Key Issues with Pharmacotherapy of β-ThalassemiaSABRINA BLASIG, JOVANA STANKOVIC, ANNA FU, JORDANA ELFASSY

PHM142

NOVEMBER 3, 2015

PHM142 Fall 2015Coordinator: Dr. Jeffrey HendersonInstructor: Dr. David Hampson

Outline• Introduction of the Disease

• Different types of β-Thalassemias• Symptoms/Diagnosis• Genetic Mutation

• Types of Treatment• Transfusion Therapy and Iron Chelation Therapy• Allogeneic Hematopoietic Stem Cell Transplant• Folic Acid Supplements

• Issues with Treatment• Summary

Introduction: β-Thalassemia• The Disorder

• Blood disorder caused by the lack of production of β-chains• Increased production of α-chains• Continual production of fetal hemoglobin (HbF)• Causes reduced production of hemoglobin

• Leads to a lack of oxygen in may parts of the body• Shortage of red blood cells (anemia)

Different Types of β-Thalassemias

1. Thalassemia Major (Cooley’s Anemia)◦ More severe◦ Usually by age 2◦ Reduced weight gain and growth◦ Jaundice (yellowing of skin and whites of eyes)◦ Enlarged spleen, liver, and heart◦ Misshapen bones

2. Thalassemia Intermedia◦ Signs and symptoms occur in early childhood or later in life◦ Mild to moderate anemia◦ Slow growth◦ Bone abnormalities

Introduction (continued)• Symptoms/Diagnosis

• Physically: pale skin, weakness, fatigue• Genetic Mutation

• Mutation in the HBB gene• B0 = no β-chain production• B+ = reduced amount of β-chains• Usually individuals have both mutations

• Inheritance• Autosomal recessive• People with only one HBB gene develop mild anemia (Thalassemia minor)• In few cases can be autosomal dominant

Types of Treatment1. Transfusion Therapy2. Folic Acid Supplements3. Allogeneic Hematopoietic Stem Cell Transplant

Transfusion Therapy• Administration of blood to increase erythrocyte levels• Regular hemoglobin levels include:

• 120 g/L to 160 g/L for females• 140 g/L to 180 g/L for males

• Initial hemoglobin level must be below 70 g/L • Cons: iron overload

• Iron chelation therapy (drug therapy)

Folic Acid Supplements• Recommended use during transfusion therapy• Optimizes erythrocyte production (basic building block for

healthy erythrocytes)

Allogeneic Hematopoietic Stem Cell Transplant

• Only treatment that cures thalassemia• Replacement of thalassemia-producing stem cells• Chemotherapy used to eliminate thalassemia-producing stem

cells• Continue on with iron chelation therapy

• Patients have a high risk of iron overload

Issues with Treatment: Transfusion Therapy and Iron Overload• Transfusion therapy can lead to iron overload and oxidative

damage• Increase in free iron = increase in the binding and conversion of H2O2 to

hydroxyl radicals• Hydroxyl radicals are extremely reactive radicals that can attack DNA,

RNA, and proteins• Fenton reaction: Fe2+ + H2O2 Fe3+ + •OH

Solutions for Transfusion Therapy• Solution: administration of iron chelation drugs that bind to

iron in the body and promote its excretion in the urine and/or stool

• Drugs:• Desferrioxamine (Desferal)• Deferasirox (Exjade)• Deferiprone (Ferriprox)

• These drugs remove iron through different pathways

Desferrioxamine (Desferal)• Administered as a slow subcutaneous infusion via portable pump• Mechanism of Action:

• Forms stable complex with iron• Chelates with lysosomal ferritin iron and hemosiderin iron• Chelate is soluble and excreted in urine and bile

• Long term use can lead to diarrhea, cramps, fever, and nephrotoxicity

Deferasirox (Exjade)• Available as a tablet• Mechanism of Action:

• Oral iron-chelating agent• Target cytosolic ferritin iron • Reduces liver iron concentrations and serum ferritin levels

• Adverse effects:• Acute renal failure• Hepatic failure• Gastrointestinal hemorrhage

• Adverse effects can be fatal

Deferiprone (Ferriprox)• For patients with thalassemia syndromes when

current chelation therapy not successful• Mechanism of Action:

• Chelates to ferric iron (Fe3+) to target cytosolic ferritin iron• No controlled trials show treatment benefits, ex

improvement in symptoms• Adverse effects:

• Agranulocytosis• Neutropenia

Issues with Treatment: Hematopoietic Stem Cell Transplant• Graft vs. Host Disease (GVHD)

• Proliferating grafts mount an immune response against the body• Body recognized as foreign by transplanted immune cells

• Adverse Effects:• Fibrosis of liver, skin, and lungs• Persistent diarrhea• Growth impairment

• Prevention:• Chronic use of immunosuppressant drugs (e.g. cyclosporine) before and

after treatment to reduce risk of GVHD• Impacts quality of life

Issues with Treatment: Hematopoietic Stem Cell Transplant (continued)• Graft Rejection

• 5-30% of transplants• Can be fatal, especially in high-risk patients• Transfusion dependence can reemerge

• Infertility• Males and females• Hormone levels should be tested periodically and if necessary, hormone

replacement therapy• Post-Transplant Late Effects Due to Chemotherapy

• Secondary cancers of the skin or soft tissue• Hypothyroidism• Growth impairment

Summary• β-thalassemia is a blood disorder caused by the lack of production

of β-chains• Causes a reduction in the production of hemoglobin anemia

Type of Treatment Treatment Problems Drugs and Adverse Effects

Transfusion Therapy Iron overload treat with iron chelating agents

Desferrioxamine (Desferal) nephrotoxicityDeferasirox (Exjade) acute renal failure, hepatic failure, GI hemorrhageDeferiprone (Ferriprox) agranulocytosis, neutropenia

Folic Acid n/a n/a

Allogeneic Hematopoietic Stem Cell Transplant (only curable treatment available)

Graft vs. Host Disease (GVHD) Graft Rejection Infertility Effects due to Chemo

Chemotherapy secondary cancers of skin or soft tissues, hypothyroidism, growth impairment

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