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Clinical management of

Sickle cell anemiaSickle cell anemia in children

Mariane de Montalembert41th European symposium on rare anemias

SofiaSofia

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Disclosures

M de Montalembert receives research support, is member of the speakers’bureau and scientific advisory board for Novartis

Training Course on Haemoglobin Disorders 2011 #3

50 millions heterozygous ASindividuals in the world ?

• Africa: 10-40% BS mutation carriers in the population200,000 to 300,000 SCD newborns /year

• USA: 1 SCD newborn/600 births in Afro-American population

70,000 to 100,000 SCD patients

• France: 405 SCD newborns in 2007 10, 000 SCD patients

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A disease without bordersData fromneonatal screening

Incidence of SCD

In EuropeBrussels (Belgium) 1/2103 (Gulbis, 1999)

France 1/2364 (Bardakdjian, AFDPHE, 2010)

Netherlands ?

Spain ?

U.K., generalized, since 2006 SCD and EE: 1/1851 (Bouva, 2009)

Polymerization of endothelial dysfunctiondesoxyHbS

years

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

Bacteremia

Pain highly variable

ACS

Ac.Spl.Seq.

Stroke

Chronic organ damage ?

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Red cell sicklingRed cell sicklingChronic inflammation

I ti l h l i

Spleen dysfunction infectionsequestration

Vasoocclusion: painVasocclusion: painVasculopathy: stroke, PHT, renal disease..

Intimal hyperplasiaImpaired NO-induced vasodilation

Severity of SCD varies widely between patients

Moderate forms PainACSCVA

Severe formsAsymptomatic patients

Penicillin, folic acid, hydration

Hydroxyurea

Chronic transfusion

Bone marrow transplantationACS = acute chest syndrome; CVA = cerebrovascular accident.

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Interaction of environmental factors with genetic polymorphisms is thewith genetic polymorphisms is the

most likely explanation for this variability

Hypoxia reoxygenationInflammation

Endothelial activationCEC

Overexpression TF

PS exposure

HaemolysisNO

Platelet activation

Red celldehydration

CEC = circulating endothellial cells; NO = nitric oxide; PS = phosphatidylserine; TF = tissue factor.

Reproduced from Stuart MJ, Nagel RL. Lancet. 2004;364:1343-60 © 2004, with permission from Elsevier.

Modified by M de Montalembert.

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Questions about genetic counselling

Very low uptake for prenatal diagnosis:Greengross P, et al. J Med Screen 1999; 6:3-10 :

- 20 333 pregnancies screened at booking in a London maternity service over 10 years

- 751 (3.7%) AS mothers- 481 partners tested- 113 (23%) pregnancies at risk for SCD- PND accepted in 16 (15%) pregnancies*- TOP indicated in 4 pregnancies for SS- performed in 3p

* PND accepted in the same hospital in the same period by 80% of couples at risk for thalassemia

Questions about genetic counselling

Wo ld the ptake of PND be better ifWould the uptake of PND be better if screening occured earlier in gestation?

When? Before gestation?

11 158 carriers of an abormal Hb screenedat birth in France in 2010:How to organize the genetic counselling for all the families?

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Causes of death in children with SCD

Year ( )

Country Incidence Causes(range)

Gill 1978–98 USA 1.1/100 pt-yr 11 sepsis (9 S.pn), 2 ASS,1 CVA

Thomas 1985–92 France (Paris)

0.29%/yr 15 sepsis (8 S.pn), 3 ASS,3 CVA

Quinn 1983–04 USA(Texas)

0.59/100 pt-yr 5 sepsis (4 S.pn), 3 ACS,2 multi-organ failure(Texas) 2 multi organ failure,

1 CVA, 1 myocardial infarct

Quinn 1983–05 USA (Texas)

0.52/100 pt-yr 5 ACS, 4 multi-organ failure, 4 S.pn sepsis

CVA = cerebrovascular accident; pt-yr = patient years; S.pn = Streptococcus pneumoniae.

Gill FM, et al. Blood. 1995;86:776-83.Thomas C, et al. Arch Pediatr. 1996;3:445-51.

Quinn CT, et al. Blood. 2004;103:4023-7.Quinn CT, et al. Blood. [Epub ahead of print 2010 Mar 1].

100

98

HbSS diagnosed in newborn period

Earlier diagnosis positively impacts survival

98

96

94

92

90

Surv

ival

(%)

HbSS diagnosed after newborn period

Vichinsky E, et al. Pediatrics. 1988;81:749-55.

90

88

860 10 20 30 40 10

YearsMonthsHbSS = haemoglobin SS.

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Neonatal screening

IEF

Confirmatory tests

PenicillinImmunization

Folic acid

Expertise centre

educationNetwork of

trained physicians

Training Course on Haemoglobin Disorders 2011 #15

Prevention of infectionsDaily Penicillin prophylaxis BUT:(Gaston MH, NEJM 1986; 314: 1593-9) - incomplete level of adherence

- increased % of peni-resistant strain

Immunisation: Pneumo 23(Adamkiewicz TV, J Pediatr 2003; 43: 438‐44)

Lack of effectiveness in children < 2 yrs

Pneumoccocal Conjugate Vaccine(Halasa NB, CID, 2007; 44: 428‐33)

Training Course on Haemoglobin Disorders 2011 #16

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FIGURE 4 Kaplan-Meier curve of IPD in children with SCD according to PCV vaccination status from January 1, 2000, through January 1, 2003 for PCV serotypes (4,

6B, 9V, 14, 18C, 19F, and23F) and untyped isolates only

Copyright ©2008 American Academy of Pediatrics

Adamkiewicz, T. V. et al. Pediatrics 2008;121:562-569

acute chest syndrome

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Pathophysiology of Acute Chest Syndrome in SCA

Rees D. Lancet 2010; 376: 2018-31

Osteomyelitis (salmonella) in a 31 month-aged SS child

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Dactylitis

Management of Acute Severe Anemia

• Acute splenic sequestration• Parvovirus B19 erythroblastopenia• Hyperhemolysis (VOC, infection)

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Acute splenic sequestration

Drop in Hb level> 2 g/dlAcute enlargment of spleen size> 2 cm

Prevention of acute splenic sequestrations

EDUCATION OF PARENTS

No consensus of the management of recurrent ASS:splenectomy at any agechronic transfusion

Owusu-Ofori S, Hirst C. Cochrane Database Syst Rev, CD003425. DOI: 10.1002/14651858.CD003425 pub2 (2002).

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Goals of Transfusion in SCD Patients

• Increase O2 carrying capacity: acute i l t f isimple transfusion

• Replace rigid sickle red cells by deformable red cells to restore blood flow: acute simple transfusion or exchange transfusiontransfusion

Severe vasoocclusive complications

‐ ACS

‐ stroke

‐ priapism, organ failure, painful crisis non responding to opiods, …

Exchange transfusion is the best option when Hb is > 8 g/dL, Simple transfusion is an alternative when Hb is < 8 g/dL, being careful notincreasing the Hb level above the baseline value

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Mild narrowingof vessel lumen

TCD

Stenosisocclusion

Moya-moyaaneurysm

Cerebral vasculopathy

TCDMRI/MRAstenosisocclusion

Lacunaatrophyinfarct

Velocity > 2 m/s ± Overt stroke ± Cerebral haemorrhageMRA = magnetic resonance angiography; MRI = magnetic resonance imaging.

Inflammation NObioavailability

Factors responsible for strokes in SCD ?

Red cell sickling

Adhesion of blood cellsto endothelium

Proliferationof intima

Genetic factors

bioavailability

Thrombus? cerebralblood flow

Which factors are the first/the main ones?

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Right MCA Left MCA

Predictive value of TCD for strokePredictive value of TCD for

stroke

130 cm/s 220 cm/s

● The probability of remaining stroke-free over time of follow-up or start of chronic transfusion (~ 70 months) was greatest with normal baseline TCD

The risk of stroke was higher with abnormal TCD than with normal or conditional TCD (p < 0.01)

Adams RJ, et al. Blood. 2004;103:3689-94.

Probability of SCD Children Remaining Stroke-Free Is Greater With Long-Term Transfusions

Incidence of stroke decreased after the STOP trial1.41.0

STOP I

rst-S

trok

e In

cide

nce

er 1

00 P

erso

n-Ye

ars)

0 2

0.4

0.6

0.8

1.0

1.2

roba

bilit

y of

Rem

aini

ng

trok

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ee

0.2

0.4

0.6

0.8

Transfusion

p = 0.002

Fullerton et al. Blood. 2004;104:336-339.

Since the publication of the STOP I trial in 1998, the annual rates of stroke for children in California have declined

Date, y

Fir

(pe

0

0.2

1991 1992 1993 1994 1995 1996 1997 1998 1999 2000Time, mo

Pr St

00 5 10 15 20 25 30

TransfusionStandard care

Adams et al. N Engl J Med. 1998;339:5-11.

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Severity of SCD varies widely between patients

Moderate forms PainACSCVA

Severe formsAsymptomatic patients

Penicillin, folic acid, hydration

Hydroxyurea

Chronic transfusion

Bone marrow transplantationACS = acute chest syndrome; CVA = cerebrovascular accident.

Intensification of treatment (1)

Hematopoietic stem celltransplantation

Consensus for those having a neurological complicationand a HLA-identical sibling

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Estimated outcomes: OS, EFS, and cumulative incidence of rejection in the 87 patients.

Bernaudin F et al. Blood 2007;110:2749-2756

median FU: 6 years (2-18 yrs)overall and event-free survival(EFS) rates: 93.1% and 86.1%

Multiple beneficial effects of hydroxyurea for SCA

Ware RE. Blood. 2010;115: 5300-11.

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Intensification of treatment (2)

Hydroxycarbamide

Consensus for those with > 3 hospitalized VOC/yrand/or > 2 ACS# consensus for severe anemia

B tBut

Secondary loss of efficacy in # 10% aging children

but

Intensification of treatment (3)

Chronic transfusion program

Almost always effective in reducing pain and ACS, and highly effective in protecting patients from recurrent

strokes

B t i dBut induces

Iron overload, which may be treated

Risk of red cell allo-immunization which may be life-threatening

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Finding enough appropriate blood supplies in the next years for SCD patients will be

a challenge

• Increase of blood needs especially for planned• Increase of blood needs, especially for planned transfusion (prevention of strokes)

• Disparity in blood groups in blood donors (mostly caucasians) and recipients (mostly Afro-caribbeans:caribbeans:– Patients with rare phenotypes– And/or poly-alloimmunizationA nearly specific complication: the delayed hemolytic

transfusion reaction

SWiTCH: Transfusions + deferasirox versus HU + phlebotomy

Aim: To compare 30 months of hydroxyurea and phlebotomy (alternative) with transfusions and deferasirox (standard) for the prevention of secondary stroke andtransfusions and deferasirox (standard) for the prevention of secondary stroke and

reduction of transfusional iron overload

Primary endpoint: Recurrent stroke rate and quantitative liver iron concentration

Hypothesis: An increased number of recurrent strokes events were predicted to occur in the alternative compared with the standard arm but this risk would be balanced by improved

Study US10Ware R & Helms R. Blood 2010;116(21):abst 844

standard arm, but this risk would be balanced by improved management of transfusional iron burden by repeated

phlebotomies

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161 paediatric patients with sickle cell anaemia (83 male, 78 female), documented stroke and iron overload (LIC 15.5 ± 10.1 mg Fe/g dw) enrolled in SWiTCH (US10)

E ll t f O t 2006 t A il 2009

SWiTCH: Transfusions + deferasirox versus HU + phlebotomy

Interim analysis on 133 patients randomized 1:1

Enrollment from Oct 2006 to April 2009Average age: 12.9 ± 4.0 years

12% already recurrent stroke before inclusion

Alternative arm67 patients

Hydroxyurea + phlebotomy

Standard arm66 patients

Transfusions + deferasirox

Study US10Ware R & Helms R. Blood 2010;116(21):abst 844

Stroke with Transfusions Changing to Hydroxyurea (SWiTCH)

Nb of Transient Median LiverNb of stroke

Nb of Transient Ischaemic

Attacks events

Median Liver Iron

Concentration (LIC)

Alternative group (n=67) 7 6 15,7 → 15,7

Standard group(n=66) 0 9 16,9 → 16,6

1 death unrelated to treatment occurred in both groups

• Conclusion of Data & Safety Monitoring Board (DSMB):– Decision to terminate SWiTCH in May 2010 : primary

endpoint not reached

Ware R & Helms R. Blood 2010;116(21):abst 844

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SWiTCH: Summary

Transfusions + chelation• Remains the gold standard for children with stroke and iron overload• Stroke recurrence was 0% on study with HbS ~30%• Iron balance (assessed by LIC) was neutral using deferasirox

Hydroxyurea + phlebotomy• Management of transfusional iron overload was not superior• Phlebotomy was well tolerated and removes substantial iron• Recurrent stroke occurred in 10% (5.6 per 100 patient-years)

S SWiTCH bj t t d f h d ft t d l

Ware R & Helms R. Blood 2010;116(21):abst 844

• Some SWiTCH subjects opted for hydroxyurea after study closure• Alternative treatment may be therapeutic option in selected cases

No stratification in this trial on the severity of the cerebral vasculopathyFurther investigation is warranted

STEP 1: Mild narrowingof vessel lumen

TCD

STEP 2 and 3: Stenosis, occlusionMoya moya, aneurysm

Cerebral vasculopathy

HU i l lik l t t t k

Number of strokesHU arm (N=67) 7Transfusion arm(N=66)

0

SWiTCH trial

HU may prevent stroke

HU is less likely to prevent strokes

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Adolescence is a critical period, also for patients

with SCDwith SCD

• Onset of up to now invisible complications• Weight of daily treatment• Fear to live the paediatric environment for the

adult oneadult one• Most centres have no transition programs• Lack of therapeutic educational programs• Lack of dedicated adult structures

Lanzkron S, et al. ASH 2010, abstract 736

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Morbidity in adults with SCDPatients’ characteristics

SS (n = 59)/Sb0-thal (n = 5) SC (n = 29)/Sb+-thal (n = 11) p*N 64 40Age (year) 27 (21–41) 29 (24-38) 0.674BloodparametersHaemoglobin (g/dL) 9.0 (8.1–9.8) 11.3 (10.6–12.2) <0.0001Leukocytes (x109/L) 9.0 (7.2–11.7) 6.9 (5.9–8.9) 0.001Fetal haemoglobin (%) 8.1 (3.8–14.6) 1.7 (1.0–3.2) <0.001

Organ damage (%)Renal failure 8 3 0.402Pulmonary hypertension 32 12 0.047Retinopathy 24 61 0.001Iron overload 17 0 0.006Cholelithiasis 66 23 <0.001

Clinical complications (%)Avascular osteonecrosis 16 8 0.223Leg ulcers 14 0 0 012

Van Beers EJ, et al. Haematologica. 2008;93:757-60.

Leg ulcers 14 0 0.012Acute chest syndrome 32 18 0.167Number of crises/year 0.472

None 27 38Less than one 47 43One or more 27 20

Stroke 11 0 0.042Priapism (% of males) 21 6 0.206

Results are medians (interquartile range). *Mann-Whitney test or two-sided Fisher-exact test.

Causes of death in Athens cohort

Cause of death HU patients Non-HU patients Cause of death (13/131 = 9.9%) (49/199 = 24.6%)Liver dysfunction 1 10Pulmonary hypertension 8 8Stroke 3 10Sudden death 3 5Vaso-occlusion crisis 1 6Acute chest syndrome 1 5Sepsis 1 1Heart failure 2 2Intervention 1 2

Voskaridou E, et al. Blood. 2010;115:2354-63.

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Is SCD in children the emerged top of an iceberg?

VOC, infections

PHT,Renal failure…

Can severe complications in adult occur in a so farmildy symptomatic child?

Most likely yes in children with a baseline Hb level< 7 g/dL

Recommended exams to be performed annually

0 -1 yr 2 yrs 3-5 yrs 6-9 yrs 10-15 yrs 16-18 yrs

Physical examination

Transcutaneous O2 sat

Laboratory tests*Assessment of adherence to tt and appointments

TCD

Liver/gallbalder ultrasoundAcademic performancesP f iPumonary function testsHip x-ray

ECG

Ophtalmologic evaluation**

* CBC, liver profile, electrolytes, BUN, creatinine, µalbuminuria,ferritin if transfused, calcium metabolism, parvovirusB19 serology until positive

** Since the age of 6 y.o. if Hb SC diseaseDe Montalembert et al, Am J Hematol2011; 86: 72-5

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Looking for risk factors?

Would it be possible to find out those children who will suffer in adulthood of the most severewill suffer in adulthood of the most severe complications of SCD, in order to intensify treatment in those patients (most likely using hydroxycarbamide)

Or is intensification of treatment to be recommended in all patients?

Brochures (www.rofsed.fr) and DVD-Rom