Dr Kate RyanDr Kate Ryan

October 2014October 2014

HaemoglobinopathiesHaemoglobinopathies (Sickle Cell and (Sickle Cell and Thalassaemia) are the commonest genetic Thalassaemia) are the commonest genetic disorders in the UKdisorders in the UK

Increasing prevalence:Increasing prevalence:Babies identified though newborn screeningBabies identified though newborn screeningImmigration into UKImmigration into UKImproved survival with medical treatmentImproved survival with medical treatment

National antenatal and newborn screening National antenatal and newborn screening programmes are in place.programmes are in place.

Abnormal haemoglobin polymerises at low oxygen tension

Red cells become rigid

Haemolysis Vaso-occlusion

National Standards and Guidelines in Sickle Cell Disease

Sickle cell disease: clinical problemsSickle cell disease: clinical problems

Anaemia Anaemia

HbHb 77--9g/dl 9g/dl

InfectionsInfections

Painful crisesPainful crises

StrokeStroke

Leg ulcersLeg ulcers

PriapismPriapism

Visual lossVisual loss

Chronic organ damageChronic organ damage

Kidneys, lungs, joints, heartKidneys, lungs, joints, heart

SS Sb0 SC Sb+

Painful Episodes 80 100 4 4Acute Chest Syndrome

12.8 9.4 5.2 3.9

Stroke 0.6 0.1 0.2 0.1

ComplicationBeta Globin Genotype

All rates expressed per 100 patient-years.

Acute complications: how common?Acute complications: how common?Data from the Cooperative Study of Sickle Cell Disease (CSSCD)

TCD Velocity (cm/ s) Interpretat ion Yearly Risk of St roke

< 170 Normal ~1%

170 and < 200 Conditional intermediate

200 Abnormal ~10%

The role of blood transfusion in secondary stroke The role of blood transfusion in secondary stroke prevention is standard care prevention is standard care

All patients with abnormal All patients with abnormal TranscranialTranscranial Doppler scan Doppler scan should be offered prophylactic blood transfusion (STOPI should be offered prophylactic blood transfusion (STOPI and STOPII)and STOPII)

Improved outcomes with transfusion for silent cerebral Improved outcomes with transfusion for silent cerebral Infarcts (SITT Trial 2014)Infarcts (SITT Trial 2014)

HydroxycarbamideHydroxycarbamide? Not shown to prevent stroke ? Not shown to prevent stroke (TWITCH and SWITCH studies)(TWITCH and SWITCH studies)

Purpose:Purpose:

To treat anaemia and improve oxygen carrying To treat anaemia and improve oxygen carrying capacity of bloodcapacity of blood

Prevent or reduce painful/Prevent or reduce painful/vasovaso--occlusive or occlusive or sequestration complications by lowering sequestration complications by lowering proportion of proportion of HbHb S relative to S relative to HbHb A (aim < 30% A (aim < 30% acute or < 50% in some chronic situations)acute or < 50% in some chronic situations)

AlloimmunisationAlloimmunisation::

Incidence prior to Incidence prior to RhRh and K matching up to 36% and K matching up to 36% (USA) but some become undetectable(USA) but some become undetectable

Lower in UKLower in UK

Usually antiUsually anti-- C E and K C E and K All patients should have full red cell All patients should have full red cell phenotype/ genotype phenotype/ genotype

Choose blood matched for Choose blood matched for RhRh genotype and genotype and KellKell

Haemolytic transfusion reactionsHaemolytic transfusion reactionsClassical 7Classical 7--10 days10 days

HyperhaemolysisHyperhaemolysisdestruction of donor and recipient cells.destruction of donor and recipient cells.

Post transfusion Post transfusion HbHb < Pre < Pre TxTx

No No HbHb A detectedA detected

ReticulocytopeniaReticulocytopenia

Acute<7days DAT Acute<7days DAT negneg, no new , no new alloallo--abab identifiedidentified

Delayed> 7 days DAT, new all0ab foundDelayed> 7 days DAT, new all0ab found

Treat with steroids and Treat with steroids and IvIgIvIg

HyperviscosityHyperviscosity

Iron OverloadIron Overload

Transfusion transmitted infectionTransfusion transmitted infection

Sickle haemoglobin has much greater viscosity especially in the Sickle haemoglobin has much greater viscosity especially in the deoxygenated statedeoxygenated state

Increasing Hb over 10g/dl carries risk of hyperviscosity symptoms in presence of large quantities of Hb S

Top up or exchange?Top up or exchange?Advantages

Top Up Exchange

Technically easier and needs fewer resources

Better control of Hb S

Less blood required Avoids hyperviscosity

Quicker Less iron accumulation

Disadvantages

Iron accumulation Needs more resources (machine, trained nurse)

Cannot achieve acute Hb S <30% without risk of hyperviscosity

Expensive

Venous access problematic

More donor exposure

Top upTop up ExchangeExchange

Severe anaemiaSevere anaemia Acute Chest SyndromeAcute Chest Syndrome

Red cell Red cell aplasiaaplasia Acute strokeAcute stroke

SplenicSplenic sequestrationsequestration Acute hepatic sequestrationAcute hepatic sequestration

Severe sepsisSevere sepsis

Acute multi organ failureAcute multi organ failure

Progressive Progressive intrahepaticintrahepatic cholestasischolestasis

Possible indications for elective blood Possible indications for elective blood transfusionstransfusions

Level A or B evidence available

Level A and B evidence unavailable

Primary stroke prevention Fetal complications in pregnancy

Secondary stroke prevention Repeated severe painful crises

Elective surgery Pulmonary hypertension

Painful crises in pregnancy Leg Ulcers

Priapism

Transfusion is not required for steady state anaemiaTransfusion in SCD should be discussed with haematologistLaboratory should be informed that blood is for a sickle cell patient so they can ensure correct blood requestedImportant to ask patient if they have had previous reactions to blood or carry a cardDo not take Hb up to >90-100g/LTransfusion is lifesaving

Thalassaemia Standards 2008Thalassaemia Standards 2008

A group of inherited disorders A group of inherited disorders resulting in reduced synthesis of resulting in reduced synthesis of one or more one or more globinglobin chains.chains.This results in an imbalance of This results in an imbalance of globinglobin chains with the excess chains with the excess chain producing the pathological chain producing the pathological effects:effects:

damage to red cell precursors damage to red cell precursors ineffective ineffective erythropoeisiserythropoeisis

damage to mature red cells damage to mature red cells haemolytic anaemiahaemolytic anaemia

Thalassaemia MajorThalassaemia MajorTransfusion dependentTransfusion dependent

Thalassaemia Thalassaemia IntermediaIntermediaLess severe anaemia and can survive without regular Less severe anaemia and can survive without regular blood transfusionsblood transfusions

Thalassaemia Minor (trait, carrier)Thalassaemia Minor (trait, carrier)Asymptomatic carrierAsymptomatic carrier

Failure to thriveFailure to thriveFatigueFatiguePoor feedingPoor feedingDevelopmental delayDevelopmental delayPoor growthPoor growthSplenomegalySplenomegalyFacial appearance etcFacial appearance etc

Requires careful monitoring (monthly from Requires careful monitoring (monthly from diagnosis)diagnosis)

When to start transfusions?When to start transfusions?Good clinical judgement cannot be replaced by any kind of clear Good clinical judgement cannot be replaced by any kind of clear instructions instructions

regarding decisions whether to transfuse a patientregarding decisions whether to transfuse a patient [[LoukopoulosLoukopoulos, Palermo , Palermo Conference]Conference]

GenotypeGenotype

Growth / thrivingGrowth / thriving

HbHb levels as welllevels as well

Earlier:

Before any problems / spleen enlarges etc

Later:

Parents accept child needs

Child may prove not to need[best taken at Centre]

Haemoglobin levels should be maintained above 9.5-10g/dl.

Cannulation will be undertaken by an experienced nurse or doctor.

Pre-arranged transfusions should be started promptly.

Good transfusion practice must be observed

Transfusions will be given on each occasion in a designated area with suitable facilities, experienced regular named nurses and familiar supervising medical team.

Transfusion therapy and monitoring iron loading in Transfusion therapy and monitoring iron loading in thalassaemiathalassaemia

1 blood unit contains 200 mg iron 1 blood unit contains 200 mg iron

A 60 kg thalassaemia patient A 60 kg thalassaemia patient receiving 45 units of blood receiving 45 units of blood annually has annually has transfusionaltransfusional iron iron intake of 9 g iron/yearintake of 9 g iron/year

0.4 mg iron/kg body wt/day0.4 mg iron/kg body wt/day

In addition, up to 4 mg/day may In addition, up to 4 mg/day may be absorbed from the gutbe absorbed from the gut

Up to 1.5 g iron/yearUp to 1.5 g iron/year

Porter JB. Br J Haematol 2001;115:239 252

200 250 mg iron:Whole blood: 0.47 mg iron/mLPure red cells: 1.16 mg iron/mL

Organ systems susceptible to iron overloadOrgan systems susceptible to iron overload

Clinical Clinical sequelaesequelae of iron overloadof iron overload

PituitaryPituitary Impaired growth, infertilityImpaired growth, infertility

HeartHeart CardiomyopathyCardiomyopathy, cardiac , cardiac

failurefailure

LiverLiver Hepatic cirrhosisHepatic cirrhosis

PancreasPancreas Diabetes mellitusDiabetes mellitus

GonadsGonads HypogonadismHypogonadism

Repeated transfusions lead to Repeated transfusions lead to iron overloadiron overload

0

10

20

5

15

25

30

0 20 40 60 80 100 140120 160

Iro

n (

mg

/g d

ry w

eig

ht)

Transfusion duration (months)

R=0.795

Harmatz P et al. Blood 2000;96:76 79, American Society Hematology, with permission

Significant correlation between transfusion duration and liver iSignificant correlation between transfusion duration and liver iron ron on biopsyon biopsy

Borgna-Pignatti C et al. Haematologica 2004; 89(10): 1187-93

NN %% NN %%

Heart failureHeart failure 133133 60.260.2 3131 50.850.8

InfectionInfection 1515 6.86.8 99 14.814.8

ArrhythmiaArrhythmia 1515 6.86.8 44 6.66.6

Myocardial infarctionMyocardial infarction 44 1.81.8

CirrhosisCirrhosis 99 4.14.1

ThrombosisThrombosis 99 4.14.1

MalignancyMalignancy 88 3.63.6 22 3.33.3

DiabetesDiabetes 77 3.23.2 22 3.33.3

AccidentAccident 44 1.81.8 11 1.61.6

Renal failureRenal failure 33 1.41.4

HIV / AIDSHIV / AIDS 33 1.41.4 22 3.33.3

Familial autoimmune disorderFamilial autoimmune disorder 22 0.90.9 11 1.61.6

AnorexiaAnorexia 11 0.50.5 11 1.61.6

Haemolytic anaemiaHaemolytic anaemia 11 0.50.5 11 1.61.6

ThrombocytopeniaThrombocytopenia 11 0.50.5

UnknownUnknown 66 2.72.7 55 8.28.2

TotalTotal 221221 6161

All patients (N=1073) All patients born after 1970* (N=720)

Causes of death in Thalassaemia

Serum ferritinSerum ferritin reflect current iron stores.reflect current iron stores.

Liver biopsyLiver biopsy gold standardgold standard Invasive Invasive

MRI techniquesMRI techniques Standard of careStandard of care

End organ functionEnd organ function Too lateToo late

DiseaseDisease--free survival related to body iron levels free survival related to body iron levels assessed by serum ferritinassessed by serum ferritin

Chelation therapy (years)

0.00

0.50

0.25

0.75

1.00

0 2 4 6 8 10 1412 16

Pro

po

rtio

n w

ith

ou

t ca

rdia

c d

isea

se

<33% ferritin measures>2500 ng/mL

33 67% ferritin measures>2500 ng/mL

>67% ferritin measures>2500 ng/mL

Cardiac disease-free survivalin patients with:

Olivieri N et al. N Eng J Med 1994;331:574 578. Massachusetts Medical Society, with permission

Olivieri NF & Brittenham GM. Blood 1997;89:739 761

Liver iron and risk from iron overload

50403020100

50

100

150

200

250

Age (years)

Hep

atic

iro

n (

µmo

L/g

wet

wei

gh

t)

50

40

30

20

10

0

Hep

atic iron

(mg

/g d

ry weig

ht)

Increased risk of complications

Normal

Thalassemia major

Threshold for cardiac disease and early death

Optimal level in thalassaemia

T2* MRI: emerging new standard for cardiac iron

Anderson LJ et al. Eur Heart J 2001;22:2171 2179, Oxford University Press, with permission

Lef

t ve

ntr

icu

lar

ejec

tio

n f

ract

ion

(%

)

0

50

70

40

30

20

10

60

80

90

0 20 40 60 9080 10010 30 50 70

Heart T2* (ms)

Cardiac T2* value of 37 in a normal heart

Cardiac T2* value of 4 in a significantly iron overloadedheart

Relationship between myocardial T2* values and left ventricular ejection fraction. Below a myocardial T2* of 20 ms, there was a progressive and significant decline in left ventricular ejection fraction (R=0·61, P<0·0001)

Goals of Goals of chelationchelation therapytherapy

What is What is chelationchelation therapy?therapy?

Chelate

Chelator MetalChelator

Toxic

ExcretionMetal

Comparison of Comparison of chelatorschelators

Property DFO Deferiprone Deferasirox

Usual dose (mg/kg/day)

25 60 75 20 30

Routesc, iv

(8 12 hours, 5 days/week)

Oral

3 times daily

Oral

Once daily

Half-life 20 30 minutes 3 4 hours 12 16 hours

Excretion Urinary, faecal Urinary Faecal

Adverse effects

Local reactions, ophthalmologic, auditory, growth

retardation, allergic

Gastrointestinal disturbances,

agranulocytosis/ neutropaenia,

arthralgia

Gastrointestinal disturbances, rash, mild

non-progressive creatinine increase,

ophthalmologic, auditory

DFO therapy improves survival in regularly transfused thalassaemia patients

Gabutti V & Piga A. Acta Haematologica 1996;95:26 36. S Karger AG, Basel, with permission

Su

rviv

al %

0

60

80

50

40

30

20

10

70

90

100

0 282624222018161412108642 30 32 34 36 38 40

Years

300 365225 300150 22575 1500 75

DFO Infusions/year

Kaplan-Meier analysis of survival in 257 consecutive

thalassaemic patientsaccording to the mean

compliance with subcutaneous DFO therapy

Deferasirox effectively decreases LIC across a range of transfusion-dependent anaemias

Thalassaemia (Study 107)

Thalassaemia (Study 107)

All anaemias(Study 108)

SCD (Study 109)

-10

-9

-8

-7

-6

-5

-4

-3

-2

-1

0

Mea

n c

han

ge

in L

IC (

mg

Fe/

g d

w)

Deferasirox 30 mg/kg/day DFO > 50 mg/kg/day

Deferasirox was non-inferior to DFO at doses of >20 mg/kg/day.

Studies 107, 108, 109Cappellini MD et al. Blood 2006;107(9):3455-3462; Porter J et al. Presented at ASH 2004 [Blood 2004;104(11):abst 3193]; Vichinsky E et al. Presented at ASH 2005 [Blood 2005;106(11):abst 313]

Decision based on Decision based on

Tolerance of current treatmentTolerance of current treatment

Current iron stores as evidenced by serum Current iron stores as evidenced by serum ferritin levels and liver/ heart imaging ferritin levels and liver/ heart imaging techniquestechniques

Trends in ferritin levelsTrends in ferritin levels

Patient choicePatient choice

Liver loading appears more important than Liver loading appears more important than cardiac loadingcardiac loading

Ferritin levels unreliableFerritin levels unreliable

Liver MRI techniques now recommendedLiver MRI techniques now recommended

Many patients have significant lifetime Many patients have significant lifetime transfusion burden even if not on regular transfusion burden even if not on regular transfusionstransfusions

Optimal iron Optimal iron chelationchelation intensity unclearintensity unclear

Transfusion may be lifesaving or reduce morbidity in Transfusion may be lifesaving or reduce morbidity in Sickle Cell Disease or ThalassaemiaSickle Cell Disease or Thalassaemia

The number of patients on transfusion is likely to The number of patients on transfusion is likely to increaseincrease

National guidelines indicate which patients with SCD National guidelines indicate which patients with SCD need transfusionsneed transfusions

Iron accumulation is a significant problem for these Iron accumulation is a significant problem for these patients and patients and chelationchelation should aim to prevent should aim to prevent complications complications

Blood should be Blood should be genotypicallygenotypically matched to prevent matched to prevent alloimmunisationalloimmunisation