La Terapia della Talassemia

Transcription

1 S.I.E. Corso nazionale di aggiornamento in ematologia clinica La Terapia della Talassemia Renzo Galanello 15/06/ Clinica Pediatrica 2-Ospedale Regionale Microcitemie.ASL8

2 Clinical characteristics of β talassemia major severe early-onset hypochromic microcytic anemia liver and spleen enlargement failure to thrive severe skeletal manifestation regular transfusions required (transfusion dependent) 15/06/2007 2

3 3 Management of Thalassemia Major Conventional RBC transfusions Iron chelation (Splenectomy) Bone marrow transplantation Prospectives gene therapy Hb F induction

4 4 AIMS OF TRANSFUSION TREATMENT Normal growth and physical activity Chronic hypoxemia Compensatory marrow hyperplasia: hypervolemia bone changes extramedullary erythropoiesis Splenomegaly and hypersplenism Gastro-intestinal iron absorption Improvement of cardiac function

5 5 Transfusional Indices (Annual) Mean hemoglobin Pure red cell consumption Iron input Mean transfusional interval

6 WEBTHAL: A THALASSEMIA-ORIENTED COMPUTERIZED CLINICAL RECORD Row data from transfusion chelation tests Complications Therapies Transfusional indexes Iron balance Appointments Print-outs Graphs Centres Cooperation 6/15/2007 6

7 7 N ml/kg/y Transfusional History By Webthal TRANSF BLOOD CONSUMP TRANSF BLOOD CONSUMP FE in mg/kg/d Linee 3 pre Hb post Hb mean Hb 1 0,9 16 0,8 14 0,7 12 0,6 10 0, Hb g % 0,4 0,3 0,2 0,1

8 8 Transfusion - Dependent Complications Iron overload Infections Immunization: (allergic reactions, alloimmunization)

9 INFECTIOUS RISK OF TRANSFUSIONS VIRAL INFECTION HBV HCV HIV HTLV ESTIMATED RISK 1 / / / < 1 / /06/ Seed et al, 2005

10 1 ml pure RBC = 1.16 mg Fe 1 blood unit = 200 mg Fe To maintain mean Hb = 12 g / dl ml/kg/y of pure RBC Mean iron imput = mg/kg/day* 6/15/ *Includes iron absorbed by the GI tract (1 to 4 mg /day).

11 Complications In Thalassemia Major Cagliari (Sardinia) 1 Cagliari (Sardinia) 1 N of patients 348 N of patients 348 % % Liver (anti HCV+) 75,0 Hypothyroidism 12,0 Colelithiasis 23,4 Hypoparathyroidism 9,0 Pulmonary hypertension Nephrolithiasis Osteoporosis 0,29 13,0 66,0 Heart disease Hepatocarcinoma Cirrhosis Diabetes 24,3 0,29 1,44 8,6 Pseudoxanthoma elasticum Thrombosis 0,57 3,6 Hypogonadism M 46,6 F 75,7 1. Galanello et al. 11

12 WHY MEASURE CARDIAC IRON? The heart is the target lethal organ 6/15/

13 How to Measure Cardiac Iron? Surrogate measures Ferritin Liver iron concentration (biopsy,squid,mri) Cardiac function Direct measures Cardiac biopsy Cardiac MR 6/15/

14 Individual variability of serum ferritin determinations age: 18 years Iron in (mg/kg/die): 2004= = % 67% T 2* 52 m sec. (21/01/06) gen gen feb feb mar mar-03 9-apr apr mag mag giu giu-03 8-lug lug-03 5-ago ago-03 9-set set-03 8-ott ott-03 5-nov nov-03 3-dic dic dic gen feb mar-04 5-apr-04 3-mag mag giu lug ago set ott nov dic-04 7-feb-05 6-apr mag giu-05 1-ago ago set oct nov gen mar mag giu ago-06 Ferritin Squid FERRITINA SQUID 6/15/

15 Procedures to evaluate liver iron concentration Liver biopsy SQUID MRI (T2*,R2-Ferriscan) 6/15/

16 MRI: Tissue Appearances in Iron Overload Normal Volunteer Severe Iron Overload 6/15/ Anderson LJ. Eur Heart J 2001; 22:

17 LIVER R2 IMAGES AND DISTRIBUTIONS LIC=0.6 mg/g Accuracy and precision over a wide range of LIC CE mark for clinical use In Europe LIC=7.7 mg/g LIC=13.4 mg/g 15/06/2007 LIC=24.5 mg/g 17 St Pierre 2005, Blood

18 Problems with Cardiac Biopsy for Routine Clinical Use Invasive with risk of complications Can only sample RV septal endocardium Iron deposition is patchy & epicardial Expensive Not widely available at high expertise 6/15/

19 Lack of Correlation: Liver and Cardiac Iron Liver Liver 6/15/ Anderson LJ. Eur Heart J 2001; 22:

20 T2* - Cardiac Risk Ranging High Intermediate Low 6/15/

21 OBJECTIVES OF CHELATION Reduce/prevent iron overload excess iron Detoxify iron Labile Iron Pool Fe 2+ + H 2 O 2 Fe 3+ + OH + OH Organ targeting 15/06/

22 DEFEROXAMINE PHARMACOLOGY + H 3 N HO O N HN O O H N O N OH N HO CH 3 (1) O Denticity hexadentate Molecular weight 657 pm for Iron Route of absorption parenteral Peak plasma conc. 7 mmol/l at 25 mg/kg Elimination initial t1/2 = 0.3 h Excretion of Fe complex urine + feces (40%) Efficiency of chelation ~ 10 %

23 Survival by Birth Cohort: Italian Study Survival Probability P< Overall 68 % of the patients are alive at the age of 35 years Età (Yr) 15/06/ Borgna-Pignatti et al,2004

24 PROBLEMS WITH DESFERAL demanding regimen side effects low compliance 15/06/

25 PHARMACOLOGY DEFERIPRONE, (L1) dimethyl-3-hydroxypyridin-4-one Denticity bidentate Molecular weight 139 pm for Iron Route of absorption oral Peak plasma conc. 126 mmol/l after 1h at 25 mg/kg Elimination t1/2 = 2-3h Excretion of Fe complex urine + feces (3-23%) Efficiency of chelation 3.8 % O N Me OH Me ZD Liu, DY Liu & C Hider 2002

26 Kaplan-Meier Analysis of Deferiprone Adverse Drug Reaction Free Over 4 Years Complete Censored Study LA-02/LA-06 Cumulative Proportion Adverse Reaction Free Agranulocytosis: 1/187 = 0.5% Neutropenia: 15/187 = 8.0% 0.2 Arthropathy: 28/187 = 15.0% 0.1 GI Symptoms: 62/187 = 33.2% Time (Months) 15/06/ Cohen et al,2000

27 Chelation Randomised Controlled Trial Myocardial T2* Ejection Fraction Myocardial T2* (ms) Deferiprone Deferoxamine p= 0.77 p= LV Ejection Fraction (%) Deferiprone Deferoxamine p= 0.34 p= Baseline 6 months 12 months 15/06/ Baseline 6 months 12 months

28 Possible Chelation Treatments Monotherapy Alternate therapy Combination therapy : simultaneous sequential 15/06/

29 Combination Therapy Clinical Studies: Changes in Ferritin Levels Gomber et al, 2004 Francis et al, 2003 Kattamis et al, 2006 Taher et al, 2002 Mourad et al, 2003 Origa et al, 2005 Alymara et al, 2004 D Angelo et al, 2004 Wonke et al, 1998 Balveer et al, 2000 Tanner et al, 2006 Pathare et al, 2004 Farmaki et al, % change /06/

30 15/06/ Porcu M. et al, 2007

31 ICL670 (Exjade): A Novel Oral Iron Chelator Selected from over 700 compounds tested Tridentate* iron chelator An oral, dispersible tablet Administered once daily Highly specific for iron Chelated iron excreted mainly in feces (< 10% in urine) O Fe *3 polar interaction sites in the binding pocket. 15/06/ Nick H, Current Medicinal Chemistry. 2003;10: OH OH N N N * * * HO

32 Secondary Efficacy Results Study 0107 Change in Ferritin by Dose Group Change in serum ferritin, μg/l DFO 3000 < ICL n = Safety population. DFO, mg/kg/day ICL670, mg/kg/day CE-32

33 CE-33 Liver Histology Baseline End of Study ICL mg/kg/day Female (28 years) LIC decreased from 16.2 to 3.3 mg Fe/g dw Average iron intake during study: 0.37 mg/kg/day Medical history: splenectomy, hepatitis C DFO 56 mg/kg/day Male (18 years) LIC decreased from 18.4 to 5.2 mg Fe/g dw Average iron intake during study: 0.35 mg/kg/day Medical history: splenectomy Magnification x10; Prussian blue staining

34 6/15/

35 Talassemia major:trattamento complicanze Endocrinopatie: terapia sostitutiva Osteoporosi: bifosfonati,calcio,vit.d Epatite cronica: IFN +/- ribavirina Cardiopatia: terapia chelante intensiva e terapia cardiologica 15/06/