Guidelines for the monitoring and management of iron overload in patients with haemoglobinopathies and rare anaemias

Abstract

This guideline was compiled according to the BSH process at https://b-s-h.org.uk/guidelines/proposing-and-writing-a-new-bsh-guideline/. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) nomenclature was used to evaluate levels of evidence and to assess the strength of recommendations. The GRADE criteria can be found at http://www.gradeworkinggroup.org. A literature review was conducted on 28 September 2018. Databases searched included MEDLINE (OVID) from 1 January 1960 to 28 September 2018 and Cochrane Database. A top-up search was conducted on 28 October 2020 to cover 29 September 2018 to 28 October 2020. Search terms were deferoxamine, deferasirox, deferiprone, thalassaemia major, transfusion, Diamond-Blackfan anaemia, and sickle cell disease. One additional paper that was missed in the searches was extracted based on author expertise. Filters were applied to include only publications written in English, randomised and non-randomised clinical trials, longitudinal cohort studies, comparative studies, meta-analyses, multicentre studies, observational studies, reviews, systematic reviews, validation studies, human and in vitro laboratory evidence with synergy indices and published between 01 January 1960 and 28 October 2020. Review of the manuscript was performed by the British Society for Haematology (BSH) Guidelines Committee General Haematology, the BSH Guidelines Committee and the General Haematology sounding board of BSH. It was also on the members section of the BSH website for comment. It has also been reviewed by the UK Thalassaemia Society and Sickle Cell Society; these organisations do not necessarily approve or endorse the contents. Iron overload (IOL), resulting from regular or intermittent blood transfusions or from increasing dietary iron absorption can cause serious and life-threatening complications. Patients at risk of IOL include those with inherited anaemias such as transfusion-dependent thalassaemia (TDT) and non-transfusion-dependent thalassaemia (NTDT), transfused sickle cell disease (SCD) and rarer anaemias such as congenital sideroblastic anaemia (CSA), congenital dyserythropoietic anaemia (CDA), Diamond-Blackfan anaemia (DBA) as well as red cell enzymopathies, membrane disorders and defects in haem synthesis pathways. The United Kingdom has approximately 15 000 patients with these disorders and diagnosis and management of IOL is important in minimising morbidity and mortality. Other disorders that are associated with IOL such as hereditary haemochromatosis or acquired anaemias such as the myelodysplastic syndromes are not covered by this guideline. The extent and severity of IOL is affected by both the underlying disorder and the intensity and duration of transfusion. Patients on regular top-up transfusions are at most risk whilst those on intermittent transfusions develop IOL more slowly. In the absence of blood transfusion, sickle cell disorders tend not to accumulate excess iron: however, manual and automated exchange transfusion may result in mild degrees of IOL or even iron deficiency.1-3 Patients with NTDT and non-transfused rare inherited anaemia (NTRIA) may develop IOL through sporadic transfusions or from chronically increased gastrointestinal (GI) iron absorption. Iron accumulation from transfusion in TDT is on average about 40-fold faster (0.4 mg/kg/day)4 than from GI iron absorption in NTDT (0·01 mg/kg/day).5 Increased GI iron absorption is less well recognised in the NTRIA syndromes and often missed; however, the pathophysiological relationships between anaemia and iron absorption are similar to that in NTDT.6, 7 Over a lifetime, transfusion-dependent patients will require changes to iron chelation regimes depending on the severity of IOL, side effects of chelation agents and lifestyle issues such as preparation for or during pregnancy (Fig 1). Monitoring for IOL and concordance with chelation therapy are the key to successful clinical outcomes. Regular monitoring of IOL informs both patients and clinicians about the effectiveness of chelation as well as sites of organ loading, allowing early intervention to control the iron burden. Most complications of IOL can be prevented or reversed before irreversible damage and dysfunction occurs.8-10 Iron distribution is determined by the underlying disease and the route and kinetics of iron loading, as well as chelator regime, dose and adherence. In general, transfusional IOL will begin in the macrophage system of liver, spleen and bone marrow and then progress to liver hepatocytes. As the liver iron concentration (LIC) increases, transferrin saturation increases, with non-transferrin-bound plasma iron (NTBI) appearing above 70% saturation. NTBI accelerates iron deposition in endocrine organs and ultimately the heart (Fig 2).11 Clinically significant IOL can occur early in young children with ineffective or absent erythropoiesis, such as DBA, CDA, and TDT. Patients with transfusion-dependent DBA are more likely to develop severe IOL compared to other transfusion-dependent patients,12, 13 with a greater propensity of myocardial IOL and higher NTBI levels.14 Some CDA-1 patients may have concurrent therapy with interferon to limit blood transfusion. With suboptimal or absent chelation, myocardial IOL and endocrine complications can occur at an early age.15-20 Complications in NTDT are typically delayed due to slower iron accumulation rates, resulting in lower toxicity of iron species. LIC can be a surrogate marker for risk of other complications including hypogonadism, hypothyroidism, osteoporosis, thrombosis and pulmonary hypertension. NTDT patients with IOL are also at higher odds of developing renal dysfunction and iron may be implicated in direct tubulointerstitial and glomerular dysfunction.21 In TDT, myocardial IOL is more likely when transfusion iron loading rates significantly exceed the iron utilisation by the bone marrow.22 In the absence of transfusion, myocardial IOL is rare even with high LIC. In NTDT the pattern of periportal hepatocellular iron distribution may explain the association with hepatocellular carcinoma (HCC) even in hepatitis C-negative patients.19, 23, 24 Complications from IOL in NTRIA syndromes are less well described but assumed to be similar to NTDT. CSA and other metabolic iron disorders may develop IOL with normal or mildly raised serum ferritin levels.25 Without transfusion SCD patients are not typically iron-overloaded and indeed may be iron deficient due to urinary loss from intravascular haemolysis.3 Children with SCD receiving top-up transfusions can rapidly develop liver IOL, but extra-hepatic involvement is unlikely if transferrin saturation and NTBI levels remain low.3, 26-28 Patients at risk of iron overload (those on regular transfusions every three months or less, NTDT and NTRIA) should be assessed for iron overload and complications of iron overload as part of the annual review (1B). The frequency of scanning is detailed in Table I. Cardiac iron deposition can manifest as arrhythmias or heart failure (HF). Accumulation of iron in the early stages can be asymptomatic but should prompt intensification of chelation. Several tachycardias have been described secondary to IOL such as atrial fibrillation (AF) and ventricular tachycardia (VT), but bradycardia and heart block may also be seen. VT is a grave indicator of heart dysfunction requiring urgent and expert assessment. Atrial arrhythmias do not always indicate severe cardiac iron toxicity and are increasingly evident in older patients, even when cardiac iron, as assessed by magnetic resonance imaging (MRI), has been normal for decades. Acute HF is now rare, but has a high immediate mortality risk, approaching 50%. The risk of HF increases as T2* falls below 10 ms. Patients with a cardiac T2* <6 ms have a >50% risk of developing HF within 12 months.29 Regular Cardiac MRI (CMR) T2* and left ventricular ejection fraction (LVEF) measurements (frequency described in Table I) are critical for identifying patients who require timely escalation of chelation intensity (frequency and/or dose). Acute HF may be preceded by a small fall in LVEF.30 Although recovery of LV function with chelation is the expected outcome for those who survive acute decompensation, a small number of patients have long-term impaired ventricular function. This may be due to coincidental dilated cardiomyopathy, unrelated to IOL, or follow a viral myocarditis. Restrictive cardiomyopathy may also occur. Pulmonary hypertension and right-sided heart failure may be seen more commonly in NTDT and post splenectomised TDT. Rarer diseases should be excluded in atypical presentations or with an inadequate response to conventional therapy with chelation and HF medication. Valve disease is approached conventionally, and successful heart surgery has been undertaken in thalassaemia patients. The pattern of liver siderosis and damage is determined by cellular iron distribution. Unbound iron species lead to cellular necrosis and eventual hepatic fibrosis, which can progress to cirrhosis especially when LIC exceeds 7 mg/g dry weight. The risk of progression can be reduced by adequate control of LIC with chelation.31, 32 Liver complications including HCC are becoming more prominent in older patients with TDT, NTDT and SCD. Coexisting hepatitis or non-siderotic liver disease will impact on liver damage and complications. Iron-mediated endocrinopathy may manifest as hypogonadotropic hypogonadism, growth retardation, hypothyroidism, hypoparathyroidism, growth hormone deficiency, diabetes mellitus and hypoadrenalism.33-35 These complications are less common in patients receiving early regular chelation. Inadequate chelation can influence the rate of new-onset endocrinopathy and the likelihood of reversal.36, 37 Damage to the pancreatic islet cells leads to impaired glucose tolerance and diabetes. Increasingly, malabsorption due to iron-mediated damage to the exocrine pancreas is being recognised. Thalassaemic bone disease has a complex pathobiology. In TDT, bone turnover is particularly high and iron is thought to encourage bone resorption by favouring osteoclast differentiation and inhibiting osteoblast activity. Reduced hepcidin levels are thought to contribute towards this process.38 Iron may cause adipose tissue remodelling leading to a pseudoxanthoma elasticum-like clinical syndrome.39 IOL is also a risk factor for vasculopathy40 and malignancies such as HCC and papillary and follicular thyroid carcinoma.41, 42 Monitoring for IOL is important in identifying existing complications, quantifying the risk of and therefore preventing future complications from developing. Functional parameters of end-organ damage have been the mainstay of monitoring IOL (Table I). However, quantification of IOL allows organ-specific measurement of iron in the heart, liver, pancreas and pituitary and may identify high-risk patients before end-organ damage occurs. Serum ferritin is important in quantifying overall risk of complications and is most useful for long-term trends. Patients should be reviewed at least annually to ensure that IOL is monitored and end-organ damage assessed. Serum ferritin broadly correlates with body IOL and its assessment can be performed frequently. However, ferritin is an acute-phase protein and may increase due to tissue damage and inflammation and is supressed by ascorbate deficiency. Ferritin is also affected by individual chelation drugs.43 The relationship between ferritin and iron stores is similar in TDT and transfused SCD44 provided serum values are taken several weeks away from a vaso-occlusive sickle crisis45 but in NTDT, ferritin may underestimate the degree of IOL.46 Long-term control of ferritin with desferrioxamine therapy has prognostic significance47 and maintenance of the ferritin below 2 500 µg/l is associated with a lower risk of cardiac disease and death.30, 33, 48, 49 Maintenance of ferritin below 1 000 µg/l may be associated with additional advantages in TDT.8, 33, 50The ferritin trend can be used as a guide for modifying chelation dosing but can be unreliable at high values (>3 000 µg/l). While low ferritin can identify patients at risk of over-chelation, ascorbate deficiency secondary to severe IOL may make this unreliable. Methods for tissue iron quantification include liver biopsy and various MRI approaches. Historical data from LIC measurements from biopsies has shown that the severity of IOL impacts on the risk of developing complications. Long-term LICs above 7 mg/g dry weight have been associated with increased risk of fibrosis and above 15 mg/g dry weight with increased risk of myocardial IOL.51, 52 Liver biopsies have procedure-associated risks and the distribution of iron in the liver may be inhomogeneous.53, 54 Liver biopsies are now undertaken only where histology will contribute to management. Magnetic resonance imaging typically measures signals from water hydrogen and this is perturbed by factors in addition to storage iron. Three magnetic time constants can be generated: T2*, T2 and T1. High tissue iron leads to short time constants, which are hard to measure reproducibly. Several approaches have been validated for both cardiac and liver iron assessment including T2* 55, 56, R2 (Ferriscan ®)57 or R2*.58 LIC values where possible should be assessed using the same methodology (T2*, R2 or R2*) sequentially for the patient as the values for LIC do not concur across different techniques for data acquisition and analysis. There may also be considerable inter-centre variability even if the same methodology is being used to acquire the data.59 Transfusion-dependent patients should be having tailored MRI assessments of LIC routinely with a frequency dependent on the severity of iron burden, the intensity of chelation and the concordance with iron chelation therapy60, 61 Cardiac T2* is the current standard measure for assessing myocardial iron deposition and T1 mapping is being used in research settings. T1 mapping makes rapid iron quantification easier for heart and liver and can be done in as little as six minutes.62, 63 Cardiac T2* values less than 20 ms are associated with increased myocardial iron and T2* less than 10 ms is associated with an increased risk of developing cardiac failure.29 Strategies to measure pancreas and pituitary iron using MRI are not as yet widely applied and their relevance in adult populations is not clear as iron-mediated damage is frequently already present. These strategies therefore remain research-based. Chelation typically decreases storage iron in the liver faster than from other tissues such as the heart. Thus, removal of pre-existing heart iron (when T2* is <20 ms) may lag behind that of the liver. By contrast, plasma NTBI is decreased rapidly by chelation, but this effect is transient, rebounding immediately after a chelator is cleared from the circulation. While iron chelation has been highly successful in reducing morbidity and mortality from IOL this requires consistent adherence to treatment, which in turn depends on health care resources and the availability of clinical expertise to support, inform and encourage patients long-term. Three chelating drugs are licensed for treatment of IOL. Detailed descriptions of the individual pharmacology and toxicology of chelating agents are extensively described elsewhere.64-67 Desferrioxamine was the first drug licensed for transfusional IOL and has to be administered subcutaneously or intravenously. Deferiprone is rapidly absorbed by the oral route and is given as a tablet, typically in three divided doses daily due to its rapid metabolism and elimination from plasma. Deferasirox is administered orally once daily as it has a long plasma half-life. The original formulation was a tablet dispersed in a glass of water prior to ingestion (deferasirox-D). This has now been replaced by a film-coated tablet (deferasirox-FCT) formulation that is better absorbed and tolerated.68-70 Due to enhanced absorption, doses need to be adjusted downwards by 0.7 × those previously recommended for the dispersible formulation. This depends on the underling diagnosis, the patient's age, the ROIL and the current body iron load and distribution. Iron excretion must generally match the ROIL to prevent body iron accumulation. Standard chelation doses are generally required for average ROIL; typically, 0.3–0.5 mg/kg of iron/day in TDT. SCD patients receiving exchange transfusions generally have lower or neutral iron loading rates compared with 'top-up' transfusion regimes, so lower doses may be adequate should iron chelation be required3 In rarer transfusion-dependent anaemias, iron excretion shows similar dose relationships to those of TDT and doses should be matched to ROIL.71 As with TDT, the risk of cardiac and other extra-hepatic iron deposition is high when erythropoietic activity is low relative to the ROIL.22 Patients with DBA often have higher ROIL and low iron utilisation by the bone marrow and need careful assessment before escalation to higher doses.12, 13, 72 For NTDT, the ROIL is an order of magnitude slower than for TDT, so lower doses are generally sufficient unless high levels of body iron have already accumulated.73 Patients with NTDT and NTRIA may tolerate venesection if haemoglobin values are reasonable; a good example of this is CDA-1 patients maintaining reasonable haemoglobin values with interferon therapy. However, some patients with NTRIA may have significant IOL with more severe anaemia and patients with CDA, pyruvate kinase deficiency and CSA are highest risk. They may require intermittent short episodes of chelation every few years to maintain safe total body iron. Guidelines and licensing for age of starting therapy vary somewhat between countries (but are based on the same data).74 In the risks of increase if chelation is early but once iron has in the endocrine system it can be to the organ data are about the of starting chelation in children or before transfusion has been for 2 years or before ferritin has UK are to begin after of red blood cells of or ferritin These are based on with In NTDT, chelation should be MRI assessment if the ferritin is above or LIC NTRIA should be assessed on a disease and individual and chelation if is evidence of IOL or LIC adjusted to the of IOL and to the is critical to both the and the of chelation therapy. Monitoring for complications of chelation should be as in Table and chelation regimes to be as in and Desferrioxamine Desferrioxamine dose in children Deferasirox for and renal function in children Desferrioxamine Desferrioxamine dose in children in renal and dose of Deferasirox if is and dose if in severe hepatic Deferiprone if of in to the for or doses Desferrioxamine or Desferrioxamine or Deferiprone of the below based on patient prior and Desferrioxamine and Deferiprone at dose of Desferrioxamine for age and cardiac iron burden. Deferiprone to at then dose increases based on side effects and severity of IOL. Deferasirox and Desferrioxamine at dose of Desferrioxamine for age and at escalation of Deferasirox at regular based on side effects and Deferasirox and Deferiprone the existing oral and the oral at its standard dose Deferasirox or a of both agents if to As above for individual agents for doses for to therapy and Desferrioxamine on to a depending on severity of iron or in divided doses Desferrioxamine dose in children Deferasirox if is and dose if in severe hepatic Deferiprone if of in to the for or doses Iron excretion depends on the frequency and dosing of chelation. high doses in transfused patients are not a to regular as this leads to iron-mediated damage between chelation response to chelation at given dose also decreases as the iron loading rate increases so that required doses are likely to be higher at higher iron loading Although ROIL between disorders and patients, the relationship between dose and iron excretion is the same across Desferrioxamine doses of mg/kg a have been but these are often to a iron at average ROIL in TDT only of patients will be in iron at mg/kg a this to of Due to desferrioxamine and children should not a daily dose generally tolerate mg/kg daily doses should be adjusted downwards as ferritin values fall in with the is also critical to response with of TDT patients with average ROIL to daily at this falls to of patients at mg/kg 20 in doses should be done in with ferritin and LIC values as well as the of in serum and The relationship of dosing to iron with is less clear as long-term LIC considerable the of dosing LIC and the response to depends on at a iron was in less than a of patients overall but in of patients where LIC mg/g dry This is required when liver iron has to where liver damage may develop mg/g dry or when myocardial iron has to levels intensification is required when is evidence of cardiac or is a high risk of this Without ferritin particularly when ferritin levels exceed 000 measurement of LIC is recommended as LIC decreases in about of such where ferritin is not The first is to evaluate the patient is treatment at the frequency and Iron may be by better concordance or by increased With treatment serum ferritin must be to and its side effects increased dosing or frequency of chelation is not the patient may require to an Patients who to iron adherence to doses of or patients who develop should be for therapy should be from the prior to therapy. As iron is in only about of patients receiving mg/kg desferrioxamine can be to iron have been used for years with evidence from randomised of and desferrioxamine are also and well a in ferritin of and in with an increase in cardiac T2* of in a of patients with severe hepatic and cardiac IOL. This is a highly and is at least randomised shows that this is highly particularly cardiac Desferrioxamine Desferrioxamine dose and/or to in of the Deferasirox dose to if or patient suboptimal in of the with Deferiprone at if the liver iron is below weight dose to in of the Desferrioxamine and Deferiprone to must be given to to tolerate above regime, then of the with given to Desferrioxamine Deferasirox or Desferrioxamine Deferiprone the normal values Acute Cardiac Desferrioxamine 24 in Deferiprone once complications such as or if to tolerate Deferiprone due to side effects in Deferasirox mg/kg In renal desferrioxamine is cleared from the plasma by the liver but not which can be by or The risk of desferrioxamine toxicity may increase if doses are not There is also increased risk of such as include desferrioxamine during or desferrioxamine subcutaneously at reduced three a between Deferasirox is if the is and should be when renal function is A small of patients can develop renal as by renal and dose or Deferasirox may be in patients already on as the drug and iron complex are may be have shown with chronically transfused patients, for example with a starting dose of at 15 mg/kg and using reducing doses as serum ferritin values Deferiprone has been shown to not accumulate in renal desferrioxamine and/or can be used in patients with disease prior to is of the may be used in low doses with monitoring for toxicity Liver fibrosis and cirrhosis are increasingly in older patients with IOL. using desferrioxamine in SCD has to liver function even in patients with hepatic disease. Desferrioxamine may liver function both by rapidly as well as more storage iron. Deferasirox has been shown to or liver fibrosis in but is in patients with severe hepatic and should be used with in three can be in patients with raised and A hepatic IOL is a cause for serious morbidity and mortality which is with monitoring and chelation therapy. patients on regular transfusion regimes and children by the age of have an MRI assessment for cardiac and liver iron burden. Patients who are not transfused but have rare inherited anaemias are at increased risk of IOL from both treatment of anaemia and increased gastrointestinal iron absorption. In from a of and due to IOL. patients should be and have annual monitoring for IOL and complications, to health outcomes. In the UK the of of and and the will clinical and of of IOL has which include clinical to and doses of chelation therapy and also include significant patient factors such as failure to for monitoring assessments and suboptimal with iron chelation due to side effects or a of of the and of IOL. These issues can be by better with patients and more and of both patients and clinical The to from and for in the literature The BSH General Haematology at the time of this guideline was The to the BSH sounding and the BSH for their in this guideline. The BSH the during the of this have a of to the BSH and which may be on board and and for and monitoring for and board for and board for and The members of the have of to of the will inform the if evidence that the strength of the in this or it The will be reviewed by the and the literature search will be every three years to search for evidence that may have been The will be and from the BSH current website if it are an will be published on the BSH website While the and in this is to be and at the time of to the the BSH the for the of this