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Iron Overload and Chelation Therapy in Patients with

Non−Transfusion-Dependent Thalassaemia

Ali Taher, MD, PhD, FRCP

Professor of Medicine, Hematology and Oncology Associate Chair, Research, Department of Internal Medicine

American University of Beirut Medical Center Beirut, Lebanon

Outline

•  Overview of non−transfusion-dependent thalassaemia (NTDT)

•  Mechanisms and consequences of iron overload (IO) in NTDT

•  Assessment of IO in NTDT •  Treatment of IO in NTDT •  Practical recommendations •  Conclusions

Thalassaemia Syndromes

Asymptomatic carrier states

Non−transfusion-dependent thalassaemia

Major, transfusion-dependent thalassaemia

•  Beta-thalassaemia intermedia •  Haemoglobin E/beta-thalassaemia (HbE/beta-thalassaemia) •  Alpha-thalassaemia intermedia (HbH disease)

Transfusions seldom required

Regular transfusions required

Musallam KM, et al. Haematologica. 2013;98:833-844.

Non−Transfusion-Dependent Thalassaemia

•  Does not require lifelong regular transfusions for survival1,2

•  Can require occasional or even frequent transfusions in certain clinical settings1

•  Includes several forms of thalassaemia arising from variants of genes regulating haemoglobin production1

•  Milder and progresses more slowly2

•  Different forms vary in clinical severity2

1. Musallam KM, et al. Haematologica. 2013;98:833-844. 2. Taher AT, et al. Am J Hematol. 2013;88:409-415.

Global Burden of Thalassaemias, Including NTDT1

1. Weatherall DJ, Clegg JB. Bull World Health Organ. 2001;79:704-712. 2. Taher A, et al. Guidelines for the Management of Non-Transfusion-Dependent Thalassaemia (NTDT). 2013. Thalassaemia International Federation. 3. Colah R, et al. Expert Rev Hematol. 2010;3:103-117.

Burden of thalassaemia is spreading to Europe, North America, and Australia because of population migration3

HbE/beta-thalassaemia2

~1 million affected worldwide >19,000 births annually

Alpha-thalassaemia intermedia2

5% of global population are carriers ~1 million affected worldwide 10,000 births annually

Beta-thalassaemia2

1.5% of global population are carriers 23,000 births annually

Statistics are based on older studies and information from a limited number of centers. Thus, they are likely underestimates.

Problems with the Current Paradigm

•  Non−transfusion-dependent thalassaemia (NTDT) considered a milder form of thalassaemia that requires little or no iron chelation1

•  Definition based on signs and symptoms early in life, but serious complications develop over time1

•  Regular monitoring and treatment initiation often delayed until complications are apparent2

•  Guidelines needed to increase awareness of the monitoring and management requirements of NTDT

1. Taher A, et al. Guidelines for the Management of Non-Transfusion-Dependent Thalassaemia (NTDT). 2013. Thalassaemia International Federation. 2. Taher AT, et al. Am J Hematol. 2013;88:409-415.

Mechanism Underlying Iron Overload in NTDT

Musallam KM, et al. Haematologica. 2013;98:833-844. Slide courtesy of Dr. Taher.

Chronic anaemia/hypoxia

Iron Overload—Transfusion-Dependent Thalassaemia Versus NTDT1

Characteristic Transfusion-Dependent NTDT Primary source of excess iron

Regular transfusions Intestinal iron absorption

Preferential distribution of iron

Reticuloendothelial system and parenchyma

Hepatocytes

SF level* High Relatively low and likely to underestimate IO*

Rate of iron accumulation

Rapid Slow (3−4 mg/day, 1000 mg/year)

LIC HIGH HIGH

1. Musallam KM, et al. Blood Rev. 2012;26S:S16-S19. 2. Taher AT, et al. Am J Hematol. 2010; 85:288-290. 3. Origa R, et al. Haematologica. 2007;92:583-588.

*Ratio of SF to LIC lower in NTDT compared with transfusion-dependent thalassaemia. Abbreviations: IO, iron overload; LIC, liver iron concentration; NTDT, non-transfusion-dependent thalassaemia; SF, serum ferritin.

Consequences of Iron Overload in NTDT

•  Hepatic –  Hepatic fibrosis1

–  Hepatocellular carcinoma1

•  Vascular –  Thrombosis1

–  Pulmonary hypertension1

–  Large cerebral vessel disease2

•  Endocrine –  Hypothyroidism1

–  Hypogonadism1 •  Neurologic

–  Silent brain infarction2

–  Decreased neuronal function2

•  Skeletal: osteoporosis1

•  Renal: tubular dysfunction1

1. Musallam KM, et al. Haematologica. 2013;98:833-844. 2. Musallam KM, et al. Blood Rev. 2012;26S:S16-S19.

Consequences of IO—NTDT versus Transfusion-Dependent Thalassaemia

Musallam KM, et al. Haematologica. 2013;98:833-844.

Increasing Age is a Risk Factor in IO-Related Morbidity

• Study of 52 patients with beta-thalassaemia intermedia

• Incidence of morbidity

higher among older patients

• Older patients likely to have or shift to SF levels of 800 ng/mL or higher

• Incidence of complications higher among patients who have or shift to SF levels of 800 ng/mL or higher

Musallam KM, et al. Presented at: 18th Congress of the European Hematology Association, 2013. Abstract S1172. Slide courtesy of Dr. Taher.

Age (years)

Patie

nts

SF ≤300 ng/mL SF >300 to <800 ng/mL SFa ≥800 ng/mL

Diabetes EMH

Hypogonadism/infertility Hypoparathyroidism

Hypothyroidism Liver disease Osteoporosis PHT Thrombosis

Assessing IO—Liver Iron Concentration

1. Taher A, et al. Guidelines for the Management of Non-Transfusion-Dependent Thalassaemia (NTDT). 2013. Thalassaemia International Federation. 2. Taher AT, et al. Am J Hematol. 2013;88:409-415. 3. Butensky E, et al. Am J Clin Pathol. 2005; 123:146-152. 4. Musallam KM, et al. Haematologica. 2011;96:1605-1612. Risk threshold graphic courtesy of Dr. Taher.

1.8 mg/g dw Normal liver iron level

6 mg/g dw 7 mg/g dw

§  Pulmonary hypertension §  Hypothyroidism §  Hypogonadism §  Endocrine/bone complicaBons

9 mg/g dw

RISK THRESHOLDS4

§  Thrombosis §  Vascular complicaBons

§  Osteoporosis

Method Advantage Disadvantage Needle biopsy2 Direct Adverse events, such

as pain at the needle site and, more rarely, sepsis or hemorrhage Variable concentration based on processing, location in liver3

Magnetic techniques (MRI, superconducting quantum imaging [SQUID])2

Noninvasive Reliable

Limited availability SQUID not accurate for concentrations between 3 and 10 mg Fe/g dry weight

The gold standard for assessing overall iron concentration1

What Happens Around the LIC 5 mg/g Threshold?

Musallam KM, et al. Blood Cells Mol Dis. 2013;51:35-38. Slide courtesy of Dr. Taher.

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 5 10 15 20 25 30 35 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

)

Pulmonary hypertension

≥7 vs <7 ≥6 vs <6

≥5 vs <5 ≥4 vs <4

≥3 vs <3

≥10 vs <10 ≥9 vs <9

≥8 vs <8

≥15 vs <15 ≥14 vs <14

≥13 vs <13 ≥12 vs <12

≥11 vs <11

Patients with a LIC ≥5 mg/g dw Have a Higher Prevalence of Morbidities

Abbreviations: LIC, liver iron concentration; PHT, pulmonary hypertension. Musallam KM, et al. Blood Cells Mol Dis. 2013;51:35-38. Slide courtesy of Dr. Taher.

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/g dw LIC ≥ 5 mg/g dw

P = .003

P = .001

P = .008

P <.001

P = .005

Prev

alen

ce (%

)

LIC <5 mg/g dw LIC ≥5 mg/g dw

LIC Treatment Thresholds— THALASSA Study

•  LIC ≥5 mg Fe/g dw --> Treatment initiation •  LIC <3 mg Fe/g dw --> Treatment withholding •  LIC ≥7 mg Fe/g dw --> Treatment dose escalation

However, LIC measurements are not always available and therefore serum ferriEn assessments may

be required

Slide courtesy of Dr. Taher.

Serum Ferritin Level Underestimates LIC in NTDT

Taher A, et al. Haematologica 2008;93:1584-1586.

Relying solely on serum ferritin level can delay monitoring of iron and initiation of therapy in NTDT

Without Iron Chelation Therapy, Serum Ferritin Level Increases with Time

0

1,000

2,000

3,000

2000

Box plot of SF level by year

SF (n

g/ml)

400

600

800

1000

1200

1400

2000

2001

2002

2003

2004

2005

2006

2009

2007

2008

2010

Mean and 95% CI plot of SF level by year

SF (n

g/ml)

2001 2002 2003 2004 2006 2007 2008 2009 2010 2005

Study of 52 patients with beta-thalassaemia intermedia followed from 2000 through 2010 SF level increased on average by 9% per year and by 67% over the entire follow-up period


SF Level ≥800 ng/mL Associated with Occurrence of Morbidity

SF ≤300 ng/mL

100%

0%

SF >300 to <800 ng/mL

47.1%

52.9%

SF ≥800 ng/mL

0%

100%

At least 1 morbidity

No

Yes

SF ≤300 ng/mL

100%

0%

SF >300 to <800 ng/mL

94.1%

5.9%

SF ≥800 ng/mL

40.7%

59.3%

MulEple morbidity

No

Yes

Pearson Chi-‐square, P = .001 Fisher’s exact, P = .001

Pearson Chi-‐square, P = .001 Fisher’s exact, P = .001


Iron Chelation Studies in NTDT

Taher AT, et al. Am J Hematol. 2013;88:409-415.

Drug Disease Type Doses Tested Study Types Largest N

Deferasirox Beta-thalassaemia intermedia

10 or 20 mg/kg/d Prospective, single-arm, open- label

11

Deferiprone Beta-thalassaemia intermedia HbE/beta-thalassaemia HbH disease

25, 50, or 75 mg/kg/d

Prospective, single-arm or control-matched, open-label Case study

30

Desferrioxamine Beta-thalassaemia intermedia

150 mg/kg over 24 hours 3 days each at 20, 50, 60, 80, and 100 mg/kg/d

Prospective, placebo-controlled, crossover Prospective, single-arm, open-label

10

Until recently, iron chelation therapy was usually overlooked in NTDT; studies were small

Iron Chelation Therapy

•  Subcutaneous desferrioxamine – 1st iron chelator studied in patients with NTDT – Optimal dosage, duration, and administration

interval not clear – Adherence limited because of pain and

inconvenience •  Oral deferiprone

– Limited study, mixed results on serum ferritin level and liver iron concentration

Taher A, et al. Guidelines for the Management of Non-Transfusion-Dependent Thalassaemia (NTDT). 2013. Thalassaemia International Federation.

THALASSA—Deferasirox in NTDT

1. Taher AT, et al. Blood. 2012;120:970-977. 2. Taher AT, et al. Am J Hematol. 2013 (in press). Study scheme graphic courtesy of Dr. Taher.

•  Multinational, prospective, randomized, placebo-controlled study1

•  Primary objective: absolute change in LIC1

Screening Randomization Completed Core Study (Week 52)

Completed Extension Study2

(Week 104)

339 166 148 130

EXTENSION

LIC 3–15: ≤10 mg/kg/day

LIC >15: ≤20 mg/kg/day

Screening (28 days)

Randomize NTDT paEents (2:1 deferasirox/

placebo)

Deferasirox 5 mg/kg/day

Deferasirox 10 mg/kg/day

Placebo 5 mg/kg/day

Placebo 10 mg/kg/day

52 weeks 24 weeks

CORE

LIC <3:Interrupt

104 weeks

DFX

LIC was measured by MRI every 6 months SF was measured monthly

Patients (N)

THALASSA Results1,2

1. Taher AT, et al. Blood. 2012;120:970-977. 2. Taher AT, et al. Presented at: 18th Congress of the European Hematology Association, 2013. Abstract S1171. 3. Taher AT, et al. Am J Hematol. 2013;88:503-506. Slide courtesy of Dr. Taher.

•  Rate of adverse events similar between deferasirox and placebo groups1

• Deferasirox 5 mg or 10 mg better than placebo in beta-thalassaemia intermedia, HbE/beta-thalassaemia, and HbH disease3

Core study Extension study

Placebo/deferasirox: median dose = 14.0 mg/kg/day

Deferasirox extension: median dose = 10.8 mg/kg/day

Deferasirox core + extension: median dose = 9.5 mg/kg/day

−10

−8

−6

−4

−2

0

2

Baseline 6 12 18 24

Mea

n A

bsol

ute

Cha

nge

in

LIC

(mg

Fe/g

dry

wt)

Time (months)

Deferasirox any dose Placebo/deferasirox any dose

LIC and SF Thresholds for DFX

•  Good correlation between SF and LIC across treatment groups in THALASSA

•  Corresponding SF thresholds identified through (ROC) analysis

LIC SF Level Initiation1, 2 5 mg Fe/g dry weight 800 ng/mL Discontinuation1, 2 3 mg Fe/g dry weight 300 ng/mL Dose escalation2 7 mg Fe/g dry weight 2000 ng/mL*

1. Taher A, et al. Guidelines for the Management of Non-Transfusion-Dependent Thalassaemia (NTDT). 2013. Thalassaemia International Federation. 2. Taher AT, et al. Presented at: 18th Congress of the European Hematology Association, 2013. Abstract S1171.

*A conservative threshold proposed on the drug label; ROC analysis found that using SF levels between 1700 and 2000 ng/mL results in 100% appropriate dose escalation and 0% risk for over-chelation. Abbreviations: DFX, deferasirox; LIC, liver iron concentration; ROC, Receiver Operating Characteristics; SF, serum ferritin.

Deferasirox

•  Approved by the FDA on January 23, 2013 as first-line therapy for iron overload in patients age ≥10 years with NTDT syndromes

•  Approved by European Medicines Agency on November 16, 2012 for chronic iron overload requiring chelation therapy when desferrioxamine is contraindicated or inadequate in patients 10 years and older with NTDT syndromes


TIF Recommendations— Treatment and Monitoring Algorithm


Thalassaemia International Federation (TIF) developed separate guidelines for NTDT to increase global awareness of the monitoring and management requirements of NTDT overall

NTDT ≥10 YEARS (≥15 years in deletional haemoglobin H disease)

LIC ≥5 (SF ≥800)

Yes

DFX 10 mg/kg/day

LIC after 6 months >7 (SF >1500–2000) and <15% decrease from

baseline

No

DFX 20 mg/kg/day

LIC ≤3 (SF ≤300)

Discontinue DFX

LIC Q 1–2 years

SFQ 3 months

TIF Recommendations— Iron Overload Assessment in NTDT

•  Assessment in all NTDT patients age ≥10 years (age threshold of 15 years used in patients with deletional HbH disease)

•  Assessment of LIC every 1−2 years, preferably by MRI

•  Assessment of SF level every 3 months; primary measure when LIC not available

•  LIC supersedes SF level when both measures available


TIF Recommendations—Treatment

•  Iron chelation therapy with deferasirox in patients age ≥10 years

•  LIC supersedes SF level when both measures

are available

Measure Initiation Threshold

Discontinuation Threshold

LIC ≥5 mg Fe/g dry weight

3 mg Fe/g dry weight

SF level ≥800 ng/mL 300 ng/mL


TIF Recommendations— Dosing and Monitoring

•  Starting dose: 10 mg/kg/day •  LIC assessments 6 months after initiation, every

6−12 months thereafter •  Concomitant SF measurements every 3 months •  Dose escalation to 20 mg/kg/day after 6 months if

–  LIC >7 mg Fe/g dry weight (or SF level reaches 1500−2000 ng/mL) AND

–  LIC reduction <15% •  LIC supersedes SF level when both

measurements available


TIF Recommendations— Safety, Monitoring, and Other Considerations

•  Safety and related dose modifications follow standard guidelines for transfusion-dependent beta-thalassaemia major

•  Encourage tea consumption, which might decrease absorption of iron from the gut

•  When frequent blood transfusions required for sustained durations of time, manage iron overload as you would for transfusion-dependent beta-thalassaemia major


Conclusions

•  NTDT describes several distinct thalassaemia syndromes that do not require regular transfusions for survival

•  Iron overload in NTDT arises from inefficient erythropoiesis and intestinal absorption, and iron accumulates in the liver

•  TIF recommends regular iron assessments in patients age ≥10 years

•  Patients should begin iron chelation therapy with deferasirox, at a starting dose of 10 mg/kg/day, when LIC reaches 5 mg Fe/g dry weight or SF level reaches 800 ng/mL or higher

•  Dose escalation to 20 mg/kg/day should occur after the first 6 months if:

–  LIC >7 mg Fe/g dry weight (or SF level reaches 1500−2000 ng/mL) AND

–  LIC reduction <15%

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