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3 Richardson D. Increase in patient

mortality at 10 days associated with

emergency department overcrowding.

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4 Sprivulis P, Da Silva J-A, Jacobs I,

Frazer A, Jelinek G. The association

between hospital overcrowding and

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departments. Med J Aust 2006; 184:

208–12.

5 Chalfin D, Trzeciak S, Likourezos A,

Group D-ES. Impact of delayed transfer

of critically ill patients from the

emergency department to the intensive

care unit. Crit Care Med 2007; 35:

1477–83.

6 Gilligan P, Winder S, Singh I, Gupta V.

The boarders in the emergency

department (bed) study. Emerg Med J

2008; 25: 265–9.

7 Mortimore A, Cooper S. The ‘4-hour

target’: emergency nurses’ views. Emerg

Med J 2007; 24: 402–4.

8 Cooke M, Wilson S, Pearson S. The

effect of a separate stream for minor

injuries on accident and emergency

waiting times. Emerg Med J 2002; 19:

28–30.

9 Duke G, Buist M, Pilcher D,

Scheinkestel C, Santamaria J,

Gutteridge G et al. Interventions to

circumvent intensive care access block: a

retrospective 2-year study across

metropolitan Melbourne. Med J Aust

2009; 190: 375–8.

10 Downing A, Wilson R, Cooke M. Which

patients spend more than 4 hours in the

Accident and Emergency department? J

Public Health 2004; 26: 172–6.

11 Orr J. The good, the bad, and the four

hour target. BMJ 2008; 337: a195.

12 Richardson D, Mountain D. Myths

versus facts in emergency department

overcrowding and hospital access block.

Med J Aust 2009; 190: 369–74.

13 Cameron P, Joseph A, McCarthy S.

Access block can be managed. Med J Aust

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DH_113018

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distribution of time that patients spend

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driven health care. BMJ 2008; 337:

a885.

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18 Richardson D. Triage, sub-triage, and

mortality: does starting treatment earlier

make a difference? Emerg Med Australas

2010; 22: A47.

HOW I TREAT

When should iron chelation therapy be considered in patientswith myelodysplasia and other bone marrow failure syndromeswith iron overload?imj_2734 450..473

R. J. Bird,1 M. Kenealy,3 C. Forsyth,5 J. Wellwood,2 M. F. Leahy,6 J. F. Seymour4 and L. B. To7

1Pathology Queensland, Princess Alexandra Hospital, Woolloongabba, 2Gold Coast Hospital, Southport, Queensland, 3Cabrini Hospital, 4Peter

MacCallum Cancer Institute, and University of Melbourne, Melbourne, Victoria, 5Wyong Hospital, Kanwal, New South Wales, 6Fremantle Hospital,

Fremantle, Western Australia and 7SA Pathology, Royal Adelaide Hospital and University of Adelaide, Adelaide, South Australia, Australia

Key wordsmyeodysplasia, iron, chelation.

CorrespondenceRobert Bird, Pathology Queensland, Princess

Alexandra Hospital, Ipswich Road,

Woolloongabba, Qld 4102, Australia.

Email: robert_bird@health.qld.gov.au

Received 2 August 2010; accepted 31 July

2011.

doi:10.1111/j.1445-5994.2012.02734.x

Abstract

Despite the absence of a robust evidence base, there is growing consensus that effective

treatment of iron overload leads to decreased morbidity and premature mortality in

patients with good prognosis myelodysplastic syndromes (MDSs). Furthermore, new

treatment modalities, including disease-modifying therapies (lenalidamide and azacyti-

dine) and reduced intensity conditioning therapies for allogeneic blood stem cell trans-

plants, are offering the prospect of longer survival for patients with traditionally less

favourable prognosis MDS, who might also benefit from iron chelation. This article

proposes assessment of patients with MDS and related bone marrow failure syndromes

to determine suitability for iron chelation. Iron chelation therapy options and monitor-

ing are discussed.

© 2012 The AuthorsInternal Medicine Journal © 2012 Royal Australasian College of Physicians450

Introduction

The purpose of this document is to propose a practicalapproach to the management of iron overload in patientswith myelodysplastic syndromes (MDSs) and relatedbone marrow disorders in Australia. A group of haema-tologists met in April 2010 to discuss evidence and inter-national consensus guidelines for the management ofiron overload. Several guidelines by expert panels, focus-ing on the management of myelodysplasia and morespecifically on MDS-related iron overload, have beenpublished1–3 and more recently a consensus statement bythe MDS Foundation Working Group4 addressing theevidence for iron chelation in MDS. It is recognised thatthere is a lack of prospective randomised studies tosupport the practice, and a multinational, randomised,placebo controlled study (TELESTO) is currently under-way, which is hoped will answer the outstanding ques-tions on the impact of iron chelation in iron overloadedMDS patients, but a conclusion is still several years away.Several retrospective studies5–7 and one prospective non-randomised study8 have provided some insights, but dataare often extrapolated from the haemoglobinopathypopulation. Despite this, there is widespread agreementthat iron overload is a problem that needs to be addressedin subsets of patients with MDS. This paper sets out theviews of the group and proposes a guideline for an Aus-tralian setting that aligns with existing internationalrecommendations.

Anaemia requiring transfusion is seen in 60% ofpatients with MDSs. Each unit of red cell concentratecontains approximately 250-mg iron, and with no physi-ological mechanism for iron excretion, accumulationinevitably occurs. This results not only in an increase intotal body iron and organ deposition but also importantfractions of non-transferrin bound iron (NTBI) and labileplasma iron (LPI), which are major mediators of thetissue damage seen in iron overload.9

The consequences of iron overload have been welldocumented in the thalassaemic population and includecardiac, hepatic and endocrine dysfunction, an increasedinfection risk and premature death. In MDS, older ageand frequent comorbidities can exacerbate iron-mediatedorgan damage, and life expectancy is generally shorter.Several retrospective studies10,11 have described the fea-tures of organ dysfunction typically seen in iron overload

in transfused MDS patients, and a large retrospectivenested case-control study found the risk of complicationstypical of iron overload to be significantly associated withtransfusion burden,12 though a causative relationship isyet to be established.

A serum ferritin >1000 mcg/L is associated with short-ened survival in patients with MDS.13 There is also evi-dence that elevated ferritin is associated with inferiorsurvival following allogeneic transplantation.14 Red celltransfusion requirement is associated with shorter sur-vival and increased risk of leukaemic transformation,15

and is an adverse prognostic indicator in the WorldHealth Organization classification-based prognosticscoring system (WPSS).16 Retrospective studies5 and aprospective but non-randomised study8 have suggestedan improvement in survival with iron chelation therapy(ICT), the latter confirmed on multivariate analysis.

In view of these new data, improved prognostic strati-fication and advances in disease-modifying therapy inMDS, a group of haematologists convened to evaluatewhen ICT should be considered and how ICT should beadministered. Their recommendations are reported here.

When should ICT be considered?

Transfusion burden

The number of packed red blood cells (PRBC) units trans-fused per month has been shown to have a significantimpact on survival in patients with refractory anaemia(RA), refractory anaemia with ringed sideroblasts(RARS), refractory cytopenia with multilineage dysplasia(RCMD), RCMD-ringed sideroblasts (RS) and del(5q). Atransfusion requirement of >2 U/month for over 1 yearhas been correlated with increased organ toxicity and willusually raise ferritin levels to >1000 mcg/L.

Level of iron overload

Serum ferritin levels are a readily available and inexpen-sive marker of body iron, but as ferritin is an acute-phasereactant, individual values may not reliably reflect ironburden. Serial measurements have been shown to bettercorrelate with iron load, and increasing mortality hasbeen shown among patients with MDS for every increasein ferritin of 500 mcg/L above 1000 mcg/L.17 Ferritinlevels may not be a good guide to cardiac iron loading,which is seen less frequently in MDS than in the thalas-saemic population.

NTBI is measurable in plasma once transferrin satura-tion exceeds 75% and leads to the formation of LPIand reactive oxygen species (ROS).18 However, the useof NTBI, LPI and ROS assays to inform clinical

Funding: None.Conflict of interest: Novartis Australia provided support forworkshop attendance and facilitation, but the development ofthese guidelines and the opinions in this document are theresponsibility of the authors. Robert Bird has received honorariafrom Novartis Australia.

Iron chelation in MDS

© 2012 The AuthorsInternal Medicine Journal © 2012 Royal Australasian College of Physicians 451

decision-making about ICT remains investigational. Liveriron concentration (LIC) obtained by liver biopsy is thegold standard for measurement of tissue iron burden butis seldom used in MDS due to the risk of haemorrhageand the availability of alternative validated non-invasivemeasures.

MDS category

The risks of iron overload are greatest among transfusion-dependent patients with low- or low–intermediate-riskdisease by the International Prognostic Scoring System(IPSS) system, as they have longer survival and are lesslikely to die from direct complications of their MDS.Patients with better prognosis include the following:1 IPSS: low, intermediate-1.2 World Health Organization classification: RA, RARS or5q-MDS.3 WPSS: low, intermediate (very low-risk WPSS isdefined by transfusion independence).

It is noteworthy that more than 85% of MDS patientsare diagnosed after age 60 years and overall 3-year sur-vival is 35%. However, within this population, prognosismay be stratified as indicated above, using WPSS or IPSS,to select out those at risk of iron accumulation whichmight impact on quality of life and survival.

Patients with higher risk MDS (IPSS: Int-2, high)should be considered for ICT if their MDS responds todisease-modifying therapy, such as azacitidine. Patientswith iron overload planned for allogeneic stem cell trans-plantation should be considered for ICT to reduce therisks of both organ dysfunction and infection in the peri-transplant phase possibly through clearance of LPI.19

Organ dysfunction

Patients with significant cardiac or hepatic dysfunctionaffecting prognosis where iron overload is the major con-tributing factor should be considered for ICT. The issue ofcardiac iron loading in MDS is controversial. Whereassome series20–22 have suggested that there is no evidenceof cardiac iron accumulation, another study23 did dem-onstrate increased cardiac iron loading. There appears tobe a poor correlation between cardiac iron load andserum ferritin.22 Therefore, it seems reasonable to con-sider T2* magnetic resonance imaging (MRI) in MDSpatients with iron overload and cardiac dysfunction todetermine the contribution of iron toxicity.

Other bone marrow failure syndromes

Patients with other transfusion-dependent diseases atrisk of iron load should also be considered for ICT.

The factors affecting ICT decision are summarised inTable 1.

How should ICT be administered

Iron chelators

Three iron chelating agents are licensed in Australia: des-ferrioxamine, deferasirox and deferipone. The first twoare Pharmaceutical Benefits Scheme listed for treatmentof iron overload in disorders of erythropoiesis, whereasdeferiprone is listed for thalassaemia major with failureor intolerance of desferrioxamine.

Deferiprone is an oral chelator, with a target dose of75 mg/kg/day. The most serious adverse event is neutro-penia, seen in 6% of patients, with agranulocytosis in1%. Hence, deferiprone is contraindicated in patientswith neutropenia, and immediate drug withdrawal is rec-ommended in patients developing neutropenia. Theseissues, and the lack of reimbursement in MDS, substan-tially limit its use.

Desferrioxamine has been in use longest mainly inthalassaemia. Prolonged parenteral administration isrequired, and subcutaneous infusion is the most commonroute utilised to obviate the need for the vascular access

Table 1 The factors affecting ICT decision

Transfusion burden Greater than two units of PRBC per month for

over 1 year

Cumulative >20–40 units of PRBC transfused

(equivalent to 5–10 g of iron)

Iron excess Serum ferritin sustained >1000 mcg/L

Disease (life

expectancy >1 year

and ferritin

>1000 mcg/L)

MDS

RA; RARS; del(5q) syndrome

Primary myelofibrosis

IPSS low, Inter-1 or -2 or those responding

to disease-modifying therapy

MDS/myeloproliferative neoplasm

CMML-1

Aplastic anaemia

All transfusion-dependent patients

Pure red cell aplasia

All transfusion-dependent patients

Allogeneic stem cell transplant

Patient factors Life expectancy >1 year manifest by:

Lack of life shortening comorbidities

Allogeneic transplant candidate

Response to disease-modifying therapy

Patients where organ function is threatened

by iron overload impacting upon QoL

CMML-1, chronic myelomonocytic leukaemia-1; ICT, iron chelation

therapy; IPSS, International Prognostic Scoring System; MDS, myelodys-

plastic syndrome; PRBC, packed red blood cells; QoL, quality of life;

RA, refractory anaemia.

Bird et al.

© 2012 The AuthorsInternal Medicine Journal © 2012 Royal Australasian College of Physicians452

devices. Dose titration requires monitoring of urinaryiron excretion. The expected rate of iron excretion is10–20 mg/day; two-thirds urinary and one-third faecal.The usual adult desferrioxamine dose range is 20–40 mg/kg/day. Doses above 80 mg/kg/day should not be usedbecause of toxicity. Infusion times from 8 to 12 h daily on5–7 days per week may be required for initial therapy.Longer infusion times increase iron excretion. Givingdesferrioxamine as an intravenous infusion concurrentlywith PRBC transfusion, without ongoing prolonged infu-sion is ineffective and cannot be justified. Desferrioxam-ine can be safely used in renal failure.

The most common side effect is infusion site inflam-mation. An increased risk of iron-dependent bacterial(Yersinia and Staphylococcus) and Zygomycetes infectionshas been reported with desferrioxamine use, whereas areduced risk of Zygomycetes infections accompanies theuse of deferasirox and deferiprone. This may be related tothe increased strength of iron binding with the latteragents,24 blocking iron availability to the mould. Visualdisturbance has been reported in long-term use, particu-larly as ferritin levels fall below 1000 mcg/L and annualophthalmological assessment is recommended.

Deferasirox is a once daily oral chelator. The mean doserequired to achieve negative iron balance in MDS is20 mg/kg/day. Depending on transfusional iron intake,higher doses may be required. Doses of up to 45 mg/kg/day have been tolerated and may be needed in patientswith severe cardiac iron loading (T2* < 10 ms) or a veryhigh iron load. Renal toxicity and tubular dysfunctionmay be encountered, especially when the ferritin fallsrapidly. The manufacturer recommends dose reductionby 10 mg/kg if the serum creatinine rises by >33% abovebaseline. Hepatic toxicity is a rare complication.

Diarrhoea, rash and nausea are commonly reportedbut usually mild. Anecdotally, these adverse events areless frequent if the dose is increased in a stepwise fashionover 3–4 weeks, or fractionated, rather than initiatingtherapy at the target once daily dose.

Combination chelation therapy has been advocatedin severe iron overload resulting in cardiac failure. Thisapproach has not been investigated in a systematicfashion. Therapeutic venesection should be considered asan alternative to ICT in patients who have become trans-fusion independent following disease-modifying therapyor haematologic stem cell transplant.

There are small published series describing significantlyimproved blood counts in some patients with MDS fol-lowing ICT.25,26 This may be mediated through inhibitionof the nuclear factor kappa-light-chain-enhancer of

activated B cells (NF-kB) pathway in MDS blasts.27

However, this observation needs confirmation in largerprospective studies.

Target and monitoring of ICT

The aim of iron chelation is to reduce iron-mediatedorgan damage. The relative importance of reduction ofiron loading in specific organs versus suppression of NTBIand LPI28 is still unclear.

In order to minimise toxicity, the intensity of ICTshould be reduced once serum ferritin drops below1000 mcg/L and withheld below 500 mcg/L.

Regular monitoring of iron burden should be per-formed to ensure that therapeutic goals are being metand to reduce the risk of toxicity from ICT. Due to inef-fective erythropoiesis, iron accumulation can occur inMDS before transfusion, so serum ferritin should be mea-sured at diagnosis. For patients with increased serumferritin, pre-existing organ damage or sustained transfu-sion dependence, serum ferritin should be monitored atleast every three months. Monitoring is required for theduration of the patient’s transfusion dependence untilthe terminal phase of their MDS. In determining theschedule of monitoring, the recommendation of the spe-cific chelator manufacturer should be observed.

In the presence of liver or cardiac dysfunction, to deter-mine the contribution of iron overload MRI is recom-mended. MRI assessment of the heart by T2* has beenvalidated as a sensitive method to determine cardiacdamage due to iron accumulation in thalassaemia andhaemochromatosis.29 A T2* of <20 ms is an indicator of anincreased risk of cardiac damage by iron accumulation,and patients with T2* of <10 ms have an increased risk ofcardiac decompensation and require intensive ICT. LIC byMRI has been validated in haemachromatosis and thalas-saemia.30 LIC >7 mg Fe/g dry weight indicates moderateiron overload, with >15 mg/g indicating severe overload.

There is currently no reimbursement on the MedicalBenefits Schedule for MRI assessment of iron loading.While most modern MRI machines are capable ofperforming these scans, reporting expertise is notwidespread.

LPI and NTBI are rapidly cleared by iron chelatortherapy, and the very rapid improvement in the clinicalstatus of some thalassaemic patients with marked cardiaciron overload has been postulated to be due to thiseffect.31LPI and NTBI assays measure the iron speciesresponsible for tissue toxicity but are not currently avail-able in service laboratories.

Iron chelation in MDS

© 2012 The AuthorsInternal Medicine Journal © 2012 Royal Australasian College of Physicians 453

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Koreth J, Alyea EP et al. Prognostic

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Bernal T, Belkaid M, Ardanaz MT et al.

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Della Porta MG, Pascutto C, Invernizzi R

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BRIEF COMMUNICATION

Changes in liquid emptying in migraine patients: diagnosedwith liquid phase gastric emptying scintigraphyimj_2741 455..478

H. Yalcin,1 E. E. Okuyucu,2 E. Ucar,3 T. Duman2 and S. Yilmazer2

Departments of 1Nuclear Medicine, 2Neurology and 3Internal Medicine, Mustafa Kemal University School of Medicine, Hatay, Turkey

Key wordsgastric stasis, migraine, gastric emptying, liquid

phase gastric scintigraphy.

CorrespondenceHulya Yalcin, Department of Nuclear Medicine,

Mustafa Kemal University School of Medicine,

31100 Hatay, Turkey.

Email: hulyapeker@yahoo.com

Received 7 January 2011; accepted 27 June

2011.

doi:10.1111/j.1445-5994.2012.02741.x

Abstract

Gastric stasis is suspected mostly to be encountered during acute migraine attack. The

aim of this study is to evaluate the liquid phase gastric emptying and motility in migraine

patients in ictal and interictal periods in comparison to normal subjects with gastric

emptying scintigraphy. Seven women with migraine and age, sex matched controls who

applied to the Neurology Department from May 2009 to May 2010 were compared.

Gastric emptying study with a standard liquid was performed one time in the non-

migraineur group and two times in the migraineur group. Non-migraineur controls and

migraineurs were compared. The mean T1/2 was longer in ictal period in migraineurs.

The T1/2 of migraineurs interictally and the control groups were similar. The T1/2 of

migraineurs ictally and migraineurs interictally were also compared. We also considered

the percentage of the radioactive material remaining in the stomach. There were no

significant differences between non-migraineurs and migraineurs interictally. However,

increased amount of radioactive material remaining in the stomach was observed in

migraineurs ictally. We concluded that the liquid emptying was delayed in spontaneous

migraine attacks in migraine without aura, however in the interictal period the emp-

tying of liquids did not differ between migraineurs and non-migraineurs.

Migraine is a disease related to severe headache associ-ated with neurological and autonomic symptoms. It ismostly seen in women aged between 25 and 55, and thisparoximal pulsatile headache is usually associated withphotophobia and phonophobia, nausea and vomiting.1

The number of migraine attacks affects the patient’squality of life. Treatment of the patients’ requirements is

more important than the diagnosis, symptoms andcomorbid disease treatment.

Pharmacokinetic studies with different drugs were per-formed to prove gastric stasis seen in migraine disease.2,3

However, a small number of these studies gave objectiveresults. On the other hand, consideration of gastric emp-tying with scintigraphy is objective and can be repeated.In the previous studies, solid gastric emptying is evalu-ated with gastric emptying scintigraphy,4,5 and also inother papers, it is observed that the absorption of drugs insolid forms was retarded and late drug effects wererelated to gastric stasis.6

Funding: None.Conflict of interest: None.

© 2012 The AuthorsInternal Medicine Journal © 2012 Royal Australasian College of Physicians 455