Evidence-Based Approach to Managing
Non-Transfusion-Dependent
Thalassemias (NTDT)
Ali T. Taher, MD, PhD, FRCP
Professor of Medicine, Hematology & Oncology
American University of Beirut Medical Center
Beirut – Lebanon
Professor of Hematology & Medical Oncology (Adj.)
Emory School of Medicine
Atlanta – USA
Non-transfusion-dependent thalassemia (NTDT)
Morbidity in NTDT– Clinical complications profile
– Ineffective erythropoiesis and anemia
– Iron overload and target organ damage
– Hypercoagulability and vascular disease
Management of NTDT– Splenectomy
– Transfusions
– Fetal hemoglobin induction
– Iron chelation
– Novel agents
Agenda
Non-transfusion-dependent thalassemia (NTDT)
Morbidity in NTDT– Clinical complications profile
– Ineffective erythropoiesis and anemia
– Iron overload and target organ damage
– Hypercoagulability and vascular disease
Management of NTDT– Splenectomy
– Transfusions
– Fetal hemoglobin induction
– Iron chelation
– Novel agents
Agenda
HbE, haemoglobin E; HbH, haemoglobin H.
1. Taher AT, et al. Br J Haematol. 2011;152:512-23.
2. Galanello R, Origa R. Orphanet J Rare Dis. 2010;5:11.
3. Vichinsky E. Hematology Am Soc Hematol Educ Program. 2007;79-83. 4
4. Muncie HL Jr, Campbell J. Am Fam Physician. 2009;80:339-44.
5. Figure adapted from Musallam KM, et al. Haematologica. 2013;98:833-44.
Occasional transfusions
required (e.g. surgery,
pregnancy, infection)
Intermittent transfusions required
(e.g. poor growth and development,
specific morbidities)
Regular, lifelong
transfusions
required for survival
Transfusions
seldom required
Transfusions not required
α-thalassaemia trait
β-thalassaemia minor
Non transfusion dependent thalassaemia (NTDT)
β-thalassaemia intermedia
Mild/moderate HbE/β-thalassaemia
HbH disease (α-thalassaemia)
HbS β-thalassaemia
HbC thalassaemia
Transfusion dependent thalassaemia (TDT)
β-thalassaemia major
Severe HbE/β-thalassaemia
Hb Barts hydrops (α-thalassaemia major)
NTDT patients do not require regular transfusions, although they may require
occasional transfusions for growth failure, pregnancy, infections, and other
specific situations1–4
NTDT: a designation based on transfusion
requirement
1Weatherall DJ. Blood Rev 2012;26 Suppl 1:S3–S6;2Available from: http://emedicine.medscape.com/article/959122-overview#a0156;3Harteveld CL and Higgs DR. Orphanet J Rare Dis 2010;5:13; 4Weatherall DJ. Blood 2010;115:4331–4336.
3
Prevalence of Hb H disease
in Europe and North
America increasing due
to migration3
β thalassemia intermedia
– most common in
Africa, Mediterranean,
India and East Europe1,2
Hb H – most common in
Southeast Asia, Middle East
and Mediterranean3
Approx. 9500 annual births4
Hb E/β thalassemia – most common in
East India, Bangladesh and Southeast Asia1
Approx. 19,000 annual births4
The increased migration flow expands the reach of these diseases
World distribution of hemoglobinopathies3
The prevalence of NTDT is increasing
worldwide due to migration
Non-transfusion-dependent thalassemia (NTDT)
Morbidity in NTDT– Clinical complications profile
– Ineffective erythropoiesis and anemia
– Iron overload and target organ damage
– Hypercoagulability and vascular disease
Management of NTDT– Splenectomy
– Transfusions
– Fetal hemoglobin induction
– Iron chelation
– Novel agents
Agenda
HCV, hepatitis C virus. Taher A, et al. Blood Cells Mol Dis. 2006;37:12-20.
Complication (% of patients affected)
β-TI β-TM
Lebanon(n = 37)
Italy(n = 63)
Lebanon(n = 40)
Italy(n = 60)
Splenectomy 90 67 95 83
Cholecystectomy 85 68 15 7
Gallstones 55 63 10 23
Extramedullaryhaemopoiesis
20 24 0 0
Leg ulcers 20 33 0 0
Thrombotic events 28 22 0 0
Cardiopathya 3 5 10 25
PHTb 50 17 10 11
Abnormal liver enzymes 20 22 55 68
HCV infection 7 33 7 98
Hypogonadism 5 3 80 93
Diabetes mellitus 3 2 12.5 10
Hypothyroidism 3 2 15 11
aFractional shortening < 35%. bDefined 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.
How it all started: realizing morbidity is
highly prevalent and different from TDT in
our clinics
Musallam KM et al. Haematologica. 2013;98:833–844.
Non-Transfusion-Dependent
Thalassemias (NTDT)
β-Thalassemia Major
(Regularly transfused)
Silent cerebral ischemia
Pulmonary hypertension
Right-sided heart failure
Cardiac siderosis
Left-sided heart failure
Splenomegaly
Gall stones
Hepatic fibrosis, cirrhosis
and cancerHepatic failure
Viral hepatitis
Diabetes mellitus
Hypogonadism
Facies
Bone deformity
(Hair on end)
Extramedullary
hematopoietic
psuedotumors
Venous thrombosis
Osteoporosis
Hypothyroidism
Hypoparathyroidism
Osteoporosis
Leg ulcers
Musallam KM, et al. Haematologica. 2013;98:833-4.
Observations were similar in reported literature
Cross-sectional study of 584 patients with β-TI from 6 comprehensive
care centres in the Middle East and Italy
β-TI, β-thalassaemia intermedia. Taher AT, et al. Blood. 2010;115:1886-92.
n = 12S. Daar
n = 127A.T. Taher
K.M. Musallam
n = 200M. Karimi
n = 51A. El-Beshlawy
n = 153M.D. Cappellini
n = 41K. Belhoul
M. Saned
The OPTIMAL CARE studyOverview on Practices in β-Thalassaemia Intermedia Management Aiming for Lowering Complication rates
Across a Region of Endemicity:
Taher AT, et al. Blood. 2010;115:1886-92.
ParameterFrequency
n (%)
Age (years)
< 18 172 (29.5 )
18–35 288 (49.3)
> 35 124 (21.2)
Male:female 291 (49.8) : 293 (50.2)
Splenectomized 325 (55.7)
Serum ferritin (µg/L)
< 1,000 376 (64.4)
1,000–2,500 179 (30.6)
> 2,500 29 (5)
Complications
Osteoporosis
EMH
Hypogonadism
Cholelithiasis
Thrombosis
Pulmonary hypertension
Abnormal liver function
Leg ulcers
Hypothyroidism
Heart failure
Diabetes mellitus
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)
TreatmentFrequency
n (%)
Hydroxyurea 202 (34.6)
Transfusion
Never
Occasional
Regular
139 (23.8)
143 (24.5)
302 (51.7)
Iron chelation
None
Deferoxamine
Deferiprone
Deferiprone +
deferoxamine
Deferasirox
248 (42.5)
300 (51.4)
12 (2.1)
3 (0.5)
21 (3.6)
High morbidity rates were confirmed
ALF, abnormal liver function; DM, diabetes
mellitus; HF, heart failure. Taher AT, et al. Br J Haematol. 2010;150:486-9.
Fre
qu
en
cy (
%)
≤ 10 years 11–20 years 21–32 years > 32 years
0
5
10
15
20
25
30
35
40
45
0
*Statistically significant trend.
6.7
13.3
16.7
40.0
26.7
3.3
6.7
16.7
26.7
3.3
13.3
20.0 20.0
3.3
6.7
10.0 10.0
3.3
6.7
33.3
13.3
10.0
20.0
13.3
3.3
6.7
10.0
13.3
0 0
3.3
16.7
0
3.3
10.0
30.0
6.7
16.7
23.3
20.0
0
16.7
23.3
*
* *
**
*
120 treatment-naive patients
Morbidities seemed to increase with
advancing age
• Leg ulcers
• Thrombotic events
• Pulmonary
hypertension
• Bone deformities
• Osteoporosis
Impaired α:β
globin ratio
• Diabetes mellitus
• Growth deficiency
• Hypothyroidism
• Hypoparathyroidism
• Hypogonadism
• Hepatic cancer
• Renal disease
Ineffective erythropoiesis haemolysis
Anaemia
Tissue oxygenation
Iron overload
• Gall stones
Hypercoagulable
state
Red cell pathology
Musallam KM, et al. Haematologica. 2013;98:833-4.
Erythroid marrow
expansion
• Hepatosplenomegaly
• Extramedullary
haematopoietic
pseudotumors
The pathophysiology and risk factors were
predicted … but not yet evaluated
Non-transfusion-dependent thalassemia (NTDT)
Morbidity in NTDT– Clinical complications profile
– Ineffective erythropoiesis and anemia
– Iron overload and target organ damage
– Hypercoagulability and vascular disease
Management of NTDT– Splenectomy
– Transfusions
– Fetal hemoglobin induction
– Iron chelation
– Novel agents
Agenda
Musallam KM, et al. Curr Opin Hematol. 2013; 20:187-92.
Ineffective erythropoiesis
Chronic anemia/hypoxia
↓ Hepcidin↑ Erythropoietin
↓ Ferroportin
↑ Intestinal iron absorption↑ Release of recycled iron
from reticuloendothelial system
Iron overload
?GDF-15
TWGF-1
HIFs
Tmprss6
TransfusionsMinor role
Ineffective erythropoiesis leads to iron
overload in NTDT
0
200
400
600
800
1000
1200
1400
1600
1800
2000
0 5 10 15
Seru
m f
err
itin
(n
g/m
L)
Hemoglobin level (g/dL)
Pearson's r=−0.5951, p b 0.001
A hemoglobin of <7 g/dL was
the level below which all
patients developed a
morbidity while a hemoglobin
of >10 g/dLwas the level after
which none of the patients had
a morbidity (area under the
curve = 0.84, 95% CI: 0.70 to
0.97, p b 0.001)
Taher AT, et al. Blood Cell Mol Dis. 2015;55:108-9.
Chronic anemia is also independently
associated with clinical morbidity and
iron overload in NTDT
Thoracic and lumbar
regions are most
commonly involved
Symptoms develop
as a result of pressure on
surrounding structures
Spinal cord compression and
possible irreversible
neurological damage is most
significant and debilitating
Haidar R et al. Eur Spine J 2010;19:871–878;
Castelli R et al. Am J Med Sci 2004;328:299–303;
Chehal A et al. Spine 2003;28:E245–E249;
Borgna-Pignatti C. Br J Haematol 2007;138:291–304.
Defective Hb F unloading
Increased bone marrow hematopoietic activity and expansion
Formation of erythropoietic tissue masses
+
Chronic anemia Hypoxia
EXTRAMEDULLARY
hematopoiesis
Liver
GlandsSpleen
Pleura
Spine
Extramedullary hematopoietic psuedotumors
in NTDT as a result of ineffective
erythropoiesis and anemia/hypoxia
Leg ulcers2Leg ulcers are more common in older
than in younger patients with β-TI
The skin at the extremities of elderly β-TI
patients can be thin due to reduced
tissue oxygenation; this makes the
subcutaneous tissue fragile and
increases the risk of lesions
Ulcers are very painful and difficult
to cure1
Risk factors: severe anaemia, ineffective
erythropoiesis, splenectomy, and
hypercoagulability levels3–5
A role for local IOL is suggested; IOL
may play a role in the pathophysiology
of leg ulcers by causing oxidative stress
and not just by local accumulation6
1. Taher AT, et al. Blood Cells Mol Dis. 2006;37:12-20.
2. Levin C, Koren A. Isr Med Assoc J. 2011;13:316-8.
3. Taher AT, et al. Blood. 2010;115:1886-92.
4. Musallam KM, et al. Blood Cells Mol Dis. 2011;47:232-4.
5. Musallam KM, et al. Cold Spring Harb Perspect Med. 2012;a013482.
6. Matta BN, et al. J Eur Acad Dermatol Venereol. 2014;28(9):1245-50.
Leg ulcers in NTDT can develop in the
context of anemia and tissue hypoxia
Non-transfusion-dependent thalassemia (NTDT)
Morbidity in NTDT– Clinical complications profile
– Ineffective erythropoiesis and anemia
– Iron overload and target organ damage
– Hypercoagulability and vascular disease
Management of NTDT– Splenectomy
– Transfusions
– Fetal hemoglobin induction
– Iron chelation
– Novel agents
Agenda
Since it was apparent that NTDT patients develop iron overload in the
absence of transfusions, the question was should we be concerned
with this iron overload?
0
100
200
300
400
500
600
700
800
900
1000
1100
1200
1300
1400
1500
1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011
Me
an
se
rum
fe
rrit
inle
ve
l a
nd
95
% C
I (n
g/m
l)
p<0.001
Musallam KM, et al. Haematologica 2014;99:e218-21.
SF levels increased over 11 years in 52
non-chelated β-TI patients: The
ORIENT study
20
25
30
35
40
45
50
55
60
65
0 500 1000 1500 2000 2500 3000 3500
Serum ferritin (ng/mL)
Card
iac
T2
* (m
s)
Normal LIC (< 3 mg Fe/g dry wt)
Mild LIC (3–7 mg Fe/g dry wt)
Moderate LIC (7–15 mg Fe/g dry wt)
Severe LIC (> 15 mg Fe/g dry wt)
Normal cardiac
R2*
0
5
10
15
20
25
30
0 20 40 60 80 100
LIC
(m
g F
e/g
dry
wt)
Cardiac R2* (Hz)
1. Origa R, et al. Haematologica. 2008;93:1095-6.
2. Roghi A, et al. Ann Hematol. 2010;89:585-9.
3. Taher AT, et al. Am J Hematol. 2010;85:288-90.
4. Mavrogeni S, et al. Int J Cardiovasc Imaging. 2008;24:849-54.
n=20 n=49
No evidence of cardiac siderosis even in NTDT patients with
considerable iron overload1-4
Iron overload and the heart
Several case reports and case series suggest an association between
iron overload and HCC in hepatitis C-negative patients with NTDT
Borgna-Pignatti C et al. Br J Haematol 2004;124:114–117;Maakaron JE et al. Ann Hepatol 2013;12:142–146;Maakaron JE et al. Br J Haematol 2013;161:1;Mancuso A. World J Hepatol 2010;2:171–174;Restivo Pantalone G et al. Br J Haematol 2010;150:245–247.
Plus iron
HCV
• Possible reasons for increased risk of HCC
in NTDT
– Iron overload is undiagnosed
(serum ferritin underestimates iron
burden compared with TDT)
– Chelation is started late or not at all
– NTDT patients survive longer than
TDT, often an older population
– Hepatocellular > macrophage
distribution
HCC is one of the most clinically severe
complications of NTDT & may be related to
iron overload
Case reports and case series in the literature reviewed for consistency between patient characteristics
HCC observed in patients with non-viral (hepatitis), non-cirrhotic livers
– Of 36 cases, 22 were β TI patients, of whom six were negative for hepatitis B or C
Survey for HCC using an abdominal ultrasound every 6 months is recommended in at-risk patients
*At diagnosisAb, antibody; AFP, alpha-fetoprotein; HBV, hepatitis B virus; HBsAg, hepatitis B surface antigen Maakaron JE et al. Ann Hepatol 2013;12:142–146.
HCC is a serious yet often overlooked complication in NTDT with appropriate screening, early detection and adequate iron chelation, complications can be minimized
Sex Age* SurvivalHCV Ab
HCV RNA
HBV AbHBs Ag
AFP (kU/L)
Serum ferritin
(ng/mL)
Serum ferritin peak (ng/mL)
LIC
M 48 Alive at 26 months – – – – 2851 1520 5250 NA
F 61 5 months + – – – 132 369 6000 NA
F 59 25 months + – NA NA NA 990 NA NA
M 73 7 months – – NA NA NA 574 NA NA
M 54 1 months – – – – 17.8 1291 2490 12.3
M 51 4 years – – Vaccinated – 3.8 5602 7138 23.9
HCC found in non-viral, non-cirrhotic livers,
highlighting the potential severity of iron
overload and its complications
Morbidity
absent
Morbidity
present
LIC
(m
g F
e/g
dry
wt)
p = 0.027p = 0.490 p = 0.245 p = 0.682p = 0.002 p < 0.001 p < 0.001 p = 0.040 p < 0.001 p < 0.001
0
3
6
9
12
15
18
21168 non-chelated
β-TI
On multivariate analysis, a 1 mg Fe/g dw increase in LIC was significantly
associated with higher odds of thrombosis, pulmonary hypertension,
hypothyroidism, osteoporosis, and hypogonadism
Adjusted for age, gender, splenectomy status, transfusion history, total
hemoglobin level, fetal hemoglobin level, platelet count, NRBC count, and
serum ferritin level
Musallam KM, et al. Haematologica. 2011;96:1605-12.
Iron overload and other morbidities
GFR, glomerular filtration rate.
Adapted from Mallat NS, et al. J Nephrol 2013;26:821-8.
Adapted from Musallam KM, Taher AT. J Am Soc
Nephrol. 2012;23:1299-302.
Glomerular dysfunction− vascular resistance results in
− GFR
Tubulointerstitial dysfunction– epithelial – mesenchymal transdifferentiation
– accumulation of extracellular matrix
– activation of fibroblasts
– diffusion capacity of oxygen
Tubulointerstitial dysfunction– direct iron cytotoxicity on tubules and
glomerular permeability causes enzymuria +
proteinuria
– moderate tubular atrophy and interstitial
fibrosis
Tubular dysfunction– vacuolization of proximal tubular epithelium
– apoptosis of tubule cell
– tubular absorption of solutes
Anemia
Iron overload
Hypoxia
Iron chelation
Glomerular dysfunction– mild to moderate glomerulosclerosis
– GFR
Glomerular dysfunction– reversible haemodynamic changes
Renal dysfunction in thalassemia is generally caused by persistent hypoxia, anemia, and
severe IOL
48% had evidence of glomerular
hyperfiltration
14% patients had proteinuria*
patients had elevated LIC>7 mg Fe/g
dw, NTBI and nucleated RBC counts
A considerable proportion of patients
showed evidence of abnormally
elevated eGFR, with a declining trend
towards advancing age
Occurrence of proteinuria associated
with anemia, hemolysis and iron
toxicity
*UPr/UCr ratio >500 mg/g Ziyadeh FN, et al. Nephron Clin Prac. 2012;121:c136-c43.
rs=0.357
P=0.011
rs=0.444
P=0.001
N=50
Renal dysfunction in β-TI is associated
with iron overload
• 127 TI patients were observed for 10 years
• 6 (4.7%) developed ESRD that required regular haemodialysis
– 4 showed no abnormality in urine sediment or proteinuria
– 2 showed glomerular-range proteinuria
• 1 reached nephrotic range (biopsy showed FSGS)
ESRD, end-stage renal disease;
FSGS, focal segmental glomerulosclerosis. Mallat NS, et al. Blood Cells Mol Dis. 2013;51:146-8.
Tubular atrophy and
interstitial fibrosis
Segmental sclerosis in
a glomerulus
Iron deposits
(Prussian blue stain)
Long-term follow-up of NTDT patients is crucial to identify TI patients at risk of end-stage renal
disease
Non-transfusion-dependent thalassemia (NTDT)
Morbidity in NTDT– Clinical complications profile
– Ineffective erythropoiesis and anemia
– Iron overload and target organ damage
– Hypercoagulability and vascular disease
Management of NTDT– Splenectomy
– Transfusions
– Fetal hemoglobin induction
– Iron chelation
– Novel agents
Agenda
Transfusion
↓ Antithrombin III
↓ Protein C
↓ Protein S
Iron overload
Endocrine & hepatic
dysfunction
Endothelial injury Expression of adhesion
molecules and tissue factor
Splenectomy
Platelet abnormalities Thrombocytosis
Chronic activation
↑ Adhesion and aggregation
Pathologic RBCs ↑ Thrombin generation
(phosphatidyl serine
exposure)
↑ Rigidity, deformability, and
aggregation
↑ Circulating
microparticles
?↑ Atherosclerosis
THROMBOSIS
↓↑ ↑ ↑
↑
Musallam KM, et al. Haematologica. 2013;98:833-4.
Hypercoagulability and vascular disease in
NTDT
Patients (N = 8,860)
– 6,670 with β-TM
– 2,190 with β-TI
146 (1.65%) thrombotic events
– 61 (0.9%) with β-TM
– 85 (3.9%) with β-TI
Risk factors for developing thrombosis in β-TI were
– age (> 20 years)
– previous thromboembolic event
– family history
– splenectomy
Taher A, et al. Thromb Haemost. 2006;96:488-91.DVT = deep vein thrombosis
PVT = portal vein thrombosis; STP = superficial thrombophlebitis
Thromboembolic events (%)
Typ
e o
f e
ve
nt
12
8
19
12
39
9
66
30
0
11
8
23
28
48
0 20 40 60 80
Others
STP
PVT
PE
DVT
Stroke
Venous
TM (n = 61)
TI (n = 85)
Thromboembolic events in a large
cohort of β-TI patients
Parameter Group OR 95% CI p value
NRBC count ≥ 300 x 106/L Group III 1.00 Referent
< 0.001Group II 5.35 2.31–12.35
Group I 11.11 3.85–32.26
Platelet count ≥ 500 x 109/L Group III 1.00 Referent
< 0.001Group II 8.70 3.14–23.81
Group I 76.92 22.22–250.00
PHT Group III 1.00 Referent
0.020Group II 4.00 0.99–16.13
Group I 7.30 1.60–33.33
Transfusion naivety Group III 1.00 Referent
0.001Group II 1.67 0.82–3.38
Group I 3.64 1.82–7.30
Group I patients had significantly higher
NRBC, platelets, and PHT occurrence, and
were mostly non-transfused
NRBC = nucleated red blood cell; PHT = pulmonary hypertension; OR = adjusted odds ratio; CI = confidence interval.
Taher AT, et al. J Thromb Haemost. 2010;8:2152-8.
OPTIMAL CARE study: multivariate analysis on
risk factors for thrombosis in splenectomised
patients
Study Number of
patients
Age (years) MRI technique Definition of infarction Prevalence of SCI
(95% CI)
Manfre et al. 1999 16 Mean: 29
Range: 9-48
0.5 Tesla
T2- spin-echo
weighted
imaging
Abnormally high signal
intensity on long TR-
weighted images
Two blinded
neuroradiologists
37.5% (18.4-61.7)
Taher et al. 2010 30 Mean: 32.1
Range: 18-54
3.0 Tesla
T1-, T2-
gradient-echo-,
FLAIR-,
diffusion-
weighted
imaging
Abnormally high signal
intensity on the T2-
and FLAIR-weighted
imagesa
Two blinded
neuroradiologists
60.0% (42.2-75.5)
Karimi et al. 2010 30 Mean: 24.3
Range: 18-34
1.5 Tesla
T1-, T2-,
FLAIR-
weighted
imaging
Abnormally high signal
intensity on the T2-
and FLAIR- weighted
images
One neuroradiologist
26.7% (14.2-44.6)
Teli et. al 2012 24 Mean: 12
Range: 4.5-20
N/A N/A 0%
Musallam KM, et al. Thromb Res. 2012;130:695-702.
aOther diagnoses were ruled out based on the radiological appearance of lesions (e.g.
viral encephalopathy or multiple sclerosis) or absence of associated risk factors and
clinical symptoms (e.g. vasculitis or Binswanger’s disease).
FLAIR, fluid attenuation inversion recovery; N/A, data not available; CI, confidence
interval.
Silent cerebral infarction in
splenectomized patients
Increasing age and transfusion naivety are associated with a
higher incidence and multiplicity of white matter lesions
Pro
ba
bil
ity o
f a
bn
orm
ali
ty
Age (years)
10 15 20 25 30 35 40 45 50 55 600.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
1.1
Pa
tie
nts
(n
)
No. of abnormalities
0
1
2
3
4
5
6
≤ 30 30–40 40–50 > 50
Non-transfused
Occasionally transfused
0
1
2
3
4
5
6
Age (years)
0 > 11
Taher AT, et al. J Thrombosis Haemost. 2010;8:54-9.
Risk factors for silent cerebral infarction
* p < 0.001 for all parameters for patients with PHT versus those without PHT
AOR = adjusted odds ratio
β-TI patients (N = 64)
Parameters PHT+* PHT−
Splenectomized%AOR (95% CI)
84.44.9 (1.9–8.5)
46.9
History of thromboembolic events%AOR (95% CI)
40.63.69 (2.38–7.05)
7.8
Nucleated RBC countMean (SD; x 106/L)AOR (95% CI)
354.2 (199.2)2.59 (1.69–6.05)
214.7 (94.5)
Transfusion naivety%AOR (95% CI)
56.23.5 (2.1–6.25)
78.1
Iron chelation naivety%AOR (95% CI)
37.52.3 (1.2–4.25)
62.5
Hydroxyurea naivety%AOR (95% CI)
17.22.6 (1.1–5.25)
34.4
Karimi M, et al. Eur J Intern Med. 2011;22:607-10.
Risk factors for PHT: OPTIMAL CARE
PASP, pulmonary artery systolic pressure;
TCG, tricuspid gradient.
Derchi G, et al. Circulation. 2014;129:338-45.
Isma’eel H, et al. Am J Cardiol. 2008;102:363-7.
PHT (defined as PASP ≥ 30 mmHg) present in 38.5%
Significantly correlated with LIC
Not correlated with age, Hb level, and SF level
LIC
(m
g F
e/g
dry
wt)
Tricuspid gradient (mmHg)
40
30
20
10
0
SF
(µg
/L)
r = 0.514
p = 0.01
r = 0.097
p = 0.513
20 40 60 80
5,000
4,000
3,000
2,000
1,000
0
SFLICTCG and SFTCG and LIC
0
10
20
30
40
50
60
70
80
90
100
18 28 38 48 58 68 78P
rob
ab
ilit
y o
f P
HT
(%
)Age (years)
All patients
Non-splenectomised
Splenectomised
PHT prevalence in thalassaemia was 2.1%
(TI 4.8%, TM 1.1%)
Risk of Pulmonary Hypertension in NTDT increases
with high LIC, advancing age, and splenectomy
***
*P < 0.05
0102030405060708090
100
β-TIβ-TM
Mean s
cale
score
Musallam KM, et al. Eur J Haematol. 2011;87:73-9.
With all this morbidity it was not surprising
that β-TI patients had poor HR-QoL
Non-transfusion-dependent thalassemia (NTDT)
Morbidity in NTDT– Clinical complications profile
– Ineffective erythropoiesis and anemia
– Iron overload and target organ damage
– Hypercoagulability and vascular disease
Management of NTDT– Splenectomy
– Transfusions
– Fetal hemoglobin induction
– Iron chelation
– Novel agents
Agenda
Splenomegaly and hypersplenism are inevitable in untransfused/rarely
transfused patients
– Due to extramedullary hematopoiesis, splenic pooling and chronic passive
congestion of the spleen
– Leads to worsening of anemia, neutropenia, thrombocytopenia
– Enlargement can be associated with abdominal pain and risk of rupture
Thus, splenectomy is a common practice in NTDT patients especially that it
can lead to an increase the total hemoglobin level by 1-2 g/dl and avoid blood
transfusions
Cholecystectomy during splenectomy is commmon in NTDT patients who are
at increased risk of gall stone formation from increased hemolysis
Taher AT, et al. Br j Haematol. 2011;152:512-23.
Abi Saad GS, et al. Br J Surg. 2011;98:751-60.
Splenectomy for NTDT patients
Infections
– Increased susceptibility to infections especially in patients <5 years
– Overwhelming post-splenectomy sepsis, which can be rapidly fatal
– Appropriate vaccinations and prophylactic antibiotics are necessary
Vascular events
– Venous thromboembolism
– Pulmonary hypertension
– Silent cerebral infarction
Taher AT, et al. Br j Haematol. 2011;152:512-23.
Abi Saad GS, et al. Br J Surg. 2011;98:751-60.
Splenectomy for NTDT patients: Adverse
events
Complication Parameter RR 95% CI p value
EMH Splenectomy 0.44 0.26–0.73 0.001
Transfusion 0.06 0.03–0.09 < 0.001
Hydroxyurea 0.52 0.30–0.91 0.022
Pulmonary hypertension Age > 35 years 2.59 1.08–6.19 0.032
Splenectomy 4.11 1.99–8.47 < 0.001
Transfusion 0.33 0.18–0.58 < 0.001
Hydroxyurea 0.42 0.20–0.90 0.025
Iron chelation 0.53 0.29–0.95 0.032
Heart failure Transfusion 0.06 0.02–0.17 < 0.001
Thrombosis Age > 35 years 2.60 1.39–4.87 0.003
Hb ≥ 9 g/dL 0.41 0.23–0.71 0.001
Serum ferritin ≥ 1,000 µg/L 1.86 1.09–3.16 0.023
Splenectomy 6.59 3.09–14.05 < 0.001
Transfusion 0.28 0.16–0.48 < 0.001
Cholelithiasis Age > 35 years 2.76 1.56–4.87 < 0.001
Female 1.96 1.18–3.25 0.010
Splenectomy 5.19 2.72–9.90 < 0.001
Transfusion 0.36 0.21–0.62 < 0.001
Iron chelation 0.30 0.18–0.51 < 0.001
Abnormal liver function Serum ferritin ≥ 1,000 µg/L 1.74 1.00–3.02 0.049
Taher AT, et al. Blood. 2010;115:1886-92.
The OPTIMAL CARE study
splenectomized patients: 325/584
Complication Parameter RR 95% CI p value
Leg ulcers Age > 35 years 2.09 1.05–4.16 0.036
Splenectomy 3.98 1.68–9.39 0.002
Transfusion 0.39 0.20–0.76 0.006
Hydroxyurea 0.10 0.02–0.43 0.002
Hypothyroidism Splenectomy 6.04 2.03–17.92 0.001
Hydroxyurea 0.05 0.01–0.45 0.003
Osteoporosis Age > 35 years 3.51 2.06–5.99 < 0.001
Female 1.97 1.19–3.27 0.009
Splenectomy 4.73 2.72–8.24 < 0.001
Transfusion 3.10 1.64–5.85 < 0.001
Hydroxyurea 0.02 0.01–0.09 < 0.001
Iron chelation 0.40 0.24–0.68 0.001
Hypogonadism Female 2.98 1.79–4.96 < 0.001
Serum ferritin ≥ 1,000 µg/L 2.63 1.59–4.36 < 0.001
Transfusion 16.13 4.85–52.63 < 0.001
Hydroxyurea 4.32 2.49–7.49 < 0.001
Iron chelation 2.51 1.48–4.26 0.001
The OPTIMAL CARE study
splenectomized patients: 325/584 (cont.)
Splenectomy was independently associated with an increased risk
of most disease-related complications
Taher AT, et al. Blood. 2010;115:1886-92.
Splenectomy is generally avoided in NTDT patients younger than 5 years
Splenectomy is reserved for cases of:
• When transfusion therapy is not possible or iron chelation therapy is unavailable
Worsening anemia leading to poor growth and development
• Leucopenia or thrombocytopenia causing clinical problems such as recurrent bacterial infection or bleeding
Hypersplensim
• Accompanied by symptoms such as left upper quadrant pain or early satiety• Massive splenomegaly (largest dimension >20 cm) with concern about possible splenic rupture
Splenomegaly
Taher AT, et al. TIF Guidelines 2013.
Splenectomy: best practice
Non-transfusion-dependent thalassemia (NTDT)
Morbidity in NTDT– Clinical complications profile
– Ineffective erythropoiesis and anemia
– Iron overload and target organ damage
– Hypercoagulability and vascular disease
Management of NTDT– Splenectomy
– Transfusions
– Fetal hemoglobin induction
– Iron chelation
– Novel agents
Agenda
*longer intervals than in β-TM and for defined durations
** in high-risk populations
Taher AT et al. Blood Rev 2012;26S:S24, Oliviery NF Blood Rev 2012;26S:S28,
Vichinsky E Blood Rev 2012;26S:31; Taher AT et al. TIF Guidelines 2013.
• Infections
•Pregnancy
•Surgery
Occasional blood
transfusions
•Childhood: poor growth and development
•Adulthood: prevention or management of specific complications
More frequent
transfusions*
•Thrombotic or cerebrovascular disease
•PHT with / without secondary heart failure
•EMH
•Leg ulcers
Prevention** Pro
gre
ss
ive
an
ae
mia
or
en
larg
em
en
t o
f th
e s
ple
en
Use of blood transfusions in NTDT
Complication Parameter RR 95% CI p value
EMH Splenectomy 0.44 0.26–0.73 0.001
Transfusion 0.06 0.03–0.09 < 0.001
Hydroxyurea 0.52 0.30–0.91 0.022
Pulmonary hypertension Age > 35 years 2.59 1.08–6.19 0.032
Splenectomy 4.11 1.99–8.47 < 0.001
Transfusion 0.33 0.18–0.58 < 0.001
Hydroxyurea 0.42 0.20–0.90 0.025
Iron chelation 0.53 0.29–0.95 0.032
Heart failure Transfusion 0.06 0.02–0.17 < 0.001
Thrombosis Age > 35 years 2.60 1.39–4.87 0.003
Hb ≥ 9 g/dL 0.41 0.23–0.71 0.001
Serum ferritin ≥ 1,000 µg/L 1.86 1.09–3.16 0.023
Splenectomy 6.59 3.09–14.05 < 0.001
Transfusion 0.28 0.16–0.48 < 0.001
Cholelithiasis Age > 35 years 2.76 1.56–4.87 < 0.001
Female 1.96 1.18–3.25 0.010
Splenectomy 5.19 2.72–9.90 < 0.001
Transfusion 0.36 0.21–0.62 < 0.001
Iron chelation 0.30 0.18–0.51 < 0.001
Abnormal liver function Serum ferritin ≥ 1,000 µg/L 1.74 1.00–3.02 0.049
Taher AT, et al. Blood. 2010;115:1886-92.
The OPTIMAL CARE studyoccasionally/regularly transfused patients: 445/584
Complication Parameter RR 95% CI p value
Leg ulcers Age > 35 years 2.09 1.05–4.16 0.036
Splenectomy 3.98 1.68–9.39 0.002
Transfusion 0.39 0.20–0.76 0.006
Hydroxyurea 0.10 0.02–0.43 0.002
Hypothyroidism Splenectomy 6.04 2.03–17.92 0.001
Hydroxyurea 0.05 0.01–0.45 0.003
Osteoporosis Age > 35 years 3.51 2.06–5.99 < 0.001
Female 1.97 1.19–3.27 0.009
Splenectomy 4.73 2.72–8.24 < 0.001
Transfusion 3.10 1.64–5.85 < 0.001
Hydroxyurea 0.02 0.01–0.09 < 0.001
Iron chelation 0.40 0.24–0.68 0.001
Hypogonadism Female 2.98 1.79–4.96 < 0.001
Serum ferritin ≥ 1,000 µg/L 2.63 1.59–4.36 < 0.001
Transfusion 16.13 4.85–52.63 < 0.001
Hydroxyurea 4.32 2.49–7.49 < 0.001
Iron chelation 2.51 1.48–4.26 0.001
Transfusion therapy was protective for thrombosis, EMH, PHT, HF,
cholelithiasis, and leg ulcers
Transfusion therapy was associated with an increased risk
of endocrinopathy
Taher AT, et al. Blood. 2010;115:1886-92.
The OPTIMAL CARE studyoccasionally/regularly transfused patients:
445/584 (cont.)
Risk factors– Minimally transfused and newly transfused patients
– Old age at first transfusion
– Ethnic and racial diverse population
– Splenectomy
– Allogeneic WBC within the transfusate
Chou ST et al. Br J Haematol. 2012;159:394-404.
Management– Fully phenotyped matched blood should be given
– Erythropoietin in combination with iron and folic acid
Alloimmunization
Non-transfusion-dependent thalassemia (NTDT)
Morbidity in NTDT– Clinical complications profile
– Ineffective erythropoiesis and anemia
– Iron overload and target organ damage
– Hypercoagulability and vascular disease
Management of NTDT– Splenectomy
– Transfusions
– Fetal hemoglobin induction
– Iron chelation
– Novel agents
Agenda
0
10
20
30
40
50
60
70
Med
ian
Hb
F (
%)
No
Yes
Extr
am
ed
ulla
ry
he
ma
top
oie
sis
Pulm
onary
hypert
ensio
n
Venous
thro
mboem
bolis
m
Heart
failu
re
Leg u
lcers
Abno
rmal liv
er
function
Dia
bete
s m
elli
tus
Hypo
thyro
idis
m
Hypo
go
na
dis
m
Oste
oporo
sis
*P<0.001; †P=0.003; ‡P=0.002
*†
***
*†
‡ ‡
63 untransfused β-TI
Musallam KM, et al. Blood. 2012;119:364-7.
Elevations in HbF ameliorate
morbidity in NTDT
Musallam KM, et al. Blood 2013;121:2199-212.
Agent Main positive findings Limitations
DNA methylation inhibitiors
5-azacytidine Marked hematological responses achieved Few studies
Small sample sizes
Safety concerns
Decitabine Hematological responses achieved
Favorable effects on red cell indices
Well-tolerated
Few studies
Small sample sizes
Hydroxyurea Hematological responses achieved
Favorable effects on red cell, hemolysis, and
hypercoagulability indices
Favorable effects on clinical morbidities
Well-tolerated
Heterogonous phenotypes studied together
Heterogeneous study endpoints evaluated
together
Ideal dose and duration of therapy still
controversial
Lack of efficacy on long-term therapy
Data on predictors of response remain
inconsistent
Short-chain fatty acids Hematological responses achieved
Favorable effects on red cell and hemolysis
indices
Well-tolerated
Small sample sizes
Lack of efficacy on long-term therapy
Erythropoietic stimulating agents Hematological responses achieved
Favorable effects on combination with
hydroxyurea
Well-tolerated
Few studies
Small sample sizes
High doses required
No additive effects with short-chain fatty
acids
Thalidomide and derivatives Hematological responses achieved
Well-tolerated
Few studies
Small sample sizes
Experience with HbF inducers in β-
thalassemia
Taher AT, et al. Blood. 2010;115:1886-92.
The OPTIMAL CARE study:
patients on hydroxyurea: 202/584
Complication Parameter RR 95% CI p value
EMH Splenectomy 0.44 0.26–0.73 0.001
Transfusion 0.06 0.03–0.09 < 0.001
Hydroxyurea 0.52 0.30–0.91 0.022
Pulmonary
hypertension
Age > 35 years 2.59 1.08–6.19 0.032
Splenectomy 4.11 1.99–8.47 < 0.001
Transfusion 0.33 0.18–0.58 < 0.001
Hydroxyurea 0.42 0.20–0.90 0.025
Iron chelation 0.53 0.29–0.95 0.032
Heart failure Transfusion 0.06 0.02–0.17 < 0.001
Thrombosis Age > 35 years 2.60 1.39–4.87 0.003
Hb ≥ 9 g/dl 0.41 0.23–0.71 0.001
Serum ferritin ≥ 1,000 μg/L 1.86 1.09–3.16 0.023
Splenectomy 6.59 3.09–14.05 < 0.001
Transfusion 0.28 0.16–0.48 < 0.001
Cholelithiasis Age > 35 years 2.76 1.56–4.87 < 0.001
Female 1.96 1.18–3.25 0.010
Splenectomy 5.19 2.72–9.90 < 0.001
Transfusion 0.36 0.21–0.62 < 0.001
Iron chelation 0.30 0.18–0.51 < 0.001
Abnormal liver
function
Serum ferritin ≥ 1,000 μg/L 1.74 1.00–3.02 0.049
Complication Parameter RR 95% CI p value
Leg ulcers Age > 35 years 2.09 1.05–4.16 0.036
Splenectomy 3.98 1.68–9.39 0.002
Transfusion 0.39 0.20–0.76 0.006
Hydroxyurea 0.10 0.02–0.43 0.002
Hypothyroidism Splenectomy 6.04 2.03–17.92 0.001
Hydroxyurea 0.05 0.01–0.45 0.003
Osteoporosis Age > 35 years 3.51 2.06–5.99 < 0.001
Female 1.97 1.19–3.27 0.009
Splenectomy 4.73 2.72–8.24 < 0.001
Transfusion 3.10 1.64–5.85 < 0.001
Hydroxyurea 0.02 0.01–0.09 < 0.001
Iron chelation 0.40 0.24–0.68 0.001
Hypogonadism Female 2.98 1.79–4.96 < 0.001
Serum ferritin ≥ 1,000 μg/L 2.63 1.59–4.36 < 0.001
Transfusion 16.13 4.85–52.63 < 0.001
Hydroxyurea 4.32 2.49–7.49 < 0.001
Iron chelation 2.51 1.48–4.26 0.001
Hydroxyurea treatment was protective for EMH, PHT, leg ulcers,
hypothyroidism, and osteoporosis
Taher AT, et al. Blood. 2010;115:1886-92.
The OPTIMAL CARE study:
patients on hydroxyurea: 202/584 (cont.)
Non-transfusion-dependent thalassemia (NTDT)
Morbidity in NTDT– Clinical complications profile
– Ineffective erythropoiesis and anemia
– Iron overload and target organ damage
– Hypercoagulability and vascular disease
Management of NTDT– Splenectomy
– Transfusions
– Fetal hemoglobin induction
– Iron chelation
– Novel agents
Agenda
There are several methods to assess iron overload in NTDT patients;
each carrying their own advantages and disadvantages1:
– Liver iron concentration (LIC)
• MRI
• Biopsy
• SQUID
– Serum ferritin
– Cardiac MRI
• No evidence of cardiac siderosis in NTDT2
• May be reserved for older patients with high LIC
– Other markers (NTBI, Transferrin Sat)3
• Few clinical studies
1. Musallam KM, et al. Blood Rev. 2012;26S:S16-9.
2. Taher A, et al. Am J Hematol. 2010;85:288-90.
3. Taher AT, et al. Br J Haematol 2009;146:569–72.
SQUID = superconducting quantum interfering device
NTBI = Non-transferrin-bound iron
Assessment of iron overload in
NTDT
1000
2000
3000
4000
5000
6000
7000
8000
9000
10,000
0 5 10 15 20 25 30 35 40 45 50
LIC (mg Fe/g dw)
Seru
m ferr
itin
level (n
g/m
l)
TI TMLinear (TI) Linear (TM)
Taher A, et al. Haematologica. 2008;93:1584-6.
Musallam KM, Taher AT. N Engl J Med. 2011;364:1476.
0
Serum ferritin underestimates
iron burden in NTDT
Patients ≥10 years of age
– Increased iron-related morbidity risk beyond this age1
Patients with a LIC ≥5 mg Fe/g dw
– Increased risk of morbidity beyond this threshold2,3
– Iron chelator efficacy beyond this threshold is established
(THALASSA)4,5
Patients with a serum ferritin ≥800 ng/ml (LIC not available)
– Best reflects a LIC of ≥5 (specificity/sensitivity analysis)6
– Increased morbidity risk beyond this threshold7
1. Taher AT, et al. Br J Haematol. 2010;150:486-9. .
2. Musallam KM, et al. Haematologica. 2011;96:1605-12.
3. Musallam KM, et al. Blood Cells Mol Dis. 2013;51:35-8.
4. Taher AT, et al. Blood. 2012;120:970-7.
5. Taher AT, et al. Ann Hematol. 2013;92(11):1485-93.
6. Taher A, et al. Br J Haematol. 2015;168(2):284-90. 7. Musallam KM, et al. Haematologica 2013;98(S1):S1172.
Which NTDT patients should receive iron
chelation therapy and at what thresholds
P=0.003
P=0.001
P=0.008
P<0.001
P=0.005
Pre
vale
nce (
%)
Musallam KM, et al. Blood Cells Mol Dis 2013;51:35-8.
14.3
18.6
8.6
28.6
7.1
34.7
43.9
24.5
58.2
23.5
0.0
10.0
20.0
30.0
40.0
50.0
60.0
Thrombosis PHT Hypothyroidism Osteoporosis Hypogonadism
LIC < 5 mg/gdw
Patients with a LIC ≥5 have a higher prevalence
of morbidities (n=168, β-TI, non-chelated)
The prevalence of any morbidity was 84.7% vs. 50% and multiple
morbidity was 60.2% vs. 16.1%, in the ≥5 and <5 groups, respectively
(p<0.001)
43.1
34.7
16.4
29.6
15.9
25.3
20.4
0 10 20 30 40 50
Multiple morbidity
Any morbidity
Hypogonadism
Osteoporosis
Hypothyroidism
Pulmonary hypertesnion
Thrombosis
Absolute risk difference Between LIC ≥5 vs. <5 mg/g (%)
20.6
28.9
34.7
33.2
34.7
31.5
29.3
30.2
28.1
24.9
21.4
26.7
28.1
0 10 20 30 40
≥3 vs. <3
≥4 vs. <4
≥5 vs. <5
≥6 vs. <6
≥7 vs. <7
≥8 vs. <8
≥9 vs. <9
≥10 vs. <10
≥11 vs. <11
≥12 vs. <12
≥13 vs. <13
≥14 vs. <14
≥15 vs. <15
Absolute risk difference (%)
LIC
(m
g/g
dw
)
Musallam KM, et al. Blood Cells Mol Dis 2013;51:35-8.
Within a clinically relevant LIC range (3-15), the LIC of 5 threshold had
the highest absolute risk difference for development of a morbidity
Morbidity rate difference around the LIC
of 5 threshold
Musallam KM, et al. Haematologica. 2014;99:e218-21.
SF ≤ 300 µg/L
SF > 300 to < 800 µg/L
SF ≥ 800 µg/LPro
po
rtio
n o
f p
ati
en
ts
su
rviv
ing
wit
ho
ut
mo
rbid
ity
Time to first morbidity (years)
1.00
0.75
0.50
0.25
0.00
0 5 10
Chi-square = 38.29
p value = 0.001
Number at risk
SF ≤ 300 μg/L 8 8 8
SF > 300 to < 800 μg/L 17 14 12
SF ≥ 800 μg/L 27 16 1
ORIENT
study
Patients with SF ≥ 800 μg/L have a
higher incidence of morbidities over 11 years
ROC, receiver operating characteristic. Taher AT, et al. Br J Haematol. 2015;168:284-90.
However, around 50% of patients with SF<800 could still have LIC >5
Patients with SF
> 800 μg/L had a high
probability of LIC ≥ 5 mg
Fe/g dry wt
SF > 2,000 μg/L was
highly predictive of LIC
≥ 7 mg Fe/g dry wt
SF ≤ 300 μg/L appears
adequate to safely
interrupt DFX therapy
100
90
80
70
60
50
40
30
20
10
0
0 10 20 30 40 50 60 70 80 90 100
1−Specificity (%)
Se
ns
itiv
ity (
%)
SF = 800 µg/L
When MRI is unavailable, SF thresholds are useful to
indicate initiation of ICT, dose escalation, and/or dose
interruption
SF >800 ng/mL is predictive of LIC >5 mg/g
NTBI, non-transferrin-bound iron;
UIE, urinary iron excretion.
1. Cossu P. Eur J Pediatr. 1981;137:267-71.
2. Pootrakul P, et al. Br J Haematol. 2003;122:305-10. 3. Porter
JB, et al. Int J Hematol. 2001;94:453.
4. Trachtenberg F, et al. Am J Hematol. 2011;85:433. 5. Delea
TE, et al. Transfusion. 2007;47:1919.
DFO1
Significant decline in serum ferritin after6 months of DFO treatment
Significant UIE after 12 hours ofcontinuous DFO (except in patientsaged < 1 year)
• In some patients, substantial UIE despite modest SF levels
• SF levels of no value in predicting UIE
• No sigificant differences in excretion across doses
Deferiprone2
Significant reductions seen in mean SF, hepatic iron, red cell membrane iron, and
serum NTBI levels
SF ± SD: initial 2168 ± 1142 μg/L; final 418 ± 247 μg/L
Significant mean increase in serum EPO also observed
Increase in Hb values in 3 patients; reduction in transfusion requirements
in 4 patients
DFO and DFP in NTDT
Taher AT, et al. Blood. 2012;120:970-7; Taher AT, et al. Ann Hematol. 2013;92:1485–93.
Randomize NTDT patients
(2:1 DFX/placebo)
Deferasirox 5 mg/kg/day
Deferasirox 10 mg/kg/day
Placebo 5 mg/kg/day
Placebo 10 mg/kg/day
52 weeks24 weeks 104 weeks
THALASSA study evaluated the efficacy of two deferasirox regimens
(5 and 10 mg/kg/day) in NTDT patients, based on the change in LIC from baseline
compared with placebo
EXTENSION
LIC 3–15 mg Fe/g dry wt:
≤ 10 mg/kg/day
LIC > 15 mg Fe/g dry wt:
≤ 20 mg/kg/day
Screening
(28 days)
CORE
LIC < 3 mg Fe/g dry wt:
interrupt
DFX
LIC was measured by MRI after every 6 months
SF was measured monthly
The THALASSA study demonstrated a significant reduction in LIC in both deferasirox arms
with a greater reduction in the 10 mg/kg/day group
Deferasirox in NTDT:
THALASSA study design
BL, baseline. Taher AT, et al. Ann Hematol. 2013; 92:1485-93.
Deferasirox core + extension: median dose = 9.5 mg/kg/day
Deferasirox extension: median dose = 10.8 mg/kg/day
Placebo/deferasirox: median dose = 14.0 mg/kg/day
Me
an
ab
so
lute
ch
an
ge
in
LIC
(mg
Fe
/g d
ry w
t)
Time (months)
-16
-14
-12
-10
-8
-6
-4
-2
0
2
4
6
BL 6 12 18 24
Deferasirox core starting dose 5 mg/kg/day
Deferasirox core starting dose 10 mg/kg/day
Placebo/deferasirox
Me
dia
n ±
25
th/7
5th
pe
rce
nti
le a
bs
olu
te
ch
an
ge
in
SF
(μ
g/L
)
Time (months)
-1,000
-800
-600
-400
-200
0
200
400
BL 3 6 9 12 15 18 21 24
Deferasirox core starting dose 5 mg/kg/day
Deferasirox core starting dose 10 mg/kg/day
Placebo/deferasirox
Deferasirox continues
to reduce iron burden over 2 years
CI, confidence interval Taher AT et al. Am J Hematol 2013;88:503-6.
-10 -8 -6 -4 -2 0 2 4
AgeAge <18 (n=21)
Age ≥18 (n=145)
GenderMale (n=89)
Female (n=77)
RaceCaucasian (n=94)
Asian (n=69)
Black (n=2)
Other (n=1)
Baseline LIC≤7 (n=31)
>7–15 (n=77)
>15 (n=57)
Baseline SF (ng/mL)>300–500 (n=17)
>500–1000 (n=67)
>1000 (n=82)
Splenectomy Yes (n=88)
No (n=78)
Underlying diseaseβ TI (n=95)
α thalassemia (n=22)
Hb E/β thalassemia (n=49)
Least squares mean difference in absolute change in LIC from baseline (95% CI)
n=7
n=47
n=28
n=26
n=29n=24
n=8n=26
n=20
n=4n=23
n=27
n=30n=24
n=29n=9
n=16
n=8n=46
n=30n=24
n=32
n=21
n=12n=20
n=22
n=7
n=20
n=27
n=28
n=26
n=32n=7
Deferasirox 10 mg/kg/day better Placebo better
n=15
Deferasirox consistently reduces iron burden across all
evaluated patient subgroups
AE, adverse event.Taher AT, et al. Blood. 2012;120:970-7.
Taher AT, et al. Ann Hematol. 2013; 92: 1485-93.
Overall incidence of AEs was comparable between deferasirox
and placebo
Most drug-related AEs were of mild-to-moderate severity and resolved
without discontinuation of treatment
AE, n (%)
Deferasirox
5 mg/kg/day
(n = 55)
Deferasirox
10 mg/kg/day
(n = 55)
Placebo
5 mg/kg/day
(n = 28)
Placebo
10 mg/kg/day
(n = 28)
Total
(N = 166)
Nausea 3 (5.5) 4 (7.3) 1 (3.6) 3 (10.7) 11 (6.6)
Skin rash 2 (3.6) 5 (9.1) 0 1 (3.6) 8 (4.8)
Diarrhoea 0 5 (9.1) 0 1 (3.6) 6 (3.6)
Headache 2 (3.6) 1 (1.8) 0 2 (7.2) 5 (3.0)
Upper abdominal
pain2 (3.6) 1 (1.8) 0 0 3 (1.8)
Abdominal pain 1 (1.8) 1 (1.8) 1 (3.6) 0 3 (1.8)
THALASSA: most common (≥ 3 patients overall) drug-related adverse events
Deferasirox 5 mg/kg/day
Deferasirox 10 mg/kg/day
Placebo 5 mg/kg/day
Placebo 10 mg/kg/day
ALT, alanine aminotransferase; UPCR, urine protein/creatinine ratio Taher A, et al. Blood. 2012;120:970-7.
0
10
20
30
40
50
60
70
80
Mean
seru
m c
reati
nin
e
±S
D (
µm
ol/
L)
Time (months)
0102030405060708090
100
Mean
ALT
±S
D (
U/L
)
Time (months)
0
50
100
150
200
250
Mean
cre
ati
nin
e c
leara
nce
±S
D (
mL/m
in)
Time (months)
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
Mean
UP
CR
±S
D (
mg
/mg
)
Time (months)
3 patients had 2 consecutive serum creatinine increases >33% above baseline and > ULN
There were no progressive changes in ALT, creatinine or UPCR in
patients treated with deferasirox or placebo
Laboratory parameters at baseline and before reaching LIC < 3 mg Fe/g dry wt
Taher AT, et al. Eur J Haematol. 2014;92:521-6.
Parameter
(mean ± SD)Baseline End of Period 1a End of Period 2a
Creatinine, μmol/L 51.8 ± 14.6 62.0 ± 21.9 61.0 ± 19.9
Creatinine clearance, mL/min 144.8 ± 42.3 129.8 ± 53.9 129.5 ± 52.3
Alanine aminotransferase, U/L 31.4 ± 20.4 16.9 ± 7.4 16.4 ± 6.8
Urinary protein/creatinine
ratio, mg/mg0.2 ± 0.1 0.3 ± 0.2 0.2 ± 0.1
a Last available assessment.
THALASSA: safety profile of deferasirox remains consistent as NTDT patients
approach target LIC < 3 for interrupting chelation
Taher AT, et al. Blood Cells Mol Dis. 2016;57:23-9.
Screening (4 weeks) to determine patient eligibility
Starting dose 10 mg/kg/day for 4 weeks
Open-label treatment (52 weeks) with deferasirox:
20 mg/kg/day for
patients with
baseline LIC >15
mg Fe/g dw
15 mg/kg/day for
patients with
baseline LIC >7 but
≤15 mg Fe/g dw
At Week 4, dose adjustments according to baseline LIC
10 mg/kg/day for
patients with
baseline LIC ≥5 but
≤7 mg Fe/g dw
At Week 24, dose adjustments according to Week 24 LIC
● Increase dose by 5–10 mg/kg/day if Week 24 LIC >15 mg Fe/g dw
● Increase dose by 5 mg/kg/day if Week 24 LIC >7 but ≤15 mg Fe/g dw and Week 24 LIC reduction from
baseline <15%
● Increase dose by 5–10 mg/kg/day if Week 24 LIC increased from baseline to the next category
● Same dose if Week 24 LIC remained in the same baseline LIC category
● Decrease dose by 5–10 mg/kg/day if Week 24 LIC decreased from baseline to the next category
• Results from THALASSA have demonstrated that more aggressive chelation should be initiated earlier in the course of treatment
• Primary objective of THETIS is to assess the efficacy of deferasirox in patients with NTDT based on change in LIC from baseline after 52 weeks of treatment
THETIS was an open-label, single-arm, multicenter
Phase IV study to evaluate the efficacy and safety of
deferasirox in NTDT patients with iron overload
Taher AT, et al. Blood Cells Mol Dis. 2016;57:23-9.
THETIS change in LIC and SF
With significant and clinically relevant reductions in iron burden
alongside a safety profile similar to that in THALASSA, these data
support earlier escalation with higher deferasirox doses in iron-
overloaded non-transfusion-dependent anaemia patients.
Taher AT, et al. TIF Guidelines. 2013 TIF guidelines. Available
from: http://thalassemia.com/documents/NTDT-TIF-guidelines.pdf.
LIC ≤ 3 mg Fe/g dry wt
(SF ≤ 300 μg/L)
Discontinue
DFX
DFX
20 mg/kg/day
LIC after 6 months > 7 mg Fe/g dry wt
(SF > 1 500–2,000 μg/L) and
< 15% decrease from baseline
NTDT ≥ 10 years
(≥ 15 years in deletional
HbH disease)
LIC Q 1–2 years
SF Q 3 months
LIC ≥ 5 mg Fe/g dry wt
(SF ≥ 800 μg/L)
Yes No
DFX
10 mg/kg/day
LIC Q 6–12 months
(SF Q 3 months)
Algorithm for Iron Overload Assessment and
Chelation Therapy in NTDT
Non-transfusion-dependent thalassemia (NTDT)
Morbidity in NTDT– Clinical complications profile
– Ineffective erythropoiesis and anemia
– Iron overload and target organ damage
– Hypercoagulability and vascular disease
Management of NTDT– Splenectomy
– Transfusions
– Fetal hemoglobin induction
– Iron chelation
– Novel agents
Agenda
Takeaways
Ineffective erythropoiesis alongside anemia are the hallmarks of disease process in NTDT
These in turn lead to increased intestinal iron absorption (iron overload) and a hypercoagulable state
Iron overload and hypercoagulability are associated with a multitude of serious clinical complications involving almost every organ system
Multiple morbidity in NTDT has significant impact on quality of life
Splenectomy should only be performed in indicated situations as it is associated with a variety of adverse events
Beneficial roles of tailored transfusion therapy, iron chelation therapy, and fetal hemoglobin induction in this patient population are established
Data from novel therapies in NTDT patients are awaited