Transcript Modern Management of Thalassaemia Major

Current status of Thalassaemia
major
Chi-Kong Li, MD.
Chief, Division of Haematology/Oncology/BMT,
Department of Paediatrics,
Prince of Wales Hospital, The Chinese University
of Hong Kong.
Modern Transfusion Management of
Thalassaemia Major
• Regular transfusion, maintain Hb >9.5 g/dl.
• Safe transfusion :
– Leucocyte removal filter (pre-storage), <5x106
Transfusion reaction, alloimmunisation
– Screening for infectious disease.
• 2-6 weeks interval to suppress bone marrow
activity, promote normal growth.
Iron overload
• 1.16 mg iron in 1 ml pure red cells (Hct)
• iron accumulation proportional to volume of
blood transfused,
• a 30 kg child may receive 4-8 gm iron /yr,
• increase iron absorption from gut,
• normal adult total body iron 55 mg/kg,
(4.0gm)
• no excretory pathway for excessive iron
Morbidity in Thalassaemia Major Patinets (I)
• Endocrine:
–
–
–
–
Hypogonadism :
Diabetes Mellitus :
Hypothyroidism (Subclinical) :
Hypoparathyroidism :
55% >15 years.
6-8%.
11%
5%
• Short Stature :
(<3%, corrected for parental height).
– Multiple factors
25-50%.
(Endocrine and bone changes)
Morbidity in Thalassaemia Major Patinets (II)
• Liver disease: HCV infection (Italy)
– HCV +ve
>14 years: 88%
<14 years: 28%
– 75% showed chronic hepatitis.
• Cardiac disease:
– Symptomatic 8.5%
– Echocardiographic abnormalies 20-60%.
Menstruation Problems in Thalassaemia Females
• Primary amenorrhoea
50%
• Secondary amenorrhoea
20%
• Memarche and regular menses 30%
Figure 1: KAPLAN MEIER SURVIVAL ANALYSIS ON 257 CONSECUTIVE
TRANSFUSION-DEPENDENT BETA THALASSEMIC PATIENTS IN TORINO
H = 147
L = 64
Cox’s F test = 1.7 p<0.03
Piga A, Torino, Italy
BMT, 1997, 19(S2):11-13.
Current Status in Hong Kong :
Thalassaemia Major
• 293 patients
• Age : 0-5 yr
:
18 (6.1%)
6-10 yr
:
45 (15%)
11-15 yr :
71 (24%)
16-20 yr :
69 (23%)
21-30 yr :
89 (30%)
• Regular chelation started since early 1980s.
Morbidity among H.K.
Thalassaemia Patients
Heart failure
:
Diabetes mellitus:
Hepatitis B carrier:
Hepatitis C carrier:
21 patients (7.3%)
18 patients (6%)
3 (1%)
47 (16%)
Diabetes in TM
80
64
70
7
69
5
DM
70
60
50
40
30
45
25
6
20
20
10
0
1971-1975
1976-1980
1981-1985
1986-1990
1991-1995
1996-2000
Complications of TM according to age
>15 years (158 patients)
<15 years (135 patients)
Cardiac Disease
12.0%
2.20%
11.4%
Diabetes Mellitus
0%
Hepatitis C
0%
27.2%
5.20%
5%
10%
15%
20%
25%
30%
Endocrine complications
(PWH, QEH, PMH, N=232)
Diabetes mellitus Hypothyroidism Hypoparathyroidism
Born before
1980 N=60,
Median onset
13 (22%)
16.5 yr (12-21)
10 (17%)
19 yr (10-25)
5 (8%)
17 yr (10-21)
Born 19801989 N=117,
Median onset
7 (6%)
14 yr (13-16)
6 (5%)
14.5 yr (10-17)
3 (2.5%)
15 yr (13-17)
0
0
0
Total
20 (8.6%)
16 (6.9%)
8 (3.4%)
M:F
10/10
6/10
4/4
Born after
1989 N=55
HKMJ 2002, 8:255-60
Ht Standard Deviation Score
Mean (SD)
95% CI
P value
Cohort 1
>20 years
-1.58 (1.45)
-1.97 to –1.19 1 vs 2: p=0.43
Cohort 2:
11-20 yeas
-1.75 (1.27)
-1.99 to –1.52 2 vs 3:
p<0.005
Cohort 3:
< 10 years
-0.51 (1.0)
-0.78 to –1.23
HKMJ 2002, 8:255-60
3 vs 1:
p<0.001
Bone diseases in TM
• Desferrioxamine induced in properly
transfused and chelated patients,
• metaphyseal sclerosis, platyspondyly, bone
infarct.
• plain X-ray, ultrasound, MRI.
• 16 of 41 patients showed varying degree of
dysplasia.
Pediatr Radiol 2002, 32:492-7
Death : 1996 -2000
• 17 deaths over past 5 years
• 11 due to cardiac diseases
• 5 died as complication of bone marrow
transplantation
• 1 died after klebsiella meningitis
BMT for Thalassaemias
• Eradicate the pathological marrow by mega-dose
chemotherapy.
• Replacement of a new healthy haematopoietic
system (HLA-Identical sibling).
• Transfusion independent.
• Free from transfusion related complications.
• Improved quality of life-physical and
psychosocial.
Disease Free Survival
Thalassaemia after BMT
1.0
Probability of Survival
.9
.8
.7
.6
.5
.4
.3
.2
Survival Function
.1
0.0
DFS 84%
0
20
40
60
80
Duration of follow up in months
BMT 2002, 29:101-5
100
Disease free survival according to age
1.0
90%
86%
.9
Probability of survival
.8
.7
62.5%
.6
Age at BMT
10-16 yr (n-=15)
.5
.4
> 16 yr (n=8)
.3
.2
< 10 yr (n=21)
.1
0.0
0
20
40
60
80
Duration of follow up in months
BMT 2002, 29:101-5.
100
Disease Free survival according to Class
1.0
100%
.9
84%
Probability of Survival
.8
.7
CLASS
.6
57%
Class 3 (n=7)
.5
.4
Class 2 (n=25)
.3
.2
Class 1 (n=8)
.1
0.0
0
20
40
60
80
Follow up in months (02/2000)
100
Changes of Ht after BMT: PWH experience
Table 2 : Changes of HtSDS according to age: Mean (SD)
Whole Group (N)
(CI)
Age >7 year
(N)
(CI)
Age 7 and under (N)
>7 year
versus  7
year,
p value
(CI)
 HtSDS at BMT
-1.47 (1.55)
(32)
(-2.01 – -0.94)
-1.99 (1.6)
(19)
(-2.72 – -1.27)
-0.79 (1.12)
(13)
(-1.4 – -0.18)
 HtSDS at latest assessment
-1.02 (1.27)
(32)
(-1.46 – -0.57)
-1.33 (1.38)
(19)
(-1.95 – -0.71)
-0.56 (0.95)
(13)
(-1.07
0.04)
 Follow up (months)
69 (23)
67 (22)
–
0.027
-
65 (26)
0.058
0.82
 Change of HtSDS
1 year
0.16 (0.52)
(32)
(-0.02 – 0.35)
-0.05 (0.46)
(19)
(-0.26 – 0.15)
0.48 (0.46)
(13)
(0.2 – 0.76)
0.003
2 year
0.24 (0.58)
(30)
(0.05 – 0.43)
0.11 (0.60)
(18)
(-0.16 – 0.39)
0.43 (0.5)
(12)
(0.14 – 0.71)
0.146
3 year
0.21 (0.81)
(30)
(-0.08 – 0.5)
0.08 (0.95)
(17)
(-0.37 – 0.53)
0.38 (0.57)
(13)
(0.04 – 0.71)
0.293
4 year
0.35 (0.75)
(24)
(0.05 – 0.65)
0.37 (0.88)
(14)
(-0.09 – 0.82)
0.33 (0.59)
(10)
(-0.04 – 0.69)
0.911
5 year
0.59 (0.86)
(16)
(0.16 – 1.01)
0.76 (0.83)
(10)
(0.24 – 1.27)
0.30 (0.92)
(6)
(-0.43 – 1.04)
0.323
0.48 (0.87)
(32)
(0.18 – 0.78)
0.66 (0.87)
(19)
(0.27 – 1.05)
0.2 (0.82)
(13)
(-0.24 – 0.65)
0.166
 Latest change of HtSDS
HtSDS: Height standard deviation score, CI : 95% confidence interval
Ped Hematol Oncol 2004, 21:411-9.
Conventional Treatment
• Improved survival,
• still with complications from iron overload
and treatment,
• poor compliance not uncommon esp at
adolescent age group,
• mortality does happen, life expectancy not
sure (>40 years)
• quality of life sub-optimal.
Future of Management of Thalassaemia major
• Oral chelators - as second line treatment,
not first line treatment yet..
• More safe BMT
• Extension of BMT to alternative donors:
unrelated bone marrow donor or cord blood.
• Gene therapy.