Iron Chelation in

Thalassaemia
Syndromes
Dr. Mohammed Adil Akhter
Member, Medical Advisory Board, Thalassaemia Federation of Pakistan
Thalassaemia specialist, Amina Bashir Memorial Thalassaemia Center
Consultant, Pediatric Hospitalist, Shaukat Khanum Memorial Cancer Hospital
Disclosures

THIS PRESENTATION DOES NOT HAVE I HAVE NO FINANCIAL INTERESTS OR

ANY CONFLICTS OF INTEREST AFFILIATIONS RELATED TO THE
CONTENT PRESENTED
Iron Chelation

Non-transfusion Transfusion
Dependent Dependent
Thalassaemia Thalassaemia
References
Iron Chelation in
Non-Transfusion
Dependent
Thalassaemia
 Correlation between severity of chronic anemia and primary iron
overload has been seen in NTDT

Iron Overload in NTDT Increased release of recycled iron from the reticuloendothelial system
results in preferential portal and hepatocyte iron loading with relative
low levels of serum iron

Ineffective Erythropoiesis
Chronic Anemia / Hypoxia

↑ Erythropoietin ↓ Hepcidin

↑ Ferroportin ↑ Release of recycled iron from

↑ Intestinal iron absorption the reticuloendothelial system

Iron Overload
↑ Liver iron concentration
↓ than expected serum ferritin
level
 Iron deposition in NTDT

Cardiac siderosis is not a
Preferentially liver siderosis
major concern in NTDT
Hepatocellular carcinoma
has been seen in viral
hepatitis negative patients
with NTDT and iron
overload

Silent brain infarcts,

Renal glomerular and Iron overload and bone
decreased neuronal function
tubular dysfunction seen as marrow stress is associated
and cerebral vessel disease
proteinuria has been with hematological
is seen in NTDT patients
reported in NTDT malignancies in NTDT
with iron overload
Ferritin levels in NTDT

Ferritin level ≥ 800ng/ml or liver iron concentration of ≥ 5mg Fe/g dry weight was
the threshold after which patients became at risk of developing morbidity

Ferritin values ≤ 300ng/ml or liver iron concentration of ≤3mg Fe/g dry weight did
not develop any morbidity

Spot measurements of serum ferritin in NTDT may underestimate iron overload

Serum Ferritin of 1000ng/ml would be projected to be a liver iron concentration of

9 Fe/g dry weight in TDT and 15 Fe/g dry weight in NTDT
Management of Iron overload in NTDT

Tea and Curcumin (turmeric) is linked to decreasing iron absorption, decreased

iron burden and oxidative stress

For resource limited settings – serum ferritin best option

Ferriscan R2-MRI scan is a reliable tool for assessing iron overload

T2* MRI of the liver does not correlate well with liver iron concentration because
of the heterogenous deposition of iron in the liver
Iron chelator approved for NTDT

Deferasirox (DFX) is the only FDA approved first line therapy for the
management of iron overload in NTDT patients 10yrs and above

Film coated tablet (FCT) can be crushed and sprinkled on soft food
and does not contain lactose
 Interrupt DFX
SF ≥800
when SF ≤300

SF every 3-6
DFX
months SF every 3-6 mths
NTDT ≥ 10 years (FCT 7mg/kg/day)
Ferriscan q12-
DT 10mg/kg/day)
24months

SF <800

Dose Escalation
 DFX dose escalation after 1 month
Baseline SF ≥800 to ≤1500 >1500 to ≤3000 >3000
Dose modification None Escalate to Escalate to
FCT FCT
11.5mg/kg/day 14mg/kg/day
DT DT
15mg/kg/day 20mg/kg/day
DFX dose escalation after 6 months
6-month SF ≥300 to ≤1500 >1500 to ≤3000 >3000
Dose modification Same dose Escalate to Escalate to
Maximum Maximum Maximum
FCT FCT FCT
7mg/kg/day 14mg/kg/day 21.5mg/kg/day
DT DT DT
10mg/kg/day 20mg/kg/day 30mg/kg/day
Iron chelation
in Transfusion
Dependent
thalassaemia
Aims of iron chelation in TDT
Preventive therapy Maintain safe levels of body iron at all times, by maintaining an iron balance

Rescue therapy Remove excess iron storded in the body

Emergency therapy Urgently intensify iron chelation in iron induced heart failure

Dose adjustment Avoiding under-chelation and over-chelation

Adherence to prescribed regimen as intermittent high dose iron chelation can bring down the serum ferritin but
Adherence to therapy does not protect the body from labile iron
Iron Chelators

Deferoxamine Deferiprone Deferasirox

(DFO) (DFP) (DFX)
• 1st line for TDT • Indicated >3yrs • 1st line when
in children 2- DFO
6yrs contraindicated
or inadequate
• 1st line in TDT in
children >6yrs
 DFO

• 20-60mg/kg 5-7 days a week

• Children’s dose upto 40mg/kg
• Over 8-12hrs

DFP
Dosages • 75 – 100mg/kg/day TID
• 75 – 100mg/kg/day BID Twice a day formulation
(TAD)

DFX

• (DT) 20-40mg/kg/day OD
• (FCT) 14-28mg/kg/day OD
 Contraindications

DFO DFP DFX

• Pregnancy although • Pregnancy • Pregnancy
has been used in 3rd • Neutropenia or risk • Hypersensitivity
trimester of cytopenia • Creatinine clearance
• Hypersensitivity (hydroxyurea) < 60ml/min
• Hypersensitivity • Hepatic impairment
(Henoch Schonlein
Purpura)
 Precautions

DFO DFP DFX

• Audiometry yearly
• Eye exam yearly
• Fevers – stop DFO (yersinia,
klebsiella)
• Renal failure, diminishing
renal function
• ANC before start and then
weekly for the first year than
every 2 – 4 weeks after that
• Avoid concommitent use of
drugs with can potentiate
neutropenia
• Monitor for arthralgia /
arthropathy
• Stop if febrile
• Creatinine for weekly for a
month on start or escalation
of dose
• Monitor proteinuria
• Concommitent use of
ulcerogenic drugs
• Liver functions
Preventive
therapy
Start chelation before iron
overload builds up or
irreversible damage occurs

Hold DFO when SF reaches

1000ng/ml due to fear of
toxicity
Rescue therapy
• Increase daily dose of chelation
• Switch chelators to ensure compliance
• Rotate or combine chelators
• DFO monotherapy is effective in producing a negative iron balance in
sufficient doses, duration and frequency
• Dose escalation 40mg/kg/day (FCT 28mg/kg/day)
• DFP monotherapy at 75mg/kg/day may be effective in 1/3 patients,
others may require 100mg/kg/day
• “True” combination therapy may be useful
 Rescue therapy in mild cardiac iron
overload (T2* 10-20ms)

DFO, DFP and DFX monotherapy may all be effective at decreasing iron overload when given without
interruption

Optimal doses are required

May take several years of consistent use to normalize

Combination of DFO and DFP should be considered

Rescue therapy in moderate cardiac iron
overload (T2* 10-20ms)

Continuous DFO+DFP or
24hr DFO and DFO+DFX can
high dose DFX be used
Patients with heart failure – Emergency
therapy

Continuous 24hr
DFP or DFX in
DFO, reversal can
optimal escalated
happen within
doses
weeks
Adjustment Cases of toxicity from
over-chelation even at
of chelator SF > 500ng/ml

doses
Summary

Chelation differs in NTDT vs TDT

Always ensure that there is a shared goal decided with

patients for chelation

Optimize doses of chelators