Approaches to management of
β-thalassemia intermedia
Ali Taher, MD, PhD, FRCP
American University of Beirut Medical Center
Agenda
● Overview of β-thalassemia intermedia (TI)
● Overview of TI complications
● Management of TI
● Splenectomy
● Transfusion
● Iron chelation therapy
● Hydroxycarbamide
● Other treatments
● Take home message
Introduction
It was previously thought that TI patients do not
require treatment
since their symptoms are mild
β-thalassemia
Minor
Mild asymptomatic anemia
Because thalassemia intermedia has such a variable
phenotype, therapy
must be tailored
for each patient.
β-thalassemia
Intermediate phenotype with
Intermedia
variable clinical severity
β-thalassemia
Major
Severe transfusiondependent anemia
Musallam KM, et al. Cold Spring Harb Perspect Med. 2012; 2:a013482
Pathophysiology
●
The clinical sequelae of β-TI are due to three main persistent
factors:
Ineffective erythropoiesis
Massive erythroid marrow hypertrophy
Chronic anemia
Gastrointestinal iron absorption
Iron overload
Ineffective erythropoiesis
Peripheral breakdown of red blood cells
Gastrointestinal iron absorption
● Mildly affected patients may be asymptomatic until adult life
● Severely affected patients generally present between 2–6 years of age
Musallam KM, et al. Cold Spring Harb Perspect Med. 2012; 2:a013482
First attempt at understanding
complications in TI vs TM
Complication
(% of patients affected)
Splenectomy
Cholecystectomy
Gallstones
Extramedullary hemopoiesis
Leg ulcers
Thrombotic events
Cardiopathy*
Pulmonary hypertension†
Abnormal liver enzymes
HCV infection
Hypogonadism
Diabetes mellitus
Hypothyroidism
TI
Lebanon
(n = 37)
90
85
55
20
20
28
3
50
20
7
5
3
3
TM
Italy
(n = 63)
67
68
63
24
33
22
5
17
22
33
3
2
2
Lebanon
(n = 40)
95
15
10
0
0
0
10
10
55
7
80
12.5
15
Italy
(n = 60)
83
7
23
0
0
0
25
11
68
98
93
10
11
*Fractional shortening < 35%. †Defined as pulmonary artery systolic pressure > 30 mmHg; a well-enveloped tricuspid
regurgitant jet velocity could be detected in only 20 patients, so frequency was assessed in these patients only.
HCV = hepatitis C virus.
Taher A, Isma’eel H, Cappellini MD. Blood Cells Mol Dis. 2006;37:12-20.
Overview on Practices in Thalassemia Intermedia
Management Aiming for Lowering Complicationrates Across a Region of Endemicity: the OPTIMAL
CARE study
● Cross-sectional study of 584 TI patients from
6 comprehensive care centers in the Middle East and
Italy
N = 127
AT Taher
KM Musallam
N = 200
M Karimi
N = 153
MD Cappellini
N = 51
A El-Beshlawy
N = 12
N = 41
S Daar
K Belhoul
M Saned
Taher AT, Musallam KM, Karimi M, et al. Blood. 2010;115:1886-92.
The OPTIMAL CARE study:
overall study population
Parameter
Age (years)
< 18
18–35
> 35
Male:female
Splenectomized
Serum ferritin (µg/L)
< 1,000
1,000–2,500
> 2,500
Complications
Osteoporosis
EMH
Hypogonadism
Cholelithiasis
Thrombosis
Pulmonary hypertension
Abnormal liver function
Leg ulcers
Hypothyroidism
Heart failure
Diabetes mellitus
EMH = extramedullary hematopoiesis.
Frequency
n (%)
172 (29.5 )
288 (49.3)
124 (21.2)
291 (49.8) : 293 (50.2)
325 (55.7)
376 (64.4)
179 (30.6)
29 (5)
134 (22.9)
124 (21.2)
101 (17.3)
100 (17.1)
82 (14)
64 (11)
57 (9.8)
46 (7.9)
33 (5.7)
25 (4.3)
10 (1.7)
Treatment
Hydroxyurea
Transfusion
Never
Occasional
Regular
Iron chelation
None
Deferoxamine
Deferiprone
Deferiprone + deferoxamine
Deferasirox
Frequency
n (%)
202 (34.6)
139 (23.8)
143 (24.5)
302 (51.7)
248 (42.5)
300 (51.4)
12 (2.1)
3 (0.5)
21 (3.6)
Taher AT, Musallam KM, Karimi M, et al. Blood. 2010;115:1886-92.
Complications of β-TI
● Hypercoagulability and thrombosis
● Brain abnormalities
● Pulmonary hypertension
● Leg ulcers
● Extramedullary hematopoiesis
● Hepatocellular carcinoma
● Renal abnormalities
● Iron overload
● ……….…
4
TI complications increase
with age
120 TI, treatment-naïve†
patients from Lebanon,
Italy, Iran, Egypt, UAE
and Oman
45
< 10 years
*
40.0
40
11–20 years
21–32 years
Frequency (%)
35
>32 years
33.3
*
30.0
30
*
*
26.7
26.7
25
*
20.0
20
13.3
*
13.3
13.3
10.0
10.0
6.7
20.0
16.7
10
5
20.0
20.0
16.7
16.7
15
23.3
23.3
6.7
3.3
6.7
3.3
3.3
0
6.7
3.3
13.3
10.0
6.7
3.3
6.7
3.3
0 0
0
16.7
13.3
10.0
10.0
16.7
3.3
0
0
*statistically significant trend; † no splenectomy, HU, transfusion or chelation
Taher AT et al. Br J Haematol 2010;150:486–489
EMH, extramedullary hematopoiesis; PHT, pulmonary hypertension;
HF, heart failure; ALF, abnormal liver function; DM, diabetes mellitus
Transfusion therapy
Musallam KM, et al. Cold Spring Harb Perspect Med. 2012; 2:a013482.
Taher AT, et al. Br J Haematol. 2011;152:512–23.
The OPTIMAL CARE study
Occasionally/regularly
transfused patients: 445/584
Complication
Parameter
RR
95% CI
p value
EMH
Splenectomy
Transfusion
Hydroxyurea
Age > 35 years
Splenectomy
Transfusion
Hydroxyurea
Iron chelation
Transfusion
Age > 35 years
Hb ≥ 9 g/dL
Serum ferritin ≥ 1,000 µg/L
Splenectomy
Transfusion
Age > 35 years
Female
Splenectomy
Transfusion
Iron chelation
Serum ferritin ≥ 1,000 µg/L
0.44
0.06
0.52
2.59
4.11
0.33
0.42
0.53
0.06
2.60
0.41
1.86
6.59
0.28
2.76
1.96
5.19
0.36
0.30
1.74
0.26–0.73
0.03–0.09
0.30–0.91
1.08–6.19
1.99–8.47
0.18–0.58
0.20–0.90
0.29–0.95
0.02–0.17
1.39–4.87
0.23–0.71
1.09–3.16
3.09–14.05
0.16–0.48
1.56–4.87
1.18–3.25
2.72–9.90
0.21–0.62
0.18–0.51
1.00–3.02
0.001
< 0.001
0.022
0.032
< 0.001
< 0.001
0.025
0.032
< 0.001
0.003
0.001
0.023
< 0.001
< 0.001
< 0.001
0.010
< 0.001
< 0.001
< 0.001
0.049
Pulmonary hypertension
Heart failure
Thrombosis
Cholelithiasis
Abnormal liver function
Taher AT, Musallam KM, Karimi M, et al. Blood. 2010;115:1886-92.
The OPTIMAL CARE study
Occasionally/regularly
transfused patients: 445/584
Complication
Parameter
Leg ulcers
Age > 35 years
Splenectomy
Transfusion
Hydroxyurea
Splenectomy
Hydroxyurea
Age > 35 years
Female
Splenectomy
Transfusion
Hydroxyurea
Iron chelation
Female
Serum ferritin ≥ 1,000 µg/L
Transfusion
Hydroxyurea
Iron chelation
RR
95% CI
p value
2.09
3.98
0.39
0.10
6.04
0.05
3.51
1.97
4.73
3.10
0.02
0.40
2.98
2.63
16.13
4.32
2.51
1.05–4.16
1.68–9.39
0.20–0.76
0.02–0.43
2.03–17.92
0.01–0.45
2.06–5.99
1.19–3.27
2.72–8.24
1.64–5.85
0.01–0.09
0.24–0.68
1.79–4.96
1.59–4.36
4.85–52.63
2.49–7.49
1.48–4.26
0.036
0.002
0.006
0.002
0.001
0.003
< 0.001
0.009
< 0.001
< 0.001
< 0.001
0.001
< 0.001
< 0.001
< 0.001
< 0.001
0.001
Transfusion therapy was protective for thrombosis, EMH, PHT,
Hypothyroidism
HF, cholelithiasis, and leg ulcers
Osteoporosis
Transfusion therapy was associated with an increased risk
of endocrinopathy
Hypogonadism
Taher AT, Musallam KM, Karimi M, et al. Blood. 2010;115:1886-92.
Transfusion
● Risk factors for alloimmunization :
●
Minimally transfused and newly transfused patients
●
Old age at first transfusion
●
Ethnic and racial diverse population
●
Splenectomy
●
Allogeneic WBC within the transfusate
• Management:
•
•
Fully phenotyped matched blood should be given
Erythropoietin in combination with iron and folic acid
Chou ST et al. Br J Haematol. 2012. [Epub ahead of print]
LIC Risk thresholds for
development of complications
in TI patients
Mean age ± SD
β-TI
β-TM
19
19
Age (years)
32.8 ± 7.9
33.0 ± 7.4
LIC (mg Fe/g dry wt)
15.0 ± 7.4
15.7 ± 9.9
RISK THRESHOLDS3
Taher et al. 20101
n
9 mg/g dry wt
7 mg/g dry wt
6 mg/g dry wt
Origa et al. 20072
n
Age (years)
LIC (mg Fe/g dry wt)
22
22
20.0 ± 5.0
23.0 ± 10.0
11.3 ± 6
11.8 ± 7
● Osteoporosis
● Thrombosis
● Vascular complications
● Pulmonary hypertension
● Hypothyroidism
● Hypogonadism
● Endocrine/bone complications
1.8 mg/g dry wt
1. Taher A, et al. Am J Hematol. 2010;85:288-90. 2. Origa R, et al. Haematologica. 2007;92:583-8.
3. Musallam KM, et al. Hematologica. 2011;96:1605-12.
Normal liver iron level
ICT in NTDT
● Chelation therapy is advisable if liver iron concentration (LIC)
5 mg/g dw
●
Direct assessment is desirable; biopsy or MRI
● If LIC measurement is not available, serum ferritin is a
reasonable alternative, taking into consideration that serum
ferritin may underestimate LIC in TI
SF chelation thresholds
53%
70%
5 mg/g
NTDT IOL threshold
dw
800 1000
ng/ml ng/ml
A serum ferritin of 800
ng/ml
increases
the
sensitivity of detecting
thalassemia
intermedia
patients
with
iron
overload
Investigational use of
deferasirox versus placebo:
THALASSA study design
Efficacy and safety of deferasirox versus placebo
in NTDT patients
Inclusion
• Male/female
• Aged ≥10 years with NTDT
• LIC ≥5 mg Fe/g dw
• Serum ferritin >300 ng/mL
Exclusion
• Regular transfusion requirement
• Chelation therapy prior to entry
• HbS thalassemia variants
• Impaired renal/liver function
Change in LIC from baseline after 1 year of treatment
compared with placebo-treated patients
Taher AT et al. Blood 2012;120(5):970-7
Effect of deferasirox on LIC
in THALASSA
LIC change from baseline to Week 52
least squares mean (mg Fe/g dw)
1
Starting deferasirox dose:
5 mg/kg/day
0.38
0
10 mg/kg/day
Placebo
Study met its primary endpoint
–1
–1.95
–2
–3
P=0.001*
–3.80
–4
P=0.009
P<0.001*
*Adjusted P-value with Dunnett’s method
Taher AT et al. Blood 2012;120(5):970-7
Effect of deferasirox on
serum ferritin in THALASSA
Serum ferritin change from
baseline to Week 52 least
squares mean (ng/mL)
150
100
50
Starting deferasirox dose:
115
5 mg/kg/day
10 mg/kg/day
0
–50
Placebo
–121
–100
–150
P<0.001*
–222
–200
–250
P=0.088
P<0.001*
*Adjusted P-value with Dunnett’s method
Taher AT et al. Blood 2012;120(5):970-7
Most common
drug-related adverse
events in THALASSA
Deferasirox
5 mg/kg/day
n=55
Deferasirox
10 mg/kg/day
n=55
Placebo
overall
Nausea
3 (5.5)
4 (7.3)
4 (7.1)
Skin rash
2 (3.6)
5 (9.1)
1 (1.8)
Diarrhea
0
5 (9.1)
1 (1.8)
Headache
2 (3.6)
1 (1.8)
2 (3.6)
Upper abdominal pain
2 (3.6)
1 (1.8)
0
Abdominal pain
1 (1.8)
1 (1.8)
1 (1.8)
Adverse events, n (%)
Taher AT et al. Blood 2012;120(5):970-7
n=56
Splenectomy
● Indications for
splenectomy
● Poor growth and
development
● Increased transfusion
demand
● Symptomatic
splenomegaly
● Hypersplenism
(leukopenia,
thrombocytopenia)
Musallam KM, et al. Cold Spring Harb Perspect Med. 2012; 2:a013482.
Taher AT, et al. Br J Haematol. 2011;152:512–23.
Splenectomy
● Splenectomy increases chances of:
● Thrombosis
● Silent brain infarcts
● Extramedullary hematopoiesis
● Pulmonary hypertension
● Leg ulcers
● Iron related endocrinopathies
● Infection
Musallam KM, et al. Cold Spring Harb Perspect Med. 2012; 2:a013482.
Taher AT, et al. Br J Haematol. 2011;152:512–23.
Thromboembolic events in
a large cohort of TI patients
● Patients (N = 8,860)
●
●
6,670 with TM
Stroke
2,190 with TI
●
Type of event
● 146 (1.65%) thrombotic events
●
48
Venous
61 (0.9%) with TM
85 (3.9%) with TI
● Risk factors for thrombosis:
age (> 20 years)
●
previous thromboembolic event
●
family history
●
splenectomy
DVT = deep vein thrombosis;
PVT = portal vein thrombosis; STP = superficial thrombophlebitis.
23
DVT
8
0
Others
19
TM (n = 61)
TI (n = 85)
8
12
0
39
12
11
PVT
STP
●
28
9
PE
66
20
30
40
60
80
Thromboembolic events (%)
Taher A, Isma'eel H, Mehio G, et al. Thromb Haemost. 2006;96:488-91.
Risk factors for thrombosis
in β-TI
Iron chelation
Hydroxyurea
Transfusion
Splenectomy, age above
35 years, and a serum ferritin level
>1000 μg/L are associated with a
higher risk for thrombosis1
0.97
0.56
0.28
6.59
Splenectomy
1.86
SF ≥ 1,000 μg/L
Hb ≥ 9 g/dL
0.41
1.27
Female
2.59
Age > 35 years
0
1Musallam
1
2
3 4 5 6 7 8 9 10 11 12 13 14 15
Adjusted odds ratio for thrombosis
KM, Taher AT. Hemoglobin 2011;35:503–510
The OPTIMAL CARE study
splenectomized patients
Complication
Parameter
RR
95% CI
p value
EMH
Splenectomy
Transfusion
Hydroxyurea
Age > 35 years
Splenectomy
Transfusion
Hydroxyurea
Iron chelation
Transfusion
Age > 35 years
Hb ≥ 9 g/dL
Serum ferritin ≥ 1,000 µg/L
Splenectomy
Transfusion
Age > 35 years
Female
Splenectomy
Transfusion
Iron chelation
Serum ferritin ≥ 1,000 µg/L
0.44
0.06
0.52
2.59
4.11
0.33
0.42
0.53
0.06
2.60
0.41
1.86
6.59
0.28
2.76
1.96
5.19
0.36
0.30
1.74
0.26–0.73
0.03–0.09
0.30–0.91
1.08–6.19
1.99–8.47
0.18–0.58
0.20–0.90
0.29–0.95
0.02–0.17
1.39–4.87
0.23–0.71
1.09–3.16
3.09–14.05
0.16–0.48
1.56–4.87
1.18–3.25
2.72–9.90
0.21–0.62
0.18–0.51
1.00–3.02
0.001
< 0.001
0.022
0.032
< 0.001
< 0.001
0.025
0.032
< 0.001
0.003
0.001
0.023
< 0.001
< 0.001
< 0.001
0.010
< 0.001
< 0.001
< 0.001
0.049
Pulmonary hypertension
Heart failure
Thrombosis
Cholelithiasis
Abnormal liver function
Taher AT, Musallam KM, Karimi M, et al. Blood. 2010;115:1886-92.
The OPTIMAL CARE study
splenectomized patients
Complication
Parameter
Leg ulcers
Age > 35 years
Splenectomy
Transfusion
Hydroxyurea
Splenectomy
Hydroxyurea
Age > 35 years
Female
Splenectomy
Transfusion
Hydroxyurea
Iron chelation
Female
Serum ferritin ≥ 1,000 µg/L
Transfusion
Hydroxyurea
Iron chelation
RR
95% CI
p value
2.09
3.98
0.39
0.10
6.04
0.05
3.51
1.97
4.73
3.10
0.02
0.40
2.98
2.63
16.13
4.32
2.51
1.05–4.16
1.68–9.39
0.20–0.76
0.02–0.43
2.03–17.92
0.01–0.45
2.06–5.99
1.19–3.27
2.72–8.24
1.64–5.85
0.01–0.09
0.24–0.68
1.79–4.96
1.59–4.36
4.85–52.63
2.49–7.49
1.48–4.26
0.036
0.002
0.006
0.002
0.001
0.003
< 0.001
0.009
< 0.001
< 0.001
< 0.001
0.001
< 0.001
< 0.001
< 0.001
< 0.001
0.001
Splenectomy
was independently associated with an increased
Hypothyroidism
risk of most disease-related complications
Osteoporosis
Hypogonadism
Taher AT, Musallam KM, Karimi M, et al. Blood. 2010;115:1886-92.
OPTIMAL CARE study: patient
stratification according to
splenectomy and TEE status
● Three groups of patients identified
●
Group I, splenectomized patients with a documented TEE (n = 73)
●
Group II, age- and sex-matched splenectomized patients without TEE (n
= 73)
●
Group III, age- and sex-matched non-splenectomized patients without
TEE (n = 73)
Type of thromboembolic event in
splenectomized TI patients (Group I)
n (%)
DVT
46 (63.0)
PE*
13 (17.8)
STP
12 (16.4)
PVT
11 (15.1)
Stroke
4 (5.5)
*All patients who had PE had confirmed DVT.
TEE = thromboembolic events.
Taher A, Musallam KM, Karimi M, et al. J Thromb Haemost. 2010;8:2152-8.
OPTIMAL CARE study:
multivariate analysis of the
risk per patient group
Parameter
Group
OR
95% CI
NRBC count ≥ 300 x 106/L
Group III
Group II
1.00
5.35
Referent
2.31–12.35
p value
< 0.001
Group I
11.11
3.85–32.26
Platelet count ≥ 500 x 109/L
Group III
1.00
Referent
Group I patients
had
significantly
higher NRBC,
Group II
8.70
3.14–23.81
platelets, and PHT occurrence, and were mostly
< 0.001
Groupnon-transfused
I
76.92
22.22–250.00
PHT
Group III
Group II
1.00
4.00
Referent
0.99–16.13
0.020
Transfusion naivety
Group I
7.30
1.60–33.33
Group III
Group II
Group I
1.00
1.67
3.64
Referent
0.82–3.38
1.82–7.30
NRBC = nucleated red blood cell; PHT = pulmonary hypertension;
OR = adjusted odds ratio; CI = confidence interval.
0.001
Taher A, Musallam KM, Karimi M, et al. J Thromb Haemost. 2010;8:2152-8.
Time-to-thrombosis (TTT)
since splenectomy
NRBC count
< 300 x 106/L
≥ 300 x 106/L
0.8
0.6
0.4
Cumulative thrombosisfree survival
1
1
Platelet count
< 500 x 109/L
≥ 500 x 109/L
0.8
0.6
0.4
•0.2
The median TTT following splenectomy 0.2
was 8 years (range 1–33 years)
• The median TTT was significantly shorter in patients with an NRBC
0
0
count
≥ 300 x 106/L (p = 0.002), a platelet count
≥ 500 x 109/L (p = 0.008),
0
5 10 15 20 25 30 35 40
0
5 10 15 20 25 30 35 40
who were
transfusion-naive
(p = since
0.009)
Duration sinceand
splenectomy
(years)
Duration
splenectomy (years)
1
Transfused
Yes
No
0.8
0.6
0.4
0.2
0
0
5 10 15 20 25 30 35 40
Duration since splenectomy (years)
Cumulative thrombosisfree survival
Cumulative thrombosisfree survival
Cumulative thrombosisfree survival
Time to thrombosis
1
Pulmonary hypertension
Yes
No
0.8
0.6
0.4
0.2
0
0
5 10 15 20 25 30 35 40
Duration since splenectomy (years)
Taher A, Musallam KM, Karimi M, et al. J Thromb Haemost. 2010;8:2152-8.
Cerebral thrombosis
●
Among 30 splenectomized patients with β-TI
● 18 (60.0%) had abnormal MRI findings
● 19 (63.3%) had abnormal PET findings
● 26 (86.7%) had abnormal MRI, abnormal PET, or both
n (%)
MRI
PET
Either MRI or PET
Number of lesions*
Single
Multiple
4 (13.3)
14 (46.7)
5 (16.7)
14 (46.7)
8 (26.7)
21 (70.0)
Bilateral lesions
13 (43.3)
1 (3.3)
13 (43.3)
Location
Frontal
Parietal
Temporal
Occipital
17 (56.7)
9 (30.0)
1 (3.3)
3 (10.0)
3 (10.0)
14 (46.7)
18 (60.0)
0 (0.0)
18 (60.0)
20 (66.7)
18 (60.0)
3 (10.0)
Musallam K et al. Ann Hematol 2012;91:235–241
HbF Modulation
● The defective production of β-chains can be
compensated for by increased ɣ-chain
production to form HbF
● Available HbF modulators include
hydroxyurea, 5-azacitidine, decitabine, shortchain fatty acids
● Studies in thalassemia and especially
thalassemia intermedia are relatively limited
Musallam KM et al. Blood 2012;119:364–367
‡
‡
Leg ulcers
†
Heart failure
*
Hypogonadism
*
Osteoporosis
*
Hypothyroidism
Diabetes mellitus
*
Abnormal liver
function
†
Venous
thromboembolism
Pulmonary
hypertension
Extramedullary
hematopoiesis
Association of HbF and
morbidity in untransfused
patients with β-TI
*
*P<0.001; †P=0.003; ‡P=0.002
Use of hydroxyurea for the
modulation of HbF in β-TI
Hydroxyurea enables some patients to become
transfusion independent or develop marked
increases in Hb levels1–3
● Some debate over long-term efficacy and safety:
1Mancuso
●
Most adverse effects with low-dose hydroxyurea over the
short and medium term are minor and can be tolerated
without discontinuation4
●
Beneficial effects may be transient and attenuate in the
long term5
●
Variable results
A et al. Br J Haematol 2006;133:105–106; 2Karimi M et al. J Pediatr Hematol Oncol 2005;27:380–
385;
A et al. Ann Hematol 2005;84:441–446; 4Karimi M et al. Pediatr Hematol Oncol 2010;27:205–221;
5Rigano P et al. Br J Haematol 2010;151:509–515
3Dixit
HU treatment may be
protective for complications
Complication
Parameter
Leg ulcers
Age > 35 years
Splenectomy
Transfusion
Hydroxyurea
Splenectomy
Hydroxyurea
Age > 35 years
Female
Splenectomy
Transfusion
Hydroxyurea
Iron chelation
Female
Serum ferritin ≥ 1,000 μg/L
Transfusion
Hydroxyurea
Iron chelation
Hypothyroidism
RR
95% CI
p value
2.09
3.98
0.39
0.10
6.04
0.05
3.51
1.97
4.73
3.10
0.02
0.40
2.98
2.63
16.13
4.32
2.51
1.05–4.16
1.68–9.39
0.20–0.76
0.02–0.43
2.03–17.92
0.01–0.45
2.06–5.99
1.19–3.27
2.72–8.24
1.64–5.85
0.01–0.09
0.24–0.68
1.79–4.96
1.59–4.36
4.85–52.63
2.49–7.49
1.48–4.26
0.036
0.002
0.006
0.002
0.001
0.003
< 0.001
0.009
< 0.001
< 0.001
< 0.001
0.001
< 0.001
< 0.001
< 0.001
< 0.001
0.001
Osteoporosis
Hydroxyurea
treatment was protective for EMH, PHT, leg ulcers,
hypothyroidism and osteoporosis
Hypogonadism
In the OPTIMAL CARE study, 202/584 patients received hydroxyurea
Taher AT et al. Blood 2010;115:1886–1892
PHT
● Pulmonary hypertension:
● Defined as mean pulmonary artery pressure ≥ 25 mm
Hg at rest with a pulmonary capillary wedge pressure
≤ 15 mm Hg and pulmonary vascular resistance > 3
Wood units
● The pathophysiology has not been extensively
studied but NO dysregulation has been speculated
● Sildenafil has been reported in few cases to be
effective
● A trial has just concluded to test its effectiveness
● Bosentan (endothelin receptor antagonist) also
reported to be effective in one patient
Taher et al. Br J Haematol. 2011;152:512-23.
EMH
● Extramedullary hematopoiesis
● Most commonly paraspinal (11-15%) of cases
● Debilitating clinical consequences
● Management
● Hypertransfusion
● HbF modulation
● Radiation
● Surgery (laminectomy)
● Individualize treatment
Taher et al. Br J Haematol. 2011;152:512-23.
Endocrine complications
● Endocrine complications
● High prevalence of 25-hydroxy vitamin D deficiency
● High prevalence of osteoporosis
● Devastating fractures and bone pain
● High doses of calcium and vitamin D
supplementation are recommended
● Bisphosphonates have been effective in TM
● No data about bisphosphonates in TI
Taher et al. Br J Haematol. 2011;152:512-23.
Pregnancy
● Pregnancy
● Delayed puberty is common
● Fertility is usually normal
● Increased risk of abortion, pre-term delivery, IUGR,
Caesarean section delivery, thromboembolic events
● Transfusions should be used carefully for fear of
alloimmunization
● Splenomegaly can interfere with the enlargement of
the uterus
● Anticoagulation should be considered
Taher et al. Brit J Haematol. 2011;152:512-23.
Thrombosis
● Anticoagulation
● TI are at high risk of thromboembolic events and
anticoagulation merits consideration
● Thrombocytosis is implicated in the pathophysiology of
thrombotic disease
● One study showed lower recurrence rate after treatment
with Aspirin but the results were not statistically
significant
● Antiplatelet therapy is a logical solution
Taher et al. Brit J Haematol. 2011;152:512-23.
Multimodal therapy
Y
Hydroxyurea
Y
Transfusion
Iron chelation
Mean number
of complications
N
N
Y
N
Y
N
Y
N
Y
N
Y
N
0.83
1.31
1.30
2.00
0.85
2.02
1.54
2.43
Taher AT, et al. Blood. 2010 ;115:1886-92.
Supportive therapy
• With the increased longevity, patients
are growing older with their diseases
and suffering more complications
which is jeopardizing their QoL.
• Supportive therapy is key to
alleviating these ailments
HR-QOL
A longer duration with a known thalassemia diagnosis was the only independent variable correlating with
higher Mental Heath Scores (P = 0.039) while multiplicity of clinical complications was the only
independent variable correlating with lower Physical Heath Scores (P = 0.032).
Musallam KM, Khoury B, Abi-Habib R, et al. Eur J Haematol. 2011;87:73-9.
Depression and
anxiety in β-TI
●
Cross-sectional study - Chronic
Care Center in Lebanon
●
80 patients:
●
●
32 β-TI [median age 24 years]
●
48 β-TM [median age 23
years])
Patients with TM had significantly
longer median duration with a
known thalassemia diagnosis
than TI patients (P<0.001)
Proportion of patients with different
combinations of diagnoses
Depression
8 (10%)
StateAnxiety
3 (3.8%)
8 (8%)
4 (5%)
TraitAnxiety
8 (10%)
Considerable proportion of adult patients with TM and TI show evidence of depression
and anxiety
Patients with TI are more liable to state anxiety than TM patients of a similar age, that is
attributed to a shorter duration of living with a thalassemia diagnosis
Musallam KM, et al. Thalassaemia International Federation 2011.
Supportive therapy
• With the increased longevity, patients
are growing older with their diseases
and suffering more complications
which is jeopardizing their QoL.
• Supportive therapy is key to
alleviating these ailments
Take home message
● TI, a once overlooked disease, displays a
myriad of complications
● Management of TI can be either palliative or
curative
● Palliative care involves transfusion and iron
chelation therapy or hydroxycarbamide in
addition to control of symptoms
● We must always keep in mind the QoL of these
patients and provide the proper counseling
and supportive therapy