Clinical Case: Managing Iron Overload in a Patient with Transfusion-Independent Thalassaemia Intermedia Ali T. Taher, MD Professor Department of Internal Medicine American University of Beirut Medical Center Beirut, Lebanon 1

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 2 2

Decision Point 1 What 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 1 What 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

Serum Ferritin vs LIC Measurement by R2 MRI in Patients with TI 10,000 Linear TI 9000 TM 8000 Linear TM 7000 6000 Serum Ferritin Level (ng/mL) 5000 4000 3000 2000 1000 Moreover, in cross sectional studies, it has been found that patients with thalassemia intermedia have ferritin levels lower than those of thalassemia major patients with the same LIC. This may be attributed to the different mechanisim of iron overload in both populations. Where thalassemia major patients develop iron overload due to repeated blood transfusions, non transfused patients with thalassemia intermedia develop iron overload secondary to chronic anemia and hypoxia which result increased intestinal iron absorption and release from the RES (thus depleting macrophage ferritin). 5 10 15 20 25 30 35 40 45 50 LIC (mg Fe/g dry weight) LIC correlated with serum ferritin levels in patients with TI (R = 0.64; P <.001) Abbreviations: LIC, liver iron concentration; TI, thalassaemia intermedia; TM, thalassaemia major. With permission from Taher A, et al. Haematologica. 2008;93:1584-1586. 5 5

LIC Measurement by R2 MRI in TI vs TM LIC Calculated from the Equations of the Plots of LIC vs Serum Ferritin 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 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) 7 7

Decision Point 2 What 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 2 What 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 20 mg/kg (r = .81) 60 mg/kg 40 mg/kg (r = .79) 60 mg/kg (r = .82) 10 40 mg/kg Urinary Iron (mg/24h) 5 20 mg/kg 5 10 15 Age (Years) 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.

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 12 12

Decision Point 3 What 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 3 What 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 values Baseline 12 months P-value Serum 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 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 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 Mean cardiac T2* and LVEF (both normal at baseline), serum creatinine, and cystatin C did not significantly change after 12 months of treatment with deferasirox 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).

Deferasirox for Nontransfusional Iron Overload in 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).

LIC (mg Fe/g dry weight) Effect of Deferasirox on Serum Ferritin and LIC in Patients with TI and Nontransfusional Iron Overload Serum ferritin at baseline Serum ferritin at 1 year Serum ferritin at 2 years LIC at baseline LIC at 1 year LIC at 2 years 1000 2000 3000 Serum Ferritin Levels (ng/mL) Patients 40 30 LIC (mg Fe/g dry weight) 20 10 Patients 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 With permission from 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 Ladis V, et al. Haematologica. 2009;94(suppl 2):509(abstr 1279).

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.

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 20 20

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 21 21