Dr Josu de la Fuente

St. Mary’s Hospital

London

bone marrow transplantation for sickle cell disease

Sickle Cell Disease

1. HbSS

2. HbSC

3. HbSb thalassaemia

• Hb S: Glu to Val position 6 in beta chain

• Hb C: Glu to Lys position 6 in beta chain

• b thalassaemia: reduced or absent production

Gabriel, Nature Education 2010

Bunn H. N Engl J Med 1997;337:762-769

Induction of Red-Cell Sickling by Polymerization of Deoxyhemoglobin S

Steinberg M. N Engl J Med 1999;340:1021-1030

Kato, Blood Reviews 2007

Karimi, Annal Hematol 2012

Kato et al, Blood Reviews 2007

Platt et al, NEJM (1994) 330:1639-1644

Quinn et al, Blood (2004) 103: 4023-4027

Survival of Patients with Sickle Cell Disease

Telfer et al, Haematologica 2007

Platt et al, NEJM (1994) 330:1639-1644

ACS rates of 7.5 events per 100 person-years, expected incidence 24.5 events per 100 person-years

Hankins et al. Blood 2005;106:2269-2275

HUSOFT Study

Normalization of Splenic Uptake

after Extended HU therapy

Charache S et al. NRJM 1995;332:1317-1322

MSH Study

Median Time from the Initiation of

Treatment to Second Painful Crisis

Steinberg, M. H. et al. JAMA 2003;289:1645-1651.

Cumulative Mortality

treatment with hydroxycarbamide

• 25% HbSS patients and 10% HbSC patients have a CVA by the age of 45 years

– ischaemic infarction peaks in the first two decades of life and from the fourth decade onwards

– haemorrhagic stroke secondary to aneurysm, sinovenous thrombosis or moyamoya disease occurs more commonly in the third decade

• arterial disease mainly affects the distal internal carotid and proximal middle and anterior cerebral arteries and is found in at least 60% of strokes

• by 16 years of age 20% of children with HbSS have silent infarcts

Ohene, Blood 1998

Stockman, NEJM 1972

Pegelow, Blood 2002

• 20% of children who had a stroke and receive regular transfusions will have a second stroke.

• 30% with a second stroke will have a third stroke despite documented S level <30%.

• risk of subsequent strokes:

– not presenting initially in the context of an acute illness (hypertension, acute chest syndrome, aplastic crisis, fever associated with infection, exchange transfusion)

– moyamoya collaterals on angiography

• monthly transfusions to keep S level <30% reduce recurrent stroke from 66-99% to 10-27%.

Scothorn, J Pediatrics 2002

Dobson, Blood 2002

Adams, NEJM 1998

Probability of Not Having a Stroke among Patients Receiving Long-Term Transfusion and Patients Receiving Standard Care

• Children 2 - 16 years of age with HbSS or S/b0 thalassaemia and no history of stroke.

• Screened for abnormal TCD (internal carotid/middle cerebral artery velocity >200 cm/s) = 40% risk of stroke over 3 years.

• 9.7% children with a peak at 2 - 8 years of age.

• 90% reduction in clinical stroke.

STOP

Adams, NEJM 2005

Probability of No End-Point Event among Patients Assigned to Continued Transfusion or No Continued Transfusion

14 patients: abnormal TCD 2 patients: stroke

• Tx ≥ 30 months

• Converted from high risk to low risk TCD

• No severe lesions on MRI/MRA

STOP II

4 years old boy with HbSS, uncomplicated in infancy

stroke at 2½ years of age

further strokes despite transfusions at 3 years of age causing a right hemiparesis and

epilepsy

further stroke at 3½ years of age when S level <20%

MRA consistent with moya-moya and occlusion of the internal carotid artery bilaterally

significant cognitive deterioration in psychometric testing

revascularisation surgery at 4 years of age followed by a generalised tonic clonic seizure

despite new vessel formation and new ischaemic lesion in the left frontal lobe

Silent Cerebral Infarcts

• Increased incidence of new stroke (1.03/100 patient years) and new or more extensive SI (7.07/100 patient years) relative to stroke incidence among all children without SI (0.54/100 patient years).

• Significant cognitive deficits that are intermediate in magnitude compared to children with overt strokes and those with normal MRI: average decrease of 5 points in full-scale IQ = 5 to 9% reduction in annual income as adults

Buchanan, Hematology 2004

• children in the lowest quartile of hemoglobin levels at baseline have higher odds of silent cerebral infarct than do those in the top quartile

• reduction in hemoglobin concentration in hospitalized children is temporally associated with an increase in new-onset silent cerebral infarcts

King, Am J Hematol 2014 Zagorsky, Intelligence 2007

Controlled Trial of Transfusions for Silent Cerebral Infarcts in Sickle Cell Anemia.

DeBaun MR et al. N Engl J Med 2014;371:699-710

SIT

• 5 and 15 years of age

• no history of stroke

• one or more silent cerebral infarcts on MRI

• neurologic examination no abnormalities corresponding to lesions

• primary end point: recurrence of an infarct (stroke or a new or enlarged silent cerebral infarct)

Boyd, J. H. et al. Blood 2006;108:2923-2927

Sickle Cell Complications and Asthma

Acute Chest Syndrome

Vaso-occlusive Crises

Quinn, Blood 2010

1. VOC despite hydroxycarbamide: four or more episodes a year requiring hospitalisation or impacting in schooling despite hydroxycarbamide treatment

2. Recurrence of acute chest syndrome despite hydroxycarbamide

3. CNS disease:

a. Stroke

b. Abnormal TCD and silent infarct or abnormal psychometric tests/poor school performance formally assessed

c. Silent infarcts with cognitive deficiency

d. Significant abnormalities in MRA despite transfusions

e. Abnormal TCD and generation of red cell alloantibodies

f. CNS disease requiring transfusions leading to significant iron overload despite best attempt at adequate management

4. Suboptimal medical care

5. AVN

Criteria for BMT in Sickle Cell Disease

2011 to 2013

aGvHD II-IV: 15.9%

limited cGvHD: 9.1%

extensive cGvHD: 6.8%

cGVHD at 18 months: 2%

n = 47

Successful HSCT

(n = 12)

Failed HSCT

(n = 13)

Red marrow area percentage (%) p=0.01

Mean ± SD 90.25 ± 4.14 94.54 ± 2.93

Range 85.16−96.36 89.27−98.67

Marrow haemosiderosis

Present 5 3

Absent 7 10

Shen, Eur Radiol 2008

Endogeneous haemopoiesis

and graft failure

hypertransfusions

thiotepa

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Results: CNS

26 patients (16 male, 10 female) had at least 2 years of follow-up:

19 evidence of CNS abnormalities:

• 13 stroke receiving regular transfusions

• 1 transient ischemic attack

• 4 cerebral infarction MRI that was clinically silent

• 1 elevated cerebral arterial velocity

After SCT:

• none had a stroke and all had stable or improved MRI scans

• most had stabilization of underlying cerebral vasculopathy

Increased risk of transplant-related neurologic events:

• 4/7 initial patients had events (2 intracranial haemorrhages)

• 21% patients had seizures

Preventative measures:

• phenytoin prophylaxis with BU, continued for 6 months or whilst on CSA

• strict control of hypertension

• prompt repletion of Mg deficiency

• maintenance of Hb 90 - 110 g/L and platelets > 50 x 109/L.

Quality of Life

Caocci, BBMT 2011

La Nasa, Blood 2013

role

limitation

physical

functioning

bodily

pain

general

health vitality social

functioning

emotional

functioning mental

health

Variables Odds ratio (95% CI) p-values

Age

2-4 years vs > 8 years

2-4 years vs ≥ 5 years

4-8 years vs ≥ 8 years

1.94 (0.54 – 6.94)

2.29 (0.71 – 7.35)

0.58 (0.09 – 3.6)

0.23

0.13

0.45

Gender

Male vs female

2.29 (0.71 – 7.3)

0.13

Ethnic origin

Middle eastern vs Asian

1.62 (0.49 – 5.41)

0.31

Ferritin

≥ 1500 μgm/L vs < 1500 μgm/L

1.4 (0.4 – 4.6)

0.4

Hepatic iron concentration

≥ 4 mg/g vs < 4 mg/g

0.8 (0.2 – 3.03)

0.5

Hepatic fibrosis (Ishak staging)

Hepatic fibrosis vs no hepatic fibrosis

≥ stage 2 fibrosis vs no hepatic fibrosis

≥stage 3 fibrosis vs no hepatic fibrosis

≥ stage 3 hepatic fibrosis vs < stage 2 hepatic fibrosis

2.1 (0.55 – 8)

3.92 (0.8 – 18.2)

14 (1.3 – 150)

13.88 (1.4 – 135.5)

0.22

0.08

0.02

0.01

Pesaro risk class

≥ Pesaro risk II vs Pesaro risk I

3.23 (0.97 – 10.7)

0.05

Itraconazole prophylaxis

Day – 10 vs day – 5

0.45 (0.12 – 1.6)

0.18

Impact of fibrosis in the development of

VOD

PRES 96 consecutive BMT: – 18 cases from 19

patients: 18.8%

– did not vary by diagnoses: p=0.39

– did not vary by regimen: • p=0.06 • severity (GCS) did not vary

p=0.07

– did not vary by degree of cerebrovascular disease in SCD: p=1

– day 0 to day +47, median onset day +20

Treatment

Bu/Cy FTTA

Patients PRES Patients PRES

Diagnosis SCD 20 3 11 4

b -Thal 41 5 24 6

Features Number Percentage

Hypertension 15 88%

Headache 13 72%

Vomiting 10 63%

Behavioral changes 9 50%

Seizure 7 41%

Altered vision 5 28%

Assessment of cerebrovascular disease:

• clinical history and examination

• TCDi

• MRI/MRA

• psychometric testing using Wechsler Intelligence Scale for Children UK 4th Edition (WISC-IV)

WISC-IV:

• to assess the thinking and reasoning abilities of children aged 6 – 16 years

• consists of a number of sub-tests divided into 4 index scores:

• Verbal Comprehension Index (VCI): ability to define words, draw conceptual similarities between words and comprehension

• Perceptual Reasoning Index (PRI): ability to solve non-verbal problems and ability to reason using designs and pictures

• Working Memory Index (WMI): short-term memory

• Processing Speed Index (PSI): simple clerical tasks under timed conditions

p = 0.05 p = 0.04

Eggleston, Bri J Haem 2007; 136: 673-676

Growth and Development

limitations of BMT

• Lack of donors • Length of Treatment:

– 2 months as an inpatient

– 4 months as outpatient

• Transplant Related Mortality

• Long Term Effects:

– Infertility

– Pubertal failure

– Chronic GvHD

– Organ toxicity

– Secondary malignancies

Availability of donors

Related donors:

• Using broad criteria of Collaborative Study: 38% of SCD patients qualify

• Only 18% of patients have an HLA-matched sibling donor who is not affected

• Thus, as few as 1-2% of the total population of children with sickle cell anaemia ultimately qualify for bone marrow transplantation

Mentzer, Am J Pediatr Hematol Oncol 1994

Unelated donors:

HLA-A,B,DRB1 matched donor projected increase in NMDP:

• 27% to 34% for Black Americans

• 45% to 54% for Asian Kollman, Transplantation 2004

Locatelli, Blood 2003

Use of Cord Blood

Adamkiewicz, J Pediatr Hematol Oncol 2006

Reduced Intensity Conditioning for Sickle Cell Disease

• Less risk of morbidity and mortality from conditioning-related toxicity:

– infertility

– neurodevelopmental effects

– endocrine dysfunction

– secondary malignancies

• Problems:

– intact immune function

– expanded haemopoietic compartment

– red cell alloimmunisation

– GvHD completely undesirable complication

Iannone BBMT 2003:

Flu/ATG/200 cGy TBI BMT/PBSCT

n = 7

Hesieh, NEJM 2009

Haploidentical Transplantation

Bolanos-Meade, 2012

hypertransfusions hydroxycarbamide 30 mg/kg

azathioprine 3 mg/kg

3 months

thiotepa 10 mg/kg

Conclusion

• BMT is feasible & able to offer long-term cure

• The challenge is to extend the number of patients who may benefit

• Time is ready for alternative sources of stem cells but this requires caution

• Understanding of the morbidity and end-organ damage

• Identification of appropriate patients who may benefit

• Participation of patients