1. Approaches to management of β-thalassemia intermedia Ali Taher, MD, PhD, FRCP American University of Beirut Medical Center

2. Agenda ● Overview of β- thalassemia intermedia (TI) ● Overview of TI complications ● Management of TI ● Splenectomy ● Transfusion ● Iron chelation therapy ● Hydroxycarbamide ● Other treatments ● Take home message

3. Introduction β-thalassemia Minor β-thalassemia Intermedia β-thalassemia Major Mild asymptomatic anemia Severe transfusion- dependent anemia variable Intermediate phenotype with variable clinical severity Musallam KM, et al. Cold Spring Harb Perspect Med. 2012; 2:a013482 It was previously thought that TI patients do not require treatment since their symptoms are mild Because thalassemia intermedia has such a variable phenotype, therapy must be tailored for each patient.

4. Pathophysiology ● The clinical sequelae of β-TI are due to three main persistent factors: ●Mildly affected patients may be asymptomatic until adult life ●Severely affected patients generally present between 2–6 years of age Ineffective erythropoiesis Massive erythroid marrow hypertrophy Chronic anemia Gastrointestinal iron absorption Iron overload Ineffective erythropoiesis Peripheral breakdown of red blood cells Gastrointestinal iron absorption Musallam KM, et al. Cold Spring Harb Perspect Med. 2012; 2:a013482

5. First attempt at understanding complications in TI vs TM Complication (% of patients affected) TITM LebanonItalyLebanonItaly (n = 37)(n = 63)(n = 40)(n = 60) Splenectomy90679583 Cholecystectomy8568157 Gallstones55631023 Extramedullary hemopoiesis202400 Leg ulcers203300 Thrombotic events282200 Cardiopathy*351025 Pulmonary hypertension † 50171011 Abnormal liver enzymes20225568 HCV infection733798 Hypogonadism538093 Diabetes mellitus3212.510 Hypothyroidism321511 Taher A, Isma’eel H, Cappellini MD. Blood Cells Mol Dis. 2006;37:12-20.HCV = hepatitis C virus. *Fractional shortening 30 mmHg; a well-enveloped tricuspid regurgitant jet velocity could be detected in only 20 patients, so frequency was assessed in these patients only.

6. Overview on Practices in Thalassemia Intermedia Management Aiming for Lowering Complication- rates Across a Region of Endemicity: the OPTIMAL CARE study ● Cross-sectional study of 584 TI patients from 6 comprehensive care centers in the Middle East and Italy Taher AT, Musallam KM, Karimi M, et al. Blood. 2010;115:1886-92. N = 12 S Daar N = 127 AT Taher KM Musallam N = 51 A El-Beshlawy N = 153 MD Cappellini N = 200 M Karimi N = 41 K Belhoul M Saned

7. The OPTIMAL CARE study: overall study population Parameter Frequency n (%) Age (years) < 18172 (29.5 ) 18–35288 (49.3) > 35124 (21.2) Male:female291 (49.8) : 293 (50.2) Splenectomized325 (55.7) Serum ferritin (µg/L) < 1,000376 (64.4) 1,000–2,500179 (30.6) > 2,50029 (5) Complications Osteoporosis EMH Hypogonadism Cholelithiasis Thrombosis Pulmonary hypertension Abnormal liver function Leg ulcers Hypothyroidism Heart failure Diabetes mellitus 134 (22.9) 124 (21.2) 101 (17.3) 100 (17.1) 82 (14) 64 (11) 57 (9.8) 46 (7.9) 33 (5.7) 25 (4.3) 10 (1.7) Treatment Frequency n (%) Hydroxyurea202 (34.6) Transfusion Never Occasional Regular 139 (23.8) 143 (24.5) 302 (51.7) Iron chelation None Deferoxamine Deferiprone Deferiprone + deferoxamine Deferasirox 248 (42.5) 300 (51.4) 12 (2.1) 3 (0.5) 21 (3.6) EMH = extramedullary hematopoiesis.Taher AT, Musallam KM, Karimi M, et al. Blood. 2010;115:1886-92.

8. Complications of β- TI ● Hypercoagulability and thrombosis ● Brain abnormalities ● Pulmonary hypertension ● Leg ulcers ● Extramedullary hematopoiesis ● Hepatocellular carcinoma ● Renal abnormalities ● Iron overload ● ……….… 4

9. TI complications increase with age Taher AT et al. Br J Haematol 2010;150:486–489 0 EMH Frequency (%) < 10 years11–20 years21–32 years>32 years 5 10 15 20 25 30 35 40 45 Leg ulcers Thrombosis PHT HF Cholelithiasis ALF DM Hypothyroidism Osteoporosis Hypogonadism 6.7 13.3 16.7 40.0 26.7 3.3 6.7 16.7 26.7 3.3 13.3 20.0 3.3 6.7 10.0 0 3.3 6.7 33.3 13.3 10.0 20.0 13.3 3.3 6.7 10.0 13.3 00 3.3 16.7 0 3.3 10.0 30.0 6.7 16.7 23.3 20.0 0 16.7 23.3 EMH, extramedullary hematopoiesis; PHT, pulmonary hypertension; HF, heart failure; ALF, abnormal liver function; DM, diabetes mellitus *statistically significant trend; † no splenectomy, HU, transfusion or chelation * * * * * * 120 TI, treatment-naïve † patients from Lebanon, Italy, Iran, Egypt, UAE and Oman

10. Transfusion therapy Musallam KM, et al. Cold Spring Harb Perspect Med. 2012; 2:a013482. Taher AT, et al. Br J Haematol. 2011;152:512–23.

11. ComplicationParameterRR95% CIp value EMHSplenectomy0.440.26–0.730.001 Transfusion0.060.03–0.09< 0.001 Hydroxyurea0.520.30–0.910.022 Pulmonary hypertensionAge > 35 years2.591.08–6.190.032 Splenectomy4.111.99–8.47< 0.001 Transfusion0.330.18–0.58< 0.001 Hydroxyurea0.420.20–0.900.025 Iron chelation0.530.29–0.950.032 Heart failureTransfusion0.060.02–0.17< 0.001 ThrombosisAge > 35 years2.601.39–4.870.003 Hb ≥ 9 g/dL0.410.23–0.710.001 Serum ferritin ≥ 1,000 µg/L1.861.09–3.160.023 Splenectomy6.593.09–14.05< 0.001 Transfusion0.280.16–0.48< 0.001 CholelithiasisAge > 35 years2.761.56–4.87< 0.001 Female1.961.18–3.250.010 Splenectomy5.192.72–9.90< 0.001 Transfusion0.360.21–0.62< 0.001 Iron chelation0.300.18–0.51< 0.001 Abnormal liver functionSerum ferritin ≥ 1,000 µg/L1.741.00–3.020.049 The OPTIMAL CARE study Occasionally/regularly transfused patients: 445/584 Taher AT, Musallam KM, Karimi M, et al. Blood. 2010;115:1886-92.

12. ComplicationParameterRR95% CIp value Leg ulcersAge > 35 years2.091.05–4.160.036 Splenectomy3.981.68–9.390.002 Transfusion0.390.20–0.760.006 Hydroxyurea0.100.02–0.430.002 HypothyroidismSplenectomy6.042.03–17.920.001 Hydroxyurea0.050.01–0.450.003 OsteoporosisAge > 35 years3.512.06–5.99< 0.001 Female1.971.19–3.270.009 Splenectomy4.732.72–8.24< 0.001 Transfusion3.101.64–5.85< 0.001 Hydroxyurea0.020.01–0.09< 0.001 Iron chelation0.400.24–0.680.001 HypogonadismFemale2.981.79–4.96< 0.001 Serum ferritin ≥ 1,000 µg/L2.631.59–4.36< 0.001 Transfusion16.134.85–52.63< 0.001 Hydroxyurea4.322.49–7.49< 0.001 Iron chelation2.511.48–4.260.001 The OPTIMAL CARE study Occasionally/regularly transfused patients: 445/584 Taher AT, Musallam KM, Karimi M, et al. Blood. 2010;115:1886-92. Transfusion therapy was protective for thrombosis, EMH, PHT, HF, cholelithiasis, and leg ulcers Transfusion therapy was associated with an increased risk of endocrinopathy

13. Transfusion ● Risk factors for alloimmunization : ● Minimally transfused and newly transfused patients ● Old age at first transfusion ● Ethnic and racial diverse population ● Splenectomy ● Allogeneic WBC within the transfusate Management : Fully phenotyped matched blood should be given Erythropoietin in combination with iron and folic acid Chou ST et al. Br J Haematol. 2012. [Epub ahead of print]

14. LIC Risk thresholds for development of complications in TI patients 1. Taher A, et al. Am J Hematol. 2010;85:288-90. 2. Origa R, et al. Haematologica. 2007;92:583-8. 3. Musallam KM, et al. Hematologica. 2011;96:1605-12. Normal liver iron level ● Pulmonary hypertension ● Hypothyroidism ● Hypogonadism ● Endocrine/bone complications RISK THRESHOLDS 3 ● Thrombosis ● Vascular complications ● Osteoporosis Mean age ± SD β-TI β-TM Taher et al. 2010 1 n Age (years) LIC (mg Fe/g dry wt) 19 32.8 ± 7.9 15.0 ± 7.4 19 33.0 ± 7.4 15.7 ± 9.9 Origa et al. 2007 2 n Age (years) LIC (mg Fe/g dry wt) 22 20.0 ± 5.0 11.3 ± 6 22 23.0 ± 10.0 11.8 ± 7 1.8 mg/g dry wt 6 mg/g dry wt 7 mg/g dry wt 9 mg/g dry wt

15. ICT in NTDT ● Chelation therapy is advisable if liver iron concentration (LIC)  5 mg/g dw ● Direct assessment is desirable; biopsy or MRI ● If LIC measurement is not available, serum ferritin is a reasonable alternative, taking into consideration that serum ferritin may underestimate LIC in TI

16. SF chelation thresholds 5 mg/g dw 1000 ng/ml 53% 800 ng/ml 70% NTDT IOL threshold A serum ferritin of 800 ng/ml increases the sensitivity of detecting thalassemia intermedia patients with iron overload

17. Investigational use of deferasirox versus placebo: THALASSA study design Efficacy and safety of deferasirox versus placebo in NTDT patients Inclusion Male/female Aged ≥10 years with NTDT LIC ≥5 mg Fe/g dw Serum ferritin >300 ng/mL Exclusion Regular transfusion requirement Chelation therapy prior to entry HbS thalassemia variants Impaired renal/liver function Change in LIC from baseline after 1 year of treatment compared with placebo-treated patients Taher AT et al. Blood 2012;120(5):970-7

18. –1.95 –3.80 0.38 Placebo 5 mg/kg/day10 mg/kg/day Starting deferasirox dose: 1 0 – 1 – 2 – 3 – 4 LIC change from baseline to Week 52 least squares mean (mg Fe/g dw) P=0.001* P<0.001* P=0.009 *Adjusted P-value with Dunnett’s method Taher AT et al. Blood 2012;120(5):970-7 Effect of deferasirox on LIC in THALASSA Study met its primary endpoint

19. Effect of deferasirox on serum ferritin in THALASSA –121 –222 115 Placebo 5 mg/kg/day10 mg/kg/day Starting deferasirox dose: Serum ferritin change from baseline to Week 52 least squares mean (ng/mL) P<0.001* P=0.088 150 100 50 0 –50 –100 –150 –200 –250 *Adjusted P-value with Dunnett’s method Taher AT et al. Blood 2012;120(5):970-7

20. Adverse events, n (%) Deferasirox 5 mg/kg/day n=55 Deferasirox 10 mg/kg/day n=55 Placebo overall n=56 Nausea3 (5.5)4 (7.3)4 (7.1) Skin rash2 (3.6)5 (9.1) 1 (1.8) Diarrhea05 (9.1)1 (1.8) Headache2 (3.6)1 (1.8)2 (3.6) Upper abdominal pain2 (3.6)1 (1.8)0 Abdominal pain1 (1.8) Most common drug-related adverse events in THALASSA Taher AT et al. Blood 2012;120(5):970-7

21. Splenectomy ● Indications for splenectomy ● Poor growth and development ● Increased transfusion demand ● Symptomatic splenomegaly ● Hypersplenism (leukopenia, thrombocytopenia) Musallam KM, et al. Cold Spring Harb Perspect Med. 2012; 2:a013482. Taher AT, et al. Br J Haematol. 2011;152:512–23.

22. Splenectomy ● Splenectomy increases chances of: ● Thrombosis ● Silent brain infarcts ● Extramedullary hematopoiesis ● Pulmonary hypertension ● Leg ulcers ● Iron related endocrinopathies ● Infection Musallam KM, et al. Cold Spring Harb Perspect Med. 2012; 2:a013482. Taher AT, et al. Br J Haematol. 2011;152:512–23.

23. Thromboembolic events in a large cohort of TI patients ● Patients (N = 8,860) ● 6,670 with TM ● 2,190 with TI ● 146 (1.65%) thrombotic events ● 61 (0.9%) with TM ● 85 (3.9%) with TI ● Risk factors for thrombosis: ● age (> 20 years) ● previous thromboembolic event ● family history ● splenectomy Taher A, Isma'eel H, Mehio G, et al. Thromb Haemost. 2006;96:488-91. DVT = deep vein thrombosis; PVT = portal vein thrombosis; STP = superficial thrombophlebitis. Thromboembolic events (%) Type of event

24. 1 Musallam KM, Taher AT. Hemoglobin 2011;35:503–510 Iron chelation Hydroxyurea Transfusion Splenectomy SF ≥ 1,000 μg/L Hb ≥ 9 g/dL Female Age > 35 years Splenectomy, age above 35 years, and a serum ferritin level >1000 μg/L are associated with a higher risk for thrombosis 1 Risk factors for thrombosis in β-TI

25. The OPTIMAL CARE study splenectomized patients ComplicationParameterRR95% CIp value EMHSplenectomy0.440.26–0.730.001 Transfusion0.060.03–0.09< 0.001 Hydroxyurea0.520.30–0.910.022 Pulmonary hypertensionAge > 35 years2.591.08–6.190.032 Splenectomy4.111.99–8.47< 0.001 Transfusion0.330.18–0.58< 0.001 Hydroxyurea0.420.20–0.900.025 Iron chelation0.530.29–0.950.032 Heart failureTransfusion0.060.02–0.17< 0.001 ThrombosisAge > 35 years2.601.39–4.870.003 Hb ≥ 9 g/dL0.410.23–0.710.001 Serum ferritin ≥ 1,000 µg/L1.861.09–3.160.023 Splenectomy6.593.09–14.05< 0.001 Transfusion0.280.16–0.48< 0.001 CholelithiasisAge > 35 years2.761.56–4.87< 0.001 Female1.961.18–3.250.010 Splenectomy5.192.72–9.90< 0.001 Transfusion0.360.21–0.62< 0.001 Iron chelation0.300.18–0.51< 0.001 Abnormal liver functionSerum ferritin ≥ 1,000 µg/L1.741.00–3.020.049 Taher AT, Musallam KM, Karimi M, et al. Blood. 2010;115:1886-92.

26. ComplicationParameterRR95% CIp value Leg ulcersAge > 35 years2.091.05–4.160.036 Splenectomy3.981.68–9.390.002 Transfusion0.390.20–0.760.006 Hydroxyurea0.100.02–0.430.002 HypothyroidismSplenectomy6.042.03–17.920.001 Hydroxyurea0.050.01–0.450.003 OsteoporosisAge > 35 years3.512.06–5.99< 0.001 Female1.971.19–3.270.009 Splenectomy4.732.72–8.24< 0.001 Transfusion3.101.64–5.85< 0.001 Hydroxyurea0.020.01–0.09< 0.001 Iron chelation0.400.24–0.680.001 HypogonadismFemale2.981.79–4.96< 0.001 Serum ferritin ≥ 1,000 µg/L2.631.59–4.36< 0.001 Transfusion16.134.85–52.63< 0.001 Hydroxyurea4.322.49–7.49< 0.001 Iron chelation2.511.48–4.260.001 The OPTIMAL CARE study splenectomized patients Taher AT, Musallam KM, Karimi M, et al. Blood. 2010;115:1886-92. Splenectomy was independently associated with an increased risk of most disease-related complications

27. OPTIMAL CARE study: patient stratification according to splenectomy and TEE status ● Three groups of patients identified ● Group I, splenectomized patients with a documented TEE (n = 73) ● Group II, age- and sex-matched splenectomized patients without TEE (n = 73) ● Group III, age- and sex-matched non-splenectomized patients without TEE (n = 73) Taher A, Musallam KM, Karimi M, et al. J Thromb Haemost. 2010;8:2152-8. Type of thromboembolic event in splenectomized TI patients (Group I) n (%) DVT46 (63.0) PE*13 (17.8) STP12 (16.4) PVT11 (15.1) Stroke4 (5.5) TEE = thromboembolic events. *All patients who had PE had confirmed DVT.

28. ParameterGroupOR95% CIp value NRBC count ≥ 300 x 10 6 /LGroup III1.00Referent < 0.001 Group II5.352.31–12.35 Group I11.113.85–32.26 Platelet count ≥ 500 x 10 9 /LGroup III1.00Referent < 0.001 Group II8.703.14–23.81 Group I76.9222.22–250.00 PHTGroup III1.00Referent 0.020 Group II4.000.99–16.13 Group I7.301.60–33.33 Transfusion naivetyGroup III1.00Referent 0.001 Group II1.670.82–3.38 Group I3.641.82–7.30 OPTIMAL CARE study: multivariate analysis of the risk per patient group NRBC = nucleated red blood cell; PHT = pulmonary hypertension; OR = adjusted odds ratio; CI = confidence interval. Taher A, Musallam KM, Karimi M, et al. J Thromb Haemost. 2010;8:2152-8. Group I patients had significantly higher NRBC, platelets, and PHT occurrence, and were mostly non-transfused

29. Time-to-thrombosis (TTT) since splenectomy Time to thrombosis Duration since splenectomy (years) Cumulative thrombosis- free survival 0 0.2 0.4 0.6 0.8 1 0510152025303540 NRBC count < 300 x 10 6 /L ≥ 300 x 10 6 /L Duration since splenectomy (years) Cumulative thrombosis- free survival 0 0.2 0.4 0.6 0.8 1 0510152025303540 Transfused Yes No Duration since splenectomy (years) Cumulative thrombosis- free survival 0 0.2 0.4 0.6 0.8 1 0510152025303540 Platelet count < 500 x 10 9 /L ≥ 500 x 10 9 /L Duration since splenectomy (years) Cumulative thrombosis- free survival 0 0.2 0.4 0.6 0.8 1 0510152025303540 Pulmonary hypertension Yes No The median TTT following splenectomy was 8 years (range 1–33 years) The median TTT was significantly shorter in patients with an NRBC count ≥ 300 x 10 6 /L (p = 0.002), a platelet count ≥ 500 x 10 9 /L (p = 0.008), and who were transfusion-naive (p = 0.009) The median TTT following splenectomy was 8 years (range 1–33 years) The median TTT was significantly shorter in patients with an NRBC count ≥ 300 x 10 6 /L (p = 0.002), a platelet count ≥ 500 x 10 9 /L (p = 0.008), and who were transfusion-naive (p = 0.009) Taher A, Musallam KM, Karimi M, et al. J Thromb Haemost. 2010;8:2152-8.

30. Cerebral thrombosis ● Among 30 splenectomized patients with β-TI ● 18 (60.0%) had abnormal MRI findings ● 19 (63.3%) had abnormal PET findings ● 26 (86.7%) had abnormal MRI, abnormal PET, or both Musallam K et al. Ann Hematol 2012;91:235–241 n (%) MRIPETEither MRI or PET Number of lesions* Single Multiple 4 (13.3) 14 (46.7) 5 (16.7) 14 (46.7) 8 (26.7) 21 (70.0) Bilateral lesions13 (43.3)1 (3.3)13 (43.3) Location Frontal Parietal Temporal Occipital 17 (56.7) 9 (30.0) 1 (3.3) 3 (10.0) 14 (46.7) 18 (60.0) 0 (0.0) 18 (60.0) 20 (66.7) 18 (60.0) 3 (10.0)

31. HbF Modulation ● The defective production of β-chains can be compensated for by increased ɣ -chain production to form HbF ● Available HbF modulators include hydroxyurea, 5-azacitidine, decitabine, short- chain fatty acids ● Studies in thalassemia and especially thalassemia intermedia are relatively limited

32. Association of HbF and morbidity in untransfused patients with β-TI Extramedullary hematopoiesis Pulmonary hypertension Venous thromboembolism Heart failure Leg ulcers Abnormal liver function Diabetes mellitus Hypothyroidism Hypogonadism Osteoporosis *P<0.001; † P=0.003; ‡ P=0.002 * † * * * * † ‡ ‡ Musallam KM et al. Blood 2012;119:364–367

33. Use of hydroxyurea for the modulation of HbF in β-TI ● Some debate over long-term efficacy and safety: ● Most adverse effects with low-dose hydroxyurea over the short and medium term are minor and can be tolerated without discontinuation 4 ● Beneficial effects may be transient and attenuate in the long term 5 ● Variable results 1 Mancuso A et al. Br J Haematol 2006;133:105–106; 2 Karimi M et al. J Pediatr Hematol Oncol 2005;27:380– 385; 3 Dixit A et al. Ann Hematol 2005;84:441–446; 4 Karimi M et al. Pediatr Hematol Oncol 2010;27:205–221; 5 Rigano P et al. Br J Haematol 2010;151:509–515 Hydroxyurea enables some patients to become transfusion independent or develop marked increases in Hb levels 1–3

34. ComplicationParameterRR95% CIp value Leg ulcersAge > 35 years2.091.05–4.160.036 Splenectomy3.981.68–9.390.002 Transfusion0.390.20–0.760.006 Hydroxyurea0.100.02–0.430.002 HypothyroidismSplenectomy6.042.03–17.920.001 Hydroxyurea0.050.01–0.450.003 OsteoporosisAge > 35 years3.512.06–5.99< 0.001 Female1.971.19–3.270.009 Splenectomy4.732.72–8.24< 0.001 Transfusion3.101.64–5.85< 0.001 Hydroxyurea0.020.01–0.09< 0.001 Iron chelation0.400.24–0.680.001 HypogonadismFemale2.981.79–4.96< 0.001 Serum ferritin ≥ 1,000 μg/L2.631.59–4.36< 0.001 Transfusion16.134.85–52.63< 0.001 Hydroxyurea4.322.49–7.49< 0.001 Iron chelation2.511.48–4.260.001 HU treatment may be protective for complications Taher AT et al. Blood 2010;115:1886–1892 In the OPTIMAL CARE study, 202/584 patients received hydroxyurea Hydroxyurea treatment was protective for EMH, PHT, leg ulcers, hypothyroidism and osteoporosis

35. PHT ● Pulmonary hypertension: ● Defined as mean pulmonary artery pressure ≥ 25 mm Hg at rest with a pulmonary capillary wedge pressure ≤ 15 mm Hg and pulmonary vascular resistance > 3 Wood units ● The pathophysiology has not been extensively studied but NO dysregulation has been speculated ● Sildenafil has been reported in few cases to be effective ● A trial has just concluded to test its effectiveness ● Bosentan (endothelin receptor antagonist) also reported to be effective in one patient Taher et al. Br J Haematol. 2011;152:512-23.

36. EMH ● Extramedullary hematopoiesis ● Most commonly paraspinal (11-15%) of cases ● Debilitating clinical consequences ● Management ● Hypertransfusion ● HbF modulation ● Radiation ● Surgery (laminectomy) ● Individualize treatment Taher et al. Br J Haematol. 2011;152:512-23.

37. Endocrine complications ● Endocrine complications ● High prevalence of 25-hydroxy vitamin D deficiency ● High prevalence of osteoporosis ● Devastating fractures and bone pain ● High doses of calcium and vitamin D supplementation are recommended ● Bisphosphonates have been effective in TM ● No data about bisphosphonates in TI Taher et al. Br J Haematol. 2011;152:512-23.

38. Pregnancy ● Pregnancy ● Delayed puberty is common ● Fertility is usually normal ● Increased risk of abortion, pre-term delivery, IUGR, Caesarean section delivery, thromboembolic events ● Transfusions should be used carefully for fear of alloimmunization ● Splenomegaly can interfere with the enlargement of the uterus ● Anticoagulation should be considered Taher et al. Brit J Haematol. 2011;152:512-23.

39. Thrombosis ● Anticoagulation ● TI are at high risk of thromboembolic events and anticoagulation merits consideration ● Thrombocytosis is implicated in the pathophysiology of thrombotic disease ● One study showed lower recurrence rate after treatment with Aspirin but the results were not statistically significant ● Antiplatelet therapy is a logical solution Taher et al. Brit J Haematol. 2011;152:512-23.

40. Multimodal therapy Mean number of complications Mean number of complications 0.83 1.31 1.30 2.00 0.85 2.02 1.54 2.43 Iron chelation Transfusion Hydroxyurea Y Y Y Y Y Y N N N N Y Y N N N N Y Y Y Y N N N N Y Y N N Taher AT, et al. Blood. 2010 ;115:1886-92.

41. Supportive therapy With the increased longevity, patients are growing older with their diseases and suffering more complications which is jeopardizing their QoL. Supportive therapy is key to alleviating these ailments

42. HR-QOL A longer duration with a known thalassemia diagnosis was the only independent variable correlating with higher Mental Heath Scores (P = 0.039) while multiplicity of clinical complications was the only independent variable correlating with lower Physical Heath Scores (P = 0.032). Musallam KM, Khoury B, Abi-Habib R, et al. Eur J Haematol. 2011;87:73-9.

43. Depression and anxiety in β-TI ● Cross-sectional study - Chronic Care Center in Lebanon ● 80 patients: ● 32 β-TI [median age 24 years] ● 48 β-TM [median age 23 years]) ● Patients with TM had significantly longer median duration with a known thalassemia diagnosis than TI patients (P<0.001) Proportion of patients with different combinations of diagnoses Considerable proportion of adult patients with TM and TI show evidence of depression and anxiety Patients with TI are more liable to state anxiety than TM patients of a similar age, that is attributed to a shorter duration of living with a thalassemia diagnosis Musallam KM, et al. Thalassaemia International Federation 2011. Depression 8 (10%) Trait- Anxiety 8 (10%) State- Anxiety 3 (3.8%) 9 (11.3%) 4 (5%) 8 (8%)

44. Supportive therapy With the increased longevity, patients are growing older with their diseases and suffering more complications which is jeopardizing their QoL. Supportive therapy is key to alleviating these ailments

45. Take home message ● TI, a once overlooked disease, displays a myriad of complications ● Management of TI can be either palliative or curative ● Palliative care involves transfusion and iron chelation therapy or hydroxycarbamide in addition to control of symptoms ● We must always keep in mind the QoL of these patients and provide the proper counseling and supportive therapy