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RESUME THALLASEMIA

Darah manusia dewasa mengandung tiga jenis hemoglobin. Hemoglobin A (HbA)

merupakan Hb terbanyak dengan struktur molekular α2β2. Selain HbA, terdapat dua jenis Hb lain,

antara lain HbF (fetal haemoglobin) dengan struktur molekular α2γ2 dan HbA2 dengan struktur

molekular α2δ2. Jadi, hemoglobin manusia dewasa (HbA) merupakan suatu tetramer yang

tersusun atas dua rantai α dan dua rantai β. Rantai α dikode oleh dua gen α-globin (α1 dan α2)

pada kromosom 11, sedangkan rantai β dikode oleh sebuah gen β-globin pada kromosom 16.

Mutasi atau delesi pada gen tersebut dapat terjadi pada thalassemia.1

What is Thalassaemia?Thalassaemia is an inherited genetic disorder that affects the production of red blood cells (RBC), which can lead to severe anemia. Thalassaemias are produced by many different genetic abnormalities that result in the absence or deficiency of a globin chain, which disrupts the production of haemoglobin.

Haemoglobin is an oxygen carrying protein made in RBC’s. It is made up of two alpha globin chains and two beta globin chains and each contains a heme molecule. The heme molecule has an iron atom in the center giving haemoglobin the ability to carry oxygen; it also gives it a reddish color, which is why our blood appears red. If the production of one of the globin chains is disrupted, then haemoglobin does not assemble properly and it loses its ability to carry oxygen. The improper assembly of haemoglobin also results in increased destruction of RBC’s.

  Alpha Thalassaemia

There are 4 alpha-globin genes on chromosome 16; therefore alpha thalassaemia has 4 different manifestations that correlate with the number of alpha-globin genes affected.

Silent Carrier Alpha Thalassaemia Trait

Haemoglobin H Disease

Alpha Thalassaemia Major (hydrop fetalis)   Beta Thalassaemia

Individuals with beta thalassaemia have deficiency in one or more of their beta-globin genes. There are only 2 genes on chromosome 11 that code for beta-globin chains, therefore the incidence of beta thalassaemia major is higher than alpha thalassaemia major or haemoglobin H disease because the probability of having a deficiency in 2 genes versus a deficiency in 3 or 4 genes is higher.

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Beta Thalassaemia Trait Beta Thalassaemia Intermedia

Beta Thalassaemia Major

Darah manusia dewasa mengandung tiga jenis hemoglobin. Hemoglobin A (HbA)

merupakan Hb terbanyak dengan struktur molekular α2β2. Selain HbA, terdapat dua jenis Hb lain,

antara lain HbF (fetal haemoglobin) dengan struktur molekular α2γ2 dan HbA2 dengan struktur

molekular α2δ2. Jadi, hemoglobin manusia dewasa (HbA) merupakan suatu tetramer yang

tersusun atas dua rantai α dan dua rantai β. Rantai α dikode oleh dua gen α-globin (α1 dan α2)

pada kromosom 11, sedangkan rantai β dikode oleh sebuah gen β-globin pada kromosom 16.

Mutasi atau delesi pada gen tersebut dapat terjadi pada thalassemia.1

Pada proses pembuahan, anak hanya mendapat sebelah gen globin beta dari ibunya dan sebelah lagi dari ayahnya. Bila kedua orang tuanya masing-masing pembawa sifat thalassemia maka pada setiap pembuahan akan terdapat beberapa kemungkinan. Kemungkinan pertama si anak mendapat gen globin yang berubah (gen thalassemia) dari bapak dan ibunya, maka anak akan menderita thalassemia. Sedangkan bila anak hanya mendapat sebelah gen thalassemia dari ibu atau ayah, maka anak hanya membawa penyakit ini. Kemungkinan lain adalah anak mendapatkan gen globin normal dari kedua orang tuanya.

Penyakti thalassemia disebabkan oleh adanya kelainan / perubahan / mutasi pada gen globin alpha atau gen globin beta sehingga produksi rantai globin tersebut berkurang dan sel darah merah mudah sekali rusak atau umurnya lebih pendek dari sel darah normal (120 hari).

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Bila kelainan pada gen globin alpha maka penyakitnya disebut THALASSEMIA ALPHA, sedangkan kelainan pada gen globin beta akan menyebabkan penyakit THALASSEMIA BETA.

KARENA DI INDONESIA THALASSEMIA BETA LEBIH SERING DIDAPAT, MAKA SELANJUTNYA KAMI HANYA AKAN MENJELASKAN MENGENAI

THALASSEMIA BETA.

Klasifikasi Thalassemia-β dan Manifestasinya5

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Homozigot Thalassemia αo.

Patofisiologi thalassemia α sebanding dengan jumlah gen yang terkena. Pada homozigot (--/--) tidak ada rantai α yang diproduksi.1

Sekilas Tentang ThalasemiaPenyakit thalasemia merupakan suatu kelainan darah bersifat genetik dimana kerusakan DNA akan menyebabkan tidak optimalnya produksi sel darah merah penderitanya serta mudah rusak sehingga kerap menyebabkan anemia.

Pusat dari mekanisme kelainan ini terletak pada salah satu gen pembentuk hemoglobin pada sel darah merah manusia, yang sekaligus juga berfungsi utama sebagai pengangkut oksigen.

Terkait dengan sifat genetik yang diturunkan pendahulunya ini, dikenal istilah 'thalasemia trait' (pembawa sifatnya).

Sebagaimana orang-orang normal, individu-individu pembawa gen ini sama sekali tidak menunjukkan adanya suatu gejala. Masalah yang lebih serius akan terjadi bila sang pasangan juga merupakan seorang pembawa sehingga lebih berpotensi melahirkan anak dengan thalasemia mayor yang nantinya akan memerlukan transfusi darah secara rutin selama hidupnya.

Tindakan transfusi ini pun bukan merupakan suatu terapi penyembuh namun hanya bersifat

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suportif dalam mengurangi gejala dan punya resiko menyebabkan penumpukan zat besi dalam tubuh pula, yang lebih lanjut bisa menyebabkan pembengkakan hati dan limpa. Ada dua jenis thalasemia yang dikenal berdasarkan gejala klinis dan tingkatan keparahannya, yaitu thalasemia mayor dimana kedua orang tuanya merupakan pembawa sifat, serta thalasemia minor dimana gejalanya jauh lebih ringan dan sering hanya sebagai pembawa sifat saja.

Pada thalasemia mayor gejala dapat muncul sejak awal masa anak-anak dengan kemungkinan bertahan hidup terbatas.

Beberapa kasus yang ditemukan selama ini juga membuat munculnya penggolongan yang lebih baru, yaitu thalasemia intermedia dimana kondisinya berada di tengah-tengah kedua bentuk tersebut.

Ferriprox (Deferiprone) therapy should be initiated and maintained by a physician experienced in the treatment of patients with thalassaemia.Deferiprone is usually given as 25 mg/kg body weight, orally, three times a day for a total daily dose of 75 mg/kg body weight. Dosage per kilogram body weight should be calculated to the nearest halftablet. See table below for recommended doses for body weights at 10 kg increments.Doses above 100 mg/kg/day are not recommended because of the potentially increased risk of adverse reactions; chronic administration of more than 2.5 times the maximum recommended dose has been associated with neurological disorders (see sections 4.4, 4.8, and 4.9).There are limited data available on the use of deferiprone in children between 6 and 10 years of age, and no data on deferiprone use in children under 6 years of age.Due to the serious nature of agranulocytosis, that can occur with the use of deferiprone, special monitoring is required for all patients. Cation must be used when the patients abosolute neutrophil count (ANC) is low, as well as when treating patients with renal insufficiency or hepatic dysfunction.

Ferriprox® (deferiprone) is an oral iron chelator. Ferriprox® is indicated for the treatment of iron overload in patients with thalassemia major when deferoxamine therapy is contraindicated or inadequate.Ferriprox® tablets first obtained marketing approval from The European Medicines Agency (EMEA) in August 1999. It is now approved in 58 countries and is under review by local regulatory authorities in many other jurisdictions. It is estimated that thousands of individuals with iron overload are being treated with Ferriprox. Recently, the EMEA has also approved Ferriprox® 100 mg/mL oral solution..

MORE RECENTLY, THE ORAL IRON CHELATOR DEFERASIROX (EXJADE, ICL670 , [NOVARTIS PHARMA AG, Basel, Switzerland]) has been approved for the treatment of iron overload in children and adults in several countries, including the United States, where it received orphan drug designation and was granted priority review status. Good bioavailability and a long half-life of 11 to 19 hours mean that deferasirox is suitable for once-daily dosing, for oral tablet, which may overcome the compliance problems associated with deferoxamine.39

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Clinical trials have established the efficacy and safety of deferasirox in a range of transfusion-dependent patients, including a large proportion of pediatric patients (42% of the total patients

enrolled in the program).40–43 During a period of 2.5 years, these trials have demonstrated that deferasirox effectively reduced liver iron concentration and serum ferritin levels in pediatric, as well as adult, patients in a dosage-dependent manner.44 Deferasirox dosing recommendations are the same for pediatric and adult patients, taking into account changes in weight over time. A starting dosage of 20 mg/kg body weight is recommended.45 After commencing therapy, serum ferritin should be monitored monthly and, if required, the dosage of deferasirox adjusted in steps of 5 or 10 mg/kg every 3 to 6 months on the basis of serum ferritin trends. The dosage can tailored to the individual patient's response and therapeutic goals (maintenance or reduction of body iron burden). Dosages of deferasirox should not exceed 30 mg/kg per day because there has been limited experience with dosages above this level.

Iron overload is an inevitable clinical consequence for patients with transfusion-dependent anemias. Iron chelation therapy is, therefore, an important and integral part of their supportive

care. Pediatric patients who are not adequately chelated risk delayed sexual maturation, retarded growth, progressive liver and heart disease, and a reduced life expectancy. To date, the reference-standard iron chelator has been deferoxamine, but the demanding regimen of regular and prolonged infusions presents a significant challenge, particularly for pediatric patients. Recent advances have led to the development of the oral chelators deferiprone and deferasirox. The potential for deferiprone to decrease cardiac disease is important. Its benefit outweighs the risk for neutropenia for many patients. Oral chelators, such as deferasirox and deferiprone, signify a notable change in clinical practice, presenting the option of a convenient oral therapy to adults and children with a range of chronic anemias.

Adult

Initial: 20 mg/kg PO qd on empty stomach 30 min ac; calculate dose to nearest whole tabMaintenance: Adjust dose by 5- to 10-mg/kg/dNote: Dissolve tab completely in water, orange juice, or apple juice, then immediately drink susp; resuspend any remaining residue in small volume of liquid and swallow

Pediatric

<2 years: Not established>2 years: Administer as in adults

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Figure 6. The concept of combination therapy.

Abbreviations: DFO, deferoxamine; DFP, deferiprone; NTBI, non-transferrin-bound iron.

Modified from Liu et al.20

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Hematology 2006 © 2006 The American Society of Hematology

New Advances in Iron Chelation Therapy ; Alan R. Cohen .

Table 1. Deferoxamine.

Characteristics    Route of Administration SQ, IV

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    Half-life 20 minutes    Primary routes of iron excretion Urine/Stool    Dose range 20–60 mg/kg/dGuidelines for Monitoring Therapy    Audiometry and eye exams annually    Serum ferritin level quarterly    Assessment of liver iron annually    Assessment of cardiac iron annually after 10 years of ageAdvantages    Long-term experience    Effective in maintaining normal or near normal iron stores    Reversal of cardiac disease with intensive therapy    May be combined with deferiproneDisadvantages    Requires parenteral infusion    Ear, eye, bone toxicity    Poor compliance

Table 2. Deferiprone.

Characteristics    Route of administration PO    Half-life 2 to 3 hours    Primary route of iron excretion Urine    Dose range 50–100 mg/kg/dGuidelines for Monitoring Therapy    CBC with differential weekly    ALT level monthly for first 3–6 months, then every 6 months    Serum ferritin level quarterly    Assessment of liver iron annually    Assessment of cardiac iron annually after 10 years of ageAdvantages    Orally active    Safety profile well established    Enhanced removal of cardiac iron    May be combined with deferoxamineDisadvantages    May not achieve negative iron balance in all patients at 75 mg/kg/day    Risk of agranulocytosis and need for weekly blood counts

Table 3. Deferasirox. ( EXJADE, ICL670 , NOVARTIS PHARMA AG, Basel, Switzerland) (DFX).3

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Characteristics Route of administration PO Half-life 8 to 16 hours Primary route of iron excretion Stool Dose range 20–30 mg/kg/dGuidelines for Monitoring Therapy Serum creatinine level monthly ALT level monthly Serum ferritin level monthly Assessment of liver iron annually Assessment of cardiac iron annually after 10 years of ageAdvantages Orally active Once daily administration Demonstrated equivalency to deferoxamine at higher doses Trials in several hematologic disordersDisadvantages Limited long-term data Need to monitor renal function May not achieve negative iron balance in all patients at highest recommended dose

IRON CHELATION THERAPY

A. Victor Hoffbrand, DM, FRCP*

These are exciting times for patients with thalassemia major (TM) and other transfusion-dependent patients with refractory anemias who need chelation therapy. Although at present deferoxamine (DFO) remains the standard of care recent data suggest that deferiprone, orally active and in clinical trials for 16 years, may for many patients be a safe and effective alternative to the more cumbersome drug DFO. There is the new possibility of combination chelation therapy with DFO and deferiprone, and a second orally active iron chelator, ICL 670, is now in early clinical trials. Figure 4 shows the chemical structures of these three compounds.

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Figure 4. The structural formulae of deferoxamine, ICL 670, and deferiprone. Pharmacokinetic and clinical characteristics of three iron chelators.

Deferoxamine DeferiproneICL 670 (deferasirox)

(DFX).3

Hexadentate Bidentate TridentateMolecular weight

560 139 373

Iron:chelator complex

1:1 1:3 1:2

Plasma clearance, T

20 minutes 53–166 minutes 1–16 hours

Oral absorption Negligible Peak 45 minutes Peak 1–2.9 hoursIron excretion Urine + fecal Urine FecalTherapeutic daily dose

40 mg/kg 75 mg/kg 20 mg/kg

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Route Parenteral Oral OralClinical experience

30 years 16 years 1–2 years

Side effects Ototoxicity, retinal toxicity, growth,

cartilage

Agranulocytosis, arthropathy, gastrointestinal disturbance, transient transaminitis, zinc

deficiency

Skin rashes, gastrointestinal

disturbance, transient transaminitis

Patogenesis dan Patofisiologi Thalassemia-β.8