Part I. Pathophysiology and management of Thalassemia Intermedia. M. Domenica Cappellini Fondazione IRCCS Policlinico University of Milan

Transcription

1 Pathophysiology and management of Thalassemia Intermedia M. Domenica Cappellini Fondazione IRCCS Policlinico University of Milan 4th European Symposium on Rare Anaemias 3rd Bulgarian Symposium on Thalassaemia Patients and Professionals Sofia November 2011 Part I

2 β-thalassemia intermedia (TI) Highly diverse group of β-thalassemia syndromes where red blood cells are sufficiently i short-lived to cause anemia but not necessarily the need for regular blood transfusions. Clinical phenotypes lie in severity between those of β-thalassemia minor and β-thalassemia major (TM). Arises from defective gene(s) leading to partial suppression of β-globin protein production. Mild Severe Completely asymptomatic until adult life Presentation at age 2 6 years Retarded growth and development Taher A, et al. Blood Cells Mol Dis. 2006;37: Guidelines for the clinical management of thalassaemia. 2nd rev ed. TIF Determinants of disease severity Molecular factors inheritance of a mild or silent β-chain mutation presence of a polymorphism for the enzyme Xmn-1 in the Gγ-promoter region, associated with increased HbF co-inheritance of α-thalassaemia increased production of α-globin chains by triplicated or quaduplicated α-genotype associated to β-heterozygosity; also from interaction of β- and δβ-thalassaemia Environmental factors may influence severity of symptoms, e.g. social conditions nutrition availability of medical care HbF = fetal hemoglobin. Taher A, et al. Blood Cells Mol Dis. 2006;37:12-20.

3 Pathophysiology summarized Excess free α-globin chains Denaturation Degradation Formation of heme and hemichromes Ineffective erythropoiesis Iron-mediated toxicity Chronic anemia Membrane Ineffective and hemolysis Hemolysis binding of erythropoiesis Iron overload IgG and C3 Removal of damaged red cells Increased erythropoietin synthesis Reduced tissue oxygenation Anemia Splenomegaly Skeletal deformities, osteopenia Erythroid marrow expansion Increased Iron absorption Iron overload Olivieri NF, et al. N Engl J Med. 1999;341: Prevalence of common complications in TI vs TM Complication TI TM (% of patients affected) Lebanon Italy Lebanon Italy (n = 37) (n = 63) (n = 40) (n = 60) Splenectomy Cholecystectomy Gallstones Extramedullary hemopoiesis Leg ulcers Thrombotic events Cardiopathy* Pulmonary hypertension Abnormal liver enzymes HCV infection Hypogonadism Diabetes mellitus Hypothyroidism *Fractional shortening < 35%. Defined as pulmonary artery systolic pressure > 30 mmhg; a well-enveloped tricuspid regurgitant jet velocity could be detected in only 20 patients, so frequency was assessed in these patients only. HCV = hepatitis C virus. Taher A, et al. Blood Cells Mol Dis. 2006;37:12-20.

4 Overview on Practices in Thalassemia Intermedia Management Aiming for Lowering Complication-rates Across a Region of Endemicity: the OPTIMAL CARE study Retrospective review of 584 TI patients from six comprehensive care centers in the Middle East and Italy N = 127 N = 153 N = 200 N = 51 N = 12 N = 41 Overall study population Parameter Frequency n (%) Complications Frequency n (%) Age (yrs) < (29.5 ) (49.3) > (21.2) Male : Female 291 (49.8) : 293 (50.2) Splenectomized 325 (55.7) Serum ferritin (ng/ml) < (64.4) (30.6) > (5) Osteoporosis EMH Hypogonadism Cholelithiasis Thrombosis Pulmonary hypertension Abnormal liver function Leg ulcers Hypothyroidisim 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) EMH = extramedullary hematopoiesis

5 120 Treatment-naïve patients g/dl) Hemoglobin ( Serum ferritin (ng g/ml) 12,0 10,0 8,0 6,0 4,0 2,0 0, Age (years) Age (years) Age vs. hemoglobin level (rs=-0.679, P<0.001) Age vs. serum ferritin level (rs=0.653, P<0.001) Taher A, et al. Br J Haematol Epub ahead of print. Complications vs. Age Complications in 120 treatment-naïve patients with TI Frequency (%) * 40,0 < 10 years years years >32 years * * 26,7 26,7 33,3 20,0 20,0 20,0 16,7 16,7 13,3 13,3 13,3 10,0 10,0 10,0 6,7 6,7 6,7 6,7 3,3 3,3 3,3 3,3 0,0 * * = statistically significant trend 30,0 23,3 23,3 20,0 * 16,7 16,7 16,7 13,3 13,3 10,0 10,0 6,7 6,7 3,3 3,3 3,3 0,0 0,0 0,0 0,0 * Taher A, et al. Br J Haematol Epub ahead of print.

6 TREATMENT OPTIONS Part I Splenectomy 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 Taher A, et al. Blood Cells Mol Dis. 2006;37: Guidelines for the clinical management of thalassaemia. 2nd rev ed. TIF 2008.

7 Splenectomy: adverse events Thromboembolic events Pulmonary hypertension Infection 10-year follow-up of 221 splenectomized patients, 6 of whom died of sepsis no need to wait & see in such patients with fever Cappellini MD, et al. Br J Haematol. 2000;111: Atichartakarn V, et al. Int J Hematol. 2003; 78: Pinna AD, et al. Surg Gynecol Obstet. 1988;167: In the OPTIMAL CARE study splenectomized patients: 325/584 Complication Parameter RR 95% CI p-value EMH Splenectomy Transfusion <0.001 Hydroxyurea Pulmonary hypertension EMH = extramedullary hematopoiesis. Age > 35 yrs Splenectomy <0.001 Transfusion <0.001 Hydroxyurea Iron chelation Heart failure Transfusion <0.001 Thrombosis Age > 35 yrs Hb 9 g/dl Ferritin 1000 ng/ml Splenectomy <0.001 Transfusion <0.001 Cholelithiasis Age > 35 yrs <0.001 Female Splenectomy <0.001 Transfusion <0.001 Iron chelation <0.001 Abnormal liver function Ferritin 1000 ng/ml

8 In the OPTIMAL CARE study splenectomized patients: 325/584 Complication Parameter RR 95% CI p-value Leg Ulcers Age > 35 yrs Splenectomy Transfusion Hydroxyurea Hypothyroidism Splenectomy Hydroxyurea Osteoporosis risk of Age most > 35 disease-related yrs complications. <0.001 Female Splenectomy <0.001 Transfusion <0.001 Hydroxyurea <0.001 Iron chelation Hypogonadism Female <0.001 Ferritin 1000 ng/ml <0.001 Transfusion <0.001 Hydroxyurea <0.001 Iron chelation Splenectomy was independently associated with an increased In the OPTIMAL CARE study Occasionally-regularly transfused patients: 445/584 Complication Parameter RR 95% CI p-value EMH Splenectomy Transfusion <0.001 Hydroxyurea Pulmonary Age > 35 yrs hypertension Splenectomy <0.001 Transfusion <0.001 Hydroxyurea Iron chelation Heart failure Transfusion <0.001 Thrombosis Age > 35 yrs Hb 9 g/dl Ferritin 1000 ng/ml Splenectomy <0.001 Transfusion <0.001 Cholelithiasis Age > 35 yrs <0.001 Female Splenectomy <0.001 Transfusion <0.001 Iron chelation <0.001 Abnormal liver Ferritin 1000 ng/ml function

9 In the OPTIMAL CARE study Occasionally-regularly transfused patients: 445/584 Complication Parameter RR 95% CI p-value Leg Ulcers Age > 35 yrs Splenectomy Transfusion Hydroxyurea Hypothyroidism Splenectomy Hydroxyurea Osteoporosis HF, Age cholelithiasis, > 35 yrs 3.51 and leg ulcers. <0.001 Female Splenectomy <0.001 Transfusion <0.001 Hydroxyurea endcorinopathy <0.001 Iron chelation Hypogonadism Female <0.001 Ferritin 1000 ng/ml <0.001 Transfusion <0.001 Hydroxyurea <0.001 Iron chelation Transfusion therapy was protective for thrombosis, EMH, PHT, Transfusion therapy was associated with an increased risk of Only significant associations presented Current evidence for the benefit of transfusions in TI Failure to thrive in childhood in the presence of significant ifi anemia Increasing anemia 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 EMH pulmonary hypertension Prior to surgical procedures Guidelines for the clinical management of thalassaemia. 2nd rev ed. TIF 2008.

10 In the OPTIMAL CARE study Chelated patients: 336/584 Complication Parameter RR 95% CI p-value EMH Splenectomy Transfusion <0.001 Hydroxyurea Pulmonary Age > 35 yrs hypertension Splenectomy <0.001 Transfusion <0.001 Hydroxyurea Iron chelation Heart failure Transfusion <0.001 Thrombosis Age > 35 yrs Hb 9 g/dl Ferritin 1000 ng/ml Splenectomy <0.001 Transfusion <0.001 Cholelithiasis Age > 35 yrs <0.001 Female Splenectomy <0.001 Transfusion <0.001 Iron chelation <0.001 Abnormal liver Ferritin 1000 ng/ml function In the OPTIMAL CARE study Chelated patients: 336/584 Complication Parameter RR 95% CI p-value Leg Ulcers Age > 35 yrs Splenectomy Transfusion Hydroxyurea Hypothyroidism Splenectomy Hydroxyurea Osteoporosis Age > 35 yrs <0.001 Female PHT, Splenectomy cholelithiasis, 4.73 and osteoporosis <0.001 Transfusion <0.001 Hydroxyurea <0.001 Iron chelation Hypogonadism Female <0.001 Ferritin 1000 ng/ml <0.001 Transfusion <0.001 Hydroxyurea <0.001 Iron chelation Iron chelathion therapy was protective for hypogonadism,

11 Serum ferritin underestimates iron burden in TI Seru um ferritin level (µg/l) TI TM 10, Linear (TI) Linear (TM) 9,000 8,000 A significant positive correlation with serum ferritin 7,000 levels was observed (R = 0.64; p < 0.001). 6,000 5,000 LIC values were similar to those in patients with TM, 4,000 but serum ferritin levels were significantly lower. 3,000 2,000 1, LIC (mg Fe/g dry wt) LIC correlated with serum ferritin levels in patients with TI (R = 0.64; p < 0.001) Taher A, et al. Haematologica. 2008;93: Mechanism of iron overload in non-transfused patients Ineffective erythropoiesis Chronic anemia Hypoxia HIFs GDF15 Erythropoietin Hepcidin Release of recycled iron from RES macrophages Ferroportin Duodenal iron absorption LIC GDF15 = growth differentiation factor 15; HIF = hypoxia-inducible transcription factor. Taher A, et al. Br J Haematol.2009;147: Serum ferritin

12 Iron chelation therapy Deferoxamine 1 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 Deferiprone 2 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 UIE = urinary iron excretion. 1 Cossu P, et al. Eur J Pediatr. 1981;137: Pootrakul P, et al. Br J Hematol. 2003;122: 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 ± ± Liver T2, ms 20.1 ± ± Liver T2*, ms 3.4 ± ± Cardiac T2*, ms 38.9 ± ± LVEF, % 66.3 ± ± Aspartate aminotransferase, U/L 64.8 ± ± Alanine aminotransferase, U/L 63.5 ± ± Serum creatinine, mg/dl 0.67 ± ± Cystatin C, mg/l 0.98 ± ± 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 Voskaridou E, et al. Br J Haematol 2010;148:332-4.

13 Effect of deferasirox on serum ferritin and LIC in patients with TI and nontransfusional iron overload Ser rum Ferritin Levels (ng/m ml) Serum ferritin at baseline Serum ferritin at 1 year Serum ferritin at 2 years LIC (mg Fe/g dry weight t) LIC at baseline LIC at 1 year LIC at 2 years 0 Patients 0 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). Ongoing clinical evaluation of deferasirox in TI Prospective, randomized, double-blind, placebo-controlled ti trial Patients (age 10 years) with non transfusion-dependent β-thalassemia (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-thalassemia, based on the change in LIC from baseline after 1 year of treatment compared with placebo-treated patients Ali T. Taher, MD, principal investigator; Study ID ICL670A2209. Taher AT, et al. Blood (ASH Annual Meeting Abstracts), 2009; 114 (22):5111.

14 In the OPTIMAL CARE study Patients on hydroxyurea: 202/584 Complication Parameter RR 95% CI p-value EMH Splenectomy Transfusion <0.001 Hydroxyurea Pulmonary hypertension EMH = extramedullary hematopoiesis. Age > 35 yrs Splenectomy <0.001 Transfusion <0.001 Hydroxyurea Iron chelation Heart failure Transfusion <0.001 Thrombosis Age > 35 yrs Hb 9 g/dl Ferritin 1000 ng/ml Splenectomy <0.001 Transfusion <0.001 Cholelithiasis Age > 35 yrs <0.001 Female Splenectomy <0.001 Transfusion <0.001 Iron chelation <0.001 Abnormal liver function Ferritin 1000 ng/ml In the OPTIMAL CARE study Patients on hydroxyurea: 202/584 Complication Parameter RR 95% CI p-value Leg Ulcers Age > 35 yrs Splenectomy Transfusion Hydroxyurea Hypothyroidism Splenectomy Hydroxyurea Osteoporosis Age > 35 yrs <0.001 ulcers, Female hypothyroidism, 1.97 and osteoporosis Splenectomy <0.001 Transfusion <0.001 Hydroxyurea <0.001 Iron chelation Hypogonadism Female <0.001 Ferritin 1000 ng/ml <0.001 Transfusion <0.001 Hydroxyurea <0.001 Iron chelation Hydroxyurea treatment was protective for EMH, PHT, leg

15 Hydroxycarbamide Experience from Iran and India most patients were reported to have become transfusionindependent in patients who were not transfused, the Hb concentration increased the combination of hydroxycarbamide with L-carnitine or magnesium could be more effective in improving hematologic parameters and cardiac status in patients with TI than hydroxyurea alone Experience from Europe constant increase of the erythrocyte volume and in HbF, but only a modest effect on total Hb concentration Karimi M, et al. J Pediatr Hematol Oncol. 2005;27: Dixit A, et al. Ann Hematol. 2005;84: Karimi M, et al. Eur J Haematol. 2010;84:52-8. Hydroxycarbamide (Cont d) Co-inheritance of α-thalassemia, the Xmn-1 HBG2 polymorphism, and the underlying β- globin genotype may be predictive of a good response to hydroxycarbamide; Hb E/βthalassemia patients generally have a good response Treatment t with hydroxycarbamide has also shown promising results in decreasing plasma markers of thrombin generation Singer ST, et al. Br J Haematol. 2005;131: Panigrahi I, et al. Hematology. 2005;10:61-3. Ataga KI, et al. Br J Haematol. 2007;139:3-13.

16 OPTIMAL CARE Multimodality therapy Hydroxyurea Y N Transfusion Y N Y N Iron chelation Y N Y N Y N Y N Mean number of complications Take-home message 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 challenging the role of splenectomy yet highlighting the benefit of transfusion, iron chelation therapy, and fetal hemoglobin induction in the management of TI; thus these approaches merit large prospective evaluation The role of antiplatelets/anticoagulants in TI merits investigation