Thalassemia

THALASSEMIA

THALASSEMIA Some children are born with defective limbs. Some with a defect in the senses. Yet, very little of us know that some children are born with a disorder of the red blood cell- a disorder that requires lifelong treatment and lifelong need to cope with a multitude of complications. Thalassemia is such a disorder- Mindanao Thalassemia Foundation, Inc., 2002

WHAT IS THALASSEMIA?COMES FROM 2 GREEK WORDSThalas meaning Sea+ Emia meaning bloodOrigin: Found in people in areas bordering the Mediterranean SeaIT IS A CONGENITAL HEMOLYTIC ANEMIA

THALASSEMIAHEME + GLOBIN = HEMOGLOBIN

Main defect: globin synthesis

Two major typesAlpha ThalassemiaBeta Thalassemia

INHERITANCE OF THALASSEMIA

Epidemiology of ThalassemiaWeatherall D, Akinyanju O, Fucharoen S, Olivieri N, and Musgrove P, Inherited Disorders of Hemoglobin." 2006. Disease Control Priorities in Developing Countries (2nd Edition). http://www.dcp2.org/pubs/DCP

Carrier frequencies of Thalassemia alleles (percent)Region-Thalassemia0-Thalassemia+-ThalassemiaAmericas0305040Eastern Mediterranean21802160Europe01912012Southeast Asia011130340Sub-Saharan Africa01201050Western Pacific0130260

CLASSIFICATION OF LPHA - THALASSEMIASilent CarriersHemoglobin HTraitHydrops Fetalis1122

Chart1

50

50

50

50

Column1

1

2

2

1

Sheet1

Column1

50

50

50

50

To resize chart data range, drag lower right corner of range.

Chart1

50

50

50

50

Column1

1

2

2

Sheet1

Column1

50

50

50

50


Chart1

50

50

50

50

Column1

1

2

Sheet1

Column1

50

50

50

50


Chart1

50

50

50

50

Column1

1

Sheet1

Column1

50

50

50

50


Chart1

50

50

50

50

Column1

Sheet1

Column1

50

50

50

50


CLASSIFICATION OF ETA - THALASSEMIAMinorMajor12

Chart1

50

50

50

50

Column1

2

2

2

Sheet1

Column1

50

50

50

50


Chart1

50

50

50

50

Column1

1

2

Sheet1

Column1

50

50

50

50


Chart1

50

50

50

50

Column1

2

2

1

1

Sheet1

Column1

50

50

50

50


CLINICAL MANIFESTATIONSPaleStunted growthDark skinEnlarged abdomen ( enlarged liver & spleen)Bulging cheekbonesFrontal bossingWidening of the bridge of the nose

PERIPHERAL SMEAR

TREATMENTBlood transfusion (prbc)Folic acidVitamin B 1-6-12Vitamin ESplenectomyChelation therapy ( removal of excess iron) either subcutaneous or oral route

IRON OVERLOADAccumulation of excess iron in the bodyCauses damage to the heartliver and other vital tissues in the bodyNon specific symptoms of fatigue, weakness, weight loss, abdominal discomfort

Organ Systems Susceptible to Iron Overload Clinical sequelae of iron overload Pituitary impaired growth, infertilityThyroid hypoparathyroidism,Heart cardiomyopathyLiver hepatic cirrhosisPancreas diabetes mellitusGonads hypogonadism

The build-up of iron in major organ systems can lead to serious organ dysfunction if not properly treated

Transfusion Therapy Results in Iron Overload1 blood unit contains 200 mg iron Overload can occur after 1020 transfusions ( estimated 1 year of monthly prbc transfusion)

Porter JB. Br J Haematol 2001;115:239252

ChelatorIronChelatorToxicExcretionIronWhat is Iron Chelation Therapy?M5.2

The Challenge of Compliance+For most patients with iron overload, transfusion must be accompanied by chelation therapy which requires the use of subcutaneous needles and infusion pumps.

Gabutti and Piga, Acta Haematologica. 1996;95:26 The Challenge of ComplianceYEARSSURVIVAL010203040506070809010002468101214161820222426283032343638400-75 infusions/yr75-150 "150-225 "225-300 "300-365 "

Drugs for Iron Chelation Therapy:Deferoxamine (Desferal)

Deferasirox (Exjade)

Deferiprone (Brand F)

Deferoxamine (Desferal, DFO)First-line treatment of transfusional iron overloadAdministered as slow subcutaneous infusion 57 nights/weekSide effectslocalized redness, swelling, itchiness and painreduced visual acuity, impaired color visionHearing lossGrowth retardation and bone changes in childrenDisadvantage: non-compliancePorter JB. Br J Haematol 2001;115:239252

Deferasirox (Exjade, ICL670)Tridentate* iron chelatorAn oral, dispersible tabletAdministered once daily (24 hr iron bodychelator)Highly specific for iron1

Deferiprone (Ferriprox, L1)Second-line treatment of iron overload when DFO therapy is contraindicated or inadequate1Tablet, three times a daySide effects of treatmentAgranulocytosis/neutropeniaArthralgia Nausea, vomiting, abdominal painIncreased levels of serum liver enzymes

IS THERE HOPE FOR A THALASSEMIC CHILD?YESSupportive treatment in correcting anemia( Periodic packed red cell transfusion)Chelation therapy to address complications of iron overloadGoal: Make children with thalassemia live long useful lives

**Thalassemias appear in virtually every ethnic group and geographic location in the world. They are most common in the Mediterranean basin and near the equator in Asia and Africa.The Thalassemia Belt extends along the shores of the Mediterranean and throughout the Arabian peninsula, Turkey, Iran, India and Southeastern Asia, including Thailand, Cambodia and southern China. The map behind the table shows the global distribution of - and -thalassemias.Mutations in the -globin chains are responsible for the three types of -thalassemia (major, intermedia and minor).There are two -chain genes on each chromosome, hence two disease alleles are possible (resulting in a total of four genotypes) in -thalassemia.In 0 thalassemia, both -chain genes on the chromosome are non-functional as individuals with homozygous genotypes produce no -chains.In + thalassemia, one of two genes on the chromosome is functional in the production of chains.An individual with a 0/+ genotype produces 1 of four -chains. This condition is known as hemoglobin H disease.

ReferenceWeatherall D, Akinyanju O, Fucharoen S, Olivieri N, and Musgrove P, "Inherited Disorders of Hemoglobin." 2006. Disease Control Priorities in Developing Countries (2nd Edition), ed., 663-680. New York: Oxford University Press. DOI: 10.1596/978-0-821-36179-5/Chpt-34

****Excess iron is deposited in major organs, resulting in organ damageThe organs that are at risk of damage due to iron overload include the liver, heart, pancreas, thyroid, pituitary gland and other endocrine organs1The liver is the principal site for iron storage and has the largest capacity for excess iron storage. Collagen formation and portal fibrosis can occur within 2 years of the start of a transfusion regimen. When the liver capacity is exceeded, iron is deposited in other organs1In the heart, iron collects in the cardiac muscle fiber cells, particularly in the ventricular wall and septum, the papillary muscles and the epicardium. Signs of myocardial damage due to iron overload present as arrythmia, cardiomegaly, heart failure and pericarditis1In patients with -thalassemia, iron loading of the anterior pituitary is primarily responsible for disrupted sexual maturation.2 Many patients experience growth failure due to growth hormone deficiency or the defective synthesis of insulin-like growth factorEven with chelation therapy, diabetes mellitus is observed in approximately 5% of adults with -thalassemia. Hyperinsulinemia often occurs with increased iron burden and progression of liver dysfunction due to iron damage. This is thought to be due to reduced hepatic insulin extraction which leads to pancreatic -cell exhaustion and reduced circulating insulin2Excess iron in patients with -thalassemia can also damage the thyroid, parathyroid and adrenal glands2

ReferencesGabutti V, Piga A. Results of long-term iron-chelating therapy. Acta Haematol 1996;95:2636Olivieri M. The beta-thalassemias. N Engl J Med 1999;341:99107

****Iron overload, a cumulative toxicity, is an inevitable, potentially life-threatening consequence of multiple blood transfusionsRed blood cell transfusion is the mainstay of therapy for thalassemia. Transfusions are initiated when hemoglobin falls below 7 g/dL, or at higher levels to help resolve specific problems such as growth impairment, bone changes or progressive splenomegalyTransfusions are administered in sufficient quantity and frequency to achieve a hemoglobin level of at least 9.3 g/dL; this level partly suppresses the erythropoietic drive that is producing ineffective red blood cells (RBCs). A regimen that maintains the mean hemoglobin level above 10.5 to 11 g/dL reduces marrow expansion, arrests bone changes and minimizes splenomegaly. This leads to a reduction in plasma fluid volume, allowing an increase in relative concentration of hemoglobin. In children, growth may improve and more normal physical activity can be expected1,2Table. Equivalent iron intake and transfusional requirements

ReferencesThalassemia management. Parts I and II. Semin Hematol 1995;32:1996:33(1)Olivieri NF & Brittenham GM. Blood 1997;89:739761**Chelation therapy involves the use of a drug that is capable of binding with a metal in the body to form what is called a chelate. By doing so, the metal loses its toxic effect, or physiological activity, and is then more readily removed from the bodyChelation therapy is generally reserved for the forms of iron overload in which phlebotomy cannot mobilize iron stores adequately or cannot be tolerated because of concurrent anemia

*****DFO is the current reference standard iron chelator for the treatment of transfusional iron overloadHowever, there are a number of challenges associated with DFO therapy24-hour iv DFO is the standard of care for cardiac failure due to iron overload**Deferasirox is a novel, orally active tridentate iron chelator with a high affinity and specificity for iron. It is indicated for the treatment of transfusional iron overload due to blood transfusions in pediatric and adult patientsThe indication shown is the Deferasirox Basic Prescribing Information indication, but Local Prescribing Information may differ**Use of deferiprone is limited to second-line therapy in patients with thalassemia major when DFO therapy is contraindicated or inadequate. This is due to the occurrence of serious side effects such as neutropenia and agranulocytosisDeferiprone is currently not licensed for use in the USA and CanadaInitial data (Pennell et al, 2006) suggest improved cardiac T2* and ejection fraction with deferiprone treatment. In this study, the mean doses administered were deferiprone 92 mg/kg/day and DFO 43 mg/kg for 5.7 days/week. The DFO dose is below that considered usual for a patient with serum ferritin >2500 g/L; the mean dose of deferiprone is in the upper range of the label recommendation and above the usual clinical dose.1 Additional prospective studies are required.Improvements in cardiac function due to reduction of cardiac iron are related to improvements in total body iron, reflected by reduced LIC and serum ferritin valuesTreatment with deferiprone may be associated with low plasma zinc levels in a minority of patients. Oral zinc supplementation is recommended in these patients2

References Pennell DJ et al. Blood 2006;107:37383744 Ferriprox [package insert]. Apotex Europe Ltd, 2004

Documents

Thalassemia