thalassemia : a dreadful disease turned to a chronic condition dimitris loukopoulos, md

THALASSEMIA : A DREADFUL DISEASE TURNED TO A CHRONIC CONDITION

Dimitris Loukopoulos, MDUniversity of Athens, Greece

A lecture dedicated to the late Professor Antonio CAO (+2012)

● 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

Thalassemia

● 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 by Itano, 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)

After the WW2; milesones in understanding the basic pathophysiology

Thalassemia Major; Bone Changes

Thalassemia Major; a protuberant spleen

Thalassemia Major; the beneficial effect of transfusions

Thalassemia Major; the beneficial effect of transfusions :

a clear increase in survival

Modell; early years

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

Progress in Thalassemia Milestones in Clinical Management

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

LiverFe = 3.7-6.8% d

wt

HeartFe = 0.6 –1.3% d

wt

ThyroidFe = 1.6 – 6.8% d

wt

PancreasFe = 1.4-3.9% d

wt

Adapted from Modell & Berdoukas, 1984

Tissue Iron Concentrations in Transfusion-dependent Thalassemia Patients

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 thalassemia

intermedia).

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

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

Shortened survival in relation to iron overload; High ferritin levels predict early death

Ladis et al, 2005

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

Normal

Severe IronOverload

Myocardial T2* MR Appearances

LiverLiver

Lack of Correlation: Liver and Cardiac Iron

A. Ejection fraction by MRI versus cardiac T2* in thalassemia

(filled circles) and sickle cell disease (hollow squares) patientsB. 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:

Various Iron Chelators; established or forgotten

Various types of “infusors”

The “pumps”

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%).

Survival in Patients with Thalassemia Treated with Deferoxamine

Gabutti and Piga, Acta Hematol, 1996

Various Iron Chelators; established or forgotten

0

1000

2000

3000

4000

5000

6000

Initial Final

Ferr

itin

, m

g/L

11

21

1884

29

36

26162/151

71

N°N°

Hoffbrand AV. et al, Blood-2003

Olivieri et al.Olivieri et al.

Al Refaie et al.Al Refaie et al.

Olivieri et al.Olivieri et al.

Al Refaie et al.Al Refaie et al.

Mazza et al.Mazza et al.

Kersten et al.Kersten et al.

Hoffbrand et al.Hoffbrand et al.

Cohen et al.Cohen et al.

Ceci et al.Ceci et al.

Maggio et al.Maggio et al.

Effect of Deferiprone on Serum Ferritin Levels

Various Iron Chelators; established or forgotten

Deferasirox

Cappellini, M. D. et al. Blood 2006;107:3455-3462

Decrease of ferritin in iron-laden patients treated with varying dosages of :

. Deferasirox

in comparison to patients receiving

iv Desferioxamine

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)

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

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 !!!

Improvement of survival depicted according to year of birth in the UK based patients

Patients born after

Age at death

“OLD” patients died young

“NEW” patients survive longer

Modell et al, 2010

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.

Professor Antonio Cao

A leader in thalassemia research, A productive scientist,An excellent clinician,An efficient organizer, and

A good friend !