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Pathophysiology and Management of Thalassaemia Intermedia 2nd Pan-European Conference on Haemoglobinopathies Berlin, 1

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Pathophysiology and Management of Thalassaemia Intermedia 2nd Pan-European Conference on Haemoglobinopathies Berlin, 1

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    2. ß-Thalassaemia intermedia (TI) ‘Highly diverse’ group of ß-thalassaemia syndromes where red blood cells (RBCs) are sufficiently short-lived to cause anaemia but without the need for regular blood transfusions Clinical phenotypes lie between those of ß-thalassaemia minor and major (TM) Arises from defective gene(s) leading to partial suppression of ß-globin protein production

    3. Molecular basis inheritance of a mild (ß+) mutation presence of a polymorphism for the enzyme Xmn-1 in the G?-promoter region, associated with increased HbF co-inheritance of ?-thalassaemia increased production of ?-globin chains by triplicated ?-genotype associated to ß-heterozygosity; also from interaction of ß- and dß-thalassaemia Environmental factors may influence severity of symptoms, e.g. social conditions nutrition availability of medical care

    4. Pathophysiology summarized Three main factors responsible for clinical manifestation of TI: Ineffective erythropoiesis Chronic anaemia Iron overload Three main factors responsible for clinical manifestation of TI: Ineffective erythropoiesis Chronic anaemia Iron overload

    5. Prevalence of common complications in TI vs TM

    6. Venous thromboembolism and hypercoagulability in splenectomized patients with thalassaemia intermedia Splenectomized TI had the highestSplenectomized TI had the highest

    7. Largest clinical experience Thromboembolic events more frequent in TI than TM 8860 Patients: 6670 with TM 2190 with TI 146 (1.65%) thrombotic events: 61 (0.9%) with TM 85 (3.9%) with TI Risk factors for developing thrombosis in TI: Age (>20 years) Previous thromboembolic event Family history Splenectomy

    8. TI patients stratified Splenectomy and anemia seem to be the main contributors to thrombotic eventsSplenectomy and anemia seem to be the main contributors to thrombotic events

    9. In 1972, Logothetis et al. described a “stroke syndrome” and neurological deficits compatible with TIAs in about 20% of 138 cases of TM in Greece1 In 1998, Borgna Pignatti et al. described TIAs accompanied by a clinical picture of headache, seizures, and hemiparesis in 2.2% of TM patients in Italy2 In 16 patients with TI, Manfrè et al. found that 37.5% showed evidence of asymptomatic brain damage including ischaemic lesions3

    12. Iron overload Iron overload occurs even in patients with TI who are not transfused: Iron loading: 2–5 g Fe/year Iron toxicity develops from age 5 years Rate of iron loading differs between TM and TI: Iron overload in TI much lower than in age-matched patients with transfusion-dependent TM Nonetheless, organ damage is apparent in both patient groups: Liver Heart Endocrine organs

    13. Mechanism of iron overload in non-transfused patients

    14. Assessing iron overload in TI Assessment of iron overload in ß-thalassemia is an important aspect of patient management Methods for assessing iron overload include serum ferritin levels Liver iron concentration (LIC) using R2 MRI SQUID liver biopsy

    15. Serum ferritin and LIC by liver biopsy Serum ferritin was significantly lower in patients with TI than in those with TM, despite similar LIC

    16. Serum ferritin and LIC by SQUID

    17. Serum ferritin underestimates iron burden in TI LIC correlated significantly with serum ferritin levels in patients with TI (r=0.64; P<0.001) While LIC values in patients with TI (n=74) were similar to those in TM (n=65), serum ferritin levels were significantly lower

    18. Non-Transferrin-Bound Iron (NTBI) Heterogeneous species Returns rapidly after chelator is removed from system Responsible for abnormal pattern of iron distribution Promotes lipid peroxidation in vitro During conditions of normal iron balance, non–transferrin-bound iron (NTBI) is not produced. In the case of BMT, transferrin saturation, which leads to the presence of NTBI in plasma, can be caused by: Frequent blood transfusions Mobilization of iron deposits from marrow cells NTBI in plasma eventually results in the iron loading of organs such as: Liver Heart Endocrine glandsDuring conditions of normal iron balance, non–transferrin-bound iron (NTBI) is not produced. In the case of BMT, transferrin saturation, which leads to the presence of NTBI in plasma, can be caused by: Frequent blood transfusions Mobilization of iron deposits from marrow cells NTBI in plasma eventually results in the iron loading of organs such as: Liver Heart Endocrine glands

    19. NTBI in TI

    21. Cardiac iron overload in 19 Lebanese patients with TI Population: 19 transfusion-independent TI patients versus 19 polytransfused TM patients Results: T2* was normal (=20 ms) in all TI patients despite similar LIC to TM

    22. Cardiac iron overload in 49 Italian patients with TI

    23. Benefit of transfusions in TI Failure to thrive in childhood in presence of significant anaemia Increasing anaemia not attributable to rectifiable factors Delayed or poor pubertal growth spurt Progressive splenic enlargement Evidence of: Bone deformities Clinically relevant tendency to thrombosis Leg ulcers extramedullary haematopoiesis Pulmonary hypertension Prior to surgical procedures

    24. Current indications for splenectomy in TI Less common than in the past before age 5 years it carries a high risk of infection and is therefore not generally recommended Main indications include growth retardation or poor health leukopenia thrombocytopenia increased transfusion demand symptomatic splenomegaly Primarily done in regularly transfused TM patients

    25. Splenectomy: adverse events Increase in thrombotic events in TI patients RBC may be acting as activated platelets, thus increasing the risk of thrombosis Pulmonary Hypertension Infection is common 10-year follow-up of 221 splenectomized patients, 6 of whom died of sepsis no need to “wait & see” in such patients with fever Thrombocytosis

    26. Iron chelation therapy Initiation of iron chelation therapy in patients with TI depends on: Rate of iron accumulation Duration of exposure to excess iron Various other factors in individual patients A direct assessment of LIC is recommended, either by biopsy or non-invasive method such as R2 MRI Chelation therapy should generally be initiated if LIC >7 mg/g dw Lower LICs must be considered: Particularly with availability of oral iron chelators

    27. Deferoxamine1 significant decline in serum ferritin after 6 months of deferoxamine treatment significant UIE after 12 hours of continuous deferoxamine (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 no significant differences in excretion across doses Deferiprone2 significant reductions seen in mean serum ferritin, hepatic iron, red-cell membrane iron, and serum NTBI levels serum ferritin ± SD: initial 2,168 ± 1,142 µg/L; final 418 ± 247 µg/L significant mean increase in serum erythropoietin also observed increase in Hb values in 3 patients; reduction in transfusion requirements in 4 patients

    29. Effect of deferasirox in TI and non-transfusional iron overload 11 patients with TI (mean age 31.7 years; 10 splenectomized) Iron overload in one noncompliant patient did not decrease; this patient was excluded from graph Changes in LIC and ferritin levels were related to deferasirox dose, but even severely iron-loaded patients, treated with 10 mg/kg/day, responded well

    30. Safety of deferasirox during treatment of up to 2 years 11 Patients with TI treated with deferasirox for 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 Year 1 (P=0.0002) Year 2 (P=0.024) Improvement probably due to decreased hepatic siderosis

    31. Ongoing clinical evaluation of deferasirox Prospective, randomized, double-blind, placebo-controlled trial1 Patients (age =10 years) with non-transfusion-dependent ß-thalassaemia (no transfusion required within 6 months prior to the study) Two doses: 5 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 ß-thalassaemia, based on the change in LIC from baseline after 1 year of treatment compared with placebo-treated patients

    32. Overview on Practices in Thalassaemia Intermedia Management Aiming for Lowering Complication-rates Across a Region of Endemicity: The OPTIMAL CARE study

    33. Overview on Practices in Thalassemia Intermedia Management Aiming for Lowering Complication-rates Across a Region of Endemicity: the OPTIMAL CARE study 584 TI patients from six comprehensive care centers in Lebanon, Italy, Iran, Egypt, United Arab Emirates, and Oman. Retrospective chart review of complications rate vs. patient and disease characteristics, and treatment options received (transfusion, iron chelation, and hydroxyurea).

    34. Patient, disease, and treatment characteristics

    35. Determinants of complication rate

    36. Determinants of complication rate (cont’d)

    37. Multimodality therapy

    38. Age-related complications in treatment-naïve TI Due to the disparity in treatment approaches undertaken after initial diagnosis, the natural history of TI is poorly understood 120 Treatment-naïve patients enrolled Assessments: Bivariate correlations between age and SF or Hb levels Differences in the rate of complications between different age quartiles Incidence density ratios (rate ratios) in those who have complications versus those who do not

    39. Age-related complications in treatment-naïve TI Complications in 120 treatment-naïve patients with TI

    40. Zooming onto Splenectomy vs. Thrombosis Data was retrieved from the Thalassemia Intermedia Registry. Three Groups of patients were identified: Group I, splenectomized patients with a documented TEE (n = 73); Group II, age- and sex-matched splenectomized patients without TEE (n = 73); and Group III, age- and sex-matched non-splenectomized patients without TEE (n = 73). Collected data included demographics, laboratory parameters, disease-complications, and received treatments that may influence TEE development.

    41. Results Group I

    42. Comparative Analysis

    43. Multivariate Analysis Patients in Group I are more likely to be: Non-transfused, OR: 3.6, 95% CI: 2.1-6.25 Have pulmonary hypertension, OR: 4.1, 95% CI: 1.99-8.47 Have nucleated RBC counts > 250 x106/l, OR: 6.59, 95% CI: 3.09-14.05 Have platelet counts > 500 x109/l, OR: 5.19, 95% CI: 2.72-9.90

    44. Summary Our understanding of the molecular basis and pathophysiology of TI significantly increased Iron overload and hypercoagulability are recently receiving increasing attention in TI Despite various treatment options are available, no clear guidelines exist. Several studies are highlighting the roles of transfusion, iron chelation therapy, and fetal hemoglobin induction in the management of TI; thus these approaches merit large prospective evaluation.

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