THALASSEMIA MAJOR - SURVIVAL

Adapted from B. Modell and V. Berdoukas, 1984

 Survival by Cohort of Birth (N=977)

85 - 97
1.00 80 - 84
75 - 79

70 - 74

0.75
Survival Probability

65 - 69

0.50
60 - 64

0.25 P<0.00005

0.00

0 5 10 15 20 25 30
Age (Yr)
Borgna-Pignatti et al. Haematologica, 2004
 Probability of death due to heart disease after age 10 yrs
100

Born <1980 ,
CumulativeDeaths(%)

80 Born 1980-89

60 60 - 64

40 65 - 69
Li et al, Hong Kong Med J, 2002.

20 70 - 74

75 - 79
85 - 97
0 80 - 84
10 15 20 25 30
Age(yrs)
 Mortality rates over 5 yr time periods
12
Mortality per 1000 pt years

Iron overload
deaths
10 Deaths other
causes

0
<1960 1960-69 1970-79 1980-89 1990-99 2000-2003
Year
 MRI T2*
Lack of Correlation: Liver and Cardiac Iron

Liver Liver
Chelation Randomised Controlled Trial

Myocardial T2* Ejection Fraction

18 75
Deferiprone Deferiprone
Deferoxamine Deferoxamine

LV Ejection Fraction (%)

17 73
Myocardial T2* (ms)

16
71

15
69
14

67
13
p= 0.77 p= p= p= 0.34 p= 0.074 p= 0.0034
12 0.040 0.023 65
Baseline 6 months 12 months Baseline 6 months 12 months
 Combined chelation in Cyprus
0.25

0.2
% with combination therapy

0.15 450 person years

0.1 0 deaths

0.05

0
1999 2000 2001 2002 2003 2004 2005
Date
 Effects of Iron Chelators on Heart:
Desferrioxamine (DFO) and Deferiprone (DFP)
DFP DFO Estimated
Author Data
(n) (n) by
5-year cardiac disease-free survival higher Clinical-
Piga et al.1 54 75
with DFP than DFO (P < .003) survival
DFP is more effective than DFO in MRI-T2*-
Anderson et al.2 15 30
reducing cardiac iron LVEF
Similar decrease in cardiac iron with
Maggio et al.3 71 73 MRI-ISR
each drug
Hoffbrand et al.4 51 – 4/51 patients died of cardiac causes Clinical

Ceci et al.5 532 – 9/532 patients died of heart failure Clinical

DFP more effective in reducing cardiac iron
MRI-T2*-
Pennell et al.6 29 31 (27% vs 13%; P = .023) and increasing LVEF
LVEF
(3.1% vs 0.3%; P = .003) than DFO
Borgna-Pignatti et al.7 750* 3,610* 52 cardiac events on DFO; 0 on DFP Clinical

*Patient-years. 1. Piga A et al. Haematologica. 2003;88:489. 2. Anderson LJ et al. Lancet.

2002;360:516. 3. Maggio A et al. Blood Cells Mol Dis. 2002;28:196. 4. Hoffbrand AV et al.
Blood. 1998;91:295. 5. Ceci A et al. Br J Haematol. 2002;118:330. 6. Pennell DJ et al. Blood.
2006;107:3738. 7. Borgna-Pignatti C et al. Blood. 2006;107:3733.
Comparison of Currently Available Iron Chelators

Property Desferrioxamine Deferiprone Deferasirox

Usual dose
25-60 75 20-30
(mg/kg/d)
SC, IV Oral Oral
Route
(8-12 hr, 5 d/wk) (3 times daily) (Once daily)
Half-life 20-30 min 3-4 hr 12-16 hr
Excretion Urinary, faecal Urinary Faecal
Licensed outside
Approved in US,
US/Canada
Status Licensed Switzerland, and
(approved in 46
30 countries
countries)
 Effects of Iron Chelators on Ferritin
Desferrioxamine, deferiprone, and deferasirox all decrease ferritin
Deferasirox shown to maintain and reduce serum ferritin levels in phase 2/3 clinical trials
in adult and paediatric patients (12-month efficacy—serum ferritin)
Ferritin

2500 β-thalassaemia SCD β-thalassaemia, MDS,

other rare anaemias
Mean Change in Serum

2000
1500
(µg/L)

1000
500
0
-500
-1000
-1500
Deferasirox 5 10 20 30
Doses (mg/kg/day)

MDS: myelodysplastic syndrome; SCD: sickle cell disease.

 Effects of Iron Chelators on
Liver Iron Concentration (LIC)
LIC: Good control with desferrioxamine or deferasirox;
inconsistent effects with deferiprone
Deferasirox shown to maintain and reduce LIC in phase 2/3 clinical trials
in adult and paediatric patients (12-month efficacy—LIC)
Fe/g dw)

10 β-thalassaemia β-thalassaemia, MDS,

SCD
8 other rare anaemias)
Mean Change in LIC (mg

6
4
2
0
-2
-4
-6
-8
-10
Deferasirox 5 10 20 30
Doses (mg/kg/d)
 Principles of stem cell transplantation for 
haemoglobinopathies
Multipotent stem cell
BFU­e red cells

CFU­GM

white blood
     cells

platelets
 SCT for haemoglobinopathies: 
conditioning
Drug Dose Schedule
Fludarabine 125 mg m2 day -12 to -7
Busulphan 14 mg/kg day -9 to -6
Cyclophosphamide 200 mg/kg day -5 to -2
 SCT for haemoglobinopathies: 
conditioning

Drug Dose Schedule

Busulphan 14 mg/kg day -9 to -6

Cyclophosphamide 200 mg/kg day -5 to -2

Campath 1H 0.1 mg/kg day -9 to -7

 Thalassaemia major: rationale for 
transplantation

• morbidity

• mortality

• quality of life
BMT for thalassaemia: the Birmingham and 
Hammersmith experience
No of Children 54
Age (years) 6.6 (2 ­ 16)
Ethnic origin:
Pakistani / Indian 39
 Mediterranean 10
Arabic 5

Lawson et al, Br J Haematol, 120: 289, 2003

BMT for Children with Thalassaemia at BCH/HH
DONOR CHARACTERISTICS

No of Children

HLA­IDENTICAL:
Brother 26
Sister 25
Parent 3

AGE (years): 5.8 (1.4 to 32)

THALASSAEMIA TRAIT: 34

Lawson et al, 2003

BMT for Children with Thalassaemia at BCH/HH

Lawson et al, 2003

SCT for thalassaemia major: Class 3 
93%

85%

Sodani et al, Blood 2004.

 BMT for Thalassaemia major:
Long­term effects

GROWTH SEXUAL
DEVELOPMENT
 Usually normal
or improved Delayed in 50%

FERTILITY OTHER
Gonadal failure Iron overload
common, esp girls Malignancy (0.9%)
Role of BMT for Thalassaemia major
Thalassaemia major: predicted survival in the UK

100
Predicted survival (%)

80

Med Rx
60
BMT

40

20

0
10 20 30

Years
Role of BMT for Thalassaemia major
PREDICTED SURVIVAL IN THALASSAEMIA MAJOR
100

80

GOOD CHEL: Med Rx

GOOD CHEL: BMT
% SURVIVAL

60

POOR CHEL: Med Rx

40 POOR CHEL: BMT

20

0
10 20 30

SURVIVAL FOR 10, 20 OR 30 YEARS

 Management of β­thalassaemia:
the role of BMT

Patient choice: quality of life

Physician choice: poor compliance
failure of medical Rx

Political choice: unavailability of good
quality medical care
 Dilemma
• Class 1 patients excellent outcome with both
conventional treatment and HSCT
• Class 3 patients poor outcome with conventional
therapy and HSCT
• Need to take decision re HSCT early usually
before known how will cope with chelation
Limitations of stem cell transplantation 
for thalassaemia major

• Transplant­related mortality

• Lack of donors for the majority of children 

• Long­term effects (concerns about fertility)

• Role of SCT in treatment of adults
 SCT for thalassaemia: mismatched 
related donors
No of patients
Transplanted 29
m/m sibling donors 13
m/m parental donors 8
other relatives 8
Event­free survival 21%
Overall survival 65%

Gaziev et al, 2000
 Unrelated donor BMT for thalassaemia

No of patients
Transplanted 32     (10 aged >16 years)
Class 1 or 2: 15
Class 3: 17
Survived 26 (81%)
Cured 22 (69%)
La Nasa et al, Blood 99: 4350-6, 2002
 Unrelated donor BMT for thalassaemia

No of patients
Transplanted 32
Extended haplo match 22
Survived 19 / 22 (86%)
Cured 17 / 22 (77%)

La Nasa et al, Blood 99: 4350-6, 2002

Cord blood transplants for thalassaemia 
major

No of patients

Transplanted 33
Survived 33
Cured 26  (79%)

              Locatelli et al, Blood 101: 2137, 2003

 Unrelated cord blood transplants for 
thalassaemia major

– 5 children aged 2­11 years
–  Conditioning: Bu 14/Cy 200 + ATG 
–  1­2 antigen mismatched CB mononuclear cells
–  Engraftment: 5/5
– Acute GVHD > grade II: 1
– Survival with 100% donor cells: 5/5 (follow up 6­15m

 Jaing et al, Biol Blood Marrow Transplant 11: 349­53, 2005
 “Mini­allografting” in thalassaemia

Hongeng et al, BMT 30: 409-410, 2002

• Girl aged 10 years received PBSC from 4 yr old sib
• Conditioning:  busulphan 8 mg/kg
fludarabine 175 mg/m2
ALG
TLI (500cGy)
• GVHD prophylaxis: CSA (d+100),MMF (d+35)
• Outcome:Alive & well with full donor engraftment at 1yr
BMT for Adults with Thalassaemia Major:
Outcome 1988­1996

No of patients %

Transplanted 107 ­
Survival 69 64
Event­free survival 66 62
Recurrence  4  4

Lucarelli et al, Blood 93:1164, 1999
 Price for one year of treatment

• 14,000 € per patient.

• chelation therapy (57%)
• transfusions (36%),
• surgical procedures (4%),
• laboratory tests (3%).
 Therefore

• worldwide, 87% of children born with thal

major die untreated,

• at least 60% of those transfused have no

access to chelation therapy
 Sickle HSCT
• Procedure ,conditioning and results almost
identical to Thal
• Chances of finding family donor much smaller
• Carriers acceptable as donors
• Long term free of Sickle problems
• No progression of Sickle organ damage
 Selection
• Contentious Very variable expression

• Agreed Sickle brain disease

• Early Sickle renal or lung disease

 Selection
• Debated
• Return to country with less health resources
• Painful crises
• Sickle bone diseease
• Silent infacts
• Sickle eye disease
 Rates of infarctive and haemorrhagic stroke in HbSS
patients by age Ohene-Frempong 1998
Hazard Function

0.0040

0.0025 Ischaemic
Stroke

Haemorrhagic
0.0010
Stroke

Age
10 20 30 40 50
years
 TIAs, Stroke, Coma
9y girl HbSS, previously well, ‘Top of class’
 Moyamoya

Severe stenosis or occlusion of the terminal

internal carotid artery / proximal middle
cerebral artery with collateral vessels Yoon 2000
 conclusion
• Role for family matched HSCT in both Thal
major and SCD
• Extension outside matched family donors more
difficult
• Will the procedure still be a use in 5-10 years
time in era of effective oral chelators ?