Thalassemia Management

M R Lokeshwar
Management of Thalassemic Child
It consists of:
- Confirmation of diagnosis
- Correction of the anemia with repeated RBCs transfusions.
- Removal of iron with iron chelating agents.
- Treatment of complications
- Correction of hemopoiesis by bone marrow transplantation.
- Prevention of the disease by antenatal diagnosis and genetic counselling.
- Pharmacological methods to increase gamma-chain synthesis.
- Gene replacement therapy.

Management of thalassemia major should be preferably done at a comprehensive thalassemia care center with outdoor transfusion facilities. A team approach includes a pediatric hematologist, a blood transfusion specialist, a psychologist and a social worker etc. This not only helps the patient and the family to face various medical and psychosocial problems, but also helps in early detection and management of complications.

Transfusion therapy in Thalassemia has two goals:
- To prevent anemia,
- To suppress endogenous erythropoiesis to avoid ineffective erythropoiesis.
Blood transfusion is mandatory for all children with Thalassemia major and for those children with Thalassemia intermedia who cannot maintain Hb above 7 gm% or for those who show evidence of growth retardation, severe bony changes or hypersplenism. Regular blood transfusions are presently the mainstay of treatment of Thalassemia.

When to transfuse:
- Transfusion is started at the time of diagnosis, that is when the child becomes clinically symptomatic.
- Thalassemia intermedia presents a complex therapeutic problem as these children may lead near normal life without being transfusion dependent. Occasionally, it may not be clear whether one is dealing with Thalassemia intermedia or major.
- Majority of Thalassemia intermedia can be detected by
*Age of onset of symptoms is usually more than two year.
*Increased indirect hyperbilirubinemia of 2 mg/dl or more.
*High reticulocyte count more than 10% at the time of diagnosis.
*Hb is usually maintained above 7-10 gm% without blood transfusion.
- If there is a doubt about the diagnosis, it is wiser to follow up these children regularly and transfusion therapy should be started only if Hb drops to less than 6-7 gm% and then regular transfusions are continued to maintain Hb level above 10-12 gm%.

What to transfuse?
- Transfuse them with triple saline washed packed cells to avoid transfusion reactions as saline washing minimises reactions due to leucocytes and plasma proteins.
- If cold centrifuge is required and is not available, simple packed cells may be given.
- Frozen cells: Freezing the RBCs to -80 degree Celsius, with an addition of glycerol to protect RBCs from damage of freezing and thawing, preserves 2,3-DPG and ATP in the red cells. Thus frozen cells can be stored as long as seven years at -20 degree Celsius. However, cost and high technology is involved, which do not permit its use even in developed countries.
- Leucocyte filters are also effective in eliminating neutrophils. Various filters available are ImmuGuard 500, Sepsea, Travanol, Ery Pure B, Pal leucocytes filters, which cost around Rs.150-500, and are not reusable. They are superfluous for those patients who have not developed febrile reactions.

How much to transfuse
- Transfusion regimen may be (1) low transfusion regimen where Hb is maintained around 6-10 gm%, (2)hypertransfusion: Hb level 10-12 gm% and supertransfusion where Hb is maintained at 12-14 gm%.
- The popular transfusion regimen of today is a hypertransfusion regime which aims at maintaining mean hemoglobin levels at12.5 gm/dl and pre-transfusion level not less than 10 gm%.
- Such a regimen permits normal growth and physical activity, suppresses erythropoiesis, thus preventing skeletal changes and gastrointestinal iron absorption and also inhibits extra-medullary hemopoiesis, thereby preventing splenomegaly and hypersplenism.
- With this regime, requirement of blood is high only at the start of therapy, and does not produce more iron overload than the low transfusion regime.
- Pre-transfusion Hb level should be high enough to inhibit bone marrow activity i.e. around 9.5-10 gm%.
- Post-transfusion Hb should not go above 16 gm/dl, since it can lead to hyperviscosity and its complications.
- When this therapy is started late in life when already hypersplenism has set in, splenectomy becomes mandatory.

Amount and Frequency of transfusion:
- It is desirable that patients receive not more than 10 cc packed cells/kg/day, which raises Hb level by about 3.5 gm/dl. In most of the patients, transfusion of about 10cc of packed RBC/kg every third week is adequate to maintain Pre-transfusion baseline Hb level at desired 10-11 gm/dl.
Rate of transfusion should be 5-7 ml/kg body weight/hour to avoid sudden increase in blood volume.
- In patients with cardiac insufficiency, transfusions may have to be given every second week and sometimes every week. - The duration of transfusion should be prolonged by decreasing the rate to 1-3 ml/kg/hr and not more than 5 ml/kg/hour.

How often to transfuse:
- Transfusions should preferably be given on an out-patient basis, at intervals of 2-4 weeks.
- Blood to be transfused should be crossmatched using Coomb's sera to minimize reactions. Blood should be taken from a voluntary donor and should be screened for hepatitis B antigen, HCV, Syphilis, malaria and HIV.
- The patients should be assessed annually for mean hemoglobin levels maintained overall blood requirement, physical growth and development, evidence of hypersplenism, antibody development and iron overload. On an average, the annual blood requirement is 180-200 ml of blood/kg. However, if the requirement exceeds this level, hypersplenism or development of anti-red cell antibodies have to be considered.

Complications of transfusions:
Febrile Reactions: It is seen in 3-20% of patients and may be due to leucocyte or platelet antibodies, antibodies against RBC antigens, allergic reactions to other plasma or blood proteins or due to pyrogens present in transfused blood. Chills followed by fever may occur within an hour of transfusion or may be delayed for 24 hours. Headache, nausea, and vomiting may be associated.
Febrile reactions usually respond to anti-pyretic and anti-histaminic agents. Leucocyte filters are also effective in eliminating neutrophils, which are responsible for pyrogenic reactions.

Hemolytic Transfusion Reactions: It occurs in 5-15% of cases. These are due to major or minor blood group mismatch and are characterized by fever, chills, tachycardia, nausea, vomiting,pallor, restlessness, anxiety, flushing of face, precordial oppression and pain, increased pulse rate and respiratory rate, generalized tingling sensation, pain in back and thigh, shock with cold and clammy skin, cyanosis and collapse. Delirium and convulsions may develop. Most feared complications are acute renal failure, hemorrhagic diathesis due to DIC and anaphylactic shock, all of which may be of life threatening proportions. Patients may develop indirect hyperbilirubinemia, hemoglobinemia, hemoglobinuria, reticulocytosis and positive Coomb's test and can occasionally go into acute renal failure and shock.
On onset of any early symptoms, transfusion should be stopped immediately. Anything unusual that alarms the mother should be respected. Older children (with Thalassemia) sometimes can even sense that something has gone wrong. As the mother always remembers the blood group of the child, it is a sound policy to show her the label on the bottle before starting the transfusion. For the first fifteen minutes, transfusion should be given slowly so as to detect any reactions at the earliest moment. If facilities are available, all patients should be typed for the common RBC antigens ie Rh, Cc, Dd, Ee, Kell, Kidd and Duffy (before starting regular transfusion). Monitoring of the antibodies must be continued life long.

Other reactions uncommonly seen and thought to be of uncertain etiology are sudden development of hypertension, convulsions, cerebral hemorrhage and edema after multiple transfusions.

Transfusion transmitted diseases like malaria, syphilis, hepatitis B, Hepatitis C, Cytomegalovirus, and HIV infection can occur. All thalassemics who are negative for the hepatitis B surface antigen and antibody, should receive Hepatitis B Vaccine -4 doses at day 0, 1 month, 2nd month and 12th month intramuscularly. It also can be given intradermally in the dose of 0.1 cc, thus reducing the cost. This has been found to be effective by some workers. However, efficacy is not well proven.

Two factors contribute to iron overload in a thalassemic child:
- Enhanced gastrointestinal absorption of iron.
- Transfusional siderosis
Normal body iron content is 3-5 gm, whereas in a thalassemic child it could be around 0.75 gm/kg. It results from increased GI absorption of iron and blood received during transfusion therapy. In normal individual 1 mg of iron/day is absorbed from the gut, while in a thalassemic child it may be as high as 10mg/day. Each cubic centimeter of packed cells contains 1-1.6 mg of iron. With an average annual transfusion requirement of 180 cc/kg of packed cells, the body accumulates 200 mg/kg of iron every year. Transfusional iron overload leads to deposition of iron in the heart leading to cardiomyopathy and irregularity of heartbeats, in the pancreas, in the Islet of Langerhans leading to diabetes, in the liver and spleen leading to hepatosplenomegaly, hepatic fibrosis and cirrhosis of liver, in the pituitary glands leading to growth retardation, delayed puberty character, in the thyroid and parathyroid gland leading to those subclinical or clinical organ dysfunction, and in the skin leading to bronze or black discoloration of skin. Increased susceptibility to bacterial infection especially Yersenia is seen with iron overload, because relatively high serum iron levels may favor bacterial growth, or because of blockage of the mononuclear phagocyte system by the excessive red cell destruction. Iron accumulation in the myocardium can lead to death, either by involving the conducting tissues or by causing intractable cardiac failure due to cardiomyopathy. Serum ferritin concentration reflects the iron overload and is usually above 1000 ug/L. S. Ferritin above 7500 ug/L are found to be lethal. Despite extensive research for ideal chelating agent, desferrioxamine is currently the only chelating agent of real value for the management of thalassemia, being able to promote the excretion of iron.

Desferrioxamine is a hydroxylamine compound produced by streptomyces pyloses. A single gram of DFO is able to bind 85 mg of iron. Desferal (Desferrioxamine) should be started before the age of 3-5 years. Given on daily basis for a minimum of 5-6 times per week, it is given subcutaneously over 6-8 hours using an infusion pump. The daily dose of Desferal is about 30-70 mg/kg and should be tailored according to the need of the patient. In general, the goal is to keep the serum ferritin level below 1000 ng/ml.

Toxicity is minimal, no tachyphylaxis has been observed. When given parenterally there may be liberation of histamine leading to bradycardia, hypo/hypertension, rigors, headache, photophobia, feeling cold and hot etc. When given subcutaneously, local pain, induration, irritability and redness may occur. Visual abnormality may occur and includes decreased acuity of vision, peripheral field vision defects, defective dark adaptation, thinning of retinal vessels, retinal stippling and abnormal visual evoked responses and cataract, in 4-10% of patients.
High incidence of high frequency sensori-neural hearing loss has been reported in 4-38% of patient. As the auditory and visual toxicity are reversible, yearly slit lamp examination and audiometry are mandatory. Delayed linear growth has also been reported in children under three years of age treated with Desferal and may be accompanied by mild skeletal abnormalities such as short trunk, sternal protrusion and genu valgum.

Ascorbic acid deficiency increases insoluble iron (hemosiderin). Vitamin C helps in conversion of hemosiderin into ferritin from which iron can be chelated. High doses of Vitamin C can lead to increased free radical reaction and lipid peroxidation resulting in tissue damage and rapid cardiac decompensation and even death. Addition of Vitamin C 100 mg daily prior to DFO therapy increases iron excretion. 60% of DFO chelated iron is excreted in urine and 40% in stool.

Over the last 20 years, more than 500 oral chelating compounds have been tried all over the world in search of an ideal chelating agent which can be effective, cheap, safe and can be given orally.
Among the various drugs under trial, few have completed animals studies, a few are being tried in human volunteers. The only drug which has entered human trial is Dimethylhydroxy Pyridone (1,2 Diemethy1-3-Hydroxy Pyrid-4-one (L1), developed in Hider's laboratory-London (40), also called as Deferiprone and is available in India with the brandname of Kelfer.

Deferiprone (L1): It mobilizes iron from transferrin, ferritin and hemosiderin. It is undergoing extensive trials in USA, UK, Canada, India and various other centres. Doses administered are 50-100 mg/kg body weight. Results show that it is 70-100% as effective as desferrioxamine. There has been no evidence of ear or eye toxicity. Urinary excretion of Ca, Cu, Mn, Mg was not affected. Kidney and liver parameters did not show any alteration. A few children had GI symptoms like nausea, vomiting, pain in abdomen and diarrhea. 20-30% children had arthropathy which was reversible after reducing the dose or on stopping L1. Physical findings included synovial thickening, synovial effusion, chondromalacia, mild flexion deformity of the knee, painful external rotation of the hip and vague generalized backache. ANA, dsDNA, antihistone antibodies were positive in a few cases. Drug-included lupus has been reported in few cases.
Absolute neutropenia and thrombocytopenia also have been reported in occasional cases. Physical examination particularly of the joints and complete blood count including platelet count must be done regularly when child is on Deferiprone (L1) therapy.

With the advent of hyper and super-transfusion therapy, splenomegaly and hypersplenism have become a rarity and hence splenectomyis usually not needed in these patients. If the child has already developed splenomegaly and signs of hypersplenism and is above 5 years of age, splenectomy is indicated. The indications for splenectomy are :
- An increase in the yearly requirement of packed cells more than double the basal requirement i.e. packed cell 200 cc/kg/year or more.
- Decrease in WBC and platelet count, which is a late manifestation of hypersplenism.
- All children needing splenectomy should receive pneumococcal vaccine
- H-influenza vaccine, and Meningococcal Vaccine 4 weeks prior to surgery.
- In endemic areas, prophylactic antimalarial treatment may be given to prevent malaria.
- Prophylactic penicillin therapy must be continued life-long.
- Episodes of infection should be treated promptly and newer antibiotics may be empirically started to prevent septicemia and other complications (if necessary these children should be hospitalized). Blood culture and sensitivity of antibiotics must be performed to guide treatment.

A ray of hope for permanent cure and better future for children with genetic disorders has brightened with the rapid advancement in the techniques and the success of bone marrow transplantation. The credit of first bone marrow transplantation in thalassemia major goes to E.Donald Thomas who performed this procedure in an 18 month old thalassemic child in 1982 using HLA matched elder sister as donor. This child was cured of thalassemia. The first BMT in thalassemia in India was successfully done by Dr.M.Chandi at Christian Medical Collage, Vellore.
The principles of bone marrow transplantation in thalassemia are:
- To destroy and prevent regeneration of defective stem cells
- Sufficient immune suppression for good engraftment of normal marrow
- To infuse stem cells with normal gene for beta globin.
- To prevent GVHD with high doses therapy of Busulphan, Cyclophosphamide, total body irradiation and other modalities.

All over the world, over 1000 transplantations have been done with a 70-80% cure rate.
The three most important adverse prognostic factors for survival and event-free survival are the presence of hepatomegaly (liver more than 2 cms. below costal margin), portal fibrosis and iron overload. (Lucarelli et al). Bone marrow transplantation is most successful in patients who are young, properly transfused, well-chelated and in good clinical shape without hepatomegaly.
The cost of BMT in India is around Rs.4-5 lacs and is being done at Christian Medical Collage, Vellore and Tata Memorial Hospital,Parel, Mumbai, and AIIMS in Delhi.

Propper et al in 1980, introduced the concept of transfusing thalassemic children with young red cells (Neocytes). In conventionally used unit of blood, red cells have a survival of 60 days. The mean age of a neocytes being 120 days, they survive in the recipient for 90 days, thus reducing the amount of blood required and prolonging the interval between two transfusions. IBM-2991 can be utilized for both washing the red cells and dividing them into populations of different ages by differential centrifugation technique. There is a reduction in the total units of blood transfused and iron overload. However this is not cost effective. The requirement of blood donors is increased and it requires costly equipment, technology and highly developed transfusion services. It is also time consuming.

Main pathology of beta thalassemia is reduced production of beta-chain leading to excess of unpaired alpha -globin chain which precipitate leading to ineffective erythropoiesis or hemolysis of RBCs resulting in anemia. It has been noted that hypomethylation of gene increases its expression and when methylated, the gene is not expressed. A number of drugs like 5'Azacytidine and Hydroxyurea have been shown to increase the production of gamma chains both in animals and human beings by causing hypomethylation of gene by decreasing the activity of the enzyme DNA methyl transferase. This increase in gamma chain synthesis prevents the Alpha chain precipitation by forming HbF (a 2 g 2) and thereby increasing the life span of red cells. 5-Azacytidine is recommended in the dose of 2 mg/kg/day intravenous infusion in ringer lactate or saline solution at the rate of 6 mg/hour for 7 days. This leads to an increase in Hb from 8 to 10.8 gm% in 2-3 weeks and an increase in fetal Hb from 1.06% to 20% on the 40th day. Side effects like nausea, vomiting, suppression of bone marrow and potential carcinogenesis have put limitations on its use in practice and unless a more effective compound with less toxicity becomes available such therapy is not recommended for thalassemia major. Augmenting the production of gamma chain reduces imbalance of globin chain and increases synthesis of HbF and thus lessening the severity of the disease. Various drugs that stimulate HbF production are 5-azacytidine, hydroxyurea, Butyrate compounds and erythropoietin.

These are found naturally increased in diabetic mothers. Their babies at birth have 100 % HbF. In vitro trials found the efficacy of these drugs in increasing the HbF production. This drug is given I.V. infusion slowly over 6-8 hours in dose of 200-400 mg/kg/day and has shown to increase HbF to 8-12% and cause a rise in Hb by 2-3 gm%. The problem with this drug is the tedious I.V. route. Oral analogue, Na Butyrate is useful in some patients to sustain the response after IV therapy. The side effects are few and include nausea, vomiting, electrolyte disturbances and occasional seizures. The actual efficacy of this drug is found to be lacking in many patients with sickle cell anemia and thalassemia intermedia. Further trials are awaited before it becomes available commercially. L-carnitine, an analogue of butyrate, has been tried in thalassemic patients but response obtained has been poor in most of the trials.

Genetic Engineering:
Insertion of normal gene in the stem cells of recipient remains a known challenging goal of future therapy. There are two main approaches to gene therapy : 1) Somatic approach in which non-germ line cells are involved. 2) Transgenic approach in which transfused gene can be expressed in subsequent generations. This therapy is still in experimental stage and likely to be therapy of future management of thalassemia.

Antenatal diagnosis and genetic counseling:
As thalassemia is inherited in an autosomal recessive manner there are 25% chances of producing thalassemia major child in each pregnancy. Population screening, identification of carriers, genetic counseling, antenatal diagnosis in women at risk and selective termination of affected fetus can prevent the birth of thalassemia major child. Prenatal diagnosis can be done by estimation of relative rate of globin biosynthesis by fetoscopy and fetal blood sampling around 16-18 weeks of intrauterine life or by analysis of foetal DNA by ultrasound guided chorionic villous biopsy at around 8-9 weeks of gestation or foetal amniocytes by amniocentesis.

With the better understanding of molecular biology and pathophysiology of thalassemia, advances in the transfusion therapy, organized quality care and effective chelation therapy, thalassemics can become fully active members of the society with proper physical, mental and sexual growth (without any disfiguration). They are able to profit from their opportunities and enjoy positions that they are entitled to in the society. With the free availability of oral chelators in near future, and establishment of more and more outdoor transfusion centres and thalassemia societies, the management of thalassemia major will become easier and economically feasible. With the advent of BMT, cure is possible. Gene therapy still remains a hope for the future. In developed countries where all these facilities are already available, more and more thalassemic children are leading a normal healthy life and even achieving parenthood. Prenatal screening and diagnosis as well as modern management of thalassemia are technologically complex and expensive, and thus their benefits remain limited only to the industrialized developed world & in certain centres in India. Unfortunately, developing countries like ours still have a long way to go.

Thalassemia Management Thalassemia Management 12/27/2013
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