Annual Sickle Cell & Thalassaemia Course September 2008

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New Treatment Strategies inHaemoglobinopathies

Dr Baba InusaConsultant and Lead,

Paediatric HaemoglobinopathyEvelina Children’s Hospital, St Thomas Hospital

26th September, 2008



New Management Strategies

• Summary of pathology

• Common clinical scenarios

• Therapeutic Approaches

• Hydroxyurea

• Summary



Single gene mutation….



… and sickled red cells.



10 year old SCA

• Massive Splenemegaly,– Repeated Transfusion, declined splenectomy

• Admitted with pain X 3 in twelve eight months

• TCD >200cm– started prophylactic transfusion, Allo-immunisation- anti-E and

transfusion reaction

• 2 further Acute Chest Syndromes– What options



8 year old Female Hb SS

• Hb SS diagnosed at Birth

• Repeated VOC and ACS and increasinglength of hospital stay

• TCD-conditional, repeat normal

• Nicosan suggested to family

• Next steps



Therapeutic approaches

• Inhibition of red cell dehydration

• Nitric oxide augmentation

• Hb F reactivation

• Anti-adhesion e.g. specific monoclonal antibodies,HU

• Anti-sickling e.g.5- hydroxymethyl-2-furfural



GARDOS Channel



Cellular hydration

Gardos channel blockers

• ICA17043

• Clotrimazole

KCl cotransport modulators

• Magnesium





Mechanisms for Sickle Cell Dehydration Blockers Deoxygenation

Clotrimazole, ICA-17403

Mg2+ HbS Polymerization

Dipyridamole

Membrane Permeabilization

K+ Na+ Ca++ HCO3

Deoxygenation

Induced pathway

Cl K +

K + Cl

Gardos Channel K-Cl Cotransport

[K+] [Na+]

[Ca++]

H+

[ K+]

H2O H2O



NITRIC OXIDE



Nitric Oxide (NO)

• Regulates blood vessel tone

• Inhibitor of vascular remodelling• Down regulates endothelial adhesion

molecules

• Inhibits platelet aggregation• Role in ischaemia-reperfusion injury

• Possible inhibitory role in HbS polymerisation



NO/Arginine diagram

Nitric oxide

Arginine synthase Nitric oxide (NO)

+

citruline

Arginine Arginase Ornithine + Urea





Foetal Haemoglobin (Hb F) interaction with

Hb SMechanism of switch for Hb F to Hb S• Gene silencing is responsible for the switch from ε-chain

(embryonic Hb) to γ -chain (Hb F).

• The switch from γ to β-chain (Hb A) synthesis is probably bycompetition and also the methylation of beta globin promoter.

Reversal of switch from Hb S to Hb F• Hypomethylation methods chromatin remodelling complex

polypyrimidine in adult cells

Beneficial Action of Hb FF dissociates to a dimer to combine with S as α2βs1 γ 1

which does not form a tetramer



Pharmacologic modifiers

Two broad groups• Drugs which modify DNA in order to promote γ -globin

expression

• Drugs that create an environment which promotes Hb Fcells production

• 1982 DeSimone et al showedazacytidine in baboons led to significantHb F elevation– De-represion of γ -chain synthesis, reversal of the switch

from β-chain

– Recruitment of early red cell precursors during recoveryfrom drug induced marrow suppression

– Direct programming of relatively late red cell precursors



Pharmacologic Hb F modifiers

• Hydroxyurea (less toxic) – early redcells (↑Hb F/F cells)

• Decitabine (5-aza-2‘-deoxycitidine)

• Arginine Butyrate infusion trial increased Hb F7% to 21% (first observation in babies of diabetic

mothers)



Foetal Haemoglobin (Hb F) interaction with

Hb S

• 1948 Janet Watson observes- Redcells of newborn with SCA do not

sickle ?inhibition due to Hb F

• Milder sickle cell features in Saudi

Arabians who were found to havehigh level of Hb F in adult life



Lentivirus vector gene therapy

reversing Hb F switch





Butyrate



Butyrates

• Short chain fatty acid

• Inhibition of histone deacetylases (HDAC)

• Increase histone acetylation

• Large volume

• Combination with HU



Decibitane



Decitabine

• Analogue of 5 azacytidine

• DNMT inhibitor

• Hypomethylation of DNA

• SC /IV

• Low dose protocols• HU responders & non responders

• Mild to moderate leucopenia

• Thrombocytosis

• Increase in HbF, Fcells, haemoglobin

• Decrease in reticulocyte & bilirubin



Hydroxycarbamide

Hydroxyurea – Success in SCD?



Hydroxycarbamide – Mode of

Action• Increases HbF levels

• Decreases wbc and plts

• Decreases adhesion of red cells to

endothelium

• Decreases adhesion molecules

• NO donor

– vasodilation



Potential mechanisms of benefits

• HU Nitric Oxide (NO) in aqueous solutions – NO suggested to be involved in the clinical response – But low levels present and has very short half-life

– Therefore unlikely unless involved in pathway of increasing HbF

• Myelo-suppressive effects on white blood cell and platelet levels

– Rapid therapeutic effects before significant increase in HbF – Past studies have shown correlation between high WCCand more severe disease

• BUT these are speculative theories only



Rosse, W. F. et al. Hematology 2000;2000:2-17

Figure 1. Mechanisms of action of hydroxyurea



Cokic, V. P. et al. Blood 2006;108:184-191

Hydroxyurea effects on blood vessels



Hydroxyurea in SCDMSH (Charache) 1995, New Eng. J. Med

Double blind RCT

Objective: To reduce

painful crisis in those

who have > 3/yr overpreceding 12 months

299 adults recruited

Trial stopped at 21

months

No important adverse

effects

0.0017348Transfusions

<0.0015125Chest syndrome

<0.0014.52.5Crises/yr

pPlaceboTreated



Possible adverse effects of HU

treatment in SCD (MSH)

L e g U

l c e r

A s e

p t i c n

e c r o s i s

( h u m e r u

s o r f e m

u r )

W e i g

h t g a

i n a t

2 y r s

( % )

0

2

4

6

8

10

12

14

16

18

HU

Placebo



Possible adverse effects of Hb

treatment in SCD (MSH)

H a i r l

o s s

S k i n

r a s h

F e v e

r

G I d i s t u

r b a n

c e

O t h e

r0

10

20

30

40

50

60

70

%

1-2 visits HU

1-2 visits Placebo

3+ visits HU

3+ visits Placebo



The future of Hydroxyurea• MSH study still following up on patients over

long term period

• Up to 40% of patients currently not responding

as expected• Maximum value of HU approx. 20%

• But cannot entirely disregard effect of HU in

some patients – Transfusion status must be taken into

consideration



Hydroxyurea in children

• Belgian Paediatric cohort – Reduced admissions and inpatient days

– No major toxicities

• HUG/KIDS – No major toxicity or growth failure

– No adverse effects on development

• Other studies – Decreased acute chest crises

– Decreased transfusions

Ferster et al 1996, 2001. Wang et al 2002



Copyright ©2007 American Society for Clinical Investigation

Frenette, P. S. et al. J. Clin. Invest. 2007;117:850-858









Long term effect of hydroxyurea therapy on TCD flow velocities Children with SCA and increased



Copyright ©2007 American Society of Hematology. Copyright restrictions may apply.

Zimmerman, S. A. et al. Blood 2007;110:1043-1047

Long-term effect of hydroxyurea therapy on TCD flow velocities. Children with SCA and increased

baseline TCD velocities received hydroxyurea therapy at MTD. The maximum TCD velocity is shown

after reaching MTD and then in long-term follow-up for 28 children. There was a significant decrease

from baseline TCD flow velocities to the MTD values ( P < .001), and this decrease was sustained at

long-term follow-up.

Median time averaged maximum velocity (TAMV) at the first transcranial doppler (TCD)



Copyright ©2008 American Society of Hematology. Copyright restrictions may apply.

Lefevre, N. et al. Blood 2008;111:963-964

Median time-averaged maximum velocity (TAMV) at the first transcranial doppler (TCD)

in patients treated and not treated with hydroxyurea for each age category. Box plots show

medians with 25 percentiles; bars represent percentiles 10-90 sd.



Effect of hydroxycarbamide on

mortality and morbidity• Data from the follow-up of MSH

patients, 233 patients; 1992 – 2001

• Estimated overall reduction in mortalityover 9 years was 40%

– High overall mortality– Average age 32 years– Severe phenotype

Steinberg et al. JAMA 2003



Hydroxycarbamide and neurological

function• Hydroxyurea lowers transcranial Doppler flow

velocities in children with SCD

– Improvement in 14/15 patients with conditional TCDsand 5/6 patients with abnormal TCDs

• May have role in patients who refuse transfusion

• No evidence of 2o stroke prevention

– 3/16 children had recurrent stroke on changing from

transfusion to hydroxycarbamide

Zimmerman et al. Blood 2007, Ware et al Blood 1999.



Hydroxycarbamide and renal

functionRetrospective single centre study

• 3 children with significant

proteinuria• Enalapril did not correct

proteinuria

• Addition of hydroxycarbamide wasassociated with normalisation of protein-creatinine ratio

Fitzhugh et al 2005



e ore y roxyurea y roxyurea at



NS

78

76 ± 23

87

85 ± 30

R PCA, cm/s

.008 114 113 ± 29 133 132 ± 29 L ACA, cm/s

.006 98 110 ± 33 127 130 ± 25 R ACA, cm/s

< .001 144 142 ± 27 166 168 ± 26 L MCA, cm/s

< .001 134 135 ± 27 162 166 ± 27 R MCA, cm/s

< .001 23.3 22.7 ± 7.9 9.9 10.3 ± 6.6 HbF, %

< .001 103 104 ± 9 88 86 ± 8 MCV, fL < .001

26.5

26.8 ± 3.0

22.0

22.5 ± 3.3

Hematocrit, %

< .001 9.4 9.4 ± 1.0 7.8 7.8 ± 1.1 Hb, g/dL

NA 6.8 7.6 ± 3.2 5.6 6.8 ± 3.5 Age, y

Median Mean ± 1 SD Median Mean ± 1 SD

P





Using hydroxycarbamide

• Monitor blood counts– Weekly initially

– Increase up to 8 weekly• Interrupt or dose reduce if:

– Hb > 3g/dl over baseline

– Retics < 1%

– Neuts < 1.5 x 109/l

– Platelets < 80 x 109/l



• Atweh GF, Schechter AN: Pharmacologic induction of fetal hemoglobin:raising the therapeutic bar in sickle cell disease. Current Opinion inHematology 2001,8:123–130.

• de Montalembert M, Belloy M, Bernaudin F, Gouraud F, Capdeville R,Mardini R, Philippe N, Jais J, Bardakdjian J, Ducrocq R, Maier-RedelspergerM, Elion J, Labie D, Girot R: Three-Year Follow-Up of Hydroxyurea

Treatment in Severely Ill Children with Sickle Cell Disease. Journal of Pediatric Hematology/Oncology 1997,19(4):313-318.

• Gulbis B, Haberman D, Dufour D, Christophe C, Vermylen C, Kagambega F,

Corazza F, Devalck C, Dresse MF, Hunninck K, Klein A, Le PQ, Loop M, MaesP, Philippet P, Sariban E, Van Geet C, Ferster A: Hydroxyurea for sickle celldisease in children and for prevention of cerebrovascular events: theBelgian experience. The American Society of Hematology2005,105(7):2685-2690.

• Steinberg MH, Barton F, Castro O, Pegelow CH, Ballas SK, Kutlar A, Orringer

E, Bellevue R, Olivieri N, Eckman J, Varma M, Ramirez G, Adler B, Smith W,Carlos T, Ataga K, DeCastro L, Bigelow C, Saunthararajah Y, Telfer M,Vichinsky E, Claster S, Shurin S, Bridges K, Waclawiw M, Bonds D, Terrin M:Follow-Up of Hydroxyurea Treatment in Severely Ill Children with Sickle CellDisease. Journal of American Medical Association 2003,289(13):1645-1651.

• Coleman E and Inusa B. Sickle cell anemia: Targeting The Role of Fetal

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Annual Sickle Cell & Thalassaemia Course September 2008

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