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There is conflicting evidence in the literature on the etiology of hypogonadism in patients with sickle cell disease (SCD). A cross-sectional study was done to determine whether hypogonadism in male patients with SCD is due to primary testicular failure or secondary pituitary/hypothalamic dysfunction and assess the association between hypogonadism and serum ferritin levels. Hormonal assessment for serum concentrations of testosterone, follicle stimulating hormone (FSH) and luteinizing hormone (LH) was done for 34 men with SCD and their charts were reviewed for relevant clinical variables. Eight men (24%) were classified hypogonadal based on their serum testosterone levels. These men have significantly lower LH (p = 0.001) and FSH (p = 0.01) levels than normogonadal men, indicating a central etiology. There was no significant difference between hypogonadal and normogonadal men with respect to ferritin levels (p = 0.71). Our study indicates a central etiology of hypogonadism in patients with SCD. In this small study ferritin level was not significantly related to hypogonadism.

Although most common in tropical regions, population migration has meant that sickle cell disease is now one of the most prevalent genetic diseases worldwide. The issues and challenges faced by physicians and patients have been discussed by an international group of experts representing 4 key regions: the USA, Europe, Latin America, and the Middle East/Africa. Conclusive evidence to support the use of transfusion therapy for the prevention of stroke has resulted in key changes to patient management in all regions, and increasing numbers of patients are benefiting from this management approach. However, it is apparent that transfusion therapy is still under-utilized, largely due to concerns over iron overload, alloimmunization, limited blood supplies, and, sometimes, due to parental refusal. Once transfused, assessment and management of body iron levels can be poor, particularly in patients who are intermittently transfused. Compliance with chelation therapy regimens is a significant challenge, but new therapeutic options are likely to overcome some of the current barriers. Key requirements in all regions were considered to be the following: to provide greater physician, patient, and family education; to ensure effective transition from pediatric to adult care; and to establish national guidelines in order to ensure best practice is consistently applied.

Senicapoc, a novel Gardos channel inhibitor, limits solute and water loss, thereby preserving sickle red blood cell (RBC) hydration. Because hemoglobin S polymerization is profoundly influenced by intracellular hemoglobin concentration, senicapoc could improve sickle RBC survival. In a 12-week, multicenter, phase 2, randomized, double-blind, dose-finding study, we evaluated senicapoc's safety and its effect on hemoglobin level and markers of RBC hemolysis in sickle cell anemia patients. The patients were randomized into 3 treatment arms: placebo; low-dose (6 mg/day) senicapoc; and high-dose (10 mg/day) senicapoc. For the primary efficacy end point (change in hemoglobin level from baseline), the mean response to high-dose senicapoc treatment exceeded placebo (6.8 g/L [0.68 g/dL] vs 0.1 g/L [0.01 g/dL], P < .001). Treatment with high-dose senicapoc also produced significant decreases in such secondary end points as percentage of dense RBCs (−2.41 vs −0.08, P < .001); reticulocytes (−4.12 vs −0.46, P < .001); lactate dehydrogenase (−121 U/L vs −15 U/L, P = .002); and indirect bilirubin (−1.18 mg/dL vs 0.12 mg/dL, P < .001). Finally, senicapoc was safe and well tolerated. The increased hemoglobin concentration and concomitant decrease in the total number of reticulocytes and various markers of RBC destruction following senicapoc administration suggests a possible increase in the survival of sickle RBCs. This study is registered at http://clinicaltrials.gov as NCT00040677.

Background/Aims: There is increasing evidence demonstrating the value of transfusions in sickle cell disease (SCD). However, resultant iron overload can be life threatening if untreated. Chelation therapy with deferoxamine requires parenteral infusions that can negatively impact quality of life and adherence to treatment. Methods: As part of a phase II trial, SCD patient-reported outcomes were evaluated. One hundred and ninety-five patients were randomized (2:1) to receive oral deferasirox (5–30 mg/kg/day) or deferoxamine (20–50 mg/kg, 5 days per week); 121 had previously received deferoxamine. Results: At each time point, significantly more patients who had previously received deferoxamine were ‘satisfied/very satisfied’ with deferasirox, or found treatment to be ‘convenient/very convenient’ compared with deferoxamine (p < 0.001). In these patients, fewer hours were lost from daily activities with deferasirox than deferoxamine treatment. Most patients (77%) preferred deferasirox, and more were willing to continue taking deferasirox than deferoxamine at end-of-study (84 vs. 11%, respectively). Conclusions: Patients with SCD are therefore more satisfied with deferasirox, which has a lower impact on daily activities than deferoxamine. Given the high levels of satisfaction, it is likely that quality of life will be improved. These results also suggest that treatment adherence with deferasirox may be better than with deferoxamine, which should lead to improved long-term outcomes.

A deficiency in airway nitric oxide (NO) could contribute to pulmonary vaso-occlusion in sickle cell disease (SCD). We measured the fractional expired concentration of NO (FENO) by chemiluminescence during a slow vital capacity maneuver against a positive pressure of 16 cm H2O at an expiratory flow rate of 50 mL/sec in 44 stable ambulatory adults with SCD and 30 healthy controls. A history of acute chest syndrome was present in 29 patients, and 22 complained of dyspnea. Mean ± SD FENO was significantly reduced in the SCD group compared with controls (14.8 ± 8.4 vs. 24.9 ± 13.5 ppb, P < 0.001). SCD patients with dyspnea had lower FENO than those without dyspnea (10.1 ± 5.7 vs. 19.6 ± 8 ppb, P < 0.001) and those with a history of ACS had lower values than those no episodes of ACS (13.0 ± 8.3 vs. 18.4 ± 7.6 ppb, P < 0.05). There was a weak correlation between FENO and percent-predicted DLCO (r = 0.4, P = 0.02) among the SCD patients. We conclude that exhaled NO is reduced in adults with SCD, and this may play a role in the pathogenesis of acute chest syndrome and chronic sickle cell lung disease. Am. J. Hematol. 72:177–184, 2003. © 2003 Wiley-Liss, Inc.

The Multicenter Study of Hydroxyurea in Sickle Cell Anemia (MSH) demonstrated the efficacy of hydroxyurea in reducing the rate of painful crises compared to placebo. We used resource utilization data collected in the MSH to determine the cost-effectiveness of hydroxyurea. The MSH was a randomized, placebo-controlled double-blind clinical trial involving 299 patients at 21 sites. The primary outcome, visit to a medical facility, was one of the criteria to define occurrence of painful crisis. Cost estimates were applied to all outpatient and emergency department visits and inpatient hospital stays that were classified as a crisis. Other resources for which cost estimates were applied included hospitalization for chest syndrome, analgesics received, hydroxyurea dosing, laboratory testing, and clinic visits for management of patient care. Annualized differential costs were calculated between hydroxyurea- and placebo-receiving patients. Hospitalization for painful crisis accounted for the majority of costs in both arms of the study, with an annual mean of $12,160 (95% CI: $9,440, $14,880) for hydroxyurea and $17,290 (95% CI: $13,010, $21,570) for placebo. The difference in means was $5,130 (95% CI: $60, $10,200; P = 0.048). Chest syndrome was the next largest cost with a mean difference of $830 (95% CI: $−340, $2,000; P = 0.16). The hydroxyurea arm was also associated with lower costs for emergency department visits, transfusion, and use of opiate analgesics. In total, the annual average cost per patient receiving hydroxyurea was $16,810 (95% CI: $13,350, $20,270) and the annual average costs per patient receiving placebo was $22,020 (95% CI: $17,340, $26,710). The difference in means was $5,210 (95% CI: $−610, $11,030; P = 0.21). The cost of hydroxyurea with the more intensive monitoring required when using this drug appears to be more than offset by decreased costs for medical care of painful crisis and analgesic use. Although the total cost difference was not significant statistically, these results suggest that hydroxyurea therapy is cost-effective compared to placebo in the management of adult patients with sickle cell anemia. If hydroxyurea can prevent development of chronic organ damage, long-term savings may be even greater. Am. J. Hematol. 64:26–31, 2000. © 2000 Wiley-Liss, Inc.

Zinc deficiency is a common nutritional problem in adult sickle-cell disease (SCD) patients. Hyperzincuria and increased requirement of zinc due to continued hemolysis in SCD are probable bases for zinc deficiency in these patients. Zinc deficiency affects adversely T-helper1 (TH1) functions and cell mediated immunity and interleukin (IL)-2 production is decreased in zinc deficient subjects. We hypothesized that zinc supplementation will improve T-helper1 function and decrease incidence of infections in patients with SCD. We tested this hypothesis in 32 SCD subjects who were divided in three groups (Grs A, B, and C). Grs A (n = 11) and B (n = 10) were zinc deficient based on cellular zinc criteria and Gr C (n = 11) were zinc sufficient. Gr A subjects were observed for 1 year (baseline), following which they received zinc acetate (50 to 75 mg of elemental zinc orally daily) for 3 years. Gr B subjects were observed for 1 year (baseline), following which they received placebo for 1 year and then switched to zinc supplementation (50 to 75 mg of elemental zinc orally daily) for 2 years. Gr C subjects did not receive any intervention inasmuch as they were zinc sufficient. Prolonged zinc supplementation resulted in an increase in lymphocyte and granulocyte zinc (P = 0.0001), and an increase in interleukin-2 production (P = 0.0001), decreased incidence of documented bacteriologically positive infections (P = 0.0026), decreased number of hospitalizations and decreased number of vaso-occlusive pain crisis (P = 0.0001). The predominant pathogens isolated were staphylococci and streptococci involving the respiratory tract and aerobic gram-negative bacteria, particularly Escherichia coli, involving the urinary tract. Further confirmation of our observations will require prospective studies of zinc supplementation in a larger number of SCD patients.

Background: Vascular complications such as stroke and pulmonary hypertension are central features of sickle cell disease (SCD) pathophysiology and are associated with early mortality among patients with SCD. Better understanding of the abnormal blood flow patterns in sickle cell disease is critical to assessing the therapeutic benefit of emerging therapies. Previous studies have shown abnormal blood flow patterns in sickle cell patients using laser speckle contrast imaging (LSCI) (Ikeda et al. poster 1080 ASH annual meeting, December 8, 2012), however, no test re-test variability or changes in response to therapeutic intervention were assessed. As part of a larger study using multiple imaging technologies to concurrently evaluate blood flow and oxygenation in several organs of healthy subjects and subjects with SCD, the present study has analyzed skin blood flow by LSCI in these patients longitudinally using a multiple visit protocol. Furthermore, we analyzed the effect of Chronic Transfusion Protocol, the most effective intervention against vascular complications on skin blood flow. Methods: We enrolled 9 SCD patients (age 30.2 ± 8.6 years 5 men / 4 women) and 4 age and ethnically matched healthy controls (age 24.5 ± 4.5 years, 2 men / 2 women). 5 of the 9 SCD patients were on Chronic Transfusion Protocol. Following a screening visit where patients consented for the study, had basic labs, 12-lead EKG and physical exam, cutaneous blood flow was directly measured using LCSI at baseline, during and after a standard brachial artery occlusion-reperfusion maneuver (inflation of an occlusive pneumatic cuff for 3-5 min depending on patient tolerance). For assessment of test, re-test reliability this visit protocol was repeated within 1-10 days for patients not on transfusion protocols and healthy volunteers. Three visits occurred for transfusion patients, the first 2-4 days prior to transfusion, the second 1-2 days post transfusion and the third 6-14 days after the first post-transfusion imaging visit. Results: Baseline microvascular blood flow measured by LSCI was greater in patients with sickle cell disease compared to healthy controls (47 + 11 vs. 27 + 3 arbitrary units (AU); p=0.002) with sickle cell patients on chronic transfusion protocols exhibiting an intermediate blood flow phenotype (32 + 7 AU p= 0.001 vs. non-transfused patients and p= 0.039 vs. HV). Surprisingly, transfusion had no impact on baseline blood flow both 1-2 days and 6-14 days following transfusions (34 + 9 AU pre-transfusion, 32 + 7 AU first post-transfusion, 33 + 6 AU second post-transfusion). Maximal microvascular blood flow was similar across all groups (86 + 14 AU sickle cell patients vs. 82 + 12 AU healthy volunteers vs. 75 + 15 AU sickle cell patients on chronic transfusion). All measured values exhibited significant longitudinal stability across visits with r2= 0.865 for baseline blood flow measurements for non-transfusion sickle cell patients and healthy volunteers between visit 1 and 2. For transfusion patients r2= 0.927 and r2= 0.866 between visits 1 and 2 and 1 and 3 respectively. No statistically significant differences were observed in our analysis of the time from half-maximum to maximum blood flow or time from maximum to half-maximum blood flow during the recovery period after occlusion across all subjects. Conclusion: Compared to healthy individuals, patients with SCD have greater baseline microvascular blood flow in skin and these numbers are stable over a multi-visit protocol. Furthermore, patients on chronic transfusion protocols exhibit lower, but not normal skin blood flow parameters. Surprisingly, these values are not impacted acutely by transfusion. These results not only further validate that LSCI could function as a non-invasive disease biomarker for vascular dysfunction in sickle cell disease but that it is sensitive enough to detect vascular changes that occur in response to effective therapy. Finally, these results suggest that the therapeutic changes in vascular function provided by Chronic Transfusion Protocols occur over the long term versus acutely. Disclosures Currier: Biogen: Employment, Other: shareholder. Dent:Biogen: Employment, Other: shareholder. Birkhoff:CHDR: Employment. Burggraaf:CHDR: Employment. de Vries:CHDR: Employment. Hobbs:Biogen: Employment, Equity Ownership, Other: shareholder. Verma:Biogen: Employment, Other: shareholder.

Pharmacologic induction of fetal hemoglobin (HbF) expression is an effective treatment strategy for sickle cell disease (SCD) and β-thalassemia. Pomalidomide is a potent structural analog of thalidomide and member of a new class of immunomodulatory drugs. Recent reports demonstrated that pomalidomide reduced or eliminated transfusion requirements in certain hematologic malignancies and induced HbF ex vivo in CD34+ progenitor cells from healthy and SCD donors. We investigated the effects of pomalidomide on erythropoiesis and hemoglobin synthesis in a transgenic mouse model of SCD. We found that 8 weeks of treatment with pomalidomide induced modest increases of HbF with similar efficacy as hydroxyurea. However, in stark contrast to hydroxyurea's myelosuppressive effects, pomalidomide augmented erythropoiesis and preserved bone marrow function. Surprisingly, combinatory therapy with both drugs failed to mitigate hydroxyurea's myelotoxic effects and caused loss of HbF induction. These findings support further evaluation of pomalidomide as a novel therapy for SCD.

Pain from vaso-occlusive crisis (VOC) is the major cause of hospitalization in patients with sickle cell disease (SCD). The beneficial therapeutic effects of inhaled nitric oxide (NO) on the pathophysiology of SCD have been reported. A double-blind, randomized, placebo-controlled clinical trial was conducted to determine whether NO breathing reduces acute VOC pain in adult patients and to study the safety of inhaled NO. Twenty-three patients experiencing acute VOC were enrolled. After randomization but before treatment, five were found to not meet final eligibility criteria. Nine patients were assigned to inhaled NO (80 ppm) and nine to placebo (21% O2). Primary outcome was the mean change in pain scores after 4 hr of inhalation, measured on a 10-cm visual analog scale (VAS). Both groups had similar baseline VAS pain scores but inhaled NO significantly reduced pain scores compared with placebo (P 5 0.02) at the end of NO inhalation. Secondary outcome was parenteral morphine use at baseline, 4, and 6 hr. Parenteral morphine use was lower in the inhaled NO group, but the difference was not statistically significant.Safety assessments included systolic blood pressure measurements,pulse oximetry readings, concentration of delivered nitrogen dioxide, and concentration of methemoglobin (metHb). None of these NO toxicities was observed.

A randomized, controlled clinical trial established the efficacy and safety of short-term use of hydroxyurea in adult sickle cell anemia. To examine the risks and benefits of long-term hydroxyurea usage, patients in this trial were followed for 17.5 years during which they could start or stop hydroxyurea. The purpose of this follow-up was to search for adverse outcomes and estimate mortality. For each outcome and for mortality, exact 95% confidence intervals were calculated, or tests were conducted at alpha = 0.05 level (P-value

Cefepime, a fourth generation cephalosporin, is widely used in hematology and oncology patients. These patients may require plasma exchange (PE) for indications such as chemotherapy- or cancer-induced thromobotic thrombocytopenic purpura to name a few. To date, no pharmacokinetic evaluation has been conducted assessing cefepime’s disposition during PE. A 2 g IV cefepime single dose was given to patients undergoing therapeutic PE. Two hours from cefepime dose administration, plasma concentration was measured. PE was then instituted and cefepime plasmapheresate concentration was measured at the completion of the PE session. Cefepime levels were measured using HPLC. The percentage removed by PE was calculated as: amount removed/2 g dose. Ten adult patients were analyzed: median age (range): 52 years (33—67) and median weight (range); 82.85 kg (47—120). PE indications were: myasthenia gravis (n = 3), transverse myelitis (n = 2), multiple sclerosis (n = 1), chronic inflammatory demyelinating polyneuropathy (n = 1), idiopathic thrombocytopenic purpura (n = 1), thrombotic thrombocytopenic purpura (n = 1), and humoral rejection post cadaveric renal allograft (n = 1). All patients except one had a creatinine clearance >60 mL/min. One patient was excluded from the pharmacokinetic analysis owing to loss of venous access during PE. For the remaining nine patients, total plasma volume removed was 3.5 L (range: 2.5—3.5) and duration of PE was 120 min (range: 94—209). The cefepime removed by PE was 3.7% (range: 2.1—6.7). A strong correlation was found between cefepime plasma concentration prior to PE and the amount of drug removed (r = 0.96, r2 = 0.92; p

Zinc deficiency is common in adult sickle-cell disease (SCD) patients. We previously demonstrated that zinc supplementation to adult SCD patients decreased the incidences of infections and hospital admissions. We hypothesize that zinc supplementation improves T-helper cell function and decreases vascular endothelial cell activation, oxidative stress, and nuclear factor-kappa B (NF-kappaB)-DNA binding in mononuclear cells (MNCs) in SCD patients. To test this hypothesis, 36 SCD patients were recruited and randomly divided into 2 groups. One group (n = 18) received 25-mg zinc orally thrice a day for 3 months. The other group (n = 18) received placebo. The results indicate that the zinc-supplemented group had decreased incidence of infections compared with the placebo group. After zinc supplementation, red blood cell, hemoglobin (Hb), hematocrit, (Hct), plasma zinc, and antioxidant power increased; plasma nitrite and nitrate (NOx), lipid peroxidation products, DNA oxidation products, and soluble vascular cell adhesion molecule-1 decreased in the zinc-supplemented group, compared with the placebo group. Zinc-supplemented patients exhibited significant decreases in lipopolysaccharide-induced tumor necrosis factor-alpha (TNF-alpha) and IL-1beta mRNAs, and TNF-induced nuclear factor of kappaB-DNA binding in MNCs, compared with the placebo group. Ex vivo addition of zinc to MNCs isolated from the placebo subjects decreased TNF-alpha and IL-1beta mRNAs. Zinc supplementation also increased relative levels of IL-2 and IL-2Ralpha mRNAs in phytohemagglutinin-p-stimulated MNCs. These results suggest that zinc supplementation may be beneficial to SCD patients.

Deferasirox is a once-daily, oral iron chelator developed for treating transfusional iron overload. Preclinical studies indicated that the kidney was a potential target organ of toxicity. As patients with sickle cell disease often have abnormal baseline renal function, the primary objective of this randomised, open-label, phase II trial was to evaluate the safety and tolerability of deferasirox in comparison with deferoxamine in this population. Assessment of efficacy, as measured by change in liver iron concentration (LIC) using biosusceptometry, was a secondary objective. A total of 195 adult and paediatric patients received deferasirox (n = 132) or deferoxamine (n = 63). Adverse events most commonly associated with deferasirox were mild, including transient nausea, vomiting, diarrhoea, abdominal pain and skin rash. Abnormal laboratory studies with deferasirox were occasionally associated with mild non-progressive increases in serum creatinine and reversible elevations in liver function tests. Discontinuation rates from deferasirox (11·4%) and deferoxamine (11·1%) were similar. Over 1 year, similar dose-dependent LIC reductions were observed with deferasirox and deferoxamine. Once-daily oral deferasirox has acceptable tolerability and appears to have similar efficacy to deferoxamine in reducing iron burden in transfused patients with sickle cell disease.

Red cell exchange transfusions remain an effective but possibly underutilized therapy in the acute and chronic treatment of sickle cell disease. In sickle cell disease, increased blood viscosity can cause complications when the hemoglobin exceeds 10 g/dL even if this is due to simple transfusion. Red cell exchange can provide needed oxygen carrying capacity while reducing the overall viscosity of blood. Acute red cell exchange is useful in acute infarctive stroke, in acute chest and the multi-organ failure syndromes, the right upper quadrant syndrome, and possibly priapism. Neither simple or exchange transfusions are likely to hasten resolution of an acute pain episode.

In a multicenter study (eight centers), we determined secretory phospholipase A(2) (sPLA(2)) levels in patients with sickle cell disease and acute chest syndrome (ACS). The diagnosis of ACS was made according to established criteria. The sPLA2 levels were determined in blood samples collected at baseline (time of diagnosis) and serially thereafter up to day 22-35 follow-up visits. Thirty-four of 43 (80%) patients with ACS had enzyme levelsor =1.00 AU at baseline. The enzyme levels decreased significantly on Days 2 through Days 25-35 after baseline. Nine of 43 (20%) patients had baseline sPLA2 values of1.00 AU with six of them never exceeding 1.00 AU at any point in time during follow-up. The data indicate that the reliability of sPLA(2( for predicting the development of ACS is not perfect (100%) as was previously reported but occurs in about 80% of the patients.

Acute chest syndrome (ACS) is the most common cause of death in patients with sickle cell anemia. Its management is primarily palliative. We performed a Phase I evaluation of purified poloxamer 188 (a non-ionic surfactant) in the management of ACS. Forty-three patients with sickle cell disease and ACS were treated with doses as high as 2960 mg/day by continuous intravenous (IV) infusion. The maximum tolerated dose has not been identified. No evidence of renal toxicity or other limiting adverse events were found. One adult patient died due to sepsis and adult respiratory distress syndrome, which were unrelated to treatment. Poloxamer 188 is safe to administer to patients with ACS, and preliminary data suggest that it may shorten its duration and the length of hospitalization in a dose related manner. Children appeared to benefit more than adults. The data and safety profile justify further studies with purified poloxamer 188 in the treatment of ACS.

The preferential accumulation of sickle blood cells in tumor vasculature is demonstrated noninvasively using MRI and sickle red blood cells loaded with Gd-DTPA and invasively by two other techniques. The distribution of red blood cells in rat brain tumors relative to normal brains were measured using three separate techniques: MRI of Gd-DTPA loaded cells, fluorescent microscopy detection of Oregon Green 488 fluorescence conjugated to a streptavidin-biotin complex that binds to red blood cell surface proteins, and autoradiography using a technetium (99m)Tc-labeling kit. Labeled red cells were infused intravenously in rats with brain tumors. Sickle cells preferentially accumulated in tumor relative to normal brain, with highest concentrations near the tumor / normal tissue boundary, whereas control normal red cells did not preferentially aggregate at the tumor periphery. This demonstrates the potential of sickle red blood cells to accumulate in the abnormal tumor vessel network, and the ability to detect their aggregation noninvasively and at high spatial resolution using MRI. The application of the noninvasive measurement of sickle cells for imaging tumor neovasculature, or as a delivery tool for therapy, requires further study.

Background. Acute chest syndrome (ACS) is the leading cause of hospitalization, morbidity, and mortality in patients with sickle cell disease. Radiographic and clinical findings in ACS resemble pneumonia; however, etiologies other than infectious pathogens have been implicated, including pulmonary fat embolism (PFE) and infarction of segments of the pulmonary vasculature. The National Acute Chest Syndrome Study Group was designed to identify the etiologic agents and clinical outcomes associated with this syndrome. Methods. Data were analyzed from the prospective study of 671 episodes of ACS in 538 patients with sickle cell anemia. ACS was defined as a new pulmonary infiltrate involving at least 1 complete segment of the lung, excluding atelectasis. In addition, the patients had to have chest pain, fever >38.5C, tachypnea, wheezing, or cough. Samples of blood and deep sputum were analyzed for evidence of bacteria, viruses, and PFE. Mycoplasma pneumoniae infection was determined by analysis of paired serologies. Detailed information on patient characteristics, presenting signs and symptoms, treatment, and clinical outcome were collected. Results. Fifty-one (9%) of 598 episodes of ACS had serologic evidence of M pneumoniae infection. Twelve percent of the 112 episodes of ACS occurring in patients younger than 5 years were associated with M pneumoniae infection. At the time of diagnosis, 98% of all patients with M pneumoniae infection had fever, 78% had a cough, and 51% were tachypneic. More than 50% developed multilobar infiltrates and effusions, 82% were transfused, and 6% required assisted ventilation. The average hospital stay was 10 days. Evidence of PFE with M pneumoniae infection was seen in 5 (20%) of 25 patients with adequate deep respiratory samples for the PFE assay. M pneumoniae and Chlamydia pneumoniae was found in 16% of patients with diagnostic studies for C pneumoniae. Mycoplasma hominis was cultured in 10 (2%) of 555 episodes of ACS and occurred more frequently in older patients, but the presenting symptoms and clinical course was similar to those with M pneumoniae. Conclusions. M pneumoniae is commonly associated with the ACS in patients with sickle cell anemia and occurs in very young children. M hominis should be considered in the differential diagnosis of ACS. Aggressive treatment with broad-spectrum antibiotics, including 1 from the macrolide class, is recommended for all patients as well as bronchodilator therapy, early transfusion, and respiratory support when clinically indicated.

Thalidomide (THAL), lenalidomide (LEN), and pomalidomide (POM) have been used successfully in the treatment of several inflammatory and neoplastic disorders (e.g. erythema nodosum leprosum, multiple myeloma, and myelodysplastic syndromes) over the past two decades. THAL, LEN, and POM use is strictly regulated as they are teratogenic, although LEN and POM are considered less teratogenic than THAL. The anti-neoplastic effects of these agents include anti-VEGF action, in addition to anti-inflammatory, immunomodulatory, and antiproliferative properties. POM has up to a >50,000 fold more potent anti-TNFα effect than THAL. These effects are suggestive of a potential benefit of these drugs as anti-inflammatory agents in sickle cell disease (SCD). Moutouh de Parseval et al (JCI, 2008) showed that POM induced fetal hemoglobin (HbF) production more potently than hydroxyurea (HU) in a dose-dependent manner in CD34+ cell cultures from peripheral blood in patients with SCD. Furthermore, while increasing concentrations of HU resulted in cytotoxicity and a sharp decline in cell viability, POM had no such effect. This was followed by the study of POM in a mouse model by our group; Meiler et al showed that POM induced HbF in a manner comparable with HU (Blood, 2011). Additionally, POM led to an increase in erythropoiesis in the marrow of sickle cell mice, an effect which was not observed with HU. We conducted a Phase I trial of POM in SCD at 2 centers (GRU Sickle Cell Center and Wayne State University) and enrolled a total of 15 patients with 3 patients for each dose level (0.5, 1.0, 2.0, 3.0, and 4.0 mg/day). Inclusion criteria included: age 18-60 years, SS or Sβ0 thal genotype, severe SCD as defined by 1 or more of the following: > 1 pain episode/year, history of acute chest syndrome, leg ulcers, or priapism in the past 3 years. Women were eligible if they were post-menopausal or had a hysterectomy. Patients had to be intolerant, unresponsive, or unwilling to undergo HU therapy and had to be off HU for at least 90 days. Dose limiting toxicities (DLT) were graded on the following scale: grade 1 (mild), grade 2 (moderate), and grade 3 (severe). Anemia grades 1, 2, 3, and 4 were based on 11−-24%, 25−-49%, 50-74%, and ≥ 75% decrease compared with baseline, respectively; grade 4 could also be < 4.5 g/dL. The median age of enrolled patients was 31.2 years (mean 33.7, range 20-52), 14 were male and all but 1 were African-American. The treatment period was 12 weeks. Most patients (14/15) completed 12 weeks of study drug; 1 subject was lost to follow-up after 10 weeks. Overall, the drug was well tolerated; there were no DLTs observed in any of the 5 dose cohorts. None of the adverse events (AEs) or serious adverse events (SAEs) were thought to be study-drug related. The most common AEs and SAEs were vaso-occlusive episodes. Three patients developed acute chest syndrome while they were on the study drug. No significant change was observed in laboratory parameters (CBC, retics, chemistries, HbF, F-cells, inflammatory markers) in patients enrolled into the 0.5, 1.0, 2.0, and 3.0 mg/day cohorts. Two of the 3 patients in the 4 mg/day cohort showed an increase in HbF, F cells, and total Hb (Table). One patient enrolled in the extended phase (3 mg/day based upon clinical benefit while on 1 mg/day; healing of chronic leg ulcer) showed a consistent increase in HbF and F cells, which became evident after 6 months of POM.Table.Hb (g/dl)HbF (%)F-cells (%)Age/SexDxDose (mg)Duration (days)BaselineFinalBaselineFinalBaselineFinal52/MSS4709.49.810.710.648.747.020/MSS4848.611.47.113.440.056.927/MSS48410.611.320.923.571.774.250/MSS346010.611.914.822.860.875.7 In summary, the results of this Phase I study of POM in SCD show that the drug is well tolerated up to a daily dose of 4 mg. An increase in HbF, F-cells, and total Hb was evident only with 4 mg/day dosing or at longer periods (> 6 months) of exposure to POM at lower doses (3 mg/day). Based upon these encouraging results, a Phase II study of ≥ 3 mg/day of POM for an extended duration is planned. Disclosures: Kutlar: Celgene Corporation: Research Funding. Swerdlow:Celgene Corporation: Research Funding. Meiler:Celgene Corporation: Research Funding. Shah:Celgene Corporation: Employment, Equity Ownership. Knight:Celgene Corporation: Employment, Equity Ownership.

Abstract 2132 Studies have provided conflicting evidence on the etiology of hypogonadism in patients with sickle cell disease. A cross-sectional study was conducted on adult men with SCD to determine whether hypogonadism in these patients is due to primary testicular failure or secondary pituitary / hypothalamic dysfunction and to look for association between hypogonadism and serum ferritin levels. The study protocol was approved by Wayne State University / Detroit Medical Center Human investigation committee. A total of 19 male patients with SCD 18 years or older following at the benign hematology clinic of Detroit Medical Center between Sep 21 to Dec 21; 2011 consented to participate in the study. Blood sample was drawn between 9AM – 11 AM and sent to the laboratory for hormonal assay. A previous pilot study (completed few months earlier) of 15 adult male patients with SCD aged 18years or older at the same site was also included in the analysis. The pilot study was approved by Wayne State University / Detroit Medical Center Human investigation committee. Serum samples from 15 patients with sickle cell disease who had blood work during their routine clinic visit at the benign hematology clinic was assessed for testosterone, FSH and LH levels. Thus a total of 34 male patients with SCD were included in the final analysis. Hormone measurements were done for total testosterone (using immunoassay), FSH and LH using two site sandwich immunoassay by chemilumino method (Siemens, Centaur XP). Additional information on body mass index (BMI), hemoglobin, total bilirubin, ferritin and creatinine levels was collected from the Electronic Medical Record (EMR). Hypogonadism was defined as serum total testosterone level of ≤250 ng/dL. Hypogonadal patients with high FSH and LH were considered as having primary/peripheral hypogonadism where as those with low FSH and LH or inappropriately normal (normal FSH and LH despite low serum testosterone) were considered to have secondary/central hypogonadism. FSH level between 1.5–12.4mIU/ml and LH level of 2–14mIU/ml was considered as normal for male adults. Stata 11.1 was used for statistical analysis. Kruskal-Wallis tests were used to assess the statistical significance of differences in hormone and ferritin levels; no adjustment was made for multiple comparisons. Almost all patients in the study have homozygous SCD-SS genotype except two patients with SCD-SC and one patient with SCD-Sβ+ thalassemia. Additional characteristics of the study population are shown in table 1. Eight of 34 men with SCD (23.6 %) were found to have hypogonadism. Hypogonadal patients were found to have significantly low LH (p=0.006) and FSH (p= 0.01) levels indicating central etiology (Figure 1 and Figure 2). There was no significant difference between hypogonadal and normogonadal with respect to ferritin level (p=0.71) (Figure 3). Our study provides evidence for a central etiology to hypogonadism in male patients with SCD. In this small study ferritin level was not significantly related to hypogonadism. Disclosures: No relevant conflicts of interest to declare.

Abstract 3221 Background: Most adult sickle cell anemia patients have received transfusion therapy. However, prospective studies evaluating the efficacy of transfusions in preventing sickle cell-related complications are lacking. The Phase II Neuropsychological Adult Sickle Cell Anemia Study is a randomized trial of chronic transfusion vs. standard of care in patients with abnormal neurocognitive function in order to determine the safety and benefits of transfusion therapy on neurocognitive function. A secondary goal of the study is to evaluate the benefit of chronic transfusion on the frequency and severity of acute sickle cell events; this is a preliminary report of this specific aim. Methods: Eligibility required normal neurological exam, WAIS III PIQ score ≤ 90, hemoglobin ≤ 9 g/dL, hemoglobin SS electrophoresis, and age between 21 and 55 years. Patients were randomly assigned to receive either standard care or transfusions. The transfusion goal was to maintain a hemoglobin of 2 g/dL rise over baseline with matched red cells for D, C/c, E/e, and Kell antigens. The protocol required simple transfusions at approximately 4 week intervals. Chelation therapy was not part of the study design. Patients underwent serial clinical and laboratory evaluations with central analysis of all clinical and transfusion events and complications. Laboratory testing of subjects in the transfusion arm included quantitative hemoglobin S/A, hemoglobin concentration, ferritin levels, and red cell antibody screening; a full hematology/chemistry panel was performed for all subjects at baseline, the study mid-point, and at the end of the study. Results: There were 20 patients in the transfusion arm (TX arm) with a mean age of 29 years vs. 16 patients in the standard care arm (SC arm) with a mean age of 30.5 years. The baseline data in the TX arm was similar to the SC arm: hemoglobin 7.8 vs. 8.0 g/dL; hematocrit 22.6% vs. 23.1%; hemoglobin F 10.5% vs. 12.5%. Thirty-five percent of patients randomized to the TX arm had a history of acute chest syndrome (ACS) vs. 31% in the SC arm; 30% of patients in the TX arm were on hydroxyurea compared to 50% in the SC arm. The TX arm patients have received an average of 5.6 transfusions (2 units per transfusion) with only one subject requiring an acute transfusion (5%); in contrast, 4 SC arm patients (25%) were transfused for acute events for a total of 7 units (average 1.8 per patient). The transfusion therapy improved the average hematologic status of patients: hemoglobin S% decreased from 85% to 32% (p=0.0003); hemoglobin and hematocrit increased from 7.6 to 9.4 g/dL (p=0.0052) and 22% to 28%, (p=0.007), respectively. Bilirubin declined from 3.6 to 2.4 mg/dL (p=0.042). In contrast, only bilirubin showed a significant decrease in the SC arm. In the TX arm, serum ferritin rose an average of 1318 to 2368 (p=.001); there was no change in liver function. There were no clinical transfusion reactions in the 120 study transfusions (360 units); however, one patient on routine screening reported a transient anti-D antibody without clinical or laboratory changes. Clinical Results: Adverse events were higher in the SC arm. Total number of adverse events in the TX arm were 23 (1.2 per person) vs. 66 in (4.1 per person) in the SC arm. There were 5 hospitalizations in the TX arm and 21 in the SC care arm, with a median number of hospitalized days per hospitalization of 5.0 and 6.0 respectively. The total number of serious events was 6 in the TX arm (0.3 per person) vs. 23 in the SC arm (1.4 per person). The total number of vaso-occlusive events in the TX arm were 14 (0.7 per person) vs. 57 (3.6 per person) in the SC arm. Acute pulmonary events occurred in 25% (4 patients) of the SC arm vs. none in the TX arm. Conclusions: This is preliminary data from the first prospective randomized study of the safety and efficacy of transfusion therapy in adults with SCD. We demonstrate the safety of transfusion therapy. Compared to standard therapy, transfusions improve or stabilize critical laboratory markers, decrease serious sickle cell anemia-related adverse events, and decrease in hospitalizations. Increase in ferritin is an expected outcome in transfused patients since chelation was not a part of this transfusion protocol. On completion of the study, the potential benefits of transfusion therapy on sickle cell disease morbidity including neurocognitive function will be reported. Disclosures: Field: Novartis Pharm: Honoraria.

Abstract 1543 Poster Board I-566 Between 1992-1995, the National Heart, Lung, and Blood Institute sponsored a multi-center, double blind, randomized, placebo-controlled Phase III clinical trial of hydroxyurea (Multicenter Study of Hydroxyurea-MSH). This trial examined whether hydroxyurea, a myelosuppressive chemotherapeutic agent that also stimulates the production of fetal hemoglobin (HbF), would reduce pain episodes in adults with sickle cell anemia. The trial was stopped early because of significant benefits of pain reduction that was sustained in a nine-year follow-up. This also suggested that patients taking hydroxyurea had improved survival. Despite our best attempts to promote contraception among MSH patients, women had children and men fathered children. One of the concerns about using hydroxyurea was that it might have teratogenic effects on offspring, particularly in the area of brain development and cognitive outcome. To address this question, all eligible adults in the MSH trial were contacted to provide consent to obtain developmental outcome data using telephone interview administration of the Vineland Adaptive Behavior Scales, 2nd Edition, Survey Form (VABS). The population mean for the VABS is 100 with a standard deviation of 15. Interviews were conducted by a trained psychologist using an interactive question and answer process, with probes to clarify any information that was unclear. Consent was obtained for parents of 22 offspring meeting criteria for inclusion. A number of the parents had multiple offspring; eight of the study parents were male and three were female. The children ranged from 6-months to 17 years of age at the time of the VABS interview. Four of the parents could not be reached for the interview. Of the remaining 18, four were ineligible because the birth occurred before hydroxyurea was started. As a group, the offspring were functioning in the average range of development in all areas: Adaptive Behavior Composite (M=102.3), Communication Domain (M=98.5), Daily Living Domain (M=103.8), Socialization Domain (M=100.2), and Motor Domain (for children under age 5; M=108.3). One child was functioning below the average range; follow-up determined that this child was in a special education program but had a developmental disability that had occurred in other family members. The number of children who met criteria for this study and whose parents could be contacted was very small, severely limiting any definitive conclusions about developmental risk for offspring. Studies of teratogenicity for prenatal substance abuse have used standardized observational tests of neurodevelopment; this study relied on parent report, which can be biased if not confirmed. When standardized tests have been used in studies of prenatal drug exposure (not hydroxyurea), subtle difficulties in executive function of offspring have been reported, sometimes years after the exposure. While our results are encouraging in that the offspring in this limited group are functioning in the average range, this observation is not conclusive and there is a need to study a larger sample of children who are offspring of adults treated with hydroxyurea according to community standards. Disclosures No relevant conflicts of interest to declare.

Abstract 2577 Poster Board II-554 Introduction: Chronic and acute pain are characteristic of sickle cell disease (SCD). Opioids are often used at large doses to achieve pain relief. This report summarizes the relationship of patient characteristics to patterns of analgesic utilization by patients in MSH, including both at-home use and use during medical contacts requiring hospital utilization (ER or in-patient admission). Patients and Methods: The sample is the N=299 patients with homozygous SCD enrolled in the MSH, a randomized double-blind placebo-controlled study of hydroxyurea (HU) as a treatment for SCD. Details of the study have been previously reported (N Engl J Med 1995). Age was examined as 4 quartiles (ages 18–24, 25–29, 30–35, and 36+). For geographic location, MSH sites were clustered into 2 regions (North/South) and 4 regions (Northeast/NE, Midwest/MW, South and West). Data on analgesics use were from three sources. (1) At biweekly follow-up visits, providers recorded the type(s) and dosage of analgesic(s) used at home during that period. (2) In biweekly at-home diaries, patients reported any analgesic use each day. Data from the diaries and the follow-up visits were matched to calculate average daily doses for each biweekly period. (3) During medical contacts, providers recorded types and doses of parenteral and oral analgesics. All doses were converted into equianalgesic doses; those for hospital contacts were divided by contact duration to obtain daily averages. Results: Males and females did not differ in frequency of at-home analgesic use or the number of different analgesics used during each biweekly period. Equianalgesic dosing at home was numerically lower for females but the difference was not statistically significant. For hospital contacts, females were marginally less likely to report any analgesics use (p=.08) but reported more use of non-steroidal anti-inflammatories (NSAIDS) (p=.009). Equianalgesic dosing for parenteral analgesics was significantly lower for females (p=.015). There were significant age differences in at-home analgesic use. The 18–24 and 36+ quartiles used analgesics less often (p=.001) and used fewer total analgesics (p Conclusion: In the MSH, patterns of analgesic utilization were sex, age, and location dependent. In hospital, females have lower dosing and less frequent use along with a greater likelihood of using NSAIDS, possibly substituting for parenteral use. By age, at-home use was lower in the youngest and oldest groups, and in hospital these age groups used more oral analgesics and NSAIDs – again, possibly substituting for parenteral use. Finally, regional differences suggested more frequent parenteral use in the NE, lower parenteral doses in the South, and more frequent oral and NSAID use in the West. Regional differences may reflect site- and provider-specific prescription policies and preferences, but sex and age may also significantly influence analgesic use in adult sickle cell patients. Disclosures: No relevant conflicts of interest to declare.

Dysregulated nitric oxide (NO) homeostasis, a consequence of hemolysis, is a central feature of endothelial dysfunction (ED) in Sickle Cell disease (SCD). In addition to ED, scavenging of NO by free heme leads to increased cell adhesion and inflammation. Vascular inflammation and the production of superoxide may decrease BH4, an essential cofactor for NO production, thus creating an acquired BH4 deficiency. Restoring BH4 levels could potentially improve ED thereby favorably impacting complications of SCD. We assessed the safety and efficacy of 6R-BH4 on endothelial function in a Phase 2a, open-label, dose escalation study in SCD subjects using a non-invasive, operatorindependent technique of peripheral arterial tonometry (Endo-PAT; Itamar, Israel). Endo-PAT (PAT) scores were quantitatively determined as the ratio between the arterial pulse wave amplitude following a 5 min arterial occlusion in the forearm to the pre-occlusion value. A value of ≤1.67 represents an impaired response or endothelial dysfunction. Only patients with HbSS and HbSC disease and at least 15 years of age were enrolled. Patients were excluded if they: were on chronic hypertransfusion; had sickle cell crisis within 30 days of screening; had a history of bone marrow or stem cell transplant or were on hydroxyurea (HU) therapy during the 3 months prior to screening. Thirty-two African-American subjects, mean age 29 years (41% male) were sequentially treated for 4 weeks each with 6R-BH4 at 2.5, 5, 10, and 20 mg/kg/day at 12 US sites. Nine subjects discontinued therapy for various reasons including loss of follow up and pregnancy. Twenty-seven subjects had baseline PAT scores and the number of subjects with PAT scores varied at each treatment dose. There were no deaths and only one subject had a drug related adverse effect resulting in discontinuation. Overall, 6R-BH4 is safe and well-tolerated in subjects with SCD. The mean PAT scores for all participants at baseline was 1.58 ± 0.43 (mean ± SD). Mean PAT scores at baseline were 1.33 ± 0.17 in 18 patients with abnormal PAT scores and 2.09 ± 0.31 (p=

Sickling disorders have long been suspected of decreasing physiologic thresholds for thrombosis, and the sickling process in tissue of being abetted by elements of the hemostatic system. The landscape of the presumed hypercoagulable state, however, has been ill-defined and differences among sickling disorders with regard to its characteristics, if any, undelineated. Learning how this landscape may reflect the pathophysiology of the sickling process may help guide further study of the interactions among the vasculature and the varieties of abnormal erythrocytes resulting from these hemoglobinopathies and define new opportunities to ameliorate the clinical manifestations of "sickle cell disease." Methods: Using laboratory strategies developed to characterize thrombophilia in non-sickling patients with thrombosis, modified for a largely non-European population, 144 patients with sickling disorders were prospectively evaluated for predisposition to thrombosis. A standard group of hemostatic studies was performed using patient samples obtained during steady-state "non-sickling" conditions, by skilled venepuncturists working consistently with this patient group. Genotypes included: HbSS 96/144 (67%); Hb SC 26/144 (18%;) Hb SSTh; 14/144 (9.5%); Hb S/AThal 8/144 (5.5%). 49/144 (34%) patients (pts) received regular automated erythrocytapheresis for prior stroke, recurrent acute chest syndrome or severe pain episodes > 6/yr. Results: As expected, 2/144 (1.4%) of pts were heterozygous for the Factor V Leiden mutation, 0/144 for the Prothrombin 20210 mutation, and 20/144 (14%) heterozygous, 1/144 ( 12 ng/dL in 38/144 patients (26%). Protein S activity levels were 175%, frequently with lesser vWFactor activity (vWF) levels, whereas Hb SSt and SThal more frequently exhibited normal vWA/vWF profiles. Factor VIII activity varied widely, exhibiting no correlation to vWF antigen or activity levels in any of the Hb genotypes. Other thrombophilic conditioners, e.g. antithrombin III activity/Ag, Factor VIII activity, plasmnogen activator inhibitor, and b2-glycoprotein I antibodies were either normal or varied as expected in a " normal," e.g European population, with no correlation to Hb genotype. Conclusions: Thrombophilia in patients with sickling disorders appears to have varied contributors: Hb SC appears most thrombophilic with levels of vWF antigen suggestive of vascular dysfunction and supportive of intravscular platelet adhesion a aggregation. Other genotypes exhibit variable phenotypes, with Hb SThal exhibiting the least thrombogenic phenotype from a aboratory assessment perspective. vWF antigen and Protein S abnormalities emphasize the likely role of inflammation and vascular dysfunction but the dysjunction of vWF and Factor VIII activity hint at greater complexity. Further study of these phenomena and the inclusion of platelet function studies may yield additional insights as to the interaction of sickling erythrocytes, their products and vascular/hemostatic interactions. For now, routine thromboprophylaxis in patients with SC disease appears essential, and likely important in all other genotypes except Hb SThal.

Zinc deficiency is common in adult sickle-cell disease (SCD) patients, due to continued hemolysis and hyperzincuria. Growth retardation, hypogonadism, and immune dysfunctions due to zinc deficiency have been described in SCD patients. Our studies show that zinc has not only anti-inflammatory functions, but is also an antioxidant. We have previously shown that zinc supplementation to adult SCD patients decreased the incidences of infection and hospital admissions. We hypothesize that zinc supplementation improves T-helper cell and vascular endothelial cell activation, and decreases oxidative stress and NF-κB activation in SCD patients. To test this hypothesis, we recruited 36 ambulatory SCD (homozygous) patients (ages 18–47 years, 11 males and 7 females in each group) and randomly divided these into 2 groups. One group (n=18) received 25 mg zinc as acetate orally thrice a day for 3 months. The other group (n=18) received placebo. All these patients were free of pain crisis for 3 months and were not receiving hydroxyurea. The results indicate that zinc supplemented group had decreased incidence of infection in comparison to the placebo group (Chi square analysis: p=0.017). After 3 months of zinc supplementation, the plasma zinc level increased. The anti-oxidant power increased and the plasma levels of NO, lipid peroxidation products (MDA+HAE), DNA oxidation product (8-OHdG), and sVCAM-1 decreased in the zinc supplemented group, compared to the placebo group (p Parameter Group Pre Post p value Δp value p value: Paired T-test; Pre (baseline) vs Post (6 m of supplementation). Δp value: T-test of the differences (pre vs post) between placebo vs Zn group) Zn (μM) Placebo 88.8±9.9 89.3±8.5 0.893 0.0001 Zn Supp. 85.6±9.3 104.2±15.0 0.0005 MDA+HAE (μM) Placebo 1.62±0.31 1.75±0.27 0.923 0.004 Zn Supp. 1.60±0.24 1.28±0.24 0.009 NO (μM) Placebo 78.5±12.6 76.7±11.8 0.256 0.051 Zn Supp. 75.2±11.2 60.9±17.1 0.021 8-OHdG (ng/ml) Plecebo 0.75±0.23 0.79±0.35 0.427 0.036 Zn Supp. 0.81±0.25 0.63±0.21 0.093 Antioxidant power (u/ml) Placebo 6.89±1.65 6.61±1.50 0.278 0.002 Zn Supp. 7.36±7.2 10.52±2.33 0.001 sVCAM-1 (ng/ml) Placebo 1587±359 1495±454 0.263 0.008 Zn Supp. 1434±455 1251±353 0.023 Relative levels of TNF-α, IL-1β, VCAM-1 mRNAs by RT-PCR were reduced in LPS-stimulated MNC isolated from zinc supplemented group, compared to placebo. In vitro zinc addition to the MNC isolated from placebo decreased TNF-α and IL-1β mRNAs. Zinc supplementation decreased TNF-induced NF-κB DNA binding (a biomarker of oxidative stress) by EMSA in isolated MNC, compared to placebo. Zinc supplementation also increased the relative level of IL-2 mRNA in PHA-stimulated MNC, compared to placebo. Our results showed that zinc supplementation to SCD patients decreased incidence of infection, and decreased oxidative stress markers. The mRNAs of TNF-α, IL-1β, and sVCAM-1, as well as TNF-induced NF-κB activation were also decreased in the zinc-supplemented subjects, suggesting that zinc supplementation may be beneficial to in SCD patients.

The Gardos channel, a calcium-activated potassium channel that spans the membrane of red blood cells (RBCs), is a key pathway in RBC dehydration affecting the intracellular concentration of hemoglobin S (Hb S). Inhibition of the Gardos channel in patients with sickle cell disease (SCD) may prevent the formation of dehydrated sickle RBCs, decrease Hb S polymerization, and reduce symptoms. In a Phase II 12-week, randomized, double-blind, placebo-controlled, dose-finding study in 90 patients with SCD, senicapoc (ICA-17043), a novel Gardos channel blocker, demonstrated statistically significant and beneficial hematologic effects including increased hemoglobin levels and decreased indicators of hemolysis. Patients from this study were eligible to enroll in a 48-week, open-label extension study in which all patients received an oral daily dose (10 mg) of senicapoc. Safety assessments included clinical laboratory data, physical exams, vital signs, ECGs, and ophthalmologic exams. Of 56 eligible patients, 44 enrolled in the open-label study. Because all patients received active drug, no formal efficacy comparisons to placebo were available. Within-subject comparison versus baseline levels from the double-blind phase indicated that the beneficial effects of senicapoc were maintained during the open-label study. Patients demonstrated increases in hemoglobin (+6%), hematocrit (+6%), and RBC count (+6%), and decreases in dense cells (−24%), reticulocytes (−19%), indirect bilirubin (−30%), and lactate dehydrogenase (−18%). Senicapoc was generally well tolerated during the open-label extension study. No deaths occurred, and there were no serious adverse events attributable to senicapoc. Twelve of 44 patients discontinued from the 48-week treatment period. Two patients discontinued due to adverse events considered possibly or probably related to study medication (elevation in gamma glutamyl transferase [GGT] level and interstitial nephritis, respectively). Two additional patients discontinued due to adverse events (sickle cell crisis and pain) not considered related to study medication. Of the 8 remaining patients, 1 was lost to follow-up, and 7 discontinued for administrative reasons. The most common adverse events (≥10% of patients) during treatment included sickle cell pain crisis, arthralgia, back pain, headache, upper respiratory tract infection, limb pain, increased GGT, pyrexia, and rash. The only adverse events that occurred in 2 or more patients and considered possibly related to study medication were GGT elevation, rash, and headache. In conclusion, senicapoc 10 mg once daily for 48 weeks appears to be safe and well tolerated in patients with SCD. Hematologic and clinical laboratory data collected in this safety extension study are consistent with the beneficial hematological effects observed during the Phase II double-blind study.

Introduction: Frequently transfused patients with SCD develop hemosiderosis, which, if untreated, results in multi-organ damage and early death. DFO is the only iron chelator (IC) approved by the FDA and is injected subcutaneously over 8–12 hours/day, 5–7 days/week. However, adherence to this therapy is difficult for patients. This report summarises patient satisfaction with deferasirox (DSX), an oral IC in development, compared to DFO in an open-label Phase II trial. Methods: A total of 195 patients with SCD were randomized and treated with DSX (n=132) or DFO (n=63). Seventy-four patients had not received IC at baseline, of whom 25 were randomized to DFO and 49 to DSX. DSX was taken orally once/day while DFO was infused via a portable pump over 8–12 hours/day, 5–7 days/week. Patient reported outcome data were documented, including satisfaction and convenience with treatment, and number of hours lost/month for taking IC. Patients with previous experiences of DFO reported preferences for DSX, DFO, or neither. At end-of-study (EOS), patients reported their willingness to continue taking the drug they were on. Results: At baseline, only 21% of patients previously treated with DFO reported that they were ‘very satisfied’ or ‘satisfied’ with DFO taken prior to the study, and only 16.5% reported that DFO was ‘very convenient’ or ‘convenient’. Further, 77.1% of them preferred DSX. Reasons included: more convenient to take (38.6%), less disruptive to their day (18.1%), less sore (15.7%) and less disruptive to sleep (6.0%). Table 1 indicates the greater satisfaction and convenience experienced by those on DSX versus DFO regardless of chelation status at baseline. At EOS, significantly more patients on DSX (84.3%) indicated they would be willing to continue DSX, compared to 10.5% of patients on DFO. Similarly, patients reported that time lost due to taking DSX ranged from 0.2–2.9 hours/month, while time lost due to taking DFO ranged from 3.2–37.4 hours/month. Table 1. Satisfaction and Convenience in Patients Previously Treated with DFO versus Treatment Naïve Patients DSX DFO Previous DFO Treatment naïve Previous DFO Treatment naïve Very Satisfied or Satisfied, % Wk 2 85.5 73.5 23.7 24.0 Wk 12 89.2 63.3 42.1 36.0 Wk 24 86.7 69.4 39.8 32.0 EOS 84.3 59.2 23.7 24.0 Very Convenient or Convenient, % Wk 2 79.5 73.5 15.8 32.0 Wk 12 83.1 71.4 36.8 24.0 Wk 24 79.5 71.4 34.2 24.0 EOS 79.5 63.3 18.4 20.0 Conclusions: Results suggest satisfaction and convenience scores are significantly higher, and the impact on daily activities is less, for patients on DSX than those on DFO. Further studies are needed to explore whether higher satisfaction and convenience will lead to better adherence to DSX. As adherence to chelation therapy impacts on survival in transfusion-dependent patients with SCD, these data indicate that DSX may significantly improve the care of transfusion-dependent patients.

The rate and extent of hemoglobin S (HbS) polymer formation in the circulating sickle erythrocyte (RBC) is strongly influenced by the intracellular concentration of HbS. ICA-17043 (bis(4-fluorophenyl)phenyl acetamide) is a novel Gardos channel inhibitor that specifically blocks Ca++-dependent K+ efflux from the human RBC. By limiting the loss of K+, Cl−, and water, this drug preserves the hydration status of the RBC, prevents increases in HbS concentration and thereby inhibits HbS-polymerization. We hypothesized that ICA-17043 could decrease both the hemolytic rate and vaso-occlusive complications of sickle cell anemia (SCA). In a recently completed multicenter, parallel-group, randomized, double-blind, dose-range-finding study, we examined the efficacy and safety of ICA-17043 in patients with SCA. In this 12-week study, 90 patients were randomized into 3 arms: placebo; low dose ICA-17043 (6 mg); and high dose ICA-17043 (10 mg). The primary outcome variable was the change in hemoglobin (Hb) from baseline to the end of the study. A total of 90 subjects were enrolled in this study, 80 of whom completed the 12-week treatment period. Using an intent-to-treat analysis, we found a significant increase from baseline of the total Hb when the subjects in the high dose arm (0.68 ± 0.11 g/dL, S.E.) were compared to those in the placebo arm (0.01 ± 0.12 g/dL), p < 0.001. Although an increase in Hb was also seen in the subjects in the low dose arm (0.28 ± 0.15 g/dL), this smaller change failed to reach statistical significance. Figure Figure In addition to the increase in Hb (as well as similar increases in hematocrit and RBC count), statistically significant decreases were noted after 12 weeks on 10 mg of ICA-17043 vs. placebo in the following variables: a) dense RBC (% with Hb >41 g/dL) [−2.41 vs. −0.08, p < 0.001]; b) reticulocyte count (%) [−4.12 vs. −0.46, p

Functional messenger RNA (mRNA) for human globin synthesis was isolated from reticulocytes of each of two patients with hemoglobin H disease. The RNA was tested for its capacity to direct globin synthesis in a messenger RNA-dependent cell-free system derived from Krebs Type II mouse ascites tumor cells. In each case, hemoglobin H disease mRNA directed the synthesis of a great excess of β-globin chains relative to α-globin chains of hemoglobin A. The β/α synthetic ratios obtained in the cell-free system at saturating concentrations of mRNA were >22 and >15, respectively, for the two hemoglobin H disease mRNA preparations, whereas the β/α synthetic ratios obtained by incubation of intact reticulocytes from these same patients were 2.6 and 2.8, respectively. The β/α synthetic ratio obtained in the cell-free system did not vary when lower concentrations of hemoglobin H disease mRNA were used. A marked decrease in the amount of functional α-globin-chain mRNA relative to β-chain mRNA is therefore associated with the decreased α-chain synthesis observed in hemoglobin H disease. This decrease in α-chain-specific mRNA activity is greater than expected from the β/α synthetic ratio of intact reticulocytes in hemoglobin H disease.