Clinical Case: Managing Iron Overload in a

Patient with Transfusion-Independent Thalassaemia

Intermedia

Ali T. Taher, MD

ProfessorDepartment of Internal Medicine

American University of Beirut Medical CenterBeirut, Lebanon

Patient Presentation

• 26-year-old fisherman of Mediterranean origin

• Diagnosed with thalassaemia intermedia at age 3 years– Chief symptoms were pallor, mild anaemia, and mild

splenomegaly

• Transfused once during childhood, before splenectomy

• Referred for evaluation of iron overload

• Physical exam nonrevealing

• Haemoglobin level 9.6 g/dL

• Steady-state serum ferritin level 520 ng/mL

Decision Point 1What Is the Best Next Step?

a. Perform liver iron concentration measurement using MRI

b. Send patient home, since transfusion history is insignificant

c. Reassure patient, since ferritin level is relatively low

d. Perform liver iron concentration measurement using biopsy

Decision Point 1What Is the Best Next Step?

a. Perform liver iron concentration measurement using MRI

CORRECT: Noninvasive; validated in thalassaemia intermedia patients; allows longitudinal follow-up

b. Send patient home, since transfusion history is insignificant

INCORRECT: Transfusion-independent thalassaemia intermedia patients are at risk of iron overload secondary to increased intestinal absorption and ineffective erythropoiesis

c. Reassure patient, since ferritin level is relatively low

INCORRECT: Serum ferritin is unreliable and underestimates iron burden in thalassaemia intermedia

d. Perform liver iron concentration measurement using biopsy

INCORRECT: Invasive; risk of sampling error; inadequate standardization between labs; follow-up difficult

1000

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0 5 10 15 20 25 30 35 40 45 50

LIC (mg Fe/g dry weight)

Ser

um

Fer

riti

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evel

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L)

TI

TM

Linear TI

Linear TM

Abbreviations: LIC, liver iron concentration; TI, thalassaemia intermedia; TM, thalassaemia major.With permission from Taher A, et al. Haematologica. 2008;93:1584-1586.

0

LIC correlated with serum ferritin levels in patients with TI (R = 0.64; P <.001)

Serum Ferritin vs LIC Measurement by R2 MRI in Patients with TI

LIC Measurement by R2 MRI in TI vs TM

Serum Ferritin (μg/L)

LIC (mg Fe/g dry wt)

In TM In TI

500 2.7 5.8

1000 5.4 11.6

1500 8.2 17.4

2000 10.9 23.2

LIC Calculated from the Equations of the Plots of LIC vs Serum Ferritin

• Extrapolating from the above table: when LIC = 7 mg Fe/g dry wt → serum ferritin is 604 μg/L in patients with TI

• LICs in patients with TM were not significantly different from values in patients with TI, whereas serum ferritin levels were statistically different between TI and TM

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

Case Continues

• Patient’s liver iron concentration on R2 MRI was 11 mg Fe/g dry weight

• Patient also underwent MRI T2* of the heart to evaluate for cardiac iron overload– Cardiac T2* = 36 ms (normal >20 ms)

Decision Point 2What Is the Best Next Step?

a. Repeat cardiac MRI T2* because it must be wrong

b. Repeat liver MRI periodically and start iron chelation therapy when LIC >15 mg Fe/g dry weight

c. Start iron chelation therapy with desferrioxamine

d. Initiate phlebotomy

Decision Point 2What Is the Best Next Step?

a. Repeat cardiac MRI T2* because it must be wrong

INCORRECT: Cardiac iron overload may be absent despite significant hepatic iron overload in patients with thalassaemia intermedia

b. Repeat liver MRI periodically and start iron chelation therapy when LIC >15 mg Fe/g dry weight

INCORRECT: Current recommendation in thalassaemia intermedia is to start chelation at LIC >7 mg Fe/g dry weight

c. Start iron chelation therapy with desferrioxamine

CORRECT: Proven effective and safe in thalassaemia intermedia

d. Initiate phlebotomy

INCORRECT: Patient has advantage of being transfusion-independent; phlebotomy will induce anaemia and mandate later transfusion

Iron Overload and Desferrioxamine Chelation Therapy in Thalassaemia Intermedia

• 6-month trial of 12-hour infusion of desferrioxamine in 10 transfusion-independent thalassaemia intermedia patients

• To determine optimal dosage for iron elimination, 5 regimens were administered each day for 3 consecutive days – 20, 40, 60, 80, and 100 mg/kg/day

– Maximum dose not exceeding 2 g/day

• Significant lowering of serum ferritin after 6 months, with tolerable safety profile

Cossu P, et al. Eur J Pediatr. 1981;137:267-271.

Urinary Iron Excretion by Dose of Desferrioxamine and Age of Patients with

Thalassaemia Intermedia

0

40 mg/kg

20 mg/kg

• Significant urinary iron excretion (UIE) after 12 hours of continuous desferrioxamine (except in patients aged <1 year)

• In some patients, substantial UIE despite modest serum ferritin levels

• Serum ferritin levels of no value in predicting UIE

With permission from Cossu P, et al. Eur J Pediatr. 1981;137:267-271.

5 10 15

Age (Years)

60 mg/kg

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10

Uri

na

ry I

ron

(m

g/2

4h

)

20 mg/kg (r = .81)

40 mg/kg (r = .79)

60 mg/kg (r = .82)

Case Continues

• After 6 months of desferrioxamine therapy the patient was re-evaluated using liver R2 MRI

– LIC = 10.5 mg Fe/g dry weight

• Patient’s wife admitted he was skipping most of his doses because the idea of carrying a pump around at his age created major discomfort

Decision Point 3What Is the Best Next Step?

a. Increase desferrioxamine dose

b. Shift the patient to deferasirox

c. Decrease desferrioxamine dose

d. Send patient to counseling

Decision Point 3What Is the Best Next Step?

a. Increase desferrioxamine dose

INCORRECT: The patient is noncompliant, and safety issues will ensue

b. Shift the patient to deferasirox

CORRECT: Given patient’s dissatisfaction with infusion treatment, an oral chelator seems a more promising alternative than continuing on desferrioxamine

c. Decrease desferrioxamine dose

INCORRECT: The patient’s noncompliance is not related to nontolerance (ie, side effects) but rather psychosocial burden

d. Send patient to counseling

INCORRECT: No current evidence on efficacy

Reduction in Iron Burden with Deferasirox at Year 1 in Patients with TI

Mean cardiac T2* and LVEF (both normal at baseline), serum creatinine, and cystatin C did not significantly change after 12 months of treatment with deferasiroxMean cardiac T2* and LVEF (both normal at baseline), serum creatinine, and cystatin C did not significantly change after 12 months of treatment with deferasirox

Mean values Baseline 12 months P-valueSerum ferritin, µg/L 2030 ± 1340 1165 ± 684 .02

Liver T2, ms 20.1 ± 4.1 23.7 ± 6.2 .01

Liver T2*, ms 3.4 ± 3.0 4.4 ± 3.0 .02

Cardiac T2*, ms 38.9 ± 5.9 39.8 ± 4.5 .64

LVEF, % 66.3 ± 8.1 66.9 ± 7.9 .76

Aspartate aminotransferase, U/L 64.8 ± 29.6 42.5 ± 18.1 .04

Alanine aminotransferase, U/L 63.5 ± 29.5 36.5 ± 17.6 .02

Serum creatinine, mg/dL 0.67 ± 0.15 0.75 ± 0.19 .07

Cystatin C, mg/L 0.98 ± 0.23 1.13 ± 0.27 .094

Deferasirox can effectively reduce iron burden in patients with TI Deferasirox can effectively reduce iron burden in patients with TI

Abbreviations: LVEF, left ventricular ejection fraction; TI, thalassaemia intermedia.With permission from Voskaridou E, et al. Haematologica. 2009;94(suppl 2):79(abstr 0204).Abbreviations: LVEF, left ventricular ejection fraction; TI, thalassaemia intermedia.With permission from Voskaridou E, et al. Haematologica. 2009;94(suppl 2):79(abstr 0204).

Deferasirox for Nontransfusional Iron Overload in Patients with

Thalassaemia Intermedia

● 11 patients with thalassaemia intermedia

– 6 male, 5 female

– Mean age 31.7 years

– 10 splenectomized

● Deferasirox regimen

– 1 year (n = 11), 2 years (n = 4)

– 10 mg/kg/day (n = 7), 20 mg/kg/day (n = 4)

– Dose adjustment after first year

● 11 patients with thalassaemia intermedia

– 6 male, 5 female

– Mean age 31.7 years

– 10 splenectomized

● Deferasirox regimen

– 1 year (n = 11), 2 years (n = 4)

– 10 mg/kg/day (n = 7), 20 mg/kg/day (n = 4)

– Dose adjustment after first year

Ladis V, et al. Haematologica. 2009;94(suppl 2):509(abstr 1279).

Effect of Deferasirox on Serum Ferritin and LIC in Patients with TI and Nontransfusional Iron Overload

Serum ferritin at baselineSerum ferritin at 1 yearSerum ferritin at 2 years

LIC at baselineLIC at 1 yearLIC at 2 years

With permission from Ladis V, et al. Haematologica. 2009;94(suppl 2):509(abstr 1279).

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PatientsPatients

• 1 patient, who was noncompliant, did not show decrease of iron overload and was excluded from graph

• Changes in LIC and ferritin levels were related to deferasirox dose, but even patients with severe iron load, treated with 10 mg/kg/day, responded well

Ladis V, et al. Haematologica. 2009;94(suppl 2):509(abstr 1279).

Safety of Deferasirox During Treatment of up to 2 Years

• Treatment was well tolerated – No serious adverse events were noted

• Creatinine and cystatin C levels did not change during treatment

• Transaminase levels significantly decreased in year 1 (P = .0002) and year 2 (P = .024) of treatment– This improvement probably due to decreased hepatic

siderosis

Ongoing Clinical Evaluation of Deferasirox

• Prospective, randomized, double-blind, placebo-controlled triala

• Patients (age ≥10 years) with non–transfusion-dependent β-thalassaemia (no transfusion required within 6 months prior to the study)

• 2 doses: 5 mg/kg/day and 10 mg/kg/day

• Screening 4 weeks; treatment period 52 weeks

• Primary objective– To assess the efficacy of deferasirox in patients with

non–transfusion-dependent β-thalassaemia, based on the change in LIC from baseline after 1 year of treatment compared with placebo-treated patients

aAli T. Taher, MD, principal investigator; Study ID ICL670A2209.aAli T. Taher, MD, principal investigator; Study ID ICL670A2209.

Case Continues

• Patient was shifted to deferasirox 20 mg/kg/day

• Over the next 2 years his liver R2 MRI measurements improved – Year 1 LIC = 5.3 mg Fe/g dry weight

– Year 2 LIC = 2.9 mg Fe/g dry weight

Conclusions

• Iron overload occurs in patients with thalassaemia intermedia in the absence of blood transfusions

• Serum ferritin underestimates the severity of iron overload in patients with thalassaemia intermedia– Hence, the use of R2 MRI to measure LIC is favored

• Initial results of the oral iron chelator deferasirox indicate that it can effectively and safely reduce iron burden in this patient population