THALASSEMIA : A DREADFUL DISEASE TURNED TO A CHRONIC CONDITION Dimitris Loukopoulos, MD

1. THALASSEMIA : A DREADFUL DISEASE TURNED TO A CHRONIC CONDITION Dimitris Loukopoulos, MD University of Athens, Greece A lecture dedicated to the late Professor Antonio CAO (+2012)

2. Thalassemia • Probably and “old” disease; sculls with “porotic osteoporosis” found in Sicily and Sardinia; may denote other conditions as well • Von Jacsch,1889 and other scientists : • “anaemia infantum pseudoleucaemica” • could also be leishmaniasis, tuberculosis, other • Thomas Cooley, 1925 : “A series of cases of • splenomegaly and peculiar bone changes” • Whipple GH and Bradford WL, 1936. • “Mediterranean disease-Thalassemia • Caminopetros J, 1936. A familial disease; decreased • osmotic fragility in both parents

3. After the WW2; milesones in understanding the basic pathophysiology • The hemoglobin of patients with thalassemia more resistant to alkali denaturation; same as fetal hemoglobin.Vecchio (Italy, 1946) • Micro-drepanocytic disease; the scientific importance of compound heterozygozity. Silvestroni+Bianco (Italy, 1944) • Hb A2 is elevated in heterozygotes (Kunkel+Wallenius, US,1955) • HbH disease (Rigas, US) / Gouttas et al, Greece, 1955) • Concept of a- and β-thalassemia put forward byItano, Pauling, • Ingram,Stretton and others (1950-1960) • 1960-1970 • Thalassemia is not confined in the Mediterranean world; • displays a striking heterogeneity. • is a typical example of ineffective erythropoiesis • results from chain imbalance • ingenuous studies of compound heterozygotes define the • β0, β+, β++types of thalassemia • (Nathan+Gunn, Fessas, Weatherall+Clegg)

4. Thalassemia Major; Bone Changes

5. Thalassemia Major; a protuberant spleen

6. Thalassemia Major; the beneficial effect of transfusions

7. Thalassemia Major; the beneficial effect of transfusions :a clear increase in survival Modell; early years

8. Progress in Thalassemia Milestones in Clinical Management • 1. TRANFUSION THERAPY; Improves quality of life • “Hypertransfusion” in an attempt to suppress ineffective erythropoiesis • Neocytes to avoid frequent transfusions • Improved genotyping to avoid allo-immunization • Splenectomy to reduce size of “splenic pool” and hemolysis • Consider : Age, preparation with appropriate vaccines, • chronic penicillin administration etc. • SAFETY : improved control of infections (HIV, HBV, HCV and other • infectious agents) • PREVENTION OF FEBRILE REACTIONS by Leucapheresis on collection of • blood, prior to or during transfusion • MAJOR PROBLEM : Shortage of blood; voluntary donation,dedicated donors; but paid donor in some countries

9. Thalassemia; Milestones in Clinical Management • 2. IRON CHELATION • Iron accumulation removes all benefits of transfusions because it causes severe organ damage through production of abundant free radicals which readily oxidize and destroy various cellular components. • Iron accumulates • in the liver (> liver failure) • in the endocrine glands (hypogonadism, hypoparathyroidism, • diabetes, other hormonal deficiencies) • in the heart (heart failure; the major cause of death) • in other organs

10. Tissue Iron Concentrations in Transfusion-dependent Thalassemia Patients Thyroid Fe = 1.6 – 6.8% d wt Heart Fe = 0.6 –1.3% d wt Liver Fe = 3.7-6.8% d wt Pancreas Fe = 1.4-3.9% d wt Adapted from Modell & Berdoukas, 1984

11. Thalassemia; Milestones in Clinical Management 3. MEASUREMENT OF THE IRON LOAD Iron load is reflected in the levels of ferritin in the serum (exceptions occur, especially in thalassemiaintermedia). Excess iron can also be measured directly by biochemical methods in liver (and other tissue) specimens, and indirectly in the liver and other organs including the heart by various non-invasive techniques, such as the SQUID , Superconducting Quantum interference device MRI , Magnetic Resonance Imaging and (Τ2 and Τ2*)Modified/Ultrarapid Magnetic Resonance Imaging Additional important information obtained by measuring the non-transferrin-bound plasma iron and/or Labile Iron Pool (NTBI/LPI) Iron accumulation increases in parallel with number of transfusions

12. Thalassemia Major; transfusional hemosiderosis. The noxious effect of transfusions.Ferritin levels and liver iron content increase with number of transfusions Total number of transfusions Total number of transfusions versus versus ferritin levels liver iron content

13. Shortened survival in relation to iron overload; High ferritin levels predict early death Ladis et al, 2005

14. Correlation of LIC with Liver T2* Voskaridou et al, 2005

15. Normal Severe Iron Overload Myocardial T2* MR Appearances

16. Lack of Correlation: Liver and Cardiac Iron Liver Liver

17. Ejection fraction by MRI versuscardiac T2* in thalassemia • (filled circles) and sickle cell disease (hollow squares) patients • Cardiac T2* as a function of transfusion duration. Sickle cell • disease patients were predominantly transfused for less than 13 years (13/17), Wood et al. Blood, 2003:

18. Various Iron Chelators; established or forgotten

19. Various types of “infusors”

20. The “pumps”

21. Survival in Patients with Thalassemia Treated with Deferoxamine Kaplan-Meier analysis of the survival of 257 consecutive patients with transfusion- dependent thalassemia, according to chelation patterns. Well chelated. DFO infusions>250/year; n=149; age 17.8+6.5 years; deaths 3 (2%) Poorly chelated.DFO infusions<250/year; n=108; age 19.7+5.9 years; deaths,58 (54%). Gabutti and Piga, Acta Hematol, 1996

22. Various Iron Chelators; established or forgotten

23. Effect of Deferiprone on Serum Ferritin Levels N° 21 11 18 84 Olivieri et al. 29 Al Refaie et al. Ferritin, mg/L 36 Olivieri et al. 26 Al Refaie et al. 162/151 Mazza et al. 71 Kersten et al. Hoffbrand et al. Cohen et al. Ceci et al. Maggio et al. Initial Final Hoffbrand AV. et al, Blood-2003

24. Various Iron Chelators; established or forgotten Deferasirox

25. Decrease of ferritin in iron-laden patients treated with varying dosages of : . Deferasirox in comparison to patients receiving iv Desferioxamine Cappellini, M. D. et al. Blood 2006;107:3455-3462

26. Effects of combined therapy (desferioxamine/deferiprone) in heavily iron laden patients after 12 months of continuous therapy; Note gradual decrease of ferritin levels (left) and clear increase of left ventricular ejection fraction (right)

27. Effects of combined therapy (desferioxamine/deferiprone) in heavily iron laden patients after 12 months of continuous therapy; Note gradual increase of Heart (left) and liver (right) T2* values

28. Thalassemia; Milestones in Clinical Management 4. ADDITIONAL MEASURES Correction of endocrine deficiencies; Normal Growth. Improvement of gonadal function. Pregnancy is now possible. Re-mineralization of bones; biphosphonates. Bone Marrow Transplantation. May offer cure to patients having a HLA-compatible sibling The future Re-induction of γ-chain (HbF) synthesis by selective recruitment of F-erythroid progenitors, de-repressing γ gene repressors or inducing the gene promoters and enhancers across the DNA sequence Gene therapy. So far one successful case. Others on the way. look forward to the next meeting !!!

30. Improvement of survival depicted according to year of birth in the UK based patients Patients born after “NEW” patients survive longer “OLD” patients died young Age at death Modell et al, 2010

32. Thalassemia; A dreadful Disease turned to a Chronic Condition ! CONTRIBUTORY FACTORS . The Patients. Through their steady insistence that something be done, their patience and their collaboration in several clinical trials and tests The medical and paramedical-nursing staff. Through their steady dedication to treating a chronic condition, with stubborn observance of the rules of good medical practice; through their kind approach to the patients and their endless patience. The success of the prevention programs wherever these were applied. Unless prevention were effective, the continuous addition of new patients would never allow the allocation of the available resources to the optimization of the care of the patients actually surviving.

33. Professor Antonio Cao A leader in thalassemia research, A productive scientist, An excellent clinician, An efficient organizer, and A good friend !