advances in management of thalassemia

Correspondence and Reprint requests : Prof. M.B. Agarwal,MD, MNAMS, Haematology centre, Ghamat Lodge, 2nd Floor804/-A, Dr B. Ambedkar Road, Above ING Vyasya Bank DadarTT, Mumbai-400 014, India.[Received: December 14, 2008; Accepted December 14,2008]

Special Article

Advances in Management of Thalassemia

M.B. Agarwal

Department of Hematology, Bombay Hospital Institute of Medical Sciences, Mumbai, India

ABSTRACT

Thalassemias represent the most common single-gene disorder causing a major public health problem in India.Thalassemia and hemoglobinopathies probably developed over 7000 years ago as a defense against malaria. In simpleterms, thalassemia is caused by a mutation in either the â-globin chain or the á-globin chain which combine equally in redcells to form hemoglobin. These mutations lead to varying degree of anemia resulting into thalassemia minor, intermediaor major. Present write up relates to advances in the management of â-thalassemia major. [Indian J Pediatr 2009; 76(2):177-184] E-mail: [email protected]

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

Conventional therapy

Over the last 3 decades, profound improvements in themanagement have been observed. The development ofregular transfusion therapy and iron chelation hasdramatically improved the quality of life. It hastransformed thalassemia from a rapidly fatal disease toa chronic disease compatible with prolonged survival.Regular and adequate red cell transfusions in adequateamount every 3 week to maintain pre-transfusionhemoglobin around 9-10 g/dl has eliminated thecomplications of anemia and compensatory bonemarrow expansion (Fig. 1a, 1b & 2). However, becausethere is 200 mg of iron in each unit of packed cells, therepetitive transfusions lead to iron overload. Theaccumulation of iron leads to significant morbidity and

Fig 1A & B. Hair-on-end appearance in inadequately transfusedthalassaemia major (age : 18 years).

Fig. 2. Severe osteopenia affecting vertebral bones (age : 24 years)

Fig. 3. Morbidities related to iron overload in relation to age.

Indian Journal of Pediatrics, Volume 76—February, 2009 177

M.B. Agarwal

178 Indian Journal of Pediatrics, Volume 76—February, 2009

mortality by damaging heart, liver and endocrineorgans ( Fig. 9 ). Fig. 3 shows morbidities related to ironoverload and their time sequence. Regular ironchelation with desferrioxamine (DFO, desferal),deferiprone (DFP, L1, kelfer, ferriprox) or deferasirox(ICL 670, Exjade, Asunra, Desirox) has extendedsurvival free of iron-induced complications. Today, thelife expectancy of patients with thalassemia major hasincreased from 25 years to over 55 years, mainly due toaggressive transfusion support and chelation coupledwith patients’ compliance with medical treatment.1

Situation in India

However, these conventional modalities are expensive,time consuming and inconvenient. In developingworld, especially India, poor availability of propermedical care, safe and adequate red blood celltransfusions together with high cost and poorcompliance with chelation therapy remain majorobstacles. Despite the increased life expectancy ofthalassemia, complications keep arising. These relate toinadequate transfusions, transfusion transmitted viraldiseases, allo-sensitization, iron overload relatedendocrine, liver and cardiac disturbances as well astoxicities of iron chelators. These make conventionaltreatment of thalassemia difficult and often fatal.1

Splenectomy, which has become rarity in westernworld, is needed in many patients in India, essentiallydue to inadequate transfusions leading tohypersplenism. Today, the same is performedlaparoscopically with lesser morbidity (Fig. 4).

hep-B) and ribavarin (for hep-C) are importantadvances. Cost, however, remains prohibitive.1

Iron overload (fig 5,6,7,8,9)

Complications secondary to iron overload should beessentially prevented. Their treatment is difficult andoften lifelong. Endocrinopathies secondary to ironoverload include hypogonadism, hypothyroidism,diabetes mellitus (Fig. 9) and hypoparathyroidism. Mostof these occur towards the end of second decade of life.These often require lifelong replacement therapy.2 Ironrelated cardiac disorders include rhythm disturbancesand cardiac failure (Fig. 7). These form the chiefmodality of death in young adults with thalassemiamajor. They need inotropic and anti-arrhythmicmedications.3-4 Hepatic iron concentration (HIC) greaterthan 15 mg/g dry weight is a risk factor for cardiacdisease. However, the exact relationship between HICand heart disease is ill-understood (Fig. 8). Iron relatedhepatic cirrhosis and fibrosis are also importantissues(Fig. 5,6).1

Fig. 4 Laparoscopic splenectomy.

Prevention of transfusion transmitted diseases (TTD)

Vaccination is an effective tool to prevent hepatitis-B.Effective screening has reduced HIV and HCVinfections. However, all of these still remain significantproblems in Indian subcontinent. Treatment of HIVinfection with “Highly Active Anti-Retroviral Therapy(HAART)” as well as hepatitis-B and hepatitis-Cinfection with pegylated interferon, lamivudine (for

Fig. 5 Hepatic iron overload.

Fig 6a & 6b. CT Scan showing tissue iron overload :Normal volunteer (A) vs Severe iron overload (B).



Assessment of overload

Effective management of iron overload requires frequentevaluation of the body iron stores.5 There is, therefore, aneed for quantitative, non-invasive methods formeasuring body iron that are safe, accurate and readilyavailable. Serum ferritin measurement, although easy toperform frequently, has too great a variability. Still ,at

present, no other simple test is a better predictor. Directassessment of hepatic iron content (HIC) by liver biopsyis the best predictor of the total body iron, but theprocedure is invasive, risky and difficult to performrepeatedly. At present, Super-conducting QuantumInterference Device Biomagnetic Liver Susceptometry(SQUID-BLS) provides the most accurate and best-validated non-invasive method for measuring liveriron (Fig. 10), however, its clinical availability isrestricted, and its use is limited to the liver.6 Thedevelopment of high-transition temperatureferritometers may improve clinical access in the future.

Recently, magnetic resonance imaging (MRI) hasbecome a widely available test, and in principle allowsthe evaluation of iron overload in all organs that may beaffected by iron overload specially heart, liver andprobably even pancreas (Fig. 8).

Cardiac iron overload cannot be accurately andeasily assessed by repeated endomyocardial biopsiesowing to the heterogeneity of iron distribution and therisk of complications. One can utilize the non-invasivemethod of MRI based relaxation parameters T2 andT2*(Fig. 8). Low T2* suggests high myocardial ironcontent and it is associated with poor ventricularfunction, myocardial arrhythmias and need for cardiacmedication. These can be used for repeated estimations.These results have now been validated.7,8

Studies have also been published comparingprecision and repeatability of the MRI-derived HICestimates, obtained by measuring T2*, R2 or the liver-to-reference SIR.7,8

Iron chelation (Fig. 11-23)

Desferrioxamine (DFO) and orally effective deferiprone(DFP), either alone or together, are effective tools for ironchelation. DFO-related problems include poor

Fig. 7 Cardiac iron overload.

Fig. 8. Lack of concordance between hepatic & cardiac ironoverload (MRI Scan).

Fig. 9. Pancreatic iron overload (above) vs normal pancreas(below): Autopsy specimen.

Fig. 10. SQUID for iron estimation in liver (SQUID : Super-conductive Quantum Interference Device).

M.B. Agarwal


compliance and local reactions at the site of injection.On the other side, DFP remains a less effective chelatorand it has the problems of marrow toxicity, arthritis, GIintolerance, zinc deficiency and the controversialhepatic fibrosis.9 Recent data has favoured DFP as amore powerful iron chelator for the cardiac ironoverload. The two together probably form the bestmodality of iron chelation. The combination fulfils theshuttle hypothesis, according to which, DFP mobilizesiron from the stores while DFO puts it out of the body.Deferasirox (Exjade, Asunra, Desirox) is the new US-FDA approved once a day, oral whole body ironchelator with better efficacy and lack of side-effects. Thedose is around 20 mg/k/d (up to 30 mg/k/d). This hasmade the conventional therapy of thalassemia,relatively more comfortable.10

Implantable central vascular access devices (CVAD)(Fig. 24) are useful. They are useful both for red bloodcell transfusions as well as intravenous DFO infusion.These, however, can lead to infections includingstaphylococcal bacteremia which can be fatal.1

Deferasirox is a tridentate iron chelator i.e., twomolecules of deferasirox are required to bind one ironitem. Deferasirox is specific for iron (Fig. 14). It iseffective in removing iron from all parts of the body. Fig.

15 shows the efficacy of deferasirox 30 mg/k/d inremoving iron from liver and its comparison with DFOin the dose of 56 mg/k/d, 5 days/wk. LIC i.e., liver ironconcentration dropped from the baseline of 16.2 mg ofiron/gm of dry weight of liver to 3.3 mg of iron/gm ofdry weight of liver in one year. These results weresimilar to those obtained with DFO.

Deferasirox restores contractile properties of cardiaccells (Fig. 16). This effect is superior to that achievableby DFO (Fig. 16). Deferasirox is effective in removingcardiac iron from cultured cardiac cells (Fig. 17). Itcauses significant improvement in cardiac T2* asassessed by MRI (Fig. 18). It also reduces labile pool ofiron (LPI) as shown in Fig. 19.

Fig. 11. Chelation therapy.

Fig. 12. Chemical structure of iron chelators.

Fig. 13. Deferasirox : Two molecules required to bind one ironitem.

Fig. 14. Deferasirox is specific for iron.

Fig. 15. Hepatic iron staining after 1 year of Deferasirox vs DFO(Desferal.

Fig. 16. Deferasirox restores contractile properties of cardiac cells.



Over oral bioavailability of deferasirox is 70%. Thepeek plasma level occurs in 1.5 - 4.0 hours. It is almost100% protein bound. 84% of dose is excreted in faeces.Area under the curve (AUC) is 50% lower in childrenunder the age of 6 years. Fig 20 shows that deferasiroxcan be given once a day as its efficacy lasts for full 24hours. Fig 21 compares the modality of iron excretion bythe use of DFO (Deferoxamine) and deferasirox(Exjade). As shown in the figure, DFO causes excretionof iron in both urine and faeces while deferasirox doesso almost exclusively through faeces.

Deferasirox is best taken 30 minutes before breakfastand preferably at the same time everyday. It is availableas dispersible tablets. The vehicle could be water,orange juice or apple juice (Fig. 22). It should not beswallowed or chewed. Deferasirox is available as tabletstrength of 400 mg and 100 mg through Novartis. It is

also available in the tablet strength of 250 mg and 500mg through Cipla. The starting dose is 20 mg/k/d butbased on iron overload, it can vary from 10 to 30 mg/k/d. Dose increment is exercised at intervals of 3 monthsand should not exceed by more than 5 mg/k/d. Thesealing dose is 30 mg/k/d. Higher doses are understudy. There is no data available on combiningdeferasirox with either DFO or deferiprone.

The reported adverse effects include non-progressiveincrease in S. creatinine (34%), minor GI tractdisturbances (26%), skin rashes not amounting todiscontinuation of the drug (7%) and rise in hepatic

Fig. 17. Deferasirox is effective in removing cardiac iron fromcultured cells.

Fig. 18. Significant improvement in cardiac T2*.

Fig. 19. Deferasirox reduces LPI (Labile pool of iron).

Fig. 20. Deferasirox is effective for 24 hours.

Fig. 21. Exjade (Deferasirox) removes iron in stool (As againstDeferoxamine which removes iron both in stool andurine).

Fig. 22. Deferasirox tablets to be dissolved in water.

M.B. Agarwal


enzymes (2%). The manufacturer also recommendsyearly examination for hearing loss and lenticularopacities, monthly blood counts and monitoringphysical growth. So far, however, there is nothing tosuggest ill effect of deferasirox on hearing, lens, bloodcounts or physical growth except for anecdotal cases.

Overall, deferasirox is a new, potent, safe, once daily,oral, whole body iron chelator which has a flexibledose schedule varying from 10 to 30 mg/k/d and itappears to be a strong contender to replace the olderiron chelators. However, that is not therecommendation at the moment as the clinical data ondeferasirox is only 3 years old. At the moment, it is

recommended for patients who cannot take DFO due toone or the other reason.

Newer complications

Newer and previously less often describedcomplications have now been well-recognised. Theseinclude :

• Hypercoagulable state

• Osteoporosis

• Hepatocellular carcinoma

• Psychosocial problems

Hypercoagulable state

Prothrombotic hemostatic abnormalities leading to achronic hypercoagulable state have been noted. Theselead to frequent occurrence of thromboemboliccomplications. Increased arterial stiffness secondary toiron induced lipid peroxidation and development ofatherogenesis-related pathologies have been noted.11

Osteoporosis

Osteopenia and osteoporosis have been noted in agingpopulation of thalassaemia major. There is serious lossof bone mineral density (BMD). This loss of BMD is ofmulti-factorial origin, however, increased osteoclastactivity plays the most important role. Osteoprotegrin(OPG) levels are low while the levels of soluble receptoractivator of nuclear factor-kappa B legend (sRANKL)have varied. Disturbed bone remodeling results fromconcerted hormonal changes such as growth hormone,insulin-like growth factor I and sex hormones.Administration of pamidronate has shown asignificant increase in BMD of the lumber spine and itis now recommended that pamidronate at a monthlydose of 30 mg is an effective treatment for thalassaemicosteoporosis.12 Alternative treatment includeszolendronic acid in the dose of 1 mg as short I.V.infusion once every 3 months.

Hepatocellular carcinoma

Hepatocellular carcinoma (HCC) can complicate livercirrhosis secondary both to iron overload and viralinfections. Italians have published 22 cases of HCC inthalassemia major, 15 of them were males and the meanage of diagnosis was 45 ± 11 years.13 Eighty-six percentwere infected by hepatitis-C virus and majority werediagnosed after 1993, suggesting that the problem isbecoming more frequent with the aging population ofthalassemia patients.13

Psychosocial problems

With most of thalassemia major patients achievingadolescence, psycho-social support has become anextremely important part of patient and familymanagement. There is a great need of meeting a genetic

Fig. 23. Median change in S. ferritin on Deferasirox therapy.

Fig. 24a & 24b. Continuous Desferal therapy using port.



counselor at regular intervals. Unfortunately, there is noformal programme on this front in India.

Transplantation

Since 1982, hematopoietic stem cell transplantation(HSCT) has become an alternative modality oftreatment.14 It is the only available procedure that maylead to cure. HSCT programme for beta thalassemiamajor is now well established in India chiefly becauseof efforts taken by CMC, Vellore. The advantages of alife, free from disease and free from daily, tedious anduncomfortable therapy, are far too many. However,there is a real risk of dying from HSCT which is relatedto patient’s age, iron overload and liver viral infections.Adults have worse outcome . Among children, threeclasses of risk have been identified on the basis ofregularity of previous iron chelation, liver enlargementand presence of portal fibrosis. The results of HSCTfrom HLA identical related donor are clear. Class 1patients have a high probability of cure with very low,early or late morbidity and mortality. The delay intransplantation allows patients to move to a riskcategory beyond class 1 and this substantially reducesthe probability of success. If a donor is available, there isno reason for denying these patients the chance ofcure.14

Although, majority of HSCT have been from HLA-identical related donor, the same from an unrelatedvolunteer, carefully selected by high-resolution HLA-typing, is an alternative for those lacking a compatiblefamily donor. The results obtained using such donorsare comparable with those obtained employing anHLA-identical sibling.14

Recently, it has also been demonstrated that cord-blood is as effective as, and possibly safer than, bonemarrow for transplantation for paediatric patients. It isalso possible that, in near future, thalassaemic adultswith poor organ function may tolerate and benefit fromtransplantation employing non-myeloablative, lesstoxic, conditioning regimens which induce mixedchimerism. This may make an allogeneic HSCT safer foradults as well as heavily iron-overloaded subjects.14

After successful HSCT, iron overload still remains animportant cause of morbidity. Regular two weeklyphlebotomy programme is safe, efficient and easilyapplicable to the ex-thalassemics.14

In past, HSCT for thalassemia was a subject ofvigorous debate. It is not a life-saving procedure. It is anelective option and has morbidity and mortality. Theethical aspects for long, remained debatable, especiallyas the conventional management of thalassemia keptimproving. Also, there were hopes for the correctivegene therapy.14 With the passage of time, morbidity andmortality of HSCT have significantly reduced. This is

due to molecular tissue typing, better conditioningregimens and wonderful developments in supporttherapy including newer antifungal agents. All thesehave made, HSCT more acceptable even for a benigndisease like thalassemia. For a country like India, it iscost-effective as very few families can afford lifelongtransfusion and chelation.

Gene therapy

Gene therapy is an exciting prospect, although, there arestill formidable obstacles to be overcome before it islikely to become feasible for the thalassemics. Theefficient gene transfer, especially of a large gene segmentlike the â globin gene and its regulators, intohaematopoietic stem cells, and sustained geneexpression, have not yet been achieved. Therefore, genetherapy must await further research.14

Prevention

Although, it is not a part of this write up, it is importantto stress that the most important advance in the field ofthalassemia is its prevention. This has been verysuccessfully achieved in Mediterranean countries i.e.,Italy, Greece, Cyprus and Sardinia. There are fourimportant aspects of prevention :

• Awareness

• Detection of carrier

• Effective counseling

• Prenatal diagnosis

Over last two decades, the programme has beensuccessfully implicated in major cities of India.However, the desired goal of zero birth rate ofthalassaemia has remained a distant goal. In theabsence of a national thalassemia preventionprogramme, this still remains a difficult but extremelydesirable goal.

REFERENCES

1 Cunningham MJ, Macklin EA, Newfeld EJ, Cohen AR.Complications of â-thalassaemia major in North America.Blood 2004; 104:34-39.

2 De SV. Growth and puberty and its management inthalassaemia. Horm Res 2002;58 Suppl 1:72-79.

3 Hui L, Leung MP, Ha SY, Chau AKT, Cheung YF. Earlydetection of left ventricular dysfunction in patients withbeta thal major by dobutamine stress echocardiography.Heart 2003; 89:669-670.

4 Westwood M, Anderson LJ, Pennell DJ. Treatment ofcardiac iron overload in thalassaemia major (Ed).Haematologica 2003;88:481-482.

5 Jensen PD. Evaluation of iron overload. Br J Haematol2004;124:697-711.

6 Fischer R, Longo F, Nielsen P, Engelhardt R, Hider RC, PigaA. Monitoring long-term efficacy of iron chelation therapyby deferiprone and desferrioxamine in patients with beta

M.B. Agarwal


thalassaemia major : Application of SQUID biomagneticliver susceptometry. Br J Haematol 2003;121:938-948.

7 Anderson LJ, Davis HB, Prescott E, Charrier CC, BunceNH, Firmin DN et al. Cardiovascular T2-star (T2*) magneticresonance for the early diagnosis of myocardial ironoverload. Eur Heart J 2001;22:2171-2179.

8 Jensen PD, Jansen FT, Christensen T, Eiskjaer H, BaandrupU, Nielsen JL. Evaluation of myocardial iron by magneticresonance imaging during iron chelation therapy withdesferrioxamine indication of close relation betweenmyocardial iron content and chelation iron pool. Blood 2003;101:4632-4639.

9 Wanless IR, Sweeney G, Dhillon AP, Guido M, Piga A,Galanello R et al. Lack of progressive hepatic fibrosis duringlong-term therapy with deferiprone in subjects withtransfusion-dependent beta-thalassaemia. Blood 2002;

100:1566-1569.10 Agarwal MB. ICL 670 : A new oral chelator : A major

breakthrough in treatment of thalassaemia. Ind J Hematol &Bl Trans 2003; 31 : 26-28.

11 Cheung YF, Chan GCF, Ha SY. Arterial stiffness andendothelial function in patients with beta-thalassaemiamajor. Circulation 2002;106:2561-2566.

12 Voskardou E, Terpos E, Spina G, Palermos J, RahemtullaA, Loutradi A et al. Pamidronate is an effective treatmentfor osteoporosis in patients with beta thalassaemia. Br JHaematol 2003; 123: 730-737.

13 Borgna-Pignatti C, Vergine G, Lombardo T et al .Hepatocellular carcinoma in the thal syndromes. Br JHaematol 2004;124:114-117.

14 Erer B, Lucarelli G. Bone marrow transplantation inthalassaemia. Turk J Hematol 1999;16:147-159.

advances in management of thalassemia

Documents