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Cerebral Infarcts in Patients with Sickle Cell Disease

Miguel R. Abboud, MDProfessor of Pediatrics

Hematology-OncologyChairman, Department of Pediatrics and

Adolescent MedicineAmerican University of Beirut Medical Center

Beirut, Lebanon

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Term Definition ImagingStroke Acute neurologic syndrome that

results from either vascular occlusion or haemorrhage, resulting in ischaemia and

neurologic symptoms or signs lasting >24 hours

Positive

Transient ischaemic attack

Acute neurologic syndrome with deficits lasting <24 hours

Negative

Silent infarct Small infarct (typically <15 mm) evidenced by MRI but no

neurologic deficits

Area of increased signal on

intermediate or T2-weighted MRI pulse sequences

Definitions

Adams RJ, et al. Hematology Am Soc Hematol Educ Program. 2001:31-46.

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Stroke Subtype by Age• Ischaemic stroke1

– 54% of cerebrovascular accidents– Highest in 1st decade and after 30 years– Peak incidence at 2–5 years

• Haemorrhagic stroke1

– Highest in 2nd decade

• Silent stroke/infarct– Radiologic findings consistent with white matter disease1

– 10%–30% of patients with sickle cell disease (SCD)1

– Associated with cognitive deficiencies1 and higher stroke risk2

1. Verduzco LA, et al. Blood. 2009;114:5117-5125. 2. Miller ST, et al. J Pediatr. 2001;139:385-390.

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● Multivariate predictors (P <.05 for each)1

– Prior transient ischaemic attack (TIA): Relative risk (RR) = 56

– Anaemia: RR = 1.85 per 1 g/dL Hb decrease– Recent acute chest syndrome: RR = 7– Acute chest syndrome rate: RR = 2.39 per event/year– Hypertension: RR = 1.31 per 10 mmHg increase

● Additional predictors– Silent infarcts: RR = 142

– Nocturnal hypoxia: Hazard ratio (HR) = 0.85 per 1% increase in O2 saturation3

1. Ohene-Frempong K, et al. Blood. 1998;91:288-294. 2. Miller ST, et al. J Pediatr. 2001;139:385-390.3. Kirkham FJ, et al. Lancet. 2001;357:1656-1659.

Risk Factors for Infarctive Stroke

5Hulbert ML, et al. J Pediatr. 2006;149:710-712.

Simple Exchange0

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Chart Title

Patie

nts

with

Rec

urre

nt

Stro

kes

(%)

8/14 8/38

Stroke Recurrence Risk After Initial Simple vs Exchange Transfusion

Transfusion Type

All children received scheduled chronic blood transfusion therapy for at least 5 years after the

first stroke and initial therapy

RR = 5.0 (1.3–18.6; P = .02)

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● Ischaemic stroke is treated with emergent simple or exchange blood transfusion1

● Without transfusion, 70% will recur within 2–3 years1

● With chronic transfusion, risk of recurrence is reduced by 90%1

Management of Stroke and Prevention of Recurrence

1. Josephson CD, et al. Transfus Med Rev. 2007;21:118-133. 2. Pegelow CH, et al. J Pediatr. 1995;126:896-899. 3. Powars D, et al. Am J Med. 1978;65:461-471.

Series10

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67

Chart Title

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(%)

Transfusion2 NoTransfusion3

8/60

Study population with transfusion vs

historical control subjects without transfusion2

Cumulative observation time = 191.7 patient-years

10/15

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Aim of study: [hydroxyurea + phlebotomy = alternative arm] vs [transfusions + deferasirox = standard arm] for 30 months to prevent

secondary stroke and reduce transfusional iron overload

161 paediatric patients with SCD and documented stroke and iron

overload enrolled in SWiTCH

133 patients randomized

1:1

Alternative armHydroxyurea + phlebotomy

n = 67

Standard armTransfusions + deferasirox

n = 66

Prediction: increased recurrence of stroke events in alternative arm but counterbalanced by better management of

iron overload with phlebotomy

Hydroxyurea for Secondary Stroke Prevention—SWiTCH

Ware RE, et al. Blood. 2010;116:Abstract 844.

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Series10

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)

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1. Ware RE, et al. Blood. 2010;116:Abstract 844. 2. NIH. Press release. June 4, 2010. Accessed 11/21/11 at: http://public.nhlbi.nih.gov/newsroom/home/GetPressRelease.aspx?id=2709.

SWiTCH—Stroke Recurrence Higher with Hydroxyurea than with Transfusions1

Study was terminated early2 due to the marked increase in secondary stroke risk

with hydroxyurea compared with transfusion therapy and no benefit of phlebotomy over

chelation in reducing iron overload

Transfusion + Deferasirox

Hydroxyurea + Phlebotomy

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Importance of Transcranial Doppler Screening in SCD

Annual Stroke Risk● Baseline risk from Cooperative Study of Sickle Cell Disease

(CSSCD) is approximately 0.5%–1%1

−If prior stroke, annual stroke risk is approximately 30%2

● Increased risk of infarctive stroke with TIA, lower baseline Hb, prior and recent acute chest syndrome (CSSCD study, no prior stroke), but yearly risk not quantitated1

● If abnormal transcranial Doppler (TCD), annual risk is 10%–13% per year3

● If MRI “silent lesions,” annual risk is approximately 2%–3%4

● Severe arterial lesions on angiography?−Assumed to be bad,5 but yearly risk has not been quantitated

1. Ohene-Frempong K, et al. Blood. 1998;91:288-294. 2. Powars D, et al. Am J Med. 1978;65:461-471. 3. Adams RJ. Arch Neurol. 2007;64:1567-1574. 4. Miller ST, et al. J Pediatr. 2001;139:385-390. 5. Abboud MR, et al. Blood. 2011;118:894-898.

10*Includes 1 patient with intracerebral haematoma.Adams RJ, et al. N Engl J Med. 1998;339:5-11.

Total Transfusion Standard*02468

101214161820

9.2

1.6

16.4

Chart Title

Patie

nts

with

Str

okes

(%)

12/130 11/67

P <.001

1/63

Median follow-up = 21.1 months

Paediatric patients with SCD and abnormal TCD velocity were randomized to transfusion or standard

care to prevent first stroke

Stroke-Free Probability Is Increased with Long-Term Transfusions

in Children with SCD

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Early TCD Screening and Intervention● Predictive factors and outcomes of cerebral vasculopathy in

the Créteil newborn SCA cohort (n = 217, SS/Sβ0)● Screened with TCD early and yearly since 1992● MRI/MRA every 2 years after age 5 years (or earlier in case

of abnormal TCD)● Transfusions for abnormal TCD and/or stenoses● Hydroxyurea to symptomatic patients with no

macrovasculopathy● Stem cell transplantation for those with HLA genoidentical

donor● Mean follow-up 7.7 years (1609 patient-years)

Bernaudin F, et al. Blood. 2011;117:1130-1140.

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Cumulative Risks in SCD Cohort with TCD Screening

• Cumulative risks by 18 years of age– Stroke: 1.9% (95% CI 0.6%–5.9%) compared with 11%– Abnormal: TCD 29.6% (95% CI 22.8%–38%) plateau at age 9 years– Stenosis: 22.6% (95% CI 15.0%–33.2%) – SI: 37.1% (95% CI 26.3%–50.7%) age 14 years

• All cerebral event risk by 14 years 49.9% (95% CI 40.5%–59.3%) • Independent predictive factors for cerebral risk

– Baseline reticulocytes count: HR 1.003 per 1 x 109/L increase– Lactate dehydrogenase: HR 2.78 per 1 IU/mL increase

• Conclusion: Early TCD screening and intensification therapy reduced risk of stroke by age 18 years from 11% to 1.9%– 50% cumulative cerebral risk suggests more preventive intervention

is needed

Bernaudin F, et al. Blood. 2011;117:1130-1140.

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TCD and Transfusions in Patients with Silent Infarcts—Conclusions

• Early TCD and transfusions effective in preventing strokes

• TCD does not screen for risk of silent infarcts• Most patients who develop silent infarcts have

normal TCD• Different strategies needed

Bernaudin F, et al. Blood. 2011;117:1130-1140.

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● 79 subjects having normalized TCD under transfusion were randomized1

– 38 to continue cRCT therapy

– 41 to discontinue cRCT therapy

● No neurologic events in the cRCT group1

Abbreviations: cRCT, chronic red cell transfusion; TCD, transcranial Doppler.1. Adams RJ, et al. N Engl J Med. 2005;353:2769-2778. 2. NIH. Press release. December 5, 2004. Accessed 11/21/11 at: http://www.nhlbi.nih.gov/new/press/04-12-05.htm.

Graphic courtesy of Dr. Miguel R. Abboud.

No RCT cRCT05

101520253035404550 Ischaemic stroke

High-risk TCD

0%

STOP II trial terminated after 2 years and concluded that it is unsafe to stop blood transfusions in patients who are at high risk of stroke2

4.9%

34.1%

Patie

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STOP II Trial—Transfusion and Stroke Prevention

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Transfusion Standard Care

Total

Stroke 0 9* 9

New or worse silent infarcts

0 6 6

No change 18 14 32

P-value <.001

Pegelow CH, et al. Arch Neurol. 2001;58:2017-2021.

STOP Trial—Transfusion Therapy vs Standard Care for Prevention of Secondary Silent Brain Infarcts

*Includes 1 patient with new or worse lesion prior to stroke.

Outcome after observation for 36 months in patients who had silent infarcts at baseline and who were randomized to

transfusion or standard care

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No Transfusion

(n = 41)

Baseline: Silent Infarct*

11 (26.8%)

New Lesion5 (50%)

No Change5 (50%)

Baseline: Normal MRI30 (73.2%)

New Lesion6 (20%)

No Change24 (80%)

Transfusion (n = 38)

Baseline: Silent Infarct 10 (26.3%)

New Lesion3 (30%)

No Change†

7 (70%)

Baseline: Normal MRI*28 (73.7%)

New Lesion 0 (0%)

No Change27 (100%)*1 patient had no follow-up MRI.

†3 patients had lesion number decrease; 1 reverting to normal scan.Abboud MR, et al. Blood. 2011;118:894-898.

STOP II Trial—Effect of Discontinuing Transfusion on Silent Brain Infarcts on MRI

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No Transfusion

(n = 41)

Baseline: Silent Infarct*

11 (26.8%)

New Lesion5 (50%)

No Change5 (50%)

Baseline: Normal MRI30 (73.2%)

New Lesion6 (20%)

No Change24 (80%)

Transfusion (n = 38)

Baseline: Silent Infarct 10 (26.3%)

New Lesion3 (30%)

No Change†

7 (70%)

Baseline: Normal MRI*28 (73.7%)

New Lesion 0 (0%)

No Change27 (100%)*1 patient had no follow-up MRI.

†3 patients had lesion number decrease; 1 reverting to normal scan.Abboud MR, et al. Blood. 2011;118:894-898.

STOP II Trial—Effect of Discontinuing Transfusion on Silent Brain Infarcts on MRI

At study end, 3/37 (8.1%) patients in the

continued-transfusion group developed new brain

MRI lesions compared with 11/40 (27.5%) in the

transfusion-halted group (P = .03)

18*Includes 1 patient with intracerebral haematoma.Adams RJ, et al. N Engl J Med. 1998;339:5-11.

Total Transfusion Standard*0

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Chart Title

Patie

nts

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12/130 11/67

P <.001

1/63

Median follow-up = 21.1 months

Paediatric patients with SCD and abnormal TCD velocity were randomized to transfusion or standard

care to prevent first stroke.

Consequence of Stroke Prevention with Blood Transfusions

IRON OVERLOAD is an inevitable consequence of

chronic transfusions in patients with SCD

Initial serum ferritin164 ± 155 ng/L

1-year serum ferritin1804 ± 773 ng/L

2-year serum ferritin2509 ± 974 ng/L

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Patient CharacteristicsGroup Age*

(y)Transfusion Duration (y)

Serum Ferritin(ng/mL)

Liver Iron* (mg/g dry wt)

SCD 14.8 ± 1.0 6.0 ± 0.6 2916 ± 233 14.33 ± 1.38

β-Thal 18.37 ± 2.1 12.2 ± 1.8 2122 ± 289 14.79 ± 2.15

Organ DysfunctionGroup Cardiac

DiseaseGrowth Delay*

Gonadal Failure

SCD 0 9% 0β-Thal 20% 27% 33%

Liver DiseaseGroup Viral

HepatitisALT

>65 U/LFibrosis Score >0

SCD 2% 7% 39%

β-Thal 33% 37% 81%

*P-value = not significant; P-value significant for all other comparisons.Vichinsky E, et al. Am J Hematol. 2005;80:70-74.

Organ Dysfunction inSickle Cell Disease and β-Thalassaemia

SCD n = 43β-Thal n = 30

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● Organ injury may require a critical iron level with prolonged exposure

● SCD biology and its secondary inflammatory state may be protective factors

● Inflammation may decrease organ injury by restricting iron to shielded sites within the reticuloendothelial system (RES) and delaying the release of iron from the RES system

● The 2 diseases may have different transport and storage proteins

Why Do SCD Patients Demonstrate Less Organ Injury than β-Thalassaemia Patients?

Vichinsky E, et al. Am J Hematol. 2005;80:70-74.

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Possible Explanations for Absence of Cardiac Iron Overload in SCD

● Nontransferrin-bound iron higher in thalassaemia major than SCD

● Other factors– Splenic tissue– Ineffective erythropoiesis– Gastrointestinal iron metabolism– Urinary iron loss

Vichinsky E, et al. Am J Hematol. 2005;80:70-74.

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Hepatocyte Siderosis Kupffer Cell Siderosis

With permission from Pierre Brissot, MD.

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How to Monitor Iron Status

● Serum ferritin– Noninvasive, available, inexpensive– Confounded by several parameters– Use long-term trends and avoid using acute-phase

values● Liver biopsy

– Gold standard– Reveals pathology– Invasive– Sampling error

● Magnetic resonance– Accurate – Expensive

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How to Manage Iron Overload

● Chelating agents– Desferrioxamine– Deferasirox– Deferiprone

Licensed for thalassaemia major only1

● Nonpharmacologic techniques– Erythrocytapheresis– Phlebotomy

1. Ferriprox (deferiprone). Summary of product characteristics. Leiden, Netherlands: Apotex; 1999.

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Simple Transfusion1

Manual Exchange

Transfusion1

Erythrocyta-pheresis1,2

Features • Easy to perform

• 1 venous access

•Time-consuming

•Manual

•Expensive•Requires 2 good venous accesses

•Good clinical tolerance

Iron overload +++ + No iron overload

Safety Allo-immunization +++Infections

Chronic Transfusion Methods

1. Sickle Cell Society. Standards for the clinical care of adults with sickle cell disease in the UK. 2008.Accessed 11/29/11 at: http://www.sicklecellsociety.org/app/webroot/files/files/CareBook.pdf. 2. Kim HC, et al. Blood. 1994;83:1136-1142.

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Properties Desferrioxamine1 Deferasirox2 Deferiprone3

Usual dose (mg/kg/d)

20–60 20–30 75 (total daily dose)

Route SC, IV(8–12 h, 5–7 d/wk)

Oral, once daily Oral, TIW

Half-life 6 h 8–16 h 2–3 hExcretion Urinary, faecal Faecal UrinaryKey adverse effects

Local reactions, ophthalmologic, auditory, growth

retardation, allergic

Gastrointestinal disturbances, rash, creatinine increase,

ophthalmologic, auditory, elevated

liver enzymes

Gastrointestinal disturbances,

agranulocytosis/ neutropaenia,

arthralgia, elevated liver enzymes

Status Licensed for SCD Licensed for SCD Not licensed for SCD

Iron Chelation Therapy is Needed to Treat Iron Overload

1. Desferal (desferrioxamine). Summary of product characteristics. Camberly, UK: Novartis; 2010. 2. Exjade (deferasirox). Summary of product characteristics. Nuremberg, Germany: Novartis; 2006. 3. Ferriprox (deferiprone). Summary of product characteristics. Leiden, Netherlands: Apotex; 1999. Graphic courtesy of Dr. Miguel R. Abboud.

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Deferasirox(n = 117)

Desferrioxamine(n = 56)

Serum Ferritin Reduction

P = NS

Deferasirox vs Desferrioxamine—Measures of Iron Overload

Data from Cochrane review of randomized-controlled trials that compared deferasirox with desferrioxamine. Abbreviations: LIC, liver iron concentration; SQUID, superconduction quantum interference device. Meerpohl JJ, et al. Cochrane Database Syst Rev. 2010;8:CD007477.

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Deferasirox(n = 83)

Desferrioxamine(n = 33)

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Measure NRisk Ratio:

Deferasirox vs Desferrioxamine

Patient satisfaction 195 3.13 (95% CI 1.99–4.93)

Convenience 195 3.85 (95% CI 2.28–6.47)

Patient’s estimate of likelihood to continue treatment

195 6.86 (95% CI 3.38–13.91)

Discontinuations 390 1.17 (95% CI 0.56–2.44)

Data from Cochrane review of randomized-controlled trials that compared deferasirox with desferrioxamine. Meerpohl JJ, et al. Cochrane Database Syst Rev. 2010;8:CD007477.

Deferasirox vs Desferrioxamine—Measures of Satisfaction and Adherence

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Conclusions

• Infarctive strokes are a devastating complication of SCD• Chronic transfusion regimens are very effective in

preventing stroke recurrence as well as new strokes in patients with abnormal transcranial Doppler

• Early transfusions seem effective in preventing development and progression of silent infarcts

• Iron accumulation in sickle cell disease is different compared with thalassaemia

• Iron chelators are effective in preventing iron overload in these patients