Evidence-Based Approach to Managing Non-Transfusion ... · Hepatic fibrosis, cirrhosis and cancer Hepatic failure Viral hepatitis Diabetes mellitus Hypogonadism Facies Bone deformity

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







– Transfusions


– 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







– Transfusions


– 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:

http://upload.wikimedia.org/wikipedia/commons/0/03/Flag_of_Italy.svg

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


Erythroid marrow

expansion

• Hepatosplenomegaly

• Extramedullary

haematopoietic

pseudotumors

The pathophysiology and risk factors were

predicted … but not yet evaluated







– Transfusions


– 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







– Transfusions


– 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


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







– Transfusions


– 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

↓↑ ↑ ↑

↑


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


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


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







– Transfusions


– 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


The OPTIMAL CARE study

splenectomized patients: 325/584


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


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







– Transfusions


– 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


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



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


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


The OPTIMAL CARE studyoccasionally/regularly transfused patients: 445/584



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


Hydroxyurea 0.05 0.01–0.45 0.003


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


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


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







– Transfusions


– 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


The OPTIMAL CARE study:

patients on hydroxyurea: 202/584


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



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


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



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


Hydroxyurea 0.05 0.01–0.45 0.003


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


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


The OPTIMAL CARE study:

patients on hydroxyurea: 202/584 (cont.)







– Transfusions


– 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


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


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



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



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







– Transfusions


– 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

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