Iron overload in thalassemia major

and sickle cell disease

Dr Fleur Samantha Benghiat

Brussels, Belgium

21.11.2015

DISCLOSURES

None

THIS TALK IS APPLICABLE FOR :

Definite Probable

Thalassemia’s X

Sickle cell disease X

Membrane disorders (e.g. sferocytosis)

Enzym defects (e.g. PKD, G6PD)

PNH

Other forms of hemolytic disease

LEARNING OBJECTIVES

1. Red blood cells (RBC)

Life of a RBC

Hemoglobin

Sickle cell disease

Thalassemia Major

Chronic blood transfusion

2. Iron

Distribution of iron

Iron overload

Iron toxicity

Associated complications

Diagnosis

Treatment: Iron chelators

RED BLOOD CELLS

BONE MARROW ERYTHROPOIESIS

Red blood cells =

Erythrocytes

O2 RBC FUNCTION

= Oxygen transportation

HEMOGLOBIN

O2

O2 O2

O2

Oxygen binds to iron on the hemoglobin molecule

Each red blood cell contains several thousand hemoglobin molecules

b-chain

b-chain a-chain

a-chain

THALASSEMIA MAJOR : NO b-CHAIN PRODUCTION

BONE MARROW INEFFECTIVE ERYTHROPOIESIS

SEVERE ANEMIA

IRON OVERLOAD

IRON ABSORPTION +++ MARROW EXPANSION

b-chain a-chain

SICKLE CELL DISEASE : MUTATION ON THE b-CHAIN

SICKLE CELL

RBC Destruction

ANEMIA

Vaso-occlusion

Chronic Organ Damage

SICKLE CELL DISEASE : TREATMENT

Treatment

Vaso-occlusion prevention

Avoid cold, dehydration,…

Management of pain

Hydroxyurea

Transfusions

Only for severe complications

IRON OVERLOAD

LEARNING OBJECTIVES

1. Red blood cells (RBC)

Life of a RBC

Hemoglobin

Sickle cell disease

Thalassemia Major

Chronic blood transfusion

2. Iron

Distribution of iron

Iron overload

Iron toxicity

Associated complications

Diagnosis

Treatment: Iron chelators

IRON : NORMAL DISTRIBUTION

STORAGE = 1000mg

Skin Gut

Menstruation Pregnancy

Pietrangelo A. NEJM 2004; 350:2383-2397

Total body iron = 4000 mg

Transferrin

IRON OVERLOAD

21.11.2015

Iron In

200mg/unit

STORAGE

No mechanism to excrete excess iron

CIRRHOSIS

Iron Chelator

Iron Out

Total body iron = 4000 mg

3U/month = 600mg/month 7,2 g/year

Pituitary → impaired growth, infertility

Thyroid → hypothyroidism

Heart → cardiomyopathy, heart failure

Liver → hepatic cirrhosis, cancer

Pancreas → diabetes mellitus

Gonads → hypogonadism

COMPLICATIONS OF IRON OVERLOAD

In the absence of treatment

Damages are inevitable

Lethal complications

IRON OVERLOAD MEASUREMENT

v

v

v American association for cancer research

v

v v

v

v v

↑ Ferritin ≠ ↑ Iron burden

BUT

↓ Ferritin = ↓ Iron burden

Liver Iron Concentration (LIC)

• LVEF measurement v

Liver and cardiac MRI (Magnetic Resonance Imaging)

MAGNETIC RESONANCE IMAGING (MRI)

= GOLD STANDARD

Heart

Liver

Before treatment After treatment

TREATMENT : WHAT IS CHELATION THERAPY?

Chelate

Chelator Iron Chelator

Toxic

Excretion Iron

With the courtesy of Dr Axelle Gilles

IRON CHELATION THERAPY IMPROVES

SURVIVAL IN THALASSAEMIA

Olivieri NF, et al. N Engl J Med. 1994;331:574-8

Well treated Ferritin < 2500

Poorly treated Ferritin > 2500

TREATMENT : AIM? WHEN TO START?

Prior transfusions

Evidence of chronic

iron overload

OR OR

After 120 mL/kg pRBC

(~ After 10-20 units)

Serum ferritin > 800 - 1000 μg/L1,2

(constantly)

OR

LIC ≥ 5 - 7 mg Fe/g dw1,2

Therapeutic

Goal3

• PREVENTION • Remove transfused iron

• RESCUE • Reduce the existing iron burden

• Slow, less efficient

• Damages often irreversible

1. Treating iron overload in patients with non-transfusion-dependent thalassemia. Taher AT et al. Am J Hematol. 88 : 409-415, 2013 2. Consequences and management of iron overload in sickle cell disease. Porter J, Garbowski M. Hematology Am Soc Hematol Educ Program. 2013:447-56 3. Porter J., Viprakasit V. Iron overload and chelation - Guidelines for the Management of Transfusion Dependent Thalassaemia, 3rd Edition (2014)

When to start chelation:

Property Deferoxamine Deferiprone Deferasirox

Usual dose

(mg/kg/day) 25–50 75–100 20–40

Route

sc, iv

(8–12 hours,

5 days/week)

Oral

3 times daily

Oral

Once daily

Half-life 20–30 minutes 3–4 hours 12–16 hours

Excretion Urinary, fecal Urinary Fecal

Adverse

effects

Local reactions,

Auditory,

Ocular,

Growth retardation,

Allergy

GI,

agranulocytosis,

neutropenia,

Arthralgia,

Liver enzymes ↑

GI,

rash,

creatinine level ↑

Indication Transfusional iron

overload

Iron overload in TM

when DFO is CI or

inadequate

Transfusional iron

overload

SCD: if DFO inadequate

TREATMENT : IRON CHELATING AGENTS

Adapted from Brittenham GM. N Engl J Med 2011;364:146

Side effect Frequency Management Recommendations

Nausea, vomiting Abdominal pain

15-26% Transient Evening, with or after food Divide dose / ↓ dose then ↑

• Renal and hepatic functions

1x/week (1st month) 1x/month • Urinanalysis 1x/month • Auditory and

ophtalmic testing 1x/year

Diarrhea (! Lactose) 5 – 20% Lactase / Loperamide /↓ dose

Rash 7-11% Transient Short course corticoids STOP - Start lower dose

Creatinine ↑ >33% 38% ↓ dose by 10mg/kg / STOP

Proteinuria 19% ↓ dose or STOP if >1mg/g creat

Liver enzyme ↑ 2 – 8% STOP - Start lower dose

Teratogenic in animals STOP before pregnancy

SIDE EFFECTS MANAGEMENT : DEFERASIROX

Transfusional iron overload and iron chelation therapy in thalassemia major and sickle cell disease. Marsella M et al. Hematol Oncol Clin North Am. 2014 Aug;28(4):703-27

Side effect Frequency Management Recommendations

Nausea, abd pain, diarrhea

3 – 25% 3%

Transient If not, Loperamide, ↓ dose

• Neutrophil count 1x/week

• Avoid other

neutropenia-inducing drugs

• Hepatic and renal functions

Neutropenia (500-1500/mm³)

7% STOP Neutro count 1x/d (> 1500) Re-Start with caution

Agranulocytosis (< 500/mm³)

2% STOP definitely, AB if infection G-CSF

Liver test ↑ 8% Transient If not, ↓ dose then ↑

Teratogenic in animals Contraception Stop before pregnancy

SIDE EFFECTS MANAGEMENT : DEFERIPRONE

Transfusional iron overload and iron chelation therapy in thalassemia major and sickle cell disease. Marsella M et al. Hematol Oncol Clin North Am. 2014 Aug;28(4):703-27

WHEN TO STOP CHELATION THERAPY?

Transfusion-dependent patients

NEVER STOP CHELATION

Dose reduction if ferritin levels <1000 mg/L1

Avoid overchelation

Transfusion-independent patients

Reduce dose if ferritin < 1000 mg/L

Stop chelation2

Ferritin ≤ 300 mg/L

LIC ≤ 3 mg Fe/g dw

1. Iron overload and chelation. Porter J, Viprakasit V. Guidelines for the management of transfusion dependent thalassemia, 3rd edition (2014) 2. Treating iron overload in patients with non-transfusion-dependentthalassemia. Taher AT et al. Am J Hematol. 88 : 409-415, 2013

CONCLUSION : ADHERENCE TO CHELATION THERAPY

Adherence = Success

Therapeutic alliance Doctor + Patient

Involvement of patients in decisions self-management

Reviews of results (MRI, ferritin levels…)

Administration

prefer oral

Side effects

Strict control

Monitoring Prevention

Dose adjustment

Transfusional iron overload and iron chelation therapy in thalassemia major and sickle cell disease. Marsella M et al. Hematol Oncol Clin North Am. 2014 Aug;28(4):703-27

SICKLE CELL DISEASE : TRANSFUSION THERAPY

Acute: simple transfusion Chronic: transfusion program

• Surgery (selected cases)

• Severe symptomatic anemia

Splenic sequestration

Severe or long-lasting aplastic crises

• Severe complications

Acute CNS stroke

Acute chest syndrome

Multiple-organ failure syndrome

• Prevention of severe complications

Prophylaxis against recurrent stroke

Prevention of 1st episode of stroke in high-risk

pediatric patients

• Hydroxyurea non-responders

• Severe chronic complications

Chronic pulmonary hypertension

Heart failure

Adapted from Stuart MJ et al. Lancet 2004;364:1343–1360; Vichinsky E. Semin Hematol 2001;38:2–4

Sickle cell disease

Transfusions

Starts later

Transfusion regime

Top up >< exchange

Sporadic >< chronic

Less increased iron absorption

Urinary iron loss (hemolysis)

Lower and later iron load

No effect on growth

Less cardiac and endocrine

involvement

Thalassemia major

Transfusions

1st year of life

Chronic transfusion

Hb > 9,5 – 10,5g/dL

Increased iron absorption

Higher and earlier iron load

Growth / sexual dvp

Liver overload by 10 yo

Extra-hepatic iron spread

Heart, endocrine glands…

IRON OVERLOAD ORGAN DAMAGE IN SCD AND TM

Transfusional iron overload and iron chelation therapy in thalassemia major and sickle cell disease. Marsella M et al. Hematol Oncol Clin North Am. 2014 Aug;28(4):703-27

IRON TOXICITY

FREE RADICALS OXIDATIVE DAMAGE

TISSUES IRON OVERLOAD

Loss of mitochondrial membrane potential

Loss of respiratory enzyme activities

Apoptosis Lipid peroxidation

Increased lysosomal fragility CELL DEATH – FIBROSIS

With the courtesy of Dr Axelle Gilles

INFECTIONS CANCER

Pituitary → LH, FSH, GH, ACTH

Para/Thyroid → TSH, T3, T4 – PTH, D-Vit, Ca, P

Heart → MRI T2*, LVEF, EKG

Liver → MRI T2*, abdominal echography

Pancreas → Glycemia, Oral Glucose Tolerance Test

Gonads → Estradiol, Progesteron, Testosteron

IRON OVERLOAD – WORK UP