Iron overload in congenital haemolytic anaemias: role of hepcidin and cytokines and predictive value of ferritin and transferrin saturation

Iron overload (IO) is poorly investigated in the congenital haemolytic anaemias (CHAs), a heterogeneous group of rare inherited diseases encompassing abnormalities of the erythrocyte membrane and metabolism, and defects of the erythropoiesis. In this study we systematically evaluated routine iron parameters and cardiac and hepatic magnetic resonance imaging, together with erythropoietin, hepcidin, non-transferrin bound iron (NTBI), and cytokine serum levels in patients with different CHAs. We found that 40% of patients had a liver iron concentration (LIC) >4 mg Fe/g dry weight. Hepatic IO was associated with ferritin levels (P = 0·0025), transferrin saturation (TfSat, P = 0·002) and NTBI (P = 0·003). Moreover, ferritin >500 μg/l plus TfSat >60% was demonstrated as the best combination able to identify increased LIC, and TfSat alteration as more important in cases with discordant values. Possible confounding factors, such as transfusions, hepatic disease, metabolic syndrome and hereditary haemochromatosis-associated mutations, had negligible effects on IO. Erythropoietin and hepcidin levels were increased in CHAs compared with controls, correlating with LIC and ferritin, respectively. Regarding cytokines, γ-interferon (IFN-γ) was increased, and both interleukin 6 and IFN-γ levels positively correlated with ferritin and hepcidin levels. Overall, these findings suggest the existence of a vicious cycle between chronic haemolysis, inflammatory response and IO in CHAs.     

Bone marrow characterization in sickle cell disease: inflammation and stress erythropoiesis lead to suboptimal CD34 recovery

Stress erythropoiesis and chronic inflammation in subjects with sickle cell disease (SCD) may have an impact on the bone marrow (BM) haematopoietic stem and progenitor cell (HSPC) quality and yield necessary for effective autologous, ex vivo HSPC gene therapy. BM from 19 subjects with SCD and five volunteers without SCD (non-SCD) was collected in different anticoagulants and processed immediately (day 0) or the following day (day 1). Inflammatory, contamination and aggregation markers within the mononuclear layer, and CD34, CD45 and Glycophorin-A (GPA) expression on HSPCs after CD34⁺ selection were analysed by conventional and imaging flow cytometry. Compared to non-SCD BM, multiple markers of inflammation, contamination (red cells, P < 0·01; platelets, P < 0·01) and aggregates (platelet/granulocytes, P < 0·01; mononuclear/red cells, P < 0·01) were higher in SCD BM. Total CD34⁺ cell count was lower in SCD BM (P < 0·05), however CD34⁺ count was higher in SCD BM when collected in acid citrate dextrose-A (ACDA) versus heparin (P < 0·05). Greater than 50% of CD34⁺ HSPCs from SCD BM are CD34^dim due to higher erythroid lineage expression (P < 0·01) as single cell CD34⁺CD45⁺GPA⁺ (P < 0·01) and CD34⁺CD45⁻GPA⁺ (P < 0·01) HSPCs. SCD BM is characterized by increased inflammation, aggregation and contamination contributing to significant differences in HSPC quality and yield compared to non-SCD BM.     

Genome-wide association study of early ischaemic stroke risk in Brazilian individuals with sickle cell disease implicates ADAMTS2 and CDK18 and uncovers novel loci

Ischaemic stroke is a common complication of sickle cell disease (SCD) and without intervention can affect 11% of children with SCD before the age of 20. Within the Trans-Omics for Precision Medicine (TOPMed), a genome-wide association study (GWAS) of ischaemic stroke was performed on 1333 individuals with SCD from Brazil (178 cases, 1155 controls). Via a novel Cox proportional-hazards analysis, we searched for variants associated with ischaemic stroke occurring at younger ages. Variants at genome-wide significance (p < 5 × 10⁻⁸) include two near genes previously linked to non-SCD early-onset stroke (<65 years): ADAMTS2 (rs147625068, p = 3.70 × 10⁻⁹) and CDK18 (rs12144136, p = 2.38 × 10⁻⁹). Meta-analysis, which included the independent SCD cohorts Walk-PHaSST and PUSH, exhibited consistent association for variants rs1209987 near gene TBC1D32 (p = 3.36 × 10⁻¹⁰), rs188599171 near CUX1 (p = 5.89 × 10⁻¹¹), rs77900855 near BTG1 (p = 4.66 × 10⁻⁸), and rs141674494 near VPS13C (1.68 × 10⁻⁹). Findings from this study support a multivariant model of early ischaemic stroke risk and possibly a shared genetic architecture between SCD individuals and non-SCD individuals younger than 65 years.     

Hydroxycarbamide treatment in sickle cell disease: estimates of possible leukaemia risk and of hospitalization survival benefit

Using health insurance claims databases we compared the frequency/incidence of acute myeloid leukaemia (AML) and inpatient mortality in sickle cell disease (SCD) subjects taking (n = 1051), or not taking (n = 9203) hydroxycarbamide (HC). Patients taking HC were older (median 19 vs. 17 years of age), had a higher proportion of males (53% vs. 38%), and their median hospitalizations per year was five times greater than in SCD patients not on HC (all P < 0·001). No new AML cases occurred in HC‐treated paediatric SCD patients. For adults, the new AML incidence with HC exposure was 10·7/10 000 patient years, vs. 4·0/10 000 patient years in subjects not on HC (P = 0·2), a possible AML risk ratio of 3·18. Adjustment for a probable database bias for AML diagnosis/ascertainment lowered the risk ratio to 0·94 (95% confidence interval = 0·16–5·47). Despite their greater disease severity, the inpatient mortality in SCD adults prescribed HC (0·29%) was lower than that of patients not taking the drug (0·42%, P = 0·032). In this SCD population we find no increased risk for AML with HC treatment. If such a risk is eventually proven, it will probably be lower than that for drugs with known AML association. By contrast, HC treatment appears to confer a survival benefit.     

Smoking,blood cells and myeloproliferative neoplasms: meta-analysis and Mendelian randomization of 2·3 million people

Meta-analyses and Mendelian randomization (MR) may clarify the associations of smoking, blood cells and myeloproliferative neoplasms (MPN). We investigated the association of smoking with blood cells in the Danish General Suburban Population Study (GESUS, n = 11 083), by meta-analyses (including GESUS) of 92 studies (n = 531 741) and MR of smoking variant CHRNA3 (rs1051730[A]) in UK Biobank, and with MPN in a meta-analysis of six studies (n (total/cases):1 425 529/2187), totalling 2 307 745 participants. In the meta-analysis the random-effects standardized mean difference (SMD) in current smokers versus non-smokers was 0·82 (0·75–0·89, P = 2·0 * 10⁻¹⁰⁸) for leukocytes, 0·09 (−0·02 to 0·21, P = 0·12) for erythrocytes, 0·53 (0·42–0·64, P = 8·0 * 10⁻²²) for haematocrit, 0·42 (0·34–0·51, P = 7·1 * 10⁻²¹) for haemoglobin, 0·19 (0·08–0·31, P = 1·2 * 10⁻³) for mean corpuscular haemoglobin (MCH), 0·29 (0·19–0·39, P = 1·6 * 10⁻⁸) for mean corpuscular volume (MCV), and 0·04 (−0·04 to 0·13, P = 0·34) for platelets with trends for ever/ex-/current smokers, light/heavy smokers and female/male smokers. Analyses presented high heterogeneity but low publication bias. Per allele in CHRNA3, cigarettes per day in current smokers was associated with increased blood cell counts (leukocytes, neutrophils), MCH, red cell distribution width (RDW) and MCV. The pooled fixed-effects odds ratio for MPN was 1·44 [95% confidence interval (CI): 1·33–1·56; P = 1·8 * 10⁻¹⁹; I² = 0%] in current smokers, 1·29 (1·15–1·44; P = 8·0 * 10⁻⁶; I² = 0%) in ex-smokers, 1·49 (1·26–1·77; P = 4·4 * 10⁻⁶; I² = 0%) in light smokers and 2·04 (1·74–2·39, P = 2·3 * 10⁻¹⁸; I² = 51%) in heavy smokers compared with non-smokers. Smoking is observationally and genetically associated with increased leukocyte counts and red blood cell indices (MCH, MCV, RDW) and observationally with risk of MPN in current and ex-smokers versus non/never-smokers.     

Association between hydroxycarbamide exposure and neurocognitive function in adolescents with sickle cell disease

Patients with sickle cell disease (SCD) are at increased risk for neurocognitive impairments. While disease-modifying treatment, such as hydroxycarbamide (hydroxyurea), may decrease this risk, it has not been systematically investigated in children with SCD. We screened neurocognitive functioning in 103 adolescents with SCD (16–17 years, 50% female) and compared outcomes between patients with a history of exposure to hydroxycarbamide (n = 12 HbSC/HbSβ⁺ thalassaemia; n = 52 HbSS/HbSβ⁰ thalassaemia) and those never treated with hydroxycarbamide (n = 31 HbSC/HbSβ⁺ thalassaemia; n = 8 HbSS/HbSβ⁰ thalassaemia). Demographic distributions were similar between the groups. After adjusting for socioeconomic status, the hydroxycarbamide group had significantly higher scores on nonverbal IQ (HbSC/HbSβ thalassaemia: P = 0·036, effect size [d] = 0·65), reaction speed (HbSS/HbSβ⁰ thalassaemia: P = 0·002, d = 1·70), sustained attention (HbSS/HbSβ⁰ thalassaemia: P = 0·014, d = 1·30), working memory (HbSC/HbSβ⁺ thalassaemia: P = 0·034, d = 0·71) and verbal memory (HbSC/HbSβ⁺ thalassaemia: P = 0·038, d = 0·84) when compared to those who did not receive hydroxycarbamide. In patients with HbSS/HbSβ⁰ thalassaemia, longer treatment duration with hydroxycarbamide was associated with better verbal memory (P = 0·009) and reading (P = 0·002). Markers of hydroxycarbamide effect, including higher fetal haemoglobin (HbF), higher mean corpuscular volume (MCV) and lower white blood cell count (WBC), were associated with better verbal fluency (HbF: P = 0·014, MCV: P = 0·006, WBC: P = 0·047) and reading (MCV: P = 0·021, WBC: P = 0·037). Cognitive impairment may be mitigated by exposure to hydroxycarbamide in adolescents with SCD.     

A Toll-like receptor 2 genetic variant modulates occurrence of bacterial infections in patients with sickle cell disease

Despite adequate immunization and penicillin prophylaxis, bacterial infections remain a leading cause of morbidity and mortality in patients with sickle cell disease (SCD). Besides hyposplenism, inflammatory and genetic factors might modulate their susceptibility to bacterial infections. We performed a candidate gene association of single nucleotide polymorphisms (SNPs) located in Toll-like receptor (TLR) genes, encoding prominent molecules for innate immune responses, with the occurrence of bacterial infections in patients with SCD. A cohort followed in centres in Brazil, France and Senegal (n = 430) was divided in two groups: patients who presented at least one episode of bacterial infection (n = 235) and patients who never had bacterial infections (n = 195). There were no differences in gender or age distribution among the groups. The frequency of the TLR2 rs4696480 TA genotype was significantly lower in the infected group (50% vs. 67%, odds ratio [OR] = 0·50, 95% confidence interval [CI] 0·34–0·75, P < 0·001), and the TT genotype was significantly higher in the infected group (15% vs. 5%, OR = 3·18, 95% CI 1·53–6·61, P < 0·001). Previous reports demonstrated higher secretion of inflammatory factors in cells from AA individuals, lower occurrence and severity of immune diseases in T carriers. The rs4696480 TA genotype might stand between deleterious effects of over inflammatory response (AA genotype) and inefficient responses (TT genotype) to infectious agents in SCD settings.     

Effect of renin-angiotensin-aldosterone system blocking agents on progression of glomerulopathy in sickle cell disease

Although renin-angiotensin-aldosterone system (RAAS) blocking agents decrease albuminuria in short-term studies, there is no evidence confirming their long-term efficacy in sickle cell disease (SCD). In a single-centre, retrospective study, we evaluated the long-term effect of RAAS blocking agents on proteinuria and declining estimated glomerular filtration rates (eGFR). Eighty-six patients on RAAS blocking agents for proteinuria, followed for a median of 2·28 years, were compared with 68 patients with proteinuria followed for 2·24 years who were not receiving such treatment. The log odds of proteinuria decreased over time in patients on RAAS blocking agents (β: −0·23, P = 0·03) and in the non-treatment group (β: −0·54, P < 0·0001), but was not statistically different between both groups (β: 0·31, P = 0·063). The eGFR declined over time in patients on RAAS blocking agents (β: −2·78, P < 0·0001) and in those not on such treatment (β: −4·7, P < 0·0001), and was statistically different between both groups (β: 1·9, P = 0·0002). Baseline eGFR was associated with mortality (Hazard rato: 0·97, P < 0·0001), but RAAS blocking agents had no significant effect on mortality. These data suggest that RAAS blockade may slow the loss of kidney function in SCD.     

Plasma histamine elevation in a large cohort of sickle cell disease patients

The role of mast cells has been questioned in sickle cell disease (SCD). We performed a prospective study evaluating plasma histamine and tryptase levels in a cohort of paediatric and adult patients, in steady state (n = 132) and during vaso-occlusive crisis (VOC) (n = 121). Histamine level was elevated in 18% of patients in steady state and in 61% during VOC. Median histamine level was significantly higher during VOC than in steady state (24·1 [7·0–45·0] vs 9·6 [6·2–14·4] nmol/l, P < 0·0001). Tryptase level was slightly increased during VOC without reaching pathological values. These results suggest a role of mast cell activation in SCD pathophysiology.     

Similar outcome of upfront‐unrelated and matched sibling stem cell transplantation in idiopathic paediatric aplastic anaemia. A study on behalf of the UK Paediatric BMT Working Party,Paediatric Diseases Working Party and Severe Aplastic Anaemia Working Party of EBMT

We explored the feasibility of unrelated donor haematopoietic stem cell transplant (HSCT) upfront without prior immunosuppressive therapy (IST) in paediatric idiopathic severe aplastic anaemia (SAA). This cohort was then compared to matched historical controls who had undergone first‐line therapy with a matched sibling/family donor (MSD) HSCT (n = 87) or IST with horse antithymocyte globulin and ciclosporin (n = 58) or second‐line therapy with unrelated donor HSCT post‐failed IST (n = 24). The 2‐year overall survival in the upfront cohort was 96 ± 4% compared to 91 ± 3% in the MSD controls (P = 0·30) and 94 ± 3% in the IST controls (P = 0·68) and 74 ± 9% in the unrelated donor HSCT post‐IST failure controls (P = 0·02).The 2‐year event‐free survival in the upfront cohort was 92 ± 5% compared to 87 ± 4% in MSD controls (P = 0·37), 40 ± 7% in IST controls (P = 0·0001) and 74 ± 9% in the unrelated donor HSCT post‐IST failure controls (n = 24) (P = 0·02). Outcomes for upfront‐unrelated donor HSCT in paediatric idiopathic SAA were similar to MSD HSCT and superior to IST and unrelated donor HSCT post‐IST failure. Front‐line therapy with matched unrelated donor HSCT is a novel treatment approach and could be considered as first‐line therapy in selected paediatric patients who lack a MSD.     

Tumour-immune microenvironment in duodenal-type follicular lymphoma

Despite duodenal-type follicular lymphoma (DTFL) being morphologically, immunophenotypically and genetically indistinguishable from nodal FL (nFL), this entity typically shows a significantly better prognosis. Here, we analysed the tumour immune microenvironments of diagnostic specimens from patients with DTFL (n = 30), limited-stage FL (LSFL; n = 19) and advanced-stage FL (ASFL; n = 31). The mean number of CD8⁺ tumour-infiltrating lymphocytes (TILs) in the neoplastic follicles was higher in DTFL (1,827/mm²) than in LSFL (1,150/mm²) and ASFL (1,188/mm²) (P = 0·002, P = 0·002, respectively). In addition, CD8⁺PD1⁻ T cells with non-exhausting phenotype were more abundant in the peripheral blood (PB) of DTFL than in LSFL and ASFL, indicating that DTFL may exhibit a better and longer-lasting T cell-mediated immune response. Moreover, whereas FOXP3⁺CTLA-4⁺ effector regulatory T cells (eTregs) were rarely observed in the neoplastic follicles of DTFL (mean: 12/mm²), they were more abundant in LSFL (78/mm²) and ASFL (109/mm²) (P = 2·80 × 10⁻⁵, P = 4·74 × 10⁻⁸, respectively), and the numbers of eTregs correlated inversely with those of CD8⁺ TILs (r = −0267; P = 0·018). Furthermore, DTFL showed significantly fewer circulating FOXP3^hiCD45RA^-CD25^hi eTregs (0·146%) than ASFL (0·497%) and healthy controls (0·639%) (P = 0·0003, P = 6·79 × 10⁻⁷, respectively). These results suggest that the augmented anti-tumour immune reactions may contribute to a better prognosis on DTFL.     

In situ BCL2 expression is an independent prognostic factor in HIV-associated DLBCL,a LYMPHOVIR cohort study

The prognostic value of cell of origin (COO) classification and BCL2 expression is not well established in diffuse large B-cell lymphoma (DLBCL) patients with human immunodeficiency virus (HIV) infection in the recent era. Phenotypic patterns were determined by immunohistochemistry (IHC) of pathological samples from patients with HIV-associated DLBCL prospectively enrolled in the French AIDS and Viral Hepatitis CO16 Lymphovir cohort between 2008 and 2015. Molecular subgroup classification into germinal centre B-cell (GCB) and non-GCB subtypes was determined using the Hans algorithm. Among 52 samples of systemic DLBCL subjected to centralized pathological analysis, 25 of the 42 tested for BCL2 expression were positive. Samples were further classified into GCB (n = 19) and non-GCB (n = 16) subtypes and 17 remained unclassified. In multivariable analysis, BCL2 expression was an independent pejorative prognostic biomarker [4-year progression-free survival (PFS): 52% for BCL2⁺ vs. 88% for BCL2⁻, P = 0·02] and tended to reduce 4-year overall survival (OS) (63% for BCL2⁺ vs. 88% for BCL2⁻, P = 0·06). The difference between CGB and non-GCB subtypes on PFS and OS did not reach significance (4-year PFS: 79% for GCB vs. 53% for non-GCB, P = 0·24 and 4-year OS: 78% for GCB vs. 69% for non-GCB, P = 0·34). BCL2 expression determined by IHC is an independent pejorative prognostic biomarker in HIV-associated DLBCL in the recent era. This supports the investigation of new therapeutic strategies in patients with BCL2 expression.     

Assessing cardiac and liver iron overload in chronically transfused patients with sickle cell disease

Transfusional iron overload represents a substantial challenge in the management of patients with sickle cell disease (SCD) who receive chronic or episodic red blood cell transfusions. Iron‐induced cardiomyopathy is a leading cause of death in other chronically transfused populations but rarely seen in SCD. Study objectives were to: (i) examine the extent of myocardial and hepatic siderosis using magnetic resonance imaging (MRI) in chronically transfused SCD patients, and (ii) evaluate the relationship between long‐term (over the 5 years prior to enrolment) mean serum ferritin (MSF), spot‐ferritin values and liver iron content (LIC) measured using MRI and liver biopsy. Thirty‐two SCD patients (median age 15 years) with transfusional iron overload were recruited from two U.S. institutions. Long‐term MSF and spot‐ferritin values significantly correlated with LIC by MRI‐R2* (r = 0·77, P < 0·001; r = 0·82, P < 0·001, respectively). LIC by MRI‐R2* had strong positive correlation with LIC by liver biopsy (r = 0·98, P < 0·001) but modest inverse correlation with cardiac MRI‐T2* (r = ?0·41, P = 0·02). Moderate to severe transfusional iron overload in SCD was not associated with aberrations in other measures of cardiac function based on echocardiogram or serum biomarkers. Our results suggest that SCD patients receiving chronic transfusions may not demonstrate significant cardiac iron loading irrespective of ferritin trends, LIC and erythropoiesis suppression.     

Intracranial 4D flow magnetic resonance imaging reveals altered haemodynamics in sickle cell disease

Stroke risk in children with sickle cell disease (SCD) is currently assessed with routine transcranial Doppler ultrasound (TCD) measurements of blood velocity in the Circle of Willis (CoW). However, there is currently no biomarker with proven prognostic value in adult patients. Four‐dimensional (4D) flow magnetic resonance imaging (MRI) may improve risk profiling based on intracranial haemodynamics. We conducted neurovascular 4D flow MRI and blood sampling in 69 SCD patients [median age 15 years (interquartile range, IQR: 12–50)] and 14 healthy controls [median age 21 years (IQR: 18–43)]. We measured velocity, flow, lumen area and endothelial shear stress (ESS) in the CoW. SCD patients had lower haematocrit and viscosity, and higher velocity, flow and lumen area, with lower ESS compared to healthy controls. We observed significant age‐related decline in haemodynamic 4D flow parameters; velocity (Spearman's ρ = −0·36 to −0·61), flow (ρ = −0·26 to −0·52) and ESS (ρ = −0·14 to −0·54) in SCD patients. Further analysis in only adults showed that velocity values were similar in SCD patients compared to healthy controls, but that the additional 4D flow parameters, flow and lumen area, were higher, and ESS lower, in the SCD group. Our data suggest that 4D flow MRI may identify adult patients with an increased stroke risk more accurately than current TCD‐based velocity.     

Clinical features and prognostic factors in solitary plasmacytoma

This study aimed to review the clinical features and outcome of 53 patients with solitary plasmacytoma managed at our Institution between 1976 and 2012. Thirty‐five patients had bone solitary plasmacytoma and 18 extramedullary solitary plasmacytoma. Tumour sizes were larger in patients with bone involvement (P = 0·003). Treatment consisted of local radiotherapy (n = 26), radiotherapy + chemotherapy (n = 15), surgery (n = 4) and chemotherapy (n = 8); the local control rate was 94·3%. Progression to multiple myeloma was recorded in 20/35 (57·1%) patients with bone involvement and in 1/18 (5·5%) patients with extramedullary disease (P = 0·0003). The 5‐year overall survival (OS) rate was 78·4%; bone solitary plasmacytoma patients had a significantly worse OS (71·9% vs. 88·2%, respectively; P = 0·029) and 5‐year progression‐free survival (PFS; 53·0% vs. 88·5%; P = 0·0003) compared to extramedullary solitary plasmacytoma patients. On univariate analysis, bone disease and size (≥5 cm) impacted negatively on PFS (P = 0·0027 and P = 0·04, respectively). Bone disease also affected OS (P = 0·04). In multivariate analysis bone location was the only independent prognostic factor for PFS (P = 0·0041) and OS (P = 0·021). Patients with bone solitary plasmacytoma have a significantly worse prognosis than extramedullary solitary plasmacytoma cases.     

Association between plasma free haem and incidence of vaso‐occlusive episodes and acute chest syndrome in children with sickle cell disease

We tested the hypothesis that extracellular haem is linked to the incidence of acute complications of sickle cell disease (SCD). Using multivariable regression analysis, higher plasma free haem, but not total plasma haem, was associated with increased odds of vaso‐occlusive crisis (VOC) [P = 0·028, odds ratio (OR); 2·05, 95% Confidence Interval (CI) = 1·08–3·89] and acute chest syndrome (ACS) [P = 0·016, OR; 2·56, CI = 1·19, 5·47], after adjusting for age and gender in children with SCD. These findings suggest that haem and factors that influence its concentration in plasma may be informative of the risk of VOC and ACS in SCD patients.     

Interim assessment of liver damage in patients with sickle cell disease using new non‐invasive techniques

We explored transient elastography (TE ) and enhanced liver fibrosis (ELF ^™) score with standard markers of liver function to assess liver damage in 193 well patients with sickle cell disease (SCD ). Patients with HbSS or HbSβ⁰ thalassaemia (sickle cell anaemia, SCA ; N  = 134), had significantly higher TE results and ELF scores than those with HbSC (N  = 49) disease (TE , 6·8 vs. 5·3, P  < 0·0001 and ELF , 9·2 vs. 8·6 P  < 0·0001). In SCA patients, TE and ELF correlated significantly with age and all serum liver function tests (LFT s). Additionally, (weak) positive correlation was found with lactate dehydrogenase (TE : r  = 0·24, P  = 0·004; ELF : r  = 0·26 P  = 0·002), and (weak) negative correlation with haemoglobin (TE : r  = −0·25, P  = 0·002; ELF : r  = −0·25 P  = 0·004). In HbSC patients, correlations were weaker or not significant between TE or ELF , and serum LFT s. All markers of iron loading correlated with TE values when corrected for sickle genotype (serum ferritin, β = 0·25, P  < 0·0001, total blood transfusion units, β = 0·25, P  < 0·0001 and LIC β = 0·32, P  = 0·046). The exploratory study suggests that, while TE could have a role, the utility of ELF score in monitoring liver damage in SCD , needs further longitudinal studies.     

Graft-versus-host disease and graft-versus-leukaemia effects in secondary acute myeloid leukaemia: a retrospective,multicentre registry analysis from the Acute Leukaemia Working Party of the EBMT

We assessed the susceptibility of secondary acute myeloid leukaemia (sAML) to graft-versus-leukaemia effects. Data from 2414 sAML patients in first (n = 2194) or second (n = 220) complete remission were included. They were given grafts from human leucocyte antigen (HLA)-matched sibling (MSD, n = 1085), 10/10 unrelated donor (MUD, n = 1066) or 9/10 mismatched unrelated donor (MMUD, n = 263). The 100-day incidence of grade II-IV acute graft-versus-host disease (GVHD) was 25% while 2-year incidence of chronic GVHD was 38%. Relapse rates declined steadily by duration of follow-up and were significantly lower in patients with chronic GVHD (P < 0·001). Limited (hazard ratio [HR] = 0·66, P < 0·001) and extensive (HR = 0·52, P < 0·001) chronic GVHD were associated with a lower incidence of relapse. Each grade III-IV acute (HR = 7·04, P < 0·001) as well as limited (HR = 1·42, P = 0·03) and extensive (HR = 3·97, P < 0·001) chronic GVHD were associated with higher non-relapse mortality (NRM). This translated to better overall survival (OS; HR = 0·61, P < 0·001) in patients with limited chronic GVHD. In contrast, grade III-IV acute and extensive chronic GVHD were associated with worse OS (HR = 3·16, P < 0·001 and HR = 1·21, P = 0·03, respectively). Further, in comparison to HLA-identical sibling recipients, MUD recipients had a lower risk of relapse (HR = 0·82, P = 0·03) but higher NRM (HR = 1·38, P = 0·004). In conclusion, these data demonstrate that sAML is susceptible to graft-versus-leukaemia effects.     

Improvement of medical care in a cohort of newborns with sickle‐cell disease in North Paris: impact of national guidelines

We conducted a retrospective study on newborns with sickle‐cell disease (SCD), born 1995–2009, followed in a multicentre hospital‐based network. We assessed patient outcomes, medical care and compliance with the national guidelines published in December 2005. Data from 1033 patients (742 SS/Sβ°‐thalassaemia) with 6776 patient‐years of follow‐up were analysed (mean age 7·1 ± 3·9 years). SCD‐related deaths (n = 13) occurred only in SS‐genotype patients at a median age of 23·1 months, mainly due to acute anaemia (n = 5, including 2 acute splenic sequestrations) and infection (n = 3). Treatment non‐compliance was associated with a 10‐fold higher risk of SCD‐related death (P = 0·01). Therapeutic intensification was provided for all stroke patients (n = 12), almost all patients with abnormal transcranial Doppler (TCD) (n = 76) or with >1 acute chest syndrome/lifetime (n = 64) and/or ≥3 severe vaso‐occlusive crises/year (n = 100). Only 2/3 of patients with baseline haemoglobin <70 g/l received intensification, mainly for other severity criteria. Overall, hydroxycarbamide was under‐prescribed, given to 2/3 of severe vaso‐occlusive patients and 1/3 of severely anaemic patients. Nevertheless, introduction of the on‐line guidelines was concomitant with an improvement in medical care in the 2006–2009 cohort with a trend towards increased survival at 5 years, from 98·3% to 99·2%, significantly increased TCD coverage (P = 0·004) and earlier initiation of intensification of therapy (P ≤ 0·01).     

Association between baseline serum hepcidin levels and infection in kidney transplant recipients: Potential role for iron overload

Background

The liver‐synthesized peptide hepcidin is a key regulator of iron metabolism and correlates with total iron stores. We analyzed the association between pre‐transplant hepcidin‐25 levels and infection after kidney transplantation (KT).

Methods

Serum hepcidin‐25 levels were measured at baseline by high‐sensitivity ELISA in 91 patients undergoing KT at our institution between December 2011 and March 2013. The impact of this biomarker on the incidence of post‐transplant infection (excluding lower urinary tract infection) during the first year was assessed by Cox regression.

Results

Mean hepcidin‐25 level was 82.3 ± 67.4 ng/mL and strongly correlated with serum ferritin (Spearman's rho = 0.703; P < .001). There were no significant differences in hepcidin‐25 levels between patients with or without overall infection (96.4 ± 67.5 vs 72.6 ± 66.7 ng/mL; P = .101). Such difference was evident for opportunistic (128.9 ± 75.0 vs 73.0 ± 62.3 ng/mL; P = .003) and, to a lesser extent, surgical‐site infection (107.5 ± 73.3 vs 76.5 ± 65.2 ng/mL; P = .087). Patients with hepcidin‐25 levels ≥72.5 ng/mL had higher 12‐month cumulative incidence of overall infection (51.2% vs 29.2%; P = .032). After multivariate adjustment, hepcidin‐25 ≥72.5 ng/mL acted as an independent risk factor for overall (adjusted hazard ratio [aHR] 3.86; 95% confidence interval [CI] 1.49‐9.96; P = .005) and opportunistic infection (aHR 4.32; 95% CI 1.18‐15.75; P = .027).

Conclusion

Elevated baseline serum hepcidin‐25 levels were associated with increased risk of infection after KT, suggesting a role for iron overload in the individual susceptibility to post‐transplant infection.