstrated that spirometry evaluation with FEV1/FVC% predicted, as a measure of lower airway obstruction, identifies a group of adults with SCA at increased risk for future vaso-occlusive pain episode. Abstract source

Background: The life span of individuals living with sickle cell disease (SCD) has increased considerably over the past three decades. Yet, as this group ages, new concerns emerge about their overall health profile – particularly with regard to cardiovascular disease (CVD), the primary cause of mortality in the United States. Metabolic syndrome (MetS) is a cluster of conditions that are associated with a 2-fold increase in CVD outcomes and a 1.5-fold increase in all-cause mortality. Little is known, however, about the prevalence of MetS risk factors among adults with SCD. As part of exploring the CVD profile of this population, we report findings from a pilot study that sought to evaluate MetS (typically defined as the presence of 3 or more risk factors).Methods: 49 adults (ages 21-66 years; 72% female) completed demographic and health behavior surveys, health-related family and personal histories, anthropometric measurements, the Block 2005 nutritional assessment, and a comprehensive blood panel. In terms of SCD genotype, 63% of participants were diagnosed with homozygous sickle cell anemia and 37% were diagnosed with hemoglobin SC disease. Descriptive and inferential statistics were used to summarize and compare MetS components stratified in separate analyses by genotype and sex.Results: The most prevalent MetS risk factors observed in our study – large waist circumference and reduced HDL levels – affected 45% and 69% of the sample, respectively. Overall, 16% of participants met traditional criteria for MetS. Table 1 summarizes mean values and shows the gender-adjusted risk for MetS. Although 78% of the sample self-reported moderate to high physical activity, nearly half of participants were overweight and had dietary saturated fat intake levels that exceeded both the national average and US Dietary Guidelines (<10%). Participants with the SC phenotype were older, consumed more calories, and had higher BMI, waist circumference, and BP values compared to those with the SS phenotype. Overall, males had worse MetS risk profiles compared to women, but no statistically significant sex differences were observed with regard to components of MetS.Conclusion: We report prevalence of MetS components, a surrogate of CVD risk, in a sample of adults living with SCD. Despite high levels of self-reported physical activity, both increased waist circumference and reduced HDL levels were notably high in our sample. These findings correspond with recent studies that indicate an upward trend in obesity and BMI among young adults with SCD. They also suggest a need to prioritize weight management, aerobic exercise, and resistance training strategies that could decrease MetS risk, but are rarely considered for this population. Abstract source

Background: Hematopoietic cell transplantation (HCT) for sickle cell disease (SCD) is potentially curative, yet applied sparingly in adults due in part to limited donor availability and to concerns about safety. We conducted a multicenter pilot clinical trial to determine ways to broaden the availability of this therapy. Objective: To determine the feasibility, efficacy, and safety of a reduced toxicity transplant conditioning regimen in adults with severe SCD receiving related and unrelated donor HCT. Methods: Patients between 16-40 years of age were enrolled between October 2012 and June 2015 at 8 participating transplant centers. Eligibility criteria included stroke; recurrent episodes of acute chest syndrome (ACS) or sickle pain in the past 2 years; 8 or more RBC transfusions/year; or a tricuspid valve regurgitant jet velocity ³ 2.7 m/sec. Patients received unmodified bone marrow from a human leukocyte antigen (HLA)-matched sibling or an unrelated donor matched for 8 of 8 HLA loci. Patients were prepared for HCT with Busulfan from day -8 to -5 (13.2 mg/kg), Fludarabine from day -7 to -3 (150 mg/m2) and Thymoglobulin from day -5 to -2 (6 mg/kg). GVHD prophylaxis consisted of cyclosporine or tacrolimus with methotrexate. Outcomes and Measures: The primary endpoint was event-free survival 1 year after HCT, with events defined as graft failure, disease recurrence, or death. The Kaplan-Meier probabilities of event-free and overall survival were determined. Donor chimerism, transplant-related toxicities and clinical and laboratory measures of SCD were secondary endpoints obtained 1 year after HCT. Serious adverse events were monitored after transplantation. Results: Twenty-two patients (13 were female) who ranged in age from 17-36 (median 22) years were enrolled. Seventeen patients received a sibling and 5 an unrelated donor HCT. An eligibility review committee confirmed subject eligibility. Enrolled subjects had stroke (2 pts), ACS (3 pts), painful crises (14 pts), RBC transfusions (6 pts) and/or tricuspid valve regurgitant jet velocity (5 pts); 8 subjects satisfied eligibility criteria for more than 1 category. There were 6 severe adverse events after transplantation in 4 patients including one death from intra-cranial hemorrhage related to posterior reversible encephalopathy syndrome. None of the patients had graft failure or SCD recurrence after HCT. Currently, 21 of 22 patients survive with stable engraftment of donor cells at a median 9.7 months (range, 1-31) after HCT. The overall and event-free survival probabilities are both 95% (90% CI 76%; 99%, Figure 1) at 12-months after HCT. Two patients developed grade I skin acute GVHD and three patients developed chronic GVHD. Full donor myeloid chimerism was observed after HCT. The median donor T-cell and RBC chimerism at 28, 100 and 180 days after HCT was 55.5% and 100%, 80% and 100%, and 87.5% and 100%, respectively. Conclusions: We report excellent outcomes after HLA-matched HCT in adults with SCD using a reduced toxicity-conditioning regimen performed in a multi-center setting. We observed very low rates of graft rejection and GVHD in this pilot study. We speculate that these outcomes, if sustained long-term after HCT, will be superior to survival in adults with SCD who receive standard supportive care. If confirmed in a larger comparative trial, this approach would broaden the availability and application of transplantation for adults with severe SCD. Abstract source

Background: Transfusion is a standard therapy for acute and chronic complications of sickle cell disease (SCD). They are complicated by a high prevalence of red cell antigen alloimmunization, which is not seen in other frequently transfused patients. Reasons for this increased prevalence are unclear. Some studies have suggested genetic predisposition to alloimmunization in all transfused patient populations. Others suggested that mismatched red cell antigens occurring commonly between blood donors of European ancestry and patients with SCD who are of African ancestry is a primary cause in SCD. Accordingly, phenotypic antigen matching and transfusion from African American donors are proposed strategies to minimize alloimmunization risk. We hypothesized that if these population differences are the etiologic basis that analysis of ancestry at the genetic level could identify significant genetic susceptibility contributions and localize susceptibility loci. Methods: The Bethesda Sickle Cell Cohort Study consisting of adults evaluated at NIH from 2001-2015 (n=721) was reviewed for transfusion history and the presence of allo-antibodies confirmed with a blood bank. Genomic DNA was genotyped with an admixture panel consisting of 2251 ancestry informative SNPs in 359 patients and in HapMap controls. A final panel of 1622 SNPs was used to infer ancestry proportions using Structure assuming 3 ancestral populations. Ancestry was analyzed in regression models along with clinical variables. Genome wide admixture mapping was performed to identify regions of the genome where the ancestry proportions differed significantly between cases and controls. We used AncestryMap for a log-additive case control study assuming various risk models. Abstract source

Introduction: Recently, there has been general interest in using marijuana as an analgesic for various types of pain. Cannabis is known to relieve severe nausea and vomiting. Anecdotally, medical marijuana has analgesic effects in patients with chronic and neuropathic pain other than sickle cell pain, decreases the frequency of migraine headache, has anti-spastic effect in multiple sclerosis, and may relieve some of the signs and symptoms of amyotrophic lateral sclerosis and Crohn’s disease. Its role in epilepsy is controversial. On the negative side long-term cannabis use is associated with periodontal disease, maternal marijuana use at 20 weeks gestation was strongly associated with spontaneous pre-term birth independent of maternal cigarette smoking and illegal synthetic cannabinoids (K2/spice) were associated with catatonia and myocardial infarction in adolescents. Studies in the transgenic sickle cell mouse showed that cannabinoid receptor-specific mechanisms ameliorate pain via inhibition of mast cell activation and neurogenic inflammation. A questionnaire study from the United Kingdom showed that 36% of the patients with sickle cell disease (SCD) have used cannabis in the previous 12 months to relieve symptoms. Another longitudinal questionnaire study in Jamaica found that marijuana was not related to the clinical severity of SCD. The objective of this study is to report the epidemiological and clinical features of the patients with SCD who were found to be taking marijuana by using random urine drug screening from 1994 to 2009. The frequency of vaso-occlusive crises (VOCs) in these patients was compared to patents with SCD whose urine drug screening showed no marijuana. The terms marijuana and cannabinoid will be used interchangeably in this Abstract. Patients & Methods: A total of 270 random urine drug screen tests were done on 72 patients representing 10% of our patients with SCD during the period of the study. Written consent was obtained from the patients for enrollment in the study that was approved by the IRB. Types of SCD were determined by routine lab tests. Urine samples, collected randomly, were analyzed for the presence of amphetamine, benzodiazepines, opiates, barbiturate, cannabinoid, propoxyphene, methadone and phencyclidine. Samples were classified as either positive or negative for cannabinoid. Statistical analysis included the two-tailed student’s t, Fisher exact and the Chi Square tests. Abstract source

ESCORT-HU (European Sickle Cell Disease (SCD) COhoRT – HydroxyUrea) is a multicenter prospective non interventional study implemented in Europe, following the European Medical Agency’s request to collect more information focused on long-term safety profile of hydroxycarbamide (HU) in SCD patients treated with HU. Primary endpoint of the study is to determine the frequency of adverse events (AEs) under HU treatment Secondary endpoints include the efficacy of HU in labeled indications (prevention of vaso-occlusive complications and of acute thoracic syndrome), frequency of hospitalizations due to SCD events and frequency of blood transfusions. Data collection on the reason for HU initiation permitted to identify in-label (in the therapeutic indication of the European marketing authorization, group 1, G1) and off-label (other therapeutic indication, group 2, G2) prescriptions of HU. Frequency of AEs (including not related to SCD and infections) was compared between adults and children, both in G1 and G2, with focus on the following subclasses: blood and lymphatic system disorders, fever, gastrointestinal disorders, infection, nervous system disorders, skin and subcutaneous tissue disorders and others. Abstract source

Introduction: Osteonecrosis of the femoral head (ONFH) is characterized by insidious onset of hip joint pain, limited range of motion and disability in sickle cell disease (SCD) patients. Prevalence of ONFH, rates of hip replacement surgery and post-operative course have not been previously described in population-based cohort studies. We retrospectively reviewed a large SCD patient cohort from California’s Office of Statewide Planning and Development (OSHPD) Patient Discharge Database (PDD), and report the risk factors and clinical outcomes for SCD patients with ONFH. Methods: Patients were ascertained from the PDD from 1991 to 2013, through an iterative search algorithm using ICD-9 codes. In addition to descriptive statistics and univariate comparisons with the chi-square test, we used multivariable Cox proportional hazards models (with age as the time scale), to analyze factors associated with ONFH diagnosis, including sex, SCD severity and antecedent acute chest syndrome (ACS; data available from 2003-2013). Patients with more severe SCD were defined as those who averaged 3 of more hospitalizations per year. Antecedent ACS was considered as a time-dependent covariate to first ONFH diagnosis after 2003. We estimated the cumulative incidence of ONFH, accounting for the competing risk of death, by SCD severity and antecedent ACS diagnoses, with differences assessed by the Gray’s test for equality. We also determined rates of all re-admissions to the PDD and emergency department within 30-90 days after hip replacement surgery, including re-admissions for venous thromboembolism (VTE) and painful vasoocclusive crises (VOC). All data were analyzed using SAS 9.4 software, and results presented as hazard ratios (HR) and 95% confidence intervals (CI). Conclusions: The overall prevalence of ONFH in this SCD cohort was 22%, and approximately 23% of the ONFH patients underwent hip arthroplasty (5% of the entire SCD cohort). Thus, ONFH is a common complication of SCD, which often requires surgical intervention. ONFH was independently associated with SCD severity and ACS, as has been previously suggested (Kato, Gladwin et al. 2007). Readmission within 30-60 days after hip surgery was common in this SCD cohort, and often due to painful VOC. Of the 144 readmissions within 90 days of discharge from hip replacement surgery, only 2 (~1%) were due to VTE, which is lower than reported in non-sickle cell patients undergoing hip replacement surgery. Our large, populations-based cohort study provides insight into the frequency and risk factors of ONFH in SCD patients, and also reveals that post-operative readmissions are common. Abstract source

Transcranial Doppler (TCD) screening in children with sickle cell anemia (SCA) identifies abnormally elevated cerebral artery flow velocities that confer an elevated risk for primary stroke. Chronic transfusions offer effective stroke prophylaxis in this setting, but must be continued indefinitely and lead to transfusional iron overload. An alternative treatment strategy that offers similar effective protection against primary stroke, and provides control of iron overload, is needed. TCD With Transfusions Changing to Hydroxyurea (TWiTCH, NCT01425307) was an NHLBI-funded Phase III multicenter randomized clinical trial comparing 24-months of standard treatment (transfusions) to alternative treatment (hydroxyurea) in children with SCA and abnormal TCD velocities. All eligible children had received at least 12 months of transfusions. TWiTCH had a non-inferiority trial design; the primary study endpoint was the 24-month TCD velocity obtained from a linear mixed model, controlling for baseline (enrollment) values, with a non-inferiority margin of 15 cm/sec. The transfusion arm maintained children at HbS <30%; an elevated liver iron concentration (LIC) identified by R2 MRI FerriScan® was managed with chelation. The hydroxyurea arm included an overlap period with transfusions until a stable maximum tolerated dose (MTD) of hydroxyurea was reached; transfusions were then replaced by serial phlebotomy to reduce iron overload. In both arms, TCD velocities were obtained every 12 weeks and reviewed centrally, with local investigators masked to the results. A centralized TCD alert algorithm monitored changes from enrollment velocities. A total of 159 children were enrolled but 38 failed screening due primarily to severe vasculopathy on brain MRA or inadequate TCD exams; 121 children were randomized (61 to transfusions, 60 to hydroxyurea) with balanced characteristics including enrollment maximum TCD velocities (145 ± 21 versus 145 ± 26 cm/sec), age, duration of transfusions, serum ferritin, and LIC. Study participants randomized to transfusions maintained an average HbS <30% throughout the study, while those on hydroxyurea reached MTD after 7 ± 2 months at an average dose of 27 mg/kg/day, with expected hematological changes including HbF ~25% throughout the treatment period. After 37% of the participants exited the study, a scheduled interim analysis suggested the primary study endpoint was likely to be achieved. NHLBI allowed the study to continue until 50% of the children exited, at which time the statistical analysis was confirmed and the study was terminated; all remaining participants moved to the exit phase. The final analysis included 42 on the transfusion arm who completed all treatment, 11 with truncated treatment, and 8 withdrawn; the hydroxyurea arm included 41 who completed all treatment, 13 with truncated treatment, and 6 withdrawn. The final calculated TCD velocities (mean ± standard error) in the transfusion and hydroxyurea arms were 143 ± 1.6 and 138 ± 1.6 cm/sec, respectively; by intention-to-treat analysis, the p-value for non-inferiority = 8.82 x 10-16 and by post-hoc analysis the p-value for superiority = 0.046. Among 29 new neurological events, all centrally adjudicated by masked reviewers, there were no strokes but 6 transient ischemic attacks (3 in each arm). One child (transfusion arm) was withdrawn per the TCD alert algorithm after developing on-study TCD velocities >240 cm/sec. Exit brain MRI/MRA exams documented no new parenchymal abnormalities but one child (transfusion arm) developed new vasculopathy. Sickle cell related serious adverse events were more common in the hydroxyurea arm than the transfusion arm (23 to 15), but none was related to study treatment or study procedures. Iron overload improved more in the hydroxyurea arm than in the transfusion arm, with a greater average change in serum ferritin (-1085 compared to -38 ng/mL, p<0.001) and LIC (average -1.9 compared to +2.4 mg/g dry weight liver, p=0.001). In the multicenter Phase III TWiTCH trial, which treated children with SCA and abnormal TCD velocities but without severe MRA vasculopathy, hydroxyurea at MTD was non-inferior and possibly superior to chronic transfusions for maintaining TCD velocities. Serial phlebotomy effectively managed iron overload. Hydroxyurea may represent an effective alternative to indefinite transfusions for the prevention of primary stroke in this high risk population. Abstract source

Introduction: Current advances in allogeneic hematopoietic cell transplant (alloHCT) may warrant a paradigm shift in managing children with sickle cell disease (SCD). This study characterizes the clinical outcomes and health care utilization (HCU) of alloHCT for pediatric SCD. We hypothesize that early alloHCT will have improved clinical outcomes, and decreased HCU. Methods: The Center for International Blood and Marrow Transplant Research database was used to identify children 21 years or less with alloHCT for SCD in the United States. Patient data included comprehensive research forms (CRF) from 2000-13 and transplant essential data (TED) forms from 2000-11. CRFs provided clinical risk factors associated with overall survival, graft failure, grade III-IV acute GVHD, and GVHD related event free survival (GREFS) - the survival free of graft failure, chronic GVHD, or death. Risk factors included age, gender, performance status, year of alloHCT, prior SCD complications and therapy, CMV status, donor type, conditioning regimen, and GVHD prophylaxis. Due to low event rates and sample size, only univariate analysis of risk factors was performed. TED data was merged with Pediatric Health Information System (PHIS) inpatient data using a probabilistic merging algorithm to determine risk factors and clinical outcomes associated with HCU. Available PHIS adjusted cost data was used to determine the total adjusted cost for all inpatient admissions per patient per hospital day. To standardize these costs, the total adjusted cost per 30 hospital days was calculated for each patient and used as the primary HCU outcome. HCU outcomes were analyzed for the alloHCT year, day 0 to day +365. Abstract source

Background: Hydroxyurea (HU) is a chemotherapeutic agent used in sickle cell patients (SCP) to reduce the frequency and intensity of sickle pain crises. It is a myelosuppressive agent with proposed long-term carcinogenic and/or leukemic effects, particularly in myeloid malignancies. Current data has failed to conclusively demonstrate this outcome in its long-term use. Yet many SCP are maintained on HU for years and therefore, could provide evidence of the long-term neoplastic effects of HU. Methods: In a retrospective review of the Wake Forest Baptist Medical Center (WFBMC) Electronic Data Warehouse (EDW) capturing data from 1980 until present, we compared the prevalence of hematologic malignancies in SCP to the general population (GPop) using the appropriate ICD-9 codes (ICD-9 200-208.xx, 238.4, 238.71, 289.83, 277.30). We then examined the use of HU in the SCP versus the GPop to compare the difference in disease prevalence as it related to HU. Finally, the statistical significance was measured with the Fisher’s exact test. Results: Of the 3,874 SCP identified in the EDW, 163/3,874 (4.2%) were on HU. 153/3,874 (3.9%) had a diagnosis of a hematologic malignancy. In the GPop, 222.000 (1.04%) were diagnosed with a hematologic malignancy and 222/2,123,301 (0.01%) were on HU. 46 (1.19%) SCP were diagnosed with a lymphoid or histiocytic neoplasm versus 8,055 (0.37%) in the GPop; 4 (10.87%) SCP were on HU. 23 (0.59%) SCP versus 3,753 (0.18%) GPop had a lymphoid leukemia diagnosis; 4 (17.39%) SCP were on HU. 39 (1.01%) SCP had a myeloid leukemia diagnosis (4,957 (0.23%) GPop); 1 (0.03%) SCP was on HU (p < 0.5884). Conclusions: In a review of data collected over 35 years, there seems to be an increased prevalence of hematologic malignancies in the SCP population, predominantly of lymphoid origin; the use of HU seems to further influence this finding. In contrast, while there is a notable mild increase in myeloid leukemia diagnoses compared to the general population, there does not seem to be the same correlation with HU. Abstract source