Int J Cardiol. 2017 Jun 29. [Epub ahead of print]

Detection of cardiac iron overload with native magnetic resonance T1 and T2 mapping in patients with thalassemia.

Krittayaphong R1, Zhang S2, Saiviroonporn P3, Viprakasit V4, Tanapibunpon P5, Komoltri C6, Wangworatrakul W7.

 

BACKGROUND:

To investigate the diagnostic performance of native cardiac magnetic resonance (CMR) T1 and T2 mapping for cardiac iron overload (CIO) in thalassemia patients.

METHODS:

All thalassemia patients who underwent CMR were enrolled on a clinical 1.5T scanner. Native T1 mapping with the Modified Look-Locker Inversion recovery (MOLLI) technique, T2 mapping using a black-blood multi-echo spin-echo technique, and conventional T2* mapping using multi-echo gradient-echo techniques were performed. CIO was defined by a T2* of <20ms; while severe CIO was considered as <10ms.

RESULTS:

A total of 200 patients were enrolled in the study (23.9±14.6years old [mean±SD], 102 male). Among these, 8 patients (4.0%) had CIO. Both native T1 and T2 times were significant different among patients with no CIO, mild-to-moderate CIO, and severe CIO (1012.7±57.7 vs. 846.4±34.4 vs 601.3±34.6ms for T1, p<0.05; 59.6±6.5 vs. 48.7±2.5 vs. 32.8±1.2ms for T2, p<0.05). The best cut-off values for detection of CIO were 887 and 52ms for T1 and T2, respectively. This yielded a sensitivity, specificity and area under the curve (AUC) of 100%, 98.4% and 0.997 respectively for T1, in comparison to 100%, 88.8% and 0.961 respectively for T2.

CONCLUSIONS:

Native T1 mapping can differentiate between severe, mild-to-moderate, and no CIO, which appears to be a promising technique for detection and assessment of myocardial iron.

 

PMID: 28688717 DOI: 10.1016/j.ijcard.2017.06.100

Haematologica. 2017 Jun 22. [Epub ahead of print]

Residual erythropoiesis protects against myocardial hemosiderosis in transfusion-dependent thalassemia by lowering labile plasma iron via transient generation of apotransferrin.

Garbowski MW1, Evans P2, Vlachodimitropoulou E2, Hider R3, Porter JB2.

 

Cardiosiderosis is a leading cause of mortality in transfusion-dependent thalassemias. Plasma non-transferrin-bound iron and its redox-active component, labile plasma iron, are key sources of iron loading in cardiosiderosis. Risk factors were identified in 73 patients with or without cardiosiderosis. Soluble transferrin receptor-1 levels were significantly lower in patients with cardiosiderosis (odds ratio 21). This risk increased when transfusion-iron loading rates exceeded the erythroid transferrin uptake rate (derived from soluble transferrin receptor-1) by >0.21mg/kg/d (odds ratio 48). Labile plasma iron was >3-fold higher where this uptake rate threshold was exceeded, but non-transferrin-bound iron and transferrin saturation were comparable. Cardiosiderosis risk was also decreased in patients with low liver iron, ferritin and labile plasma iron, or high bilirubin, reticulocyte counts or hepcidin. We hypothesized that high erythroid transferrin uptake rate decreases cardiosiderosis through increased erythroid re-generation of apotransferrin. To test this, iron uptake and intracellular reactive oxygen species were examined in HL-1 cardiomyocytes under conditions modelling transferrin effects on non-transferrin-bound iron speciation with ferric citrate. Intracellular iron and reactive oxygen species increased with ferric citrate concentrations especially where iron-to-citrate ratios exceeded 1:100, i.e. conditions favoring kinetically labile monoferric rather than oligomer species. Excess iron-binding equivalents of apotransferrin inhibited iron uptake, decreased intracellular reactive oxygen species and labile plasma iron, under conditions favoring monoferric species. In conclusion, high transferrin iron utilisation, relative to the transfusion-iron load rate, decreases the cardiosiderotic risk. A putative mechanism is the transient re-generation of apotransferrin by an active erythron, rapidly binding labile plasma iron-detectable ferric monocitrate species.

 

PMID: 28642302 DOI: 10.3324/haematol.2017.170605

Hematology. 2017 Jun 7 [Epub ahead of print]

Revisiting beta thalassemia intermedia: past, present, and future prospects.

Ben Salah N1, Bou-Fakhredin R2, Mellouli F3, Taher AT2.

 

BACKGROUND:

The spectrum of thalassemias is wide ranging from thalassemia minor, which consists of mild hypochromic microcytic anemia without obvious clinical manifestations, to thalassemia major (TM), which is characterized by severe anemia since the first years of life and is transfusion dependent. Thalassemia intermedia (TI) describes those patients with mild or moderate anemia.

OBJECTIVE:

To describe the genetic features and major clinical complications of TI, and the therapeutic approaches available in the management of this disease.

METHODS:

Publications from potentially relevant journals were searched on Medline.

RESULTS AND DISCUSSION:

Over the past decade, the understanding of TI has increased with regard to pathophysiology and molecular studies. It is now clear that clinical presentation and specific complications make TI different from TM. It is associated with greater morbidity, a wider spectrum of organ dysfunction and more complications than previously thought.

CONCLUSION:

TI is not a mild disease. The interplay of three hallmark pathophysiologic factors (ineffective erythropoiesis, chronic anemia, and iron overload) leads to the clinical presentations seen in TI. New treatment modalities are currently being investigated to broaden the options available for TI management.

 

PMID: 28589785 DOI: 10.1080/10245332.2017.1333246

Am J Hematol. 2017 May;92(5):420-428.

New film-coated tablet formulation of deferasirox is well tolerated in patients with thalassemia or lower-risk MDS: Results of the randomized, phase II ECLIPSE study.

Taher AT1, Origa R2, Perrotta S3, Kourakli A4, Ruffo GB5, Kattamis A6, Goh AS7, Cortoos A8, Huang V8, Weill M9, Merino Herranz R9, Porter JB10.

 

Once-daily deferasirox dispersible tablets (DT) have a well-defined safety and efficacy profile and, compared with parenteral deferoxamine, provide greater patient adherence, satisfaction, and quality of life. However, barriers still exist to optimal adherence, including gastrointestinal tolerability and palatability, leading to development of a new film-coated tablet (FCT) formulation that can be swallowed with a light meal, without the need to disperse into a suspension prior to consumption. The randomized, open-label, phase II ECLIPSE study evaluated the safety of deferasirox DT and FCT formulations over 24 weeks in chelation-naïve or pre-treated patients aged ≥10 years, with transfusion-dependent thalassemia or IPSS-R very-low-, low-, or intermediate-risk myelodysplastic syndromes. One hundred seventy-three patients were randomized 1:1 to DT (n = 86) or FCT (n = 87). Adverse events (overall), consistent with the known deferasirox safety profile, were reported in similar proportions of patients for each formulation (DT 89.5%; FCT 89.7%), with a lower frequency of severe events observed in patients receiving FCT (19.5% vs. 25.6% DT). Laboratory parameters (serum creatinine, creatinine clearance, alanine aminotransferase, aspartate aminotransferase and urine protein/creatinine ratio) generally remained stable throughout the study. Patient-reported outcomes showed greater adherence and satisfaction, better palatability and fewer concerns with FCT than DT. Treatment compliance by pill count was higher with FCT (92.9%) than with DT (85.3%). This analysis suggests deferasirox FCT offers an improved formulation with enhanced patient satisfaction, which may improve adherence, thereby reducing frequency and severity of iron overload-related complications.

 

PMID: 28142202 DOI: 10.1002/ajh.24668

Haematologica. 2017 Mar;102(3):e80-e84

Selective silencing of α-globin by the histone demethylase inhibitor IOX1: a potentially new pathway for treatment of β-thalassemia.

Mettananda S1,2, Fisher CA1, Sloane-Stanley JA3, Taylor S3, Oppermann U4,5, Gibbons RJ1, Higgs DR6,7.

 

PMID: 27810991 PMCID: PMC5394973 DOI: 10.3324/haematol.2016.155655

Pediatr Blood Cancer. 2017 Jan;64(1):188-196.

One-year results from a prospective randomized trial comparing phlebotomy with deferasirox for the treatment of iron overload in pediatric patients with thalassemia major following curative stem cell transplantation.

Inati A1,2, Kahale M2, Sbeiti N3, Cappellini MD4, Taher AT5, Koussa S6, Nasr TA6, Musallam KM5, Abbas HA7, Porter JB8.

 

BACKGROUND:

Iron overload is well documented in patients with β-thalassemia major, and patients who have undergone hematopoietic stem cell transplantation (HSCT) remain at risk as a result of pre- and immediate post-HSCT transfusions.

PROCEDURE:

This is a prospective, randomized, 1-year clinical trial that compares the efficacy and safety of the once-daily oral iron chelator deferasirox versus phlebotomy for the treatment of iron overload in children with β-thalassemia major following HSCT.

RESULTS:

Patients (aged 12.4 years) received deferasirox (n = 12, 10 mg/kg/day starting dose) or phlebotomy (n = 14, 6 ml/kg/2 weeks) for 1 year. In two and five patients, deferasirox dose was increased to 15 and 20 mg/kg/day, respectively. Magnetic resonance imaging (MRI)-assessed liver iron concentration (LIC) decreased with deferasirox (mean 12.5 ± 10.1 to 8.5 ± 9.3 mg Fe/g dry weight [dw]; P = 0.0005 vs. baseline) and phlebotomy (10.2 ± 6.8 to 8.3 ± 9.2 mg Fe/g dw; P = 0.05). LIC reductions were greater with deferasirox than with phlebotomy for patients with baseline serum ferritin 1,000 ng/ml or higher (-8.1 ± 1.5 vs. -3.5 ± 5.7 mg Fe/g dw; P = 0.048). Serum ferritin and non-transferrin-bound iron also decreased significantly. In two patients with severe cardiac siderosis, a clinically relevant improvement in myocardial T2* was seen, following phlebotomy and deferasirox therapy (n = 1 each). Adverse effects with deferasirox were skin rash, gastrointestinal upset, and increased liver function tests (all n = 1), while those for phlebotomy were difficulty with venous access (n = 4) and distress during procedure (n = 1). Parents of 13/14 children receiving phlebotomy wished to switch to deferasirox, with 1/14 being satisfied with phlebotomy.

CONCLUSIONS:

Deferasirox treatment or phlebotomy reduces iron burden in pediatric patients with β- thalassemia major post-HSCT, with a manageable safety profile.

 

PMID: 27576370 DOI: 10.1002/pbc.26213

Eur J Heart Fail. 2017 Apr;19(4):479-489.

Heart failure in haemoglobinopathies: pathophysiology, clinical phenotypes, and management.

Farmakis D1, Triposkiadis F2, Lekakis J1, Parissis J1.

 

Hereditary haemoglobinopathies, mainly beta-thalassemia and sickle cell disease, constitute the most common monogenic disorders in humans, and although once geographically confined, they are currently globally distributed. They are demanding clinical entities that require multidisciplinary medical management. Despite their genotypic and phenotypic heterogeneity, the haemoglobinopathies share several similarities in pathophysiology, clinical manifestations, therapeutic requirements, and complications, among which heart failure (HF) represents a leading cause of mortality and morbidity. However, haemoglobinopathies have generally been addressed in a rather fragmentary manner. A unifying approach focusing on the underlying similarities of HF attributes in the two main entities might contribute to their better understanding, characterization, and management. In the present review, we attempt such an approach to the pathophysiology, clinical phenotypes, and management of HF in haemoglobinopathies.

 

PMID: 28000341 DOI: 10.1002/ejhf.708

Blood. 2017 Mar 16;129(11):1548-1556.

Sickle cell disease: an international survey of results of HLA-identical sibling hematopoietic stem cell transplantation.

Gluckman E1,2, Cappelli B2, Bernaudin F3, Labopin M4, Volt F1,2, Carreras J5, Pinto Simões B6, Ferster A7, Dupont S8, de la Fuente J9, Dalle JH10, Zecca M11, Walters MC12, Krishnamurti L13, Bhatia M14, Leung K15, Yanik G16, Kurtzberg J17, Dhedin N18, Kuentz M3, Michel G19, Apperley J20, Lutz P21, Neven B22, Bertrand Y23, Vannier JP24, Ayas M25, Cavazzana M26,27,28, Matthes-Martin S29, Rocha V1,30,31, Elayoubi H1,2, Kenzey C1,2, Bader P32, Locatelli F33,34, Ruggeri A1,2,35, Eapen M5; Eurocord, the Pediatric Working Party of the European Society for Blood and Marrow Transplantation, and the Center for International Blood and Marrow Transplant Research.

 

Despite advances in supportive therapy to prevent complications of sickle cell disease (SCD), access to care is not universal. Hematopoietic cell transplantation is, to date, the only curative therapy for SCD, but its application is limited by availability of a suitable HLA-matched donor and lack of awareness of the benefits of transplant. Included in this study are 1000 recipients of HLA-identical sibling transplants performed between 1986 and 2013 and reported to the European Society for Blood and Marrow Transplantation, Eurocord, and the Center for International Blood and Marrow Transplant Research. The primary endpoint was event-free survival, defined as being alive without graft failure; risk factors were studied using a Cox regression models. The median age at transplantation was 9 years, and the median follow-up was longer than 5 years. Most patients received a myeloablative conditioning regimen (n = 873; 87%); the remainder received reduced-intensity conditioning regimens (n = 125; 13%). Bone marrow was the predominant stem cell source (n = 839; 84%); peripheral blood and cord blood progenitors were used in 73 (7%) and 88 (9%) patients, respectively. The 5-year event-free survival and overall survival were 91.4% (95% confidence interval, 89.6%-93.3%) and 92.9% (95% confidence interval, 91.1%-94.6%), respectively. Event-free survival was lower with increasing age at transplantation (hazard ratio [HR], 1.09; P < .001) and higher for transplantations performed after 2006 (HR, 0.95; P = .013). Twenty-three patients experienced graft failure, and 70 patients (7%) died, with the most common cause of death being infection. The excellent outcome of a cohort transplanted over the course of 3 decades confirms the role of HLA-identical sibling transplantation for children and adults with SCD.

 

PMID: 27965196 PMCID: PMC5356458 [Available on 2018-03-16] DOI: 10.1182/blood-2016-10-745711

Blood. 2017 May 18;129(20):2719-2726.

Treating sickle cell disease by targeting HbS polymerization.

Eaton WA1, Bunn HF2.

 

Although the root cause of sickle cell disease is the polymerization of hemoglobin S (HbS) to form fibers that make red cells less flexible, most drugs currently being assessed in clinical trials are targeting the downstream sequelae of this primary event. Less attention has been devoted to investigation of the multiple ways in which fiber formation can be inhibited. In this article, we describe the molecular rationale for 5 distinct approaches to inhibiting polymerization and also discuss progress with the few antipolymerization drugs currently in clinical trials.

 

PMID: 28385699 PMCID: PMC5437829 DOI: 10.1182/blood-2017-02-765891

N Engl J Med. 2017 Feb 2;376(5):429-439.

Crizanlizumab for the Prevention of Pain Crises in Sickle Cell Disease.

Ataga KI1, Kutlar A1, Kanter J1, Liles D1, Cancado R1, Friedrisch J1, Guthrie TH1, Knight-Madden J1, Alvarez OA1, Gordeuk VR1, Gualandro S1, Colella MP1, Smith WR1, Rollins SA1, Stocker JW1, Rother RP1.

 

BACKGROUND:

The up-regulation of P-selectin in endothelial cells and platelets contributes to the cell-cell interactions that are involved in the pathogenesis of vaso-occlusion and sickle cell-related pain crises. The safety and efficacy of crizanlizumab, an antibody against the adhesion molecule P-selectin, were evaluated in patients with sickle cell disease.

METHODS:

In this double-blind, randomized, placebo-controlled, phase 2 trial, we assigned patients to receive low-dose crizanlizumab (2.5 mg per kilogram of body weight), high-dose crizanlizumab (5.0 mg per kilogram), or placebo, administered intravenously 14 times over a period of 52 weeks. Patients who were receiving concomitant hydroxyurea as well as those not receiving hydroxyurea were included in the study. The primary end point was the annual rate of sickle cell-related pain crises with high-dose crizanlizumab versus placebo. The annual rate of days hospitalized, the times to first and second crises, annual rates of uncomplicated crises (defined as crises other than the acute chest syndrome, hepatic sequestration, splenic sequestration, or priapism) and the acute chest syndrome, and patient-reported outcomes were also assessed.

RESULTS:

A total of 198 patients underwent randomization at 60 sites. The median rate of crises per year was 1.63 with high-dose crizanlizumab versus 2.98 with placebo (indicating a 45.3% lower rate with high-dose crizanlizumab, P=0.01). The median time to the first crisis was significantly longer with high-dose crizanlizumab than with placebo (4.07 vs. 1.38 months, P=0.001), as was the median time to the second crisis (10.32 vs. 5.09 months, P=0.02). The median rate of uncomplicated crises per year was 1.08 with high-dose crizanlizumab, as compared with 2.91 with placebo (indicating a 62.9% lower rate with high-dose crizanlizumab, P=0.02). Adverse events that occurred in 10% or more of the patients in either active-treatment group and at a frequency that was at least twice as high as that in the placebo group were arthralgia, diarrhea, pruritus, vomiting, and chest pain.

CONCLUSIONS:

In patients with sickle cell disease, crizanlizumab therapy resulted in a significantly lower rate of sickle cell-related pain crises than placebo and was associated with a low incidence of adverse events. (Funded by Selexys Pharmaceuticals and others; SUSTAIN ClinicalTrials.gov number, NCT01895361 .).

 

PMID: 27959701 PMCID: PMC5481200 [Available on 2017-08-02] DOI: 10.1056/NEJMoa1611770

Haematologica. 2017 Feb;102(2):246-259.

ARQ 092, an orally-available, selective AKT inhibitor, attenuates neutrophil-platelet interactions in sickle cell disease.

Kim K1, Li J1, Barazia A1, Tseng A1, Youn SW1, Abbadessa G2, Yu Y2, Schwartz B2, Andrews RK3, Gordeuk VR4,5, Cho J6.

 

Previous studies identified the Ser/Thr protein kinase, AKT, as a therapeutic target in thrombo-inflammatory diseases. Here we report that specific inhibition of AKT with ARQ 092, an orally-available AKT inhibitor currently in phase Ib clinical trials as an anti-cancer drug, attenuates the adhesive function of neutrophils and platelets from sickle cell disease patients in vitro and cell-cell interactions in a mouse model of sickle cell disease. Studies using neutrophils and platelets isolated from sickle cell disease patients revealed that treatment with 50-500 nM ARQ 092 significantly blocks αMβ2 integrin function in neutrophils and reduces P-selectin exposure and glycoprotein Ib/IX/V-mediated agglutination in platelets. Treatment of isolated platelets and neutrophils with ARQ 092 inhibited heterotypic cell-cell aggregation under shear conditions. Intravital microscopic studies demonstrated that short-term oral administration of ARQ 092 or hydroxyurea, a major therapy for sickle cell disease, diminishes heterotypic cell-cell interactions in venules of sickle cell disease mice challenged with tumor necrosis factor-α. Co-administration of hydroxyurea and ARQ 092 further reduced the adhesive function of neutrophils in venules and neutrophil transmigration into alveoli, inhibited expression of E-selectin and intercellular adhesion molecule-1 in cremaster vessels, and improved survival in these mice. Ex vivo studies in sickle cell disease mice suggested that co-administration of hydroxyurea and ARQ 092 efficiently blocks neutrophil and platelet activation and that the beneficial effect of hydroxyurea results from nitric oxide production. Our results provide important evidence that ARQ 092 could be a novel drug for the prevention and treatment of acute vaso-occlusive complications in patients with sickle cell disease.

 

PMID: 27758820 PMCID: PMC5286933 DOI: 10.3324/haematol.2016.151159

Am J Hematol. 2017 Jun 7. [Epub ahead of print]

Losartan for the nephropathy of sickle cell anemia: A phase-2, multicenter trial.

Quinn CT1, Saraf SL2, Gordeuk VR2, Fitzhugh CD3, Creary SE4, Bodas P5, George A6, Raj AB7, Nero AC8, Terrell CE1, McCord L9, Lane A1, Ackerman HC3, Yang Y3, Niss O1, Taylor MD10, Devarajan P11, Malik P1.

 

Nephropathy is a common and progressive complication of sickle cell anemia (SCA). In SCA mice, we found that hyperangiotensinemia in the absence of hypertension underlies nephropathy, and its downregulation by losartan, an angiotensin-II-receptor-1 blocker, reduced albuminuria and progression of nephropathy. Therefore, we performed a phase-2 trial of oral losartan, given for 6 months, to explore whether it reduced albuminuria in children and adults with SCA. Participants were allocated to groups defined by class of baseline urinary albumin-to-creatinine ratio (UACR): no albuminuria (NoA), microalbuminuria (MicroA), and macroalbuminuria (MacroA). The primary endpoint was a ≥25% reduction UACR from baseline. There were 32 evaluable participants (mean age 24 years; NoA = 14, MicroA = 12, MacroA = 6). The primary endpoint was met in 83% of the MacroA group (P < 0.0001) and 58% of the MicroA group (P < 0.0001). Median fold-change in UACR was -0.74 for MacroA and -0.46 for MicroA. In MacroA and MicroA, UACR classification improved in 50% but worsened in 11%. Urine osmolality and estimated glomerular filtration rate (eGFR) did not change significantly. Losartan was discontinued in three participants [leg cramps, N = 1; decline in eGFR >25% (142➝104 mL/minute/1.73 m2 ), N = 1; rise in serum creatinine >50% (0.2➝0.3 mg/dL), N = 1]. Albuminuria was associated with diastolic dysfunction and impaired functional capacity, although cardiopulmonary status was unchanged after 6 months of losartan therapy. In summary, losartan decreased urinary albumin excretion in most participants with albuminuria. Those with macroalbuminuria had the greatest benefit. This study forms the basis for a phase-3, randomized, placebo-controlled trial of losartan for the nephropathy of SCA.

 

PMID: 28589652 DOI: 10.1002/ajh.24810

Am J Hematol. 2017 Jun;92(6):569-582.

The role of carbon monoxide and heme oxygenase in the prevention of sickle cell disease vaso-occlusive crises.

Gomperts E1, Belcher JD2, Otterbein LE3, Coates TD4, Wood J4, Skolnick BE1, Levy H1, Vercellotti GM2.

 

Sickle Cell Disease (SCD) is a painful, lifelong hemoglobinopathy inherited as a missense point mutation in the hemoglobin (Hb) beta-globin gene. This disease has significant impact on quality of life and mortality, thus a substantial medical need exists to reduce the vaso-occlusive crises which underlie the pathophysiology of the disease. The concept that a gaseous molecule may exert biological function has been well known for over one hundred years. Carbon monoxide (CO), although studied in SCD for over 50 years, has recently emerged as a powerful cytoprotective biological response modifier capable of regulating a host of physiologic and therapeutic processes that, at low concentrations, exerts key physiological functions in various models of tissue inflammation and injury. CO is physiologically generated by the metabolism of heme by the heme oxygenase enzymes and is measurable in blood. A substantial amount of preclinical and clinical data with CO have been generated, which provide compelling support for CO as a potential therapeutic in a number of pathological conditions. Data underlying the therapeutic mechanisms of CO, including in SCD, have been generated by a plethora of in vitro and preclinical studies including multiple SCD mouse models. These data show CO to have key signaling impacts on a host of metallo-enzymes as well as key modulating genes that in sum, result in significant anti-inflammatory, anti-oxidant and anti-apoptotic effects as well as vasodilation and anti-adhesion of cells to the endothelium resulting in preservation of vascular flow. CO may also have a role as an anti-polymerization HbS agent. In addition, considerable scientific data in the non-SCD literature provide evidence for a beneficial impact of CO on cerebrovascular complications, suggesting that in SCD, CO could potentially limit these highly problematic neurologic outcomes. Research is needed and hopefully forthcoming, to carefully elucidate the safety and benefits of this potential therapy across the age spectrum of patients impacted by the host of pathophysiological complications of this devastating disease.

 

PMID: 28378932 DOI: 10.1002/ajh.24750

Am J Hematol. 2017 Jul;92(7):622-631.

Inhaled steroids reduce pain and sVCAM levels in individuals with sickle cell disease: A triple-blind, randomized trial.

Glassberg J1, Minnitti C2, Cromwell C3, Cytryn L3, Kraus T4, Skloot GS5, Connor JT6, Rahman AH7, Meurer WJ8.

 

Clinical and preclinical data demonstrate that altered pulmonary physiology (including increased inflammation, increased blood flow, airway resistance, and hyper-reactivity) is an intrinsic component of Sickle Cell Disease (SCD) and may contribute to excess SCD morbidity and mortality. Inhaled corticosteroids (ICS), a safe and effective therapy for pulmonary inflammation in asthma, may ameliorate the altered pulmonary physiologic milieu in SCD. With this single-center, longitudinal, randomized, triple-blind, placebo controlled trial we studied the efficacy and feasibility of ICS in 54 nonasthmatic individuals with SCD. Participants received once daily mometasone furoate 220 mcg dry powder inhalation or placebo for 16 weeks. The primary outcome was feasibility (the number who complete the trial divided by the total number enrolled) with prespecified efficacy outcomes including daily pain score over time (patient reported) and change in soluble vascular cell adhesion molecule (sVCAM) levels between entry and 8-weeks. For the primary outcome of feasibility, the result was 96% (52 of 54, 95% CI 87%-99%) for the intent-to-treat analysis and 83% (45 of 54, 95% CI 71%-91%) for the per-protocol analysis. The adjusted treatment effect of mometasone was a reduction in daily pain score of 1.42 points (95%CI 0.61-2.21, P = 0.001). Mometasone was associated with a reduction in sVCAM levels of 526.94 ng/mL more than placebo (95% CI 50.66-1003.23, P = 0.03). These results support further study of ICS in SCD including multicenter trials and longer durations of treatment. www.clinicaltrials.gov (NCT02061202).

 

PMID: 28370266 – DOI: 10.1002/ajh.24742

Am J Hematol. 2017 Jan;92(1):77-81.

Hydroxyurea effectiveness in children and adolescents with sickle cell anemia: A large retrospective, population-based cohort.

Quarmyne MO1,2, Dong W3, Theodore R1, Anand S1, Barry V2, Adisa O1,2, Buchanan ID1,4, Bost J5, Brown RC1,2, Joiner CH1,2, Lane PA1,2.

 

The clinical efficacy of hydroxyurea in patients with sickle cell anemia (SCA) has been well established. However, data about its clinical effectiveness in practice is limited. We evaluated the clinical effectiveness of hydroxyurea in a large pediatric population using a retrospective cohort, pre-post treatment study design to control for disease severity selection bias. The cohort included children with SCA (SS, Sβ0 thalassemia) who received care at Children’s Healthcare of Atlanta (CHOA) and who initiated hydroxyurea in 2009-2011. Children on chronic transfusions, or children with inadequate follow up data and/or children who had taken hydroxyurea in the 3 years prior were excluded. For each patient healthcare utilization, laboratory values, and clinical outcomes for the 2-year period prior to hydroxyurea initiation were compared to those 2 years after initiation. Of 211 children with SCA who initiated hydroxyurea in 2009-2011, 134 met eligibility criteria. After initiation of hydroxyurea, rates of hospitalizations, pain encounters, and emergency department visits were reduced by 47% (<0.0001), 36% (P = 0.0001) and 43% (P < 0.0001), respectively. Average hemoglobin levels increased by 0.7 g/dl (P < 0.0001). Hydroxyurea effectiveness was similar across gender, insurance types and age, although there was a slightly greater reduction in hospitalizations in younger children. Am. J. Hematol. 92:77-81, 2017. © 2016 Wiley Periodicals, Inc.

 

PMID: 27761932 PMCID – DOI: 10.1002/ajh.24587

JAMA. 2017 Feb 7;317(5):507-515.

Association of Sickle Cell Trait With Hemoglobin A1c in African Americans.

Lacy ME¹, Wellenius GA¹, Sumner AE², Correa A³, Carnethon MR⁴, Liem RI⁵, Wilson JG⁶, Sacks DB⁷, Jacobs DR Jr⁸, Carson AP⁹, Luo X¹⁰, Gjelsvik A¹, Reiner AP¹¹, Naik RP¹², Liu S¹³, Musani SK³, Eaton CB¹, Wu WC¹⁴.

IMPORTANCE:

Hemoglobin A1c (HbA1c) reflects past glucose concentrations, but this relationship may differ between those with sickle cell trait (SCT) and those without it.

OBJECTIVE:

To evaluate the association between SCT and HbA1c for given levels of fasting or 2-hour glucose levels among African Americans.

DESIGN, SETTING, AND PARTICIPANTS:

Retrospective cohort study using data collected from 7938 participants in 2 community-based cohorts, the Coronary Artery Risk Development in Young Adults (CARDIA) study and the Jackson Heart Study (JHS). From the CARDIA study, 2637 patients contributed a maximum of 2 visits (2005-2011); from the JHS, 5301 participants contributed a maximum of 3 visits (2000-2013). All visits were scheduled at approximately 5-year intervals. Participants without SCT data, those without any concurrent HbA1c and glucose measurements, and those with hemoglobin variants HbSS, HbCC, or HbAC were excluded. Analysis of the primary outcome was conducted using generalized estimating equations (GEE) to examine the association of SCT with HbA1c levels, controlling for fasting or 2-hour glucose measures.

EXPOSURES:

Presence of SCT.

MAIN OUTCOMES AND MEASURES:

Hemoglobin A1c stratified by the presence or absence of SCT was the primary outcome measure.

RESULTS:

The analytic sample included 4620 participants (mean age, 52.3 [SD, 11.8] years; 2835 women [61.3%]; 367 [7.9%] with SCT) with 9062 concurrent measures of fasting glucose and HbA1c levels. In unadjusted GEE analyses, for a given fasting glucose, HbA1c values were statistically significantly lower in those with (5.72%) vs those without (6.01%) SCT (mean HbA1c difference, -0.29%; 95% CI, -0.35% to -0.23%). Findings were similar in models adjusted for key risk factors and in analyses using 2001 concurrent measures of 2-hour glucose and HbA1c concentration for those with SCT (mean, 5.35%) vs those without SCT (mean, 5.65%) for a mean HbA1c difference of -0.30% (95% CI, -0.39% to -0.21%). The HbA1c difference by SCT was greater at higher fasting (P = .02 for interaction) and 2-hour (P = .03) glucose concentrations. The prevalence of prediabetes and diabetes was statistically significantly lower among participants with SCT when defined using HbA1c values (29.2% vs 48.6% for prediabetes and 3.8% vs 7.3% for diabetes in 572 observations from participants with SCT and 6877 observations from participants without SCT; P<.001 for both comparisons).

CONCLUSIONS AND RELEVANCE:

Among African Americans from 2 large, well-established cohorts, participants with SCT had lower levels of HbA1c at any given concentration of fasting or 2-hour glucose compared with participants without SCT. These findings suggest that HbA1c may systematically underestimate past glycemia in black patients with SCT and may require further evaluation.

Lancet. 2017 Jul 15;390(10091):311-323.

Sickle cell disease.

Ware RE¹, de Montalembert M², Tshilolo L³, Abboud MR⁴.

 

Sickle cell disease is a common and life-threatening haematological disorder that affects millions of people worldwide. Abnormal sickle-shaped erythrocytes disrupt blood flow in small vessels, and this vaso-occlusion leads to distal tissue ischaemia and inflammation, with symptoms defining the acute painful sickle-cell crisis. Repeated sickling and ongoing haemolytic anaemia, even when subclinical, lead to parenchymal injury and chronic organ damage, causing substantial morbidity and early mortality. Currently available treatments are limited to transfusions and hydroxycarbamide, although stem cell transplantation might be a potentially curative therapy. Several new therapeutic options are in development, including gene therapy and gene editing. Recent advances include systematic universal screening for stroke risk, improved management of iron overload using oral chelators and non-invasive MRI measurements, and point-of-care diagnostic devices. Controversies include the role of haemolysis in sickle cell disease pathophysiology, optimal management of pregnancy, and strategies to prevent cerebrovascular disease.

 

DOI: 10.1016/S0140-6736(17)30193-9.