Treatment of Thalassemia Major
Current management aims to prevent the crippling effects of anaemia, and iron overload to ensure normal growth & development.
Principals of management:
• Blood Transfusion-Packed cells (RBCs) transfusion to maintain normal haemoglobin (pre-transfusion Hb above >10gm/dl.) throughout life
• Hepatitis B vaccination before start of transfusion therapy or as early as possible
• Prevention and management of transfusion reactions
• Prevention and management of transfusion transmitted infections like Hepatitis B, C, HIV etc.
• Iron Chelation
• Splenectomy (if required)
• Endocrinal Management
• Psychosocial support
• BMT
• Prevention
BLOOD TRANSFUSION
Diagnosis of Thalassemia must be established before transfusion therapy is started. There should be no haste to transfuse blood in a child just because the Hb is 7 gm/dl or less. A proper diagnosis of anaemia must be made before first blood transfusion since it masks the original blood picture and increases the difficulty for the definitive diagnosis of Thalassemia Major or other haemoglobinopathies.
It is equally important to have the following investigations:
- Complete Red cell typing (ABO, Rhesus, Kell, Kidd, Duffy, C,c, E.e,).
- Screening of patients for Hepatitis B, Hepatitis C and HIV.
- Haematological & DNA Studies
- Family studies by HPLC for genetic counseling.
- HLA Typing of siblings & parents
- Initiation of Hepatitis B vaccination (if not already given)
When to start transfusion
Generally the diagnosis of Thalassemia Major is made when the Hb has already fallen below 6 gm/dl.
If at the time of diagnosis Hb is above 8 gm/dl the transfusion should be postponed till the haemoglobin level remains above 8gm/dl.
If the Hb is between 7-8 gm/dl, growth & development of the child should be closely monitored. If the child’s growth doesn’t follow as expected, transfusions should be started.
If the haemoglobin level falls below 7gm/dl blood transfusion therapy should be initiated.
Decision to start transfusion should not be delayed indefinitely because some changes are irreversible.
Transfusion Regimen
Pre-transfusion Haemoglobin level should always be kept > 9.5 gm as far as possible.
The advantages are:
- Normal Growth & Development.
- Decrease in facial deformity
- Bones are strong.
- Decreased incidence of enlargement of heart
- Enlargement of Spleen doesn’t occur.
- Reduction in absorption of iron from gut.
- Physical & Psychological wellbeing.
- It helps if the patient undergoes for BMT later in life.
If the child is already on low transfusion it is better to change to High transfusion regimen as early as possible. It will require just 3-4 extra transfusions for 1-2 months.
If spleen is extra large, change of regimen from low to high fails then only option is removal of spleen.
Type of blood to be transfused
Red Blood Cells should be fresh (not more than 4-5 days old). Presence of even smallest amount of plasma or white blood cells can provoke antibody formation or allergic reactions.
These can be prevented or reduced considerably by using leucocyte depleting filters.
Amount & Rate of transfusion:
The amount & rate of transfusion depends on the patient’s Hb level, status of the heart and the preparations used. When there is no cardiac problem it is advisable to give 10-15 ml packed RBCs/kg in about 3-4 hrs. Transfusion time should never exceed 6 hrs.
When the heart is affected or Hb level is less than 5gm/dl small transfusions at 1-2 weekly intervals are recommended along with a diuretic (Lasix) and the infusion rate should not exceed 2ml/kg/hr.
Approximately 180 ml/Kg of pure red cells per year are required to maintain Hb level above 10gm/dl in patients whose spleen has not been removed. When spleen has been removed, patients require 133 mg/kg of pure red cells/year.
Transfusion Interval:
3-4 weekly intervals are ideal to maintain pre-transfusion haemoglobin near 10gm/dl without disturbing the social & psychological aspect of the patient.
In presence of heart problems & Hb < 5gm/dl, 1-2 weekly interval schedules has to be followed.
Evaluation of transfusion treatment: the clinical record
The following data should be regularly recorded at each transfusion:
- Date of transfusion
- Bag number of the blood transfused
- Amount of blood transfused
- Height
- Weight
- Size of liver & spleen
- Transfusion reactions (details)
IRON OVERLOAD
In thalassemia major, due to increased activity of bone marrow, body absorbs increased quantities of iron, as much as 3-4 mg/day depending upon severity of anemia. Absorption depends upon iron content in food & it may increase up to 10 mg/day if iron tonics are given.
On an average each unit of blood contains 200-250 mg of iron. A patient receiving 15-30 unit of blood/year receives between 3-6gm of iron i.e. about 3-6 times the normal annual iron requirement of 1gm.
There is a tremendous range of variability in end organ toxicity among patients who seemingly have the same amount of tissue iron i.e. end organ function, as well as tissue iron concentration, must be serially monitored during the management of chronic iron overload.
Iron loading of the liver can be detected after about six months of monthly transfusions, while cardiac loading takes about eight to ten years. The liver loads linearly with time, whereas the heart remains devoid of iron for years. However, once it starts, iron loading of the heart is very rapid. Evidence of liver dam age can occur after about four years of transfusions.
Evaluation of Iron Overload
I Serum Ferritin:
Serum iron & TIBC are of no value to know iron overload. Serum ferritin reflects iron stores in the body tissues and is a good indicator of iron storage status. Serum ferritin levels are disproportionately increased in fever, infections, chronic liver disease, arthritis etc. and decreased in vitamin C deficiency. It is a convenient way to monitor iron over load. The change in ferritin is a reasonable predictor of change in total body iron. While there is about a 70 percent correlation of ferritin with LIC (liver Iron concentration) in population studies, there is tremendous scatter in the relation, so fer ritin is a poor marker of absolute iron content in an individual patient
II Liver biopsy:
Liver biopsy & quantitative measurement of liver iron, is highly reliable though it is invasive and entails elevated risk. It should be reserved only for special indications. The LIC is reported in wet weight and dry weight. The LIC in patients with thalassemia should always be maintained below 7,000 µg/g dry weight and 1,100 µg/g wet weight in order to avoid iron-induced organ damage.
III MRI T2*
MRI has enabled to measure the amount of iron in the organs and tissue-specific factors. The onset of cardiac dysfunction is more complex and less well understood. A cardiac T2* greater than 20 ms is not associated with iron-induced cardiac dysfunction. A car diac T2* between 10 and 20 ms indicates excess iron in the heart and represents a warning for potential cardiac dysfunction. If the T2* is less than 10 ms, the risk of cardiac dysfunction is high, and treatment should be considered emergent.
Under full chelation with desferioxamine, about 50 per cent of liver iron can be removed in four to six months. It takes about 17 months to remove half of the heart iron.
IV SQUID - Superconducting QUantum Interference Device (Ferritometer)
It is non-invasive, sensitive, and accurate, works on high-power magnetic field. Iron interferes with the field and changes in the field are detected. It is an effective way to non-invasively monitor LIC. This device is not easily available. Only 4 machines are available worldwide
IRON CHELATION
When to start Chelation?
Serum ferritin levels should be assessed after 12-15 transfusions. Chelation therapy should be initiated when serum ferritin is above 1000ng/ml.
1. DESFERAL (Desferioxamine)
Dose 25-50 mg/kg/day subcutaneous with the help of infusion pump over 8-12 hours. Ten percent Desferal solution is prepared in water for injection i.e. one vial of Desferal is dissolved in 5ml water for injection. If more than one vial is to be administered 2.5 to 5 ml of water for injection can be added per vial of Desferal. Desferal solution should not be stored for more than 24 hours. Subcutaneous Desferal can be given in the abdomen at 1” away from umbilicus, antero-medial thighs and in adolescents/adults also at triceps. It should be given subcutaneous over 8-12 hours.
Infusion pumps and special 27G short needle, long tubing scalp vein sets are available with Thalassemia Societies at subsidized cost.
Desferal should never be added in blood bag. However, it can be given along with blood transfusion with the help of infusion pump in the same i v canula. If the pump is not available then Desferal solution can be further diluted in 50-100ml of 5% Dextrose or Normal saline and given by separate line with help of 3 way canola together with blood transfusion alongwith diuretics
If patient is incapable of using subcutaneous Desferal due to local drug reactions like pain, tenderness or swelling, intravenous Desferal can be given. But intravenous Desferal should be initiated only in consultation with referral center.
General Desferal dose recommendations
S.Ferritin < 2000 ng/L 25mg/Kg/day
S.Ferritin 2000-3000 ng/L 35mg/kg/day
S.Ferritin >3000 ng/L 50mg/kg/day
Vitamin C - 50-150 mg should be given after setting the pump on. Desferal with high dose of Vitamin C (500 mg) may cause cardiac impairment. However, this side effect is reversible on withdrawal of Vitamin C.
High-dose, continuous Desferal
An aggressive chelation regimen is recommended when liver iron is greater than 20 mg/g dry weight, or cardiac T2* is less than 20. Deferoxamine at 60 mg/kg per day, 24 hours per day, 7 days per week may be indicated with patients with severe iron over load and vital organ dysfunction. Patients with a T2* less than 10 ms or a liver iron greater than 30 mg/g dry weight are candidates for this therapy. If the patient has cardiac dys function, this therapy is mandatory and must be emer gently started. Other indications are:-
a) patient is highly overloaded and had not used any chelation for long,
b) patient is preparing for BMT,
c) patient is planning for pregnancy with high serum ferritin,
Desferal can be administered intra venously using a central line. The intravenous therapeu tic dose is 60 mg/kg per day. Continuous intravenous infusion can remove large quantities of iron and is very effective in reversing the cardiac complications. Intravenous infusions of Desferal are given very slowly. Rapid intravenous infusion may lead to collapse.
Undesirable effects:
- Frequent pain, swelling, burning, itching, and rashes at site of injection/infusion occasionally accompanied by fever, chills and lethargy.
- High doses of Desferal especially in patients with low S. ferritin may lead to the visual & hearing side effects.
- Desferal increases susceptibility to Yersinia enterocolitica & Yersinia pseudotuberculosis infection.
- Concurrent treatment with prochlorperazine (Stemetil) may lead to temporary impairment of consciousness.
- Use of Desferrioxamine should be avoided during pregnancy if serum ferritin level is between 1000-2000 ng/ml. However in patients with higher serum ferritin levels Desferal can be given safely after Ist Trimester.
L1/DEFERIPRONE/KELFER
Dose-75-100 mg/Kg/day in two or three divided oral doses. It is available in 250 and 500 mg capsules. When child cannot swallow capsules, the capsule can be opened and medicine can be mixed with honey or sweetening agent and be given.
Adverse Effects
Nausea, vomiting, diarrhoea, abdominal pain & distension (5%) All these symptoms are mild and subside on continuation of treatment. Addition of anti acids, anti vomiting drugs help in reducing these symptoms.
Pain in joints is observed in 10-20% of cases. Incidence decreases with reduction of dose (upto 50mg/kg/day) or on withdrawal of drug. Pain killers along with Glucosamine help in relieving the symptoms. If not, the drug should be temporarily withdrawn. It may be restarted again after some time. Absence removal destruction
Deficiency or elimination of white cells, neutrophils or platelets has been observed in 1-2% of cases. It is reversible on discontinuation of therapy.
Monitoring of Patients on Kelfer
i) Hb, TLC, DLC & platelet count every 3-4 weekly interval or whenever there is any sign of infection.
In case of infection, Deferiprone should be stopped immediately and get CBC (Hb, TLC, DLC, Platelet) done. Kelfer should be stopped if TLC is below 3,000 cu mm or absolute neutrophil count <1,000 cumm or platelet count < 1,00,000 cu mm. It may be re-started after counts return to normal under close supervision of the doctor. However in case of recurrent loss of neutrophils, leucocytes or platelets the Kelfer should not be re-started. If the neutrophil count drops to <500 cu mm or severe infection the child should be referred to a referral center. (Kelfar should not be restarted if the above side effects are noted because of this drug)
COMBINATION THERAPY
It should be given in consultation with the referral centre.
Indications:
- If serum ferritin level is high (>5000 ng/ml)
- In presence of cardiac or endocrine dysfunction
- Patients who can not afford Desferal
- Patients who are intolerant to full dose of Kelfer
Dose
- It should be individualized based upon the patient’s condition and several other factors
DEFRASIROX/ICL670C/EXJADE “ASUNRA/DESIROX”
It is a new once daily oral iron chelator. It should be taken empty stomach at least 30 minutes before food, preferably at the same time each day. The tablets are dispersed by stirring in a glass of water or apple or orange juice (100 to 200 mL) until a fine suspension is obtained. After the suspension has been swallowed, any residue must be resuspended in a small volume of water or juice and swallowed. The tablets must not be chewed or swallowed whole.
Dosage
- The recommended initial daily dose of Defrasirox is 20-30 mg/kg body weight.
- 20 mg/kg body weight for patients well-managed with Desferal or Kelfer,
- 30 mg/kg for those whose S. ferritin is high (>2000 ng/ml) or their blood transfusion requirement is high.
- 10 mg/kg for thalassaemia intermedia, if transfusions are required occasionally and S. ferritin is not high.
- In India, many patients will require 30 mg/kg as their initial S. ferritin may be quite high due to lack of adequate iron chelation in the past.
- Above 30 mg/kg not recommended since there is no experience with doses above this leel.
- Ferritin level consistently below 500 ng/ml requires an interruption of treatment
S. ferritin be monitored every month, the dose of Defrasirox be adjusted based on the S. ferritin and tailored to the individual patient’s response and therapeutic goals.
Adverse (toxic) effects:
- 20% of patients may complain nausea, vomiting, diarrhoea, or abdominal pain. Maintain adequate hydration in patients who develop diarrhoea or vomiting.
- Skin rash are found in about 5% of patients. For mild to moderate skin rashes, defrasirox may be continued without dose adjustment, since the rash often resolves spontaneously. For more severe rashes, interruption of treatment may be necessary.
- Mild, increases in serum creatinine level, may occur in about 35% of patients. It is recommended that serum creatinine be assessed before starting defrasirox and monitored regularly thereafter. Defrasirox be reduced by 10 mg/kg if a non-progressive rise in serum creatinine by >33% above the average of the pre-treatment measurements is observed.
- Urine albumin should also be performed monthly.
- Elevations of SGOT, SGPT & alkaline phosphatase were reported in about 2% of patients. Liver function be monitored every month. If there is a persistent and progressive increase in liver enzymes defrasirox should be interrupted.
- Deficiency or elimination of white cells, neutrophils or platelets has been observed in 1-2% of cases. It is reversible on discontinuation of therapy. Hb, TLC, DLC & platelet count should be done intermittently and defrasirox should be discontinued for those having unexplained reduction of blood cells.
- Hearing loss and early cataracts have been very rarely observed in patients. Hearing & Eye testing (including fundoscopy) is recommended before the start of treatment and every year. If disturbances are noted, dose is reduced or interruption may be considered.
Most of these reactions are dose-dependent, generally transient and mostly resolve even if defrasirox is continued or by reducing the dose.
Defrasirox has not been used in patients with kidney or liver disorders and must be used with caution in such patients.
No growth retardation has been noticed. However body weight and longitudinal growth should be monitored at regular intervals.
Defrasirox must not be combined with other iron chelator (Desferal or Kelfer) therapies as the safety of such combinations has not been established.
EVALUATION OF IRON OVERLOAD
Serum ferritin is a convenient way to monitor iron over load. Since fer ritin is a poor marker of absolute iron content in any patient, it is important to have 3 to 5 fer ritin measurements in a year to determine the direction of change in iron. Because of the sensitivity of ferritin levels to inflammation, vitamin C, and iron, changes between two consecutive measures can be very misleading. A patient can almost completely empty the liver of iron and reduce ferritin to very low levels even though significant amounts of iron may remain in the heart.
Heart involvement is the most life-threatening of the iron-related complications. The heart often remains iron-free for many years. Once iron loading starts in heart, it pro gresses very rapidly. Removal of iron from the heart progresses very slowly with a half-life of approximately 17 months. The heart often does not unload until the liver iron drops to very low levels. The foundation of effective treatment of iron in heart problems is continous exposure to chelation. This can reduce dysfunction even before the heart begins to unload iron.
SPLENECTOMY
Inadequately transfused thalassemia major and thalassemia intermedia patients invariably develop splenomegaly (enlargement of spleen). It results in increased blood requirement, increased iron load & enhanced risk of blood transfusion transmitted infections. Children may develop deficiency or of white cells, neutrophils or platelets and it becomes difficult to maintain pre-transfusion Hb near 10gm/dl. Some children may also have protruded abdomen
Indications of Splenectomy (surgical removal of spleen)
* Enlargement of spleen with fall in mean annual Hb concentration
* Increase of annual blood requirement by 50% or more over initial requirement.
* Packed red cell consumption of more than 250 ml/kg/year.
* Deficiency or of white cells, neutrophils or platelets.
* Reduced red cell survival of 15 days or less by Chromium studies.
* Splenomegaly resulting in abdominal discomfort.
Frequent blood transfusions at early intervals may help in avoiding splenectomy in early stages.
Splenectomy, preferably be postponed to after 5th year of age. Patient should be immunized against Pneumococcal, Meningococcal A & C and Haemophilus influenza B (HiB) at least 4 weeks prior to operation.
Care After Splenectomy
Penicillin tablets or injection Benzethine Penicillin every 3 weeks life long or at least till 25 years of age. It is advisable to give Aspirin 50-100mg/day if platelet count exceeds 8,00,000/mm3. After removal of spleen infections should be dealt with broad-spectrum antibiotics immediately without waiting for laboratory reports and patient should be referred to major center.
ENDOCRINE COMPLICATIONS
Growth Impairment
Delayed Puberty
Hypothyroidism
Hypoparathyroidism
Osteoporosis
Diabetes Mellitus
Growth
Growth parameters should be recorded twice a year.
Weight: It should be measured before breakfast with minimum clothing.
Length while lying down: It is recorded until 2 years of age.
Standing height is recorded after 2 years of age.
Sitting height: is measured from top of head to buttocks while the child is sitting.
All these measurements should preferably be recorded on the growth charts for proper monitoring and early detection of growth retardation.
Delayed puberty: Complete lack of pubertal development in girls by the age of 13 years and in boys by 14 years.
Hypogonadism: Testicular size (less than 4 ml) and the absence of breast development by the age of 16 years.
Arrested puberty: Lack of pubertal progression over a year or longer.
If there is any endocrine complication the patient should be referred to a referral centre for detailed investigation, diagnosis and treatment.
CARDIAC COMPLICATIONS
Iron-induced damage to heart muscles results in heart failure, other complications and sudden death in thalassemics. The average age of presenting cardiac symptoms in a non-chelated thalassemic is 11 years with the range 6-18 years. Over 60% of these develop heart failure by 16 years of age with the range of 6-25 years, 50% of those who develop cardiac failure die within one year if left untreated. Patients should be referred to a referral centre for proper diagnosis and treatment.
Cardiac Examination: - 12 lead ECG
Tread Mill Test
X-Ray- Chest
Echocardiogram
HOLTER
MUGA SCAN
- ECG shows changes in T waves and ST segments of anterior chest leads. Sometimes R & S waves are also affected suggesting bilateral enlargement. Conduction disturbance in the form of bundle branch block may be seen.
- 24 hour Holter ECG analysis is the standard method for detecting the cardiac arrhythmia.
- Tread Mill Test (TMT) is of value for identifying patients at risk for cardiac arrhythmias or ventricular dysfunction.
- Echocardiography: Echocardiography reveals functioning of various heart chambers along with reduction in ejection fraction.
- Doppler analysis of intracardiac flows may give the best insight into abnormalities of diastolic function.
Treatment plan
- Asymptomatic patients with normal heart condition
- No restrictions to physical activity and body exercise.
- Asymptomatic patients with moderate cardiac impairment
- No restriction to physical activity
- Medication
- Symptomatic patients with severe cardiac impairment
- Restriction of physical activity
- Slow blood transfusion with diuretics
- Management of cardiac complications should be under the guidance of referral centre.
D I E T
- High calorie, high protein nutritious diet
- Foods rich in iron should be avoided e.g. meat, liver, kidney, egg yolk, green vegetables, jaggery etc.
- Food should not be cooked in iron pots.
- Meals should include bread, cereals, milk, moong dal, soya bean etc. to reduce the iron absorption
- Vitamin C rich fruits e.g. citrus fruits should be avoided along with meals.
- Strong tea be taken along with meals.
- Milk and milk products should be frequently taken.
LIFE EXPECTANCY AND QUALITY OF LIFE
It depends on the treatment. Overall survival is given below:
No Diagnosis/No Treatment 1-5 years.
Only Blood Transfusion & No Chelation 8-18 years
Repeated blood transfusion to maintain Hb10 gm along with
iron chelation to maintain S.Ferritin 1000mg NORMAL
However transfusion transmitted infections like Hepatitis B, C and HIV does affect the quality of life & total life span. With the current management the Thalassemics live a normal healthy life. They attend school, play sports, and take part in all sorts of social activities. In countries where ideal treatment is available many Thalassemics are now touching sixty. They are doctors, engineers, professors, executives, self-employed, married and have their own “Normal” children. Even in India many Thalassemics have crossed thirty, highly educated, employed, living happy married life with normal children
Cure
Bone Marrow Transplantation in Thalassemia
Bone Marrow Transplantation (BMT) is a good option for permanent cure of Thalassemia Major patients provided an HLA matched real brother or sister is available. If naive cells for transplantation are collected from the peripheral blood it is called stem cell transplantation (SCT) and if from placental blood then it is termed as cord blood transplantation (CBT).
Peripheral stem cells are richest and cord blood is the poorest stem cell source. The most rapid engraftment is observed with peripheral blood transplants and the slowest with cord blood transplants. The risk of developing graft versus host disease (GVHD) also varies with the source of stem cells. Peripheral blood transplants show an increase in chronic GVHD compared with bone marrow, while cord blood transplants have a lower risk of GVHD.
Donor Requirement for Thalassemia major
An HLA identical sibling is the ideal donor. A sibling who is identical in the HLA-A, B and DR is considered HLA identical. In spite of HLA identity, there is always variation in the minor histocompatibility.
Blood group compatibility is not essential. After successful BMT, the blood group of the recipient will also change. The donor may be normal or Thalassemia carrier/minor. In that case after successful transplant, the patient will be Thalassemia carrier/minor which is acceptable.
Partially matched sibling donor, or an unrelated HLA identical donor are not routinely recommended for Thalassemia major, as life is good with adequate blood transfusions and chelation.
Risk Factors Transplantation
- Three classes of patients can be identified on the basis of the inadequacy of iron chelation, liver enlargement, and the presence of portal fibrosis in the liver:
- patients in class 1 have none of the above characteristics,
- patients in class 2 have one or two of the above characteristics, and
- patients in class 3 have all above three characteristics.
- The repeated blood transfusions lead to formation of antibodies, and this results in increased graft rejection. Blood transfusions with leucocyte filters minimise the chances of antibody formation. Some patients receive blood transfusions from their family members. Blood transfusion from family members increases the chances of graft rejection.
- In thalassemia patients receiving a transplant from an HLA-identical sibling, the incidence of rejection is directly related with the patient's class of risk, Currently class 1, class 2 and class 3 patients receiving bone marrow transplantation (BMT) from an HLA-identical related donor have 87, 85 and 80% of probability of thalassaemia-free survival.
- The result of transplant in adult patients is less successful.
A Hickman catheter is inserted prior to the transplant. This catheter is needed for chemotherapy, infusion of stem cells, frequent blood sampling, intravenous antibiotics, blood components and intravenous nutrition.
Conditioning Procedure
Patient is given extremely high doses of chemotherapy or radiotherapy or both. The aim is:
a) Eradication of the abnormal cells,
b) Suppression of the immune system of the host (recipient) so that the allograft is not rejected, and
c) Clearing a “physical space” to allow adequate growth of the donor stem cells.
The conditioning is also toxic to other organs like the liver, lungs, kidneys, gastrointestinal tract and reproductive system.
After conditioning therapy, patients require multiple red cell and platelet transfusions during the 2-4 week period, till engraftment occurs.
The Actual Transplantation
The donor’s bone marrow is collected by repeated aspiration from the hip bone, under general or spinal anesthesia and collected in a bag. Bone marrow is transfused through the veins and the donor marrow cells enter into the recipient’s marrow space. It takes about two to three weeks to engraft that is the time when the stem cells start producing adequate number of RBCs, WBCs and platelets. During this period very intensive support is required. Engraftment is considered established when the neutrophil count reaches 500/cu mm on 3 successive days.
Infection remains an important cause of disease & death after bone marrow transplantation.
Patient’s defense system has been destroyed with chemotherapy and is at risk of developing transfusion associated - graft versus host disease (TA-GVHD) with a very high mortality. To prevent this, blood products should be irradiated prior to transfusion. With proper precautions this is not a major problem.
Growth Factors are administered to reduce the duration of engraftment, mostly in cases with delayed engraftment.
Toxicity related to Conditioning
a) jaundice, enlargement of liver, pain right upper abdomen, fluid in abdomen
b) passing of blood in the urine, painful urination and increased urinary frequency
c) convulsions
d) lung problems
e) skin, nail and oral complications.
Failure to engraft or graft rejection is a difficult complication due to many factors like inadequate stem cell numbers, infections, graft-versus-host disease and immunological mediated processes. Bone marrow graft may get rejected by functional host lymphocytes, which survive the conditioning regimen.
Acute GVHD: This occurs within the first 3 months after transplant. It classically affects three tissues, namely the skin, gut and liver and may be accompanied by fever. The severity can be graded according to the extent of skin involvement, degree of hyperbilirubinemia and severity of diarrhoea.
Chronic GVHD: This develops later than 100 days after transplant and often follows acute GVHD but may also develop de novo. Clinically it resembles auto immune disorders like scleroderma with skin rash, sclerosing bronchioloitis and liver dysfunction. The death rate varies from 20% to 40%. Management is with drugs which suppress immune system like cyclosporine, prednisolone etc. in various combinations. After a year or so these drugs can be tapered off.
GVHD is more common in older patients and those with one or more HLA mismatches or unrelated HLA matched transplants. It is for this reason that unrelated or older Thalassemic patients do not do well with BMT.
Infections remain a major complication in the post transplant period. Viral infections are important causes of diseased state & death. Bacterial infections again predominate after three to six months, similar to the condition in patients whose spleen has been removed.
The procedure is similar to BMT except for differences in the method of collection of the stem cells and slight changes in the engraftment potential. Administration of some medicines for 4 to 5 days results in a high circulating stem cells which can be collected by a cell separator. The cells are collected from veins and it takes two to four hours. The donor need not be admitted, does not require anesthesia and is spared the needle pricks for marrow aspiration.
CORD BLOOD STEM CELL TRANSPLANTATION
Placental blood, which is routinely discarded during delivery, is potentially has vast supply of fetal hematopoietic stem cells. Cord blood (CB) stem cells have distinct advantages of enriched proportion of immature stem cells and higher growth rate. The small number and relative immaturity of naïve T cells of cord blood lymphocytes is expected to reduce the risk and severity of graft versus host disease (GVHD). The activation pattern of cord blood T cells is less in magnitude than that in adult counterparts.
The main limitation of cord blood transplants (CBT) is the limited number of nucleated cells available in a unit. As compared to bone marrow transplantation, the time for engraftment in cord blood transplantation is much longer, taking a month for neutrophils to engraft and more than fifty days for platelet engraftment. There is also a higher incidence of rejection. This leads to a high transplant related death. The main advantage of CBT is a lower incidence and gravity of graft versus host disease. There is very limited experience with unrelated CBT in Thalassemia major. The high incidence of graft rejection after related cord blood transplantation suggests that it is not the procedure of choice. Moreover, the procedure of cord blood transplantation is more complicated than bone marrow transplantation, as it takes longer for engraftment and initial death rate is higher.
Fewer than 25% of thalassemia patients have a nonaffected HLA-matched sibling donor; for undergoing transplantation, the remaining patients need to find a suitable, HLA-compatible donor within the registries of unrelated volunteers now enrolling more than 9 million donors worldwide.
In a recent study involving 68 thalassemia patients transplanted in six Italian BMT Centers from unrelated volunteer donors, disease-free survival (DFS) with transfusion independence was 65.8%
In India unrelated transplants are not being carried out at present.
INDIAN EXPERIENCE
Christian Medical College, Vellore, where the first BMT was done in 1986 is also one of the largest centres in the world performing BMTs in Thalassemia major. AIIMS, New Delhi is another large centre where BMTs on Thalassemia major have been performed. A number of other centres have started these therapeutic procedures.
RECOMMENDATINS FOR TRANSPLANTATION IN THALASSEIA MAJOR
a) As soon as a child is diagnosed to have Thalassemia major, the parents must be counselled about the curative therapy i.e. BMT from an HLA identical sibling. HLA matching with the siblings should be done as soon as possible. If there is an HLA mached donor, the patient should be referred to a transplant center.
b) Blood transfusion to the patients should be from unrelated donors. It should be emphasized that blood from the parents, and blood relatives should not be infused to the patient as this will increase the risk of graft rejection.
c) Blood transfusions should be with leucocyte filters, to reduce the chances of alloimmunisation.
d) Regular iron chelation should be commenced to reduce the iron overload and improve the outcome of BMT.
f) Unrelated bone marrow or cord blood transplants are complicated, with a higher risk of graft rejection and graft versus host disease. Most centers in India are not carrying out unrelated transplants for thalassemia major.
