When to consider transfusion therapy for patients with non‐transfusion‐dependent thalassaemia

Non‐transfusion‐dependent thalassaemia (NTDT) refers to all thalassaemia disease phenotypes that do not require regular blood transfusions for survival. Thalassaemia disorders were traditionally concentrated along the tropical belt stretching from sub‐Saharan Africa through the Mediterranean region and the Middle East to South and South‐East Asia, but global migration has led to increased incidence in North America and Northern Europe. Transfusionists may be familiar with β‐thalassaemia major because of the lifelong transfusions needed by these patients. Although patients with NTDT do not require regular transfusions for survival, they may require transfusions in some instances such as pregnancy, infection or growth failure. The complications associated with NTDT can be severe if not properly managed, and many are directly related to chronic anaemia. Awareness of NTDT is important, and this review will outline the factors that should be taken into consideration when deciding whether to initiate and properly plan for transfusion therapy in these patients in terms of transfusion interval and duration of treatment.     

Optimising management of deferasirox therapy for patients with transfusion‐dependent thalassaemia and lower‐risk myelodysplastic syndromes

Effective iron chelation therapy is an important part of treatment in patients with transfusion‐dependent thalassaemia and lower‐risk myelodysplastic syndromes (MDS). Key strategies for optimising iron chelation therapy include ensuring good adherence and preventing and managing adverse events (AEs). Good adherence to iron chelation therapy with deferoxamine and deferasirox has been linked to improved survival and/or reductions in complications related to iron overload; however, maintaining good adherence to iron chelators can be challenging. Patients with transfusion‐dependent thalassaemia or lower‐risk MDS showed better adherence to the deferasirox film‐coated tablet (FCT) formulation than to the deferasirox dispersible tablet formulation in the ECLIPSE trial, reflecting in part the improved palatability and convenience of deferasirox FCT. As well as affecting adherence, AEs may lead to dose reduction, interruption or discontinuation, resulting in suboptimal iron chelation therapy. Preventing and successfully managing AEs may help limit their impact on adherence, and following dosage and administration recommendations for iron chelators such as deferasirox may help minimise AEs and optimise treatment in patients with transfusion‐dependent thalassaemia and lower‐risk MDS.     

Deferasirox effect on renal haemodynamic parameters in patients with transfusion‐dependent β thalassaemia

Some patients with β thalassaemia experience non‐progressive creatinine increases with deferasirox, mostly within normal limits; the mechanisms involved are not fully elucidated. The effects of deferasirox on renal haemodynamics, including glomerular filtration rate (GFR) and renal plasma flow (RPF), were investigated in a Phase I, open‐label study in β thalassaemia major patients with iron overload. Patients received deferasirox 30 mg/kg/d up to Week 8, followed by a 2‐week washout period, and extended treatment up to Week 104 with a 4‐week washout period. In the short‐term study (n = 11), mean GFR and RPF declined from baseline to Week 8 (mean [%] change:?9·2 [?9·5%] and ?105·7 ml/min [?17·8%], respectively). A similar pattern was observed during the long‐term study (n = 5); mean GFR and RPF decreased up to Week 52 (?19·1 [?17·7%] and ?155·6 ml/min [?26·1%]), with similar change at Week 104 (?18·4 [?17·2%] and ?115·9 ml/min [?19·6%]). Measures returned to baseline values after each washout. Serum creatinine and creatinine clearance followed a similar pattern. Effects of deferasirox on renal haemodynamics were mild and reversible for up to 2 years of treatment, with no progressive worsening of renal function over time. www.clinicaltrials.gov : NCT00560820.     

Defining serum ferritin thresholds to predict clinically relevant liver iron concentrations for guiding deferasirox therapy when MRI is unavailable in patients with non‐transfusion‐dependent thalassaemia

Liver iron concentration (LIC) assessment by magnetic resonance imaging (MRI) remains the gold standard to diagnose iron overload and guide iron chelation therapy in patients with non‐transfusion‐dependent thalassaemia (NTDT). However, limited access to MRI technology and expertise worldwide makes it practical to also use serum ferritin assessments. The THALASSA (assessment of Exjade^® in non‐transfusion‐dependent THALASSemiA patients) study assessed the efficacy and safety of deferasirox in iron‐overloaded NTDT patients and provided a large data set to allow exploration of the relationship between LIC and serum ferritin. Using data from screened patients and those treated with deferasirox for up to 2 years, we identified clinically relevant serum ferritin thresholds (for when MRI is unavailable) for the initiation of chelation therapy (>800 μg/l), as well as thresholds to guide chelator dose interruption (<300 μg/l) and dose escalation (>2000 μg/l). (clinicaltrials.gov identifier: NCT00873041).     

The impact of liver steatosis on the ability of serum ferritin levels to be predictive of liver iron concentration in non‐transfusion‐dependent thalassaemia patients

This study analysed the impact of liver steatosis (LS) on the parameters of iron overload in 110 patients with non‐transfusion dependent thalassaemia (NTDT). LS was diagnosed by ultrasound. Liver iron concentration (LIC) measurements were available for 64 patients who underwent a magnetic resonance imaging (MRI) scan. LS was frequent (35·5%) and was significantly more prevalent in males than in females (49·0% vs. 24·6%, P = 0·008). Patients with LS had significant higher levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), ALT/AST ratio and ferritin than those without, but LIC values were comparable. An ALT/AST ratio >0·89 predicted the presence of LS with a sensitivity of 0·872 and a specificity of 0·901 (P < 0·0001). Ferritin levels correlated with LIC values (R = 0·558, P < 0·0001) but the correlation was stronger in patients without LS (R = 0·656, P < 0·0001) than in patients with LS (R = 0·426, P = 0·05). LS is a frequent issue in NTDT patients and should be suspected in the presence of an ALT/AST ratio >0·89. Recently, serum ferritin thresholds that predict clinically relevant LIC for guiding iron chelation therapy when MRI is unavailable have been determined. Our data show that LS may cause increase in ferritin levels and may be responsible for anticipating/exceeding chelation treatment in NTDT patients in the absence of LIC evaluation.     

Iron overload across the spectrum of non‐transfusion‐dependent thalassaemias: role of erythropoiesis,splenectomy and transfusions

Non‐transfusion‐dependent thalassaemias (NTDT ) encompass a spectrum of anaemias rarely requiring blood transfusions. Increased iron absorption, driven by hepcidin suppression secondary to erythron expansion, initially causes intrahepatic iron overload. We examined iron metabolism biomarkers in 166 NTDT patients with β thalassaemia intermedia (n  = 95), haemoglobin (Hb) E/β thalassaemia (n  = 49) and Hb H syndromes (n  = 22). Liver iron concentration (LIC ), serum ferritin (SF ), transferrin saturation (TfSat) and non‐transferrin‐bound iron (NTBI ) were elevated and correlated across diagnostic subgroups. NTBI correlated with soluble transferrin receptor (sTfR ), labile plasma iron (LPI ) and nucleated red blood cells (NRBC s), with elevations generally confined to previously transfused patients. Splenectomised patients had higher NTBI , TfSat, NRBC s and SF relative to LIC , than non‐splenectomised patients. LPI elevations were confined to patients with saturated transferrin. Erythron expansion biomarkers (sTfR , growth differentiation factor‐15, NRBC s) correlated with each other and with iron overload biomarkers, particularly in Hb H patients. Plasma hepcidin was similar across subgroups, increased with >20 prior transfusions, and correlated inversely with TfSat, NTBI , LPI and NRBC s. Hepcidin/SF ratios were low, consistent with hepcidin suppression relative to iron overload. Increased NTBI and, by implication, risk of extra‐hepatic iron distribution are more likely in previously transfused, splenectomised and iron‐overloaded NTDT patients with TfSat >70%.     

Hepatitis E virus is a leading cause of acute-on-chronic liver disease:experience from a tertiary centre in Bangladesh

BACKGROUND:Acute-on-chronic liver failure(ACLF) is common in Bangladesh.Acute viral E hepatitis is sporadically encountered in this country each year,with a rising incidence in the rainy season.This study aimed to identify the etiology of ACLF in Bangladesh. METHODS:In this retrospective study,69 ACLF patients were included.They presented to our department at the Bangabandhu Sheikh Mujib Medical University in Dhaka.History of diseases was recorded and appropriate investigations were conducted in all patient...     

A randomized phase I/II trial of HQK‐1001, an oral fetal globin gene inducer,in β‐thalassaemia intermedia and HbE/β‐thalassaemia

β‐thalassaemia intermedia (BTI) syndromes cause haemolytic anaemia, ineffective erythropoiesis, and widespread complications. Higher fetal globin expression within genotypes reduces globin imbalance and ameliorates anaemia. Sodium 2,2 dimethylbutyrate (HQK‐1001), an orally bioavailable short‐chain fatty acid derivative, induces γ‐globin expression experimentally and is well‐tolerated in normal subjects. Accordingly, a randomized, blinded, placebo‐controlled, Phase I/II trial was performed in 21 adult BTI patients (14 with HbE/β⁰ thalassaemia and seven with β⁺/β⁰ thalassaemia intermedia, to determine effective doses for fetal globin induction, safety, and tolerability. HQK‐1001 or placebo were administered once daily for 8 weeks at four dose levels (10, 20, 30, or 40 mg/kg per day), and subjects were monitored for laboratory and clinical events. Pharmacokinetic profiles demonstrated a t_1/2 of 10–12 h. Adverse events with HQK‐1001 treatment were not significantly different from placebo treatment. The 20 mg/kg treatment doses increased median HbF above baseline levels by 6·6% and 4·4 g/l (P < 0·01) in 8/9 subjects; total haemoglobin (Hb) increased by a mean of 11 g/l in 4/9 subjects. These findings identified a safe oral therapeutic which induces fetal globin in BTI. Further investigation of HQK‐1001 with longer dosing to definitively evaluate its haematological potential appears warranted.     

Hepatitis E virus prevalence in Flemish blood donors

Transmission of hepatitis E virus (HEV) through transfusion of blood components has already been reported in several European countries. Here, we assessed the HEV prevalence in Flemish blood donors. This study is of importance in order to assess the risk of HEV transmission through blood transfusion. We analysed 38 137 blood donation samples that were collected by the Red Cross Flanders during the period May‐June 2015. All samples were screened for the presence of HEV RNA and a selection for HEV‐specific IgM/IgG. After pooling per 6, 11 pools reacted positive during RNA screening. Reactive pools were deconstructed, and individual samples were retested. After deconstruction, seven samples were confirmed as HEV RNA positive. Serological screening of the confirmed RNA‐positive samples showed that six out of these seven samples were HEV IgM positive, of which three donors were also IgG positive. Serological screening was also performed on the samples that constituted the four initially HEV RNA reactive pools where RNA positivity was not confirmed on the individual level. In three pools, we found indirect evidence of recent HEV exposure. Within 356 randomly selected samples, 31 donations were HEV IgG positive. Here we show that at least 1:5448 of blood donations in Flanders may originate from donors that are actively infected with HEV. Upon transfusion, these donations may pose a major threat towards patients at risk. Finally, a serological analysis showed that the anti‐HEV IgG prevalence in Flemish blood donors is 8.71%.