Thalassemia55

Thalassemia in BangladeshRecent epidemiological data show that Bangladesh is one of the most highly affected countries with haemoglobin disorder in Asia with the following carrier & frequency rates

a) Thalassemia Major – 4.1%b) Haemoglobin E – 6.1%c) Anticipated new affected births annually: 6435 – based on

carrier rates, population size & other demographic indices.d) Prevalence: Living patients – 50,000-60,000

Ref:Thalassemia International Federation.

Special Article

Advances in Management of β Thalassemia

Presented by : Dr. S. M Jasim Uddin.

Registrar Department of Haematology .Ward : 37.Chittagong Medical College & Hospital.

Chittagong.

Ref: Indian Journal of paediatrics, Vol 76, Feb,2009 &Mediterranean Journal of Haematology & Infectious Diseases,Dec 2009

Abstract

Thalassemias represent the most common single-gene disorder causing a major public health problem.Thalassemia and hemoglobinopathies probably developed over 7000 years ago as a defense against malaria. In simple terms, Thalassemia is caused by a mutation in either the ɑ-globin chain or the β -globin chain which combine equally in red cells to form hemoglobin. These mutations lead to varying degree of anemia resulting into thalassemia minor, intermedia or major.

Present write up relates to advances in the management of β -thalassemia major

Key words : Thalassemias; Hemoglobinopathies; Anemia; Single-gene disorder; Management

Ref:Indian Journal of paediatrics,Vol 76,Feb,2009

Clinical Types of β-Thalassemias :


Common presentations of TDT :

• Anaemia• Jaundice• hepatosplenomegaly• Bone deformity• Endocrine abnormalities• Cardiac dysfunction & cardiomyopathy.


Presentation of NTDT :

• Infrequent blood transfusion• Mild to moderate anaemia specially in other

comorbid condition.• Hyperbilirubinemia with episodic jaundice.• Leg ulcer• Mild hepatosplenomegaly.


Diagnosis for Thalassemia:

1. CBC : anaemia, low red cell indices.2. PBF : Hypochomia, Microcytosis, Target cells,

Schistocytes, Spherocytes & Normoblasts.3. Hb ELECTROPHORESIS : Low Hb A, Raised A2 & F.4. HPLC (High performance liquid

chromatography) : Not available in all centres.5. GENETIC TESTING: Used in research Lab.


Peripheral blood film

Hb-Electrophoresis of β-Thalassemia Major

ADVANCES IN GENERAL MANAGEMENT• Early detection of carrier/affected individuals

• Start of folic acid therapy.

• Regular & scheduled red cell transfusion: hypertransfusion / super transfusion.

• Iron monitoring & chelation therapy

• Splenectomy

• Haemoglobin F inducers : Hydroxyurea, 5 Azacitidine, butyrate.

Ref: Guidelines for clinical management of Thalassemia 2nd revised edition

Safe Transfusion

• Transfusion of red cell is the cornerstone of treatment in thalassemia patient.

• Repeated transfusion may cause: 1.Risk of unwanted transmission of diseases:

Minimized by improvement of donor screening & using leucocyte filter including Viruses specially CMV.

2. Alloimmunization with HLA antigen : Minimized by leucodepletion by using Leucocyte filter.

3.GVHD or Immunological reaction prevented by gamma irradiation of donor blood.


Transfusion therapy FAQ related to transfusion therapy in thalassemia

1. When & whom to initiate transfusion ?2. How blood is processed for safe & effective

transfusion?3. Is there any optimum haemoglobin level for effective

transfusion?4. Do transfusion requirements affect the iron chelation?5. What are the most serious transfusion related events?


Transfusion therapy………contd

When & whom to transfused1. Confirm laboratory diagnosis of TDT like thalassemia major2. Laboratory criteria: Hb < 7.0 g/dl in 2 occasions in 2 weeks

apart(excluding all other contributory causes such as infections) Or

3. Laboratory & clinical criteria including:- Hb > 7.0 g/dl with - -facial changes- -poor growth - -fractures &- Extramedullary haematopoeisis:


Blood products: Recommendation & Consideration

1. ABO & Rh compatibility2. C, E & Kell antigen3. Leuco-reduction 4. T & B cell depletion 5. Storage product (CPD-A, OAS) 6. Haematocrit values7. Transfusion interval 2-5 weeks to maintain pre-transfusion Hb level 9.0-10.5 g/dl & 11-12 g/dl for co-morbid cardiac patients but not to exceed post-transfusion Hb level 14-15 g/dl.


SPECIFIC MANAGEMENT (CURATIVE)Hematopoietic Stem Cell Transplantation (HCT)

• HSCT has become an alternative modality of treatment.• The best results have been obtained with HLA-matched siblings.• Outcome of SCT is influenced by hepatomegaly,portal fibrosis &

previous inadequate iron chelation.• Recently it has been demonstrated that cord blood

transplantation is effective & safe than matched related BMT for paediatric patients.

• Haplo identical HSCT is also feasible in patient with thalassemia who lacks a matched related donor.

Ref:Indian Journal of Pediatrics,Vol76,Feb 2009 & Blood 2010 : 115 (16); 1296-1302

Complications & it’s Advanced Managements

• Iron overload• Transfusion transmitted diseases• Bone deformity• Venous thrombosis ,leg ulcers & stroke• Hypersplenism• Massive splenomegaly & splenic rupture• Osteoporosis• Delayed puberty• Short stature.

Ref: N ENGL J MED 353;11 September 15, 2005

Management of Thalassemia & Treatment Related Complication

Ref: N ENGL J MED 353;11 September 15, 2005

Iron Overload

• Iron overload causes most of the mortality & morbidity associated with thalassemia(TDT).

• Iron deposits mainly in the liver,heart & endocrine glands and causes tissue damage, ultimately organ failure.

• Cardiac failure are still the primary cause of death.• Both transfusional iron overload & excess

gastrointestinal absorption are contributory. Ref:The New England Journal of Medicine,Sep,2005

Ref:The New England Journal of Medicine,Sep,2005

Methods of Monitoring Iron Loading

•Serum ferritin• Liver biopsy - LIC• MRI for Fe•SQUID-BLS (Super Conducting Interface Device Biomagnetic Liver Susceptometry)

Ref:Indian Journal of Pediatrics,Vol 76,Feb,2009

Serum Ferritin• Serum ferritin is easy to perform frequently

• Serum ferritin does not give reliable information on degree of patient iron loading


LIVER BIOPSY(Perl’s stain) Hepatic Iron Overload.


Clinical Implication of Ferritin Levels & Liver IronConcentration

• )

• ,

• . .

Liver iron conc. (mg/g dw)

Ferritin level (ng/mL)

Clinical implications

<2 <500 Low iron stores; consider decreasing or holding chelation temporarily

2–7 500–1499 Ideal range

continue current chelation

>7–15 1500–2500 Increased iron stores; increase chelator dose and/or change chelator if ferritin and/or liver iron trend is not improving

>15 >2500 Elevated iron stores associated with increased risk of complications and death; increase chelator dose and/ or change chelator; consider combination chelation therapy

04/12/2023 Ref:Mediterranean Journal of Haematology & Infectious Disease.Dec 2009

Why Is Measurement of Liver Iron Concentration Important?

• A patient’s liver iron concentration (LIC) value is the best measure of total body iron stores

• A patient’s LIC value enables better informed decisions on when to– Initiate chelation therapy– Increase chelation dose– Decrease chelation dose– Change mode of chelator delivery (eg, IV mode)

Ref: New Engl J Med. 2000;343:327-331

LIC Is a Reliable Measure of Total Body Iron Stores in Patients with Thalassaemia Major

There is a very strong correlation between LIC and total body iron stores in thalassaemia major patients.

Ref: N ew Engl J Med. 2000;343:327-331

MRI :(Methods of Measurement of Tissue Iron Concentrations)

• Relaxometry measurement of R2 is the most widespread method for measurement of liver iron concentration

• Relaxometry measurement of T2* is the most widespread method for assessing iron in the heart.

• Ref:New Engl J Med. 2000;343:327-331

Monitoring Iron Overload by MRI

An R2 image of an iron-overloaded human liver superimposed on a T-2 weighted image.Bright areas represent high iron concentration; dark areas represent low iron concentration.

Clark PR, et al. Magn Reson Med. 2003;49:572-575.

Why Is Measurement of Heart Iron Important?

• Heart iron measurements (by cardiac MRI) have been shown to have a high sensitivity and specificity for predicting cardiac failure within 12 months for thalassaemia major patients

• In a study of 652 thalassaemia major patients– 83% of patients who developed arrhythmia had a cardiac

T2* of <20 ms– 98% of patients who developed heart failure had a cardiac

T2* of <10 ms

Kirk P, et al. Circulation. 2009;120: in press.

When to Measure Iron in the Liver vs the Heart

• Patients on regular blood transfusion– Measure liver iron annually– Measure heart iron annually after 20 units have been

transfused• Patients with hereditary haemochromatosis

– Measure liver iron at diagnosis if >40 years of age and serum ferritin >1000 ng/mL

• Patients with thalassaemia intermedia– Measure liver and heart iron annually after age 10 years– If the baseline cardiac T2* in normal range, subsequent

cardiac T2* no more frequent than 3–5 years unless there is difficulty controlling the liver iron

Ref: New Engl J Med. 2000;343:327-331

Goals of Iron Chelation Therapy

• Prolong survival

• Maintain iron balance/induce negative iron balance

• Avoid accumulation of toxic free iron

• Prevent/reverse organ dysfunction

• Avoid chelator toxicity

• Maximize adherence to prescribed therapy

• Maximize quality of life Ref:Mediterranean Journal of Haematology & Infectious Disease,Dec 2009

When & How to Start Chelation?

a.Chelation is started after 10-20 transfusions, and when serum ferritin is in the range of 1000-2500 μg/L; this

usually occurs after 12-18 months of transfusion and after 2 years of age.

b. In general chelation can be delayed until 4 years without any significant known detrimental effect.

c. Children aged 4-6 years are started on desferrioxamine, and if this is not effective, can be changed to deferasirox.

d. Children over 6 years can be started on desferrioxamine or deferasirox, with an increasing trend towards using deferasirox in first line.

Ref:Mediterranean Journal of Haematology & Infectious Disease,Dec 2009

Available Iron Chelators:

1. Desferioxamine (DFO)2. Deferiprone (DFP)3. Deferasirox (DFX)

Ref:Mediterranean Journal of Haematology & Infectious Disease,Dec 2009

Characteristics of DFO,DFP,DFX

Desferrioxamine Deferiprone Deferasirox

Structure Hexadentate Bidentate Tridentate

MWT 560 139 373

Iron-Chelator Complex

1:1 1:3 1:2

t ½ 20 min 53-166 min 1-16 hrs

Absorption Negligible Peak 45 min Peak 1-2.9 hrs

Iron Excretion Urine+Faecal Urine Faecal

Therapeutic Daily Dose

40 mg/kg 75-100 mg/kg 20-30 mg/kg

Route Parentral Oral Oral

Clinical Experience > 40 years > 20 years > 8 years

Ref:Mediterranean Journal of Haematology & Infectious Disease.Dec 2009

Adverse Effects of DFO,DFP & Deferasirox Desferrioxamine Deferiprone Deferasirox

1.Generalized sensitivity reactions,

2.Local soreness related to the site of injection,

3.Exacerbation of the urinary tract infections ,

4.Hearing loss

5.Visual neurotoxicity

6.Growth and bone defects

1.Agranulocytosis

2.Painful joints,

3.Gastrointestinal side – effects

4.Transient transaminitis,

5.Zinc defi ciency

1.Abdominalpain,nausea, vomitingdiarrhoea,

2.Skin rashes.

3.Non - progressive increases in serum creatinine


Continuous Desferal Therapy Using Port

Indian Journal of Paediatrics,Vol 76,Feb 2009

Combination therapy with Deferiprone and Desferrioxamine

Increased efficiency : additive or synergistic effect

• Fewer DFO infusions: improved adherence• Optimize chelation from different pools: DFO

for liver, deferiprone for heart• Reduced dosage of individual chelator may

minimize chelator toxicity.


Deferasirox• New,potent,once daily,oral iron chelator.• Effective removing iron from all parts of the body.• It is specific for iron.• Restores contractile properties of cardiac cells.• Significantly improve cardiac T2* as assessed by

MRI.• Reduce labile pool of iron.• Adverse effects include non-progressive increase

in S.creatinine,GI tract disturbances,skin rash,rise in hepatic enzymes.

Indian Journal of Pediatrics,Vol 76,Feb 2009

Deferasirox is Specific For Iron


Deferasirox Restores Contractile Properties of Cardiac Cells


Significant Improvement in Cardiac T2*


Deferasirox Reduces LPI


Deferasirox is Effective for 24hrs


Deferasirox Tablets to be Dissolved in Water


Splenectomy Splenectomy may cause more transfusion requirement &

invites many life threatening events. It should generally be avoided in NTDT patients younger than 5 years.

Splenectomy should be reserved for cases of: 1.Worsening anaemia leading to poor growth & development,

when transfusion therapy is not possible or iron chelation therapy is unavailable

2.Hypersplenism which roughly measured by yearly BT 230 ml/kg/yr of 75% haematocrit donor

3.Massive splenomegaly with concern about possible splenic rupture


Gene Therapy• Gene therapy may become a reliable tool for

thalassemia in future.• This therapeutic strategy involves insertion of a

normally functioning β-globin or γ-globin gene into the patient’s autologus hematopoietic stem cells.

• The major problems associated to gene therapy are “vector” construction & expression of wanted gene.

• Therefore,gene therapy must await further research.

Ref:Indian Journal of Pediatrics,Vol76,Feb 2009

Prevention

• Mass awareness• Family screening & carrier detection• Antenatal diagnosis• Discourage marriage between traits/carriers.


Prenatal Diagnosis

• β/γ ratio: <0.025 in fetal blood – Thal major

• Chorionic villous biopsy at 10-12 wks

• Amniocentesis at 15-18th wk gestation Analysis of fetal DNA

• PCR to detect β globin gene

Ref: New Engl J Med. 2000;343:327-331

CONCLUSION

TDT is responsible for most of the morbidity & mortality of thalassemias through transfusion related complications & iron overload.Iron overload limits the curative options(BMT) in future.Traditional chelation with DFO has less complaince & less effect for cardiac iron, can be overcome by newer chelators.BMT & Gene therapy has future prospects.

Take Home Message

All the advances in the overall management of thalassemia is still behind

PREVENTION

Thank you

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