Bone marrow transplantation for b-thalassaemia major - CiteSeerX

British Journal of Haematology, 2003, 120, 289–295

Bone marrow transplantation for b-thalassaemia major: the UK experience in two paediatric centres Sarah E. Lawson, 1 Irene A. G. Roberts, 2 Persis Amrolia, 2 Inderjeet Dokal, 2 Richard Szydlo 2 and Philip J. Darbyshire 1 1Department of Haematology, Birmingham Children’s Hospital, Birmingham, and 2Children’s BMT Unit, Imperial College School of Medicine, Hammersmith Hospital, London, UK Received 19 March 2002; accepted for publication 6 August 2002

Summary. Stem cell transplantation (SCT) remains the only cure for thalassaemia major. Recent advances in medical treatment make it even more important that accurate information is available regarding outcome of SCT in relevant patient populations in order to guide informed decisions regarding the most appropriate treatment for individual thalassaemia patients. We report the results of 55 consecutive first related allogeneic bone marrow transplants (BMT) for children with b-thalassaemia major performed in two UK paediatric centres over 10 years. Between February 1991 and February 2001, 55 children underwent 57 allogeneic BMT. The median age at BMT was 6Æ4 years and the majority of patients (73%) originated from the Indian subcontinent. Using the Pesaro risk classification, 17 patients were class 1, 27 were class 2 and 11 were class 3. Actuarial overall survival and thalassaemia-free survival at 8 years were 94Æ5% (95% CI 85Æ1–98Æ1) and 81Æ8% (95%

CI 69Æ7–89Æ8) respectively. Despite the majority of patients being in class 2 or 3, transplant-related mortality was low (5Æ4%). The principal complication was graft rejection accompanied by autologous reconstitution that occurred in 13Æ2% of transplants. Following modification of the conditioning regimen in 1993, the rejection rate fell to 4Æ6% and remained low. Acute graft-versus-host disease (GVHD) of grade II–IV occurred in 31% and chronic GVHD in 14Æ5%. These data compare favourably with survival with medical treatment for thalassaemia major and suggest that allogeneic BMT remains an important treatment option for children with b-thalassaemia major, particularly when compliance with iron chelation is poor.

b-thalassaemia major is an important cause of morbidity and premature death in young adults worldwide. It first became a significant problem in the UK in the mid-1950s (Modell et al, 1997) and recent data from the UK Thalassaemia Registry indicate that there are now more than 800 patients in the UK with b-thalassaemia major or other transfusion-dependent thalassaemias (Modell et al, 2000). The principal clinical problem in b-thalassaemia major is severe dyserythropoiesis resulting in transfusion-dependent anaemia, usually presenting in the first year of life. In the developed world, life expectancy is 25–55 years, depending on compliance with medical treatment (Modell et al, 2000). By contrast, in the developing world the vast majority of affected children die before the age of 20 years because of the unavailability of most forms of effective treatment.

There are two main approaches to management: bone marrow transplantation (BMT) and medical management. These have recently been reviewed (Olivieri, 1999; Rund & Rachmilewitz, 2000). Although animal models suggest that the long-sought goal of gene therapy is likely to be achievable in the future (Sadelain, 1997), the only curative treatment currently available for patients with b-thalassaemia major is BMT, or stem cell transplantation using cord or peripheral blood haemopoietic stem cells (Lucarelli et al, 1990, 1999; Issaragrisil et al, 1995; Locatelli et al, 2000; Angelucci & Lucarelli, 2001). The first successful BMT for thalassaemia major was performed in 1982 (Thomas et al, 1982), and now over 1500 transplants have been performed worldwide with the most experience from Pesaro, Italy. Overall survival rates of approximately 80% with event-free survival (EFS) rates of 70% are now reported (Lucarelli et al, 1995, 1998; Galimberti et al, 1997; Angelucci & Lucarelli, 2001). Reports from centres outside Italy have generally shown similar or slightly inferior results for reasons that are not clear (Vellodi et al, 1994; Walters et al,

Correspondence: Dr S. E. Lawson, Department of Haematology, Birmingham Children’s Hospital, Birmingham, B4 6NH, UK. E-mail: [email protected] 2003 Blackwell Publishing Ltd

Keywords: b-thalassaemia, bone marrow transplantation, children.

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1994; Shing et al, 1996; Clift & Johnson, 1997; Boulad et al, 1998; Ghavamzadeh et al, 1998; Lee et al, 1998). The mainstay of medical treatment is regular blood transfusion accompanied by iron chelation therapy to combat the tissue damage caused by transfusion-related iron overload. Newer therapies include inducers of haemoglobin and haemoglobin F production, and antioxidants, but their therapeutic role in b-thalassaemia major is not yet clear (Olivieri, 1999; Rund & Rachmilewitz, 2000). Blood transfusion and chelation have dramatically improved survival and quality of life over the last two decades, and have changed a previously fatal disease with early deaths, to a chronic but progressive disease compatible with prolonged survival. Median survival now exceeds 50 years in wellchelated patients (Borgna-Pignatti et al, 1998; Olivieri, 1999), leading to debate about the role of allogeneic BMT in the management of thalassaemia major in well-resourced countries with almost universal access to good medical care (Lucarelli & Weatherall, 1991; Roberts, 1997). Nevertheless, recent data from the UK Thalassaemia Registry indicate that, despite the availability of good medical treatment, approximately 50% of affected patients in the UK die before the age of 35 years (Modell et al, 2000). To evaluate the role of BMT in children with thalassaemia major treated in the UK, we have reviewed the outcome of 55 consecutive first allogeneic BMTs from two paediatric centres with a special interest in BMT for haemoglobinopathies. Actuarial overall survival and EFS were 94Æ5% and 81Æ8%, respectively, confirming that, despite improvements in medical treatment, stem cell transplantation remains an important therapeutic option for children with b-thalassaemia major, particularly where compliance with optimal chelation therapy is poor or good medical treatment is not available. PATIENTS AND METHODS Between February 1991 and February 2001, 55 patients received 57 allogeneic bone marrow transplants for b-thalassaemia major at either Birmingham Children’s Hospital (BCH; n ¼ 29) or Hammersmith Hospital, London (HH; n ¼ 28). Two of the transplants were second transplants and have therefore been excluded from this analysis: the data presented are for the remaining 55 patients. All patient and transplant details were collected retrospectively from case notes and the UK Children’s BMT Registry data collection forms. Clinical details. Patient details are shown in Table I. There were 26 boys and 29 girls. Fifty-three of the 55 patients were homozygous or compound heterozygotes for b-thalassaemia major; two had Eb-thalassaemia. The median age of the patients at the time of BMT was 6 years 5 months, with a range of 2–16 years 11 months. The ethnic origin of the patients is detailed in Table I: the majority of patients (40/55) were from the Indian subcontinent. Virology pre-BMT. The cytomegalovirus (CMV) status of patients and donors pretransplant is shown in Table I. Of the 55 transplants, only 12 donor/recipient pairs were CMV

Table I. The clinical and BMT-related details of 55 patients with b-thalassaemia major undergoing first allogeneic BMT from HLAidentical family donors. Age Median Range Ethnic origin Indian subcontinent* Greek/Turkish Middle East Italian Chinese Sex Male:female Conditioning regimen Bu 14 mg/kg/Cy 200 mg/kg Bu 14 mg/kg/Cy 200 mg/kg + ALG or Campath Bu 14 mg/kg/Cy 120 mg/kg Bu 14 mg/kg/Cy 120 mg/kg + Campath Bu 14 mg/kg/Cy 200 mg/kg + fludarabine + ALG Bu 14 mg/kg/Cy 200 mg/kg + fludarabine Bu 16 mg/kg/Cy 120 mg/kg + Campath Bu 16 mg/kg/Cy 200 mg/kg + ALG CMV status Recipient negative:donor negative Recipient negative:donor positive Recipient positive:donor negative Recipient positive:donor positive Donors HLA-identical sibling Phenotypical HLA-identical parent

6 years 5 months 2–16 years 11 months 40 7 5 2 1 26:29 3 39 1 2 4 3 1 2 12 6 13 24 52 3

*Indian subcontinent: Pakistan, India, Bangladesh, Kashmir, Bengal. Middle East: Jordan, Iran, Kuwait. Bu, busulphan; Cy, cyclophosphamide.

negative and in 43 pairs either the donor or the recipient were CMV positive. Four patients had antibodies to hepatitis C and four had positive hepatitis A serology prior to transplant. No patients had evidence of previous infection with hepatitis B and none had biochemical or histological evidence of chronic hepatitis. Pesaro class and iron overload pre-BMT. Using the Pesaro risk classification (Lucarelli et al, 1990), the 55 patients were classified as follows: 17 patients were class 1, 27 class 2 and 11 class 3 at the time of BMT (Table II). Serum ferritin measurements were performed in all patients prior to transplantation. The median serum ferritin was 1795 lg/l with a range of 505–7490 lg/l (normal range 10–63 lg/l). Liver biopsies were performed in all patients aged > 3 years (n ¼ 44) pretransplant. Patients aged < 3 years did not undergo liver biopsy because in patients receiving BMT for thalassaemia the presence of fibrosis is unreported at this age and the risk of biopsy complications is relatively high (Muretto et al, 1989). These patients were considered not to have hepatic fibrosis. All patients who had

2003 Blackwell Publishing Ltd, British Journal of Haematology 120: 289–295

BMT for Thalassaemia Major Table II. The details of Pesaro class, iron and liver status pretransplant in 55 patients undergoing BMT for b-thalassaemia major. Pesaro class 1 2 3 Serum ferritin (lg/l) Median Range Normal range Liver biopsy (n ¼ 44) Siderosis only Siderosis and fibrosis Siderosis, fibrosis and cirrhosis Liver iron (dry weight mg/g) Median Range Normal range

17 27 11 1795 505–7490 10–63 8 (18%) 28 (64%) 8 (18%) 10Æ1 0Æ85–49Æ43 0Æ35–1Æ35

a biopsy taken showed evidence of hepatic siderosis. Of these, eight patients had siderosis alone with no evidence of fibrosis (18%), 28 had fibrosis (64%) and eight had evidence of cirrhosis (18%). Dry-weight liver iron measurements were made in 34 patients. The median dry weight liver iron measurement was 10Æ1 mg/g with a range of 0Æ85– 49Æ43 mg/g (normal range 0Æ35–1Æ35 mg/g). Details of iron and liver status pretransplant are shown in Table II. Conditioning regimens. The conditioning regimen for the majority of patients employed the standard combination of busulphan 14 mg/kg on d )9 to )6 and cyclophosphamide 200 mg/kg on d )5 to )2 (Lucarelli et al, 1990; Angelucci & Lucarelli, 2001). Alterations to these standard doses were made in six patients. Four patients in Pesaro class 2 or 3 received cyclophosphamide at the reduced dose of 120 mg/kg. One of these patients received an increased dose of busulphan at 16 mg/kg. The majority of patients had immunosuppressive agents added to the conditioning regimen in order to reduce the incidence of graft rejection. These included antilymphocyte globulin (ALG) at 12Æ5 mg/kg/d for 3–5 d, Campath 1G or 1H at 5–10 mg/d for 3–5 d and 5 mg/d for 3 d, respectively, and fludarabine at 25 mg/m2/d for 2–5 d. Details of the conditioning regimens are shown in Table I. Donor details. In 52 transplants, patients received bone marrow from a human leucocyte antigen (HLA)-identical sibling, while in three transplants marrow was from a phenotypically HLA-identical parent. In 38 transplants (69%), the donor had b-thalassaemia trait. In the remaining 17 transplants, the donors had no evidence of a haemoglobinopathy. Veno-occlusive disease prophylaxis. Prophylaxis for hepatic veno-occlusive disease differed between the two centres. At BCH, prophylaxis with intravenous (i.v.) or subcutaneous heparin (unfractionated or low-molecular-weight) was given to two patients prior to December 1994 and to all patients (n ¼ 17) thereafter as a routine measure. This was not the practice at HH.

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GVHD prophylaxis. Graft-versus-host disease (GVHD) prophylaxis differed slightly between the two centres. At BCH, GVHD prophylaxis was cyclosporin A alone (2Æ5 mg/kg intravenously twice daily) commencing on d )1 in 27 of 28 patients; one patient received methotrexate (8 mg/m2/d) on d +1, +3, +6 and +8 in addition to cyclosporin A. At HH, standard prophylaxis, since 1994, has been cyclosporine with short methotrexate (10 mg/m2/d on d +3 and +6) (n ¼ 21); prior to 1994, patients received either cyclosporine alone (n ¼ 4) or cyclosporine with four doses of methotrexate (8 mg/m2/d) on d +2, +4, +8 and +12 (n ¼ 3). Antimicrobial prophylaxis. CMV prophylaxis was with aciclovir (10 mg/kg three times daily i.v. or 500 mg/m2 three times daily i.v. according to donor and recipient CMV status) and i.v. immunoglobulin (0Æ4 g/kg once weekly). Antifungal prophylaxis was daily oral fluconazole, antibacterial prophylaxis was ciprofloxacin and mouth care was with chlorhexidine mouthwash. Broad-spectrum antibiotics were given in the event of fever, with liposomal amphotericin being added if fever persisted, or if there was a suggested or documented fungal infection. All patients were nursed in air-filtered rooms with reverse barrier nursing, and received a non-microbial sterile diet. Granulocyte colony stimulating factor (G-CSF; lenograstim 0Æ5 MIU/kg/day) was commenced on d +8 and continued daily until engraftment at BCH, but was not used routinely at HH. In the latter institution, G-CSF was administered to those patients with delayed engraftment (n ¼ 5). Statistical analysis. The Mann–Whitney U-test was used to compare groups. Probabilities of survival and EFS were calculated by the Kaplan–Meier method. The cumulative incidence procedure was used to calculate the probabilities of transplant-related mortality and rejection. All cited P-values are two-sided, and confidence intervals (CI) refer to 95% boundaries. RESULTS Fifty-five first allogeneic related bone marrow transplants were performed in patients with transfusion-dependent thalassaemia major at the two centres over a 10-year period. The median duration of follow up was 6 years 3 months (range 11 months to 11 years). Engraftment All patients showed evidence of engraftment (neutrophil count of > 0Æ5 · 109/l for 3 d). The median time to engraftment was 17 d (range 10–53 d) for all patients. For those at BCH, the median time was 15 d (range 10–23 d) and for those at HH it was 21 d (range 13–53 d) (P < 0Æ05). It is not clear whether this reflects the use of G-CSF at BCH, the use of methotrexate at HH or is indicative of other factors. Overall and EFS Actuarial 5-year survival for the 55 patients is 94Æ5% with an EFS of 81Æ8% (Fig 1). Three of the 55 patients died, and, of the remaining 52 patients, 44 are alive and well and free


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Fig 1. The probability of survival, EFS and rejection post-HLAmatched related BMT in the UK.

of thalassaemia and eight have transfusion-dependent anaemia. Overall survival and EFS rates for Pesaro class 1, 2 and 3 patients are 89% and 100%, 91% and 89%, 89% and 73% respectively. Non-rejection mortality There were three deaths, giving an overall mortality rate of 5Æ4%. The causes of death were grade IV acute GVHD and multi-organ failure (n ¼ 1), septic shock with multi-organ failure (n ¼ 1) and CMV pneumonitis (n ¼ 1). Rejection Graft rejection was observed in eight of the 55 transplants giving a 2-year probability of 13Æ2% (95% CI 6Æ5–24Æ9); in all patients, this was followed by autologous reconstitution (Fig 1). The median time to rejection was 3 months (range 2–30 months). Of these patients, four have had no further treatment and are transfusion-dependent, three have had successful second transplants and are transfusion-independent, and one has had unsuccessful infusions of donor CD34+ and CD3+ cells, and remains transfusion dependent. The incidence of graft rejection fell in recent years with the modification of the protocol as outlined in the methods, and since 1993 only 2/43 patients (4Æ6%) have experienced rejection. There was no significant difference in the risk of graft rejection in relation to Pesaro class (class 1, 11%; class 2, 11% and class 3, 27%). GVHD There was no, or only minimal (grade I), acute GVHD in 38/55 transplants (69%). Grade II GVHD was observed in eight patients (14Æ5%) and nine patients (16Æ4%) had grade III–IV acute GVHD. Thus, the overall incidence of acute GVHD of grade II–IV was 31%, which is similar to the incidence reported in other series (Gaziev et al, 1997; Angelucci & Lucarelli, 2001). Chronic GVHD was observed in eight patients (14Æ5%), representing a lower incidence than that reported by others. In six of these patients, chronic GVHD was limited and affected the skin only. Two patients had extensive chronic GVHD: one affecting the skin and lungs, and one affecting the skin, mouth and conjunctivae.

Complications The conditioning regimen was well tolerated by all patients. The majority of patients experienced episodes of fever during the period of neutropenia and responded to broad-spectrum antibiotics. Other more serious complications were minimal. Four (7%) patients developed hepatic veno-occlusive disease of mild–moderate severity, all of whom were managed conservatively. Six patients experienced CMV reactivation and one patient developed fatal CMV pneumonitis. Other infective complications included two episodes of pneumococcal sepsis in one patient, cerebral and bowel Aspergillus fumigatus (n ¼ 1), an unidentified chest infection requiring admission to intensive care (n ¼ 1), a severe herpes zoster infection with corneal ulceration (n ¼ 1) and Pneumocystis carinii pneumonia (n ¼ 1). One patient experienced transient red cell aplasia at 4 months following an ABO mismatched transplant and required blood transfusion until recovery. DISCUSSION Stem cell transplantation (SCT) remains the only cure for thalassaemia major. Recent advances in medical treatment, including safer transfusion and chelation regimens that are less difficult to use (Wonke et al, 1998a), make it even more important that accurate information is available concerning the outcome of SCT in relevant patient populations, in order to guide informed decisions about the most appropriate form of treatment of thalassaemia for individual patients. We, therefore, analysed the results of 55 consecutive allogeneic BMT for thalassaemia major carried out at two UK paediatric centres over the past 10 years. Overall survival and EFS were 94Æ5% and 81Æ8%, respectively, and transplant-related mortality was low (3/55 patients). These results support the continuing role of BMT as a therapeutic option for thalassaemia major. Data from the Pesaro group indicate that the survival curves plateau at 2–3 years after BMT and there is no evidence yet of late deaths due to second malignancy or chronic organ damage (Angelucci & Lucarelli, 2001). This is in contrast to the recent data from the UK Thalassaemia Registry (Modell et al, 2000) which show a steady decline in survival from the second decade with fewer than 50% of patients remaining alive during their 30s. The principal reason for this disappointing survival rate appears to be poor compliance with the chelation regimens needed to prevent ongoing cardiac and hepatic damage (Borgna-Pignatti et al, 1998; Modell et al, 2000). Data from Torino show that where compliance with chelation therapy is good and consistent, 90% of patients survive into their 30s whereas where compliance is poor fewer than 10% will survive to their 40th birthday (Piga et al, 1997). The data from medical therapy, together with our experience, suggest that allogeneic BMT remains an important treatment option for children with thalassaemia major even in areas where optimal medical treatment is readily available. It is likely to play a particularly important role in children with poor or erratic compliance with iron chelation therapy, a situation that is clearly associated with


BMT for Thalassaemia Major dismal long-term survival (< 20% survival into the fourth decade). For those children and families who cope and comply well with chelation therapy, BMT offers the prospect of an improved quality of life, free from transfusion and lifelong chelation. However, BMT is unlikely to have a significant impact on the survival of these patients, at least during the first two to three decades. While the potential benefits of BMT are clear, the disadvantages and hazards are harder to predict. Our data show that, despite the majority of patients being in Pesaro class 2 or 3, transplant-related mortality was low and in this cohort was only 3Æ6%, similar to that reported by others for class 1 patients (Angelucci & Lucarelli, 2001). The principal complication in the present study was graft rejection accompanied by autologous reconstitution and transfusion-dependence. This occurred in 13Æ2% of transplants overall, but following modification of the BMT protocol in 1993, the incidence fell to 4Æ6% and remained low. The reasons for the reduction in graft rejection are not clear, but are likely to be multifactorial and include reduction in the dose of methotrexate used for GVHD prophylaxis, use of Campath/ALG/fludarabine pre-BMT, and use of hypertransfusion in the peritransplant period (Roberts et al, 1997; Amrolia et al, 2001). One of the other worrying hazards of BMT is the development of chronic GVHD and, therefore, the substitution of one unpleasant chronic disease for another. The low incidence of extensive chronic GVHD in this group of patients (2/55) is reassuring. It may be due to the ethnic constitution and high rate of consanguinity in the study group or may be due to the use of Campath, ALG and/or fludarabine in the conditioning regimen (Hale & Waldmann, 1996). A further important consideration when evaluating the current role of BMT for thalassaemia major is the longterm complications of BMT. These include infertility, growth disturbances and endocrine complications. Preexisting iron overload also requires treatment either by regular phlebotomy or chelation therapy (Roberts, 1997). For the majority of patients, growth is normal after BMT (Gaziev et al, 1993), but approximately one third of boys and two thirds of girls fail to spontaneously enter puberty after BMT (De et al, 1991), which is a proportion similar to that of patients treated medically (Borgna-Pignatti et al, 1998; Wonke et al, 1998b; Olivieri, 1999). No study has systematically compared the growth and development of patients treated by medical therapy with those treated with BMT. However, available data suggest that BMT probably does not have more adverse consequences than medical therapy, except perhaps for patients who maintain an excellent compliance with iron chelation for the crucial years before and around puberty. Effects on fertility are more worrying (Sanders et al, 1996). Although there are few data, successful pregnancy has been reported (Borgna-Pignatti et al, 1996). Nevertheless the chances of conception following conditioning with busulphan and cyclophosphamide are very low (Sanders et al, 1996). Cryopreservation of ovarian and testicular tissue may offer some prospect for the future, but remain

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of unproven value and are not without hazard (Grundy et al, 2001). The decision of whether or not to proceed to BMT is a difficult one both for clinicians and for the patients and their families. The main responsibility of clinicians is to present the relative advantages and disadvantages of BMT compared with the available medical treatment which, for the vast majority of patients, is currently limited to regular blood transfusion together with iron chelation, given the generally disappointing clinical results to date with HbF inducers (Reich et al, 2000). There have been no controlled trials of BMT versus medical treatment for thalassaemia major. Therefore, evaluation of these two very different treatment approaches depends upon comparisons being made between the quality of life, the morbidity, the mortality and arguably the costs in separate populations of patients (Karnon et al, 1999;Vassiliou et al, 2001). Nevertheless, some general conclusions can be drawn. The advantages of BMT are firstly an improvement in quality of life for the vast majority of transplanted patients. Secondly, for patients with a history of erratic compliance with chelation therapy who have a low chance of reaching their fifth decade, BMT offers a much greater chance of long-term survival. Indeed virtually all successfully transplanted patients alive 2 years after transplant can expect long-term, transfusion-free survival as there is no evidence to date of unexpected late mortality or life-threatening morbidity (Angelucci & Lucarelli, 2001). It is, however, unclear whether there is a survival advantage of BMT for well-chelated patients, as 80% of such patients survive to the age of 40 years (Davis et al, 2001). The disadvantages of BMT are principally the significant transplant-related mortality and the high risk of infertility. By comparison, treatment with blood transfusion/chelation offers children an excellent prospect for survival into adulthood with a very low risk of death during childhood, but this is achievable only at the expense of a difficult, invasive and often painful regimen with which many families find it impossible to comply. The costs of medical treatment are considerable: recent calculations estimated the lifetime treatment cost in the UK at £803 002 in comparison with approximately £50 000 for a transplant at the time of estimation (Karnon et al, 1999). Finally, despite the undoubted benefits that BMT can confer to patients with thalassaemia, the major practical limitation to its role as a therapeutic option is the unavailability of an HLA-identical donor in 2/3 families. The use of alternative donors confers a much higher risk of major morbidity and mortality (Sullivan et al, 1998; La et al, 2000), and is not currently recommended in most centres (Goldman et al, 1998), although it is possible that reduced-intensity non-myeloablative conditioning regimens may reduce the risks if a reliable protocol can be developed for patients with haemoglobinopathies (Slavin et al, 1998; Storb et al, 1998; Gomez-Almaguer et al, 2000). In conclusion, for the majority of children with b-thalassaemia major and an HLA-identical sibling donor, BMT offers the only chance of cure and the return of life expectancy and quality of life to normal. Results in the UK


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are comparable to the Pesaro group who have the largest experience in the world. Of the 55 patients transplanted in our centres, 52 were alive and 44 were cured of their disease with a median follow-up of over 6 years. BMT is, however, associated with a significant mortality and morbidity, including late effects on fertility and growth. It is, therefore, essential that the risks and disadvantages are discussed with patients and families before the decision to proceed with BMT is taken. The outcome compares favourably with medical treatment and suggests that allogeneic BMT remains an important treatment option for children with thalassaemia major, particularly where compliance with chelation therapy is poor or reliable medical treatment is unavailable. REFERENCES Amrolia, P.J., Vulliamy, T., Vassiliou, G., Lawson, S., Bryon, J., Kaeda, J., Dokal, I., Johnston, R., Veys, P., Darbyshire, P. & Roberts, I.A. (2001) Analysis of chimaerism in thalassaemic children undergoing stem cell transplantation. British Journal of Haematology, 114, 219–225. Angelucci, E. & Lucarelli, G. (2001) Bone marrow transplantation in b-thalassaemia. In: Disorders of Hemoglobin: Genetics, Pathophysiology and Clinical Management (ed. by M. Steinberg, B. Forget & R.L. Nagel), p. 1052. Cambridge University Press, Cambridge. Borgna-Pignatti, C., Marradi, P., Rugolotto, S. & Marcolongo, A. (1996) Successful pregnancy after bone marrow transplantation for thalassaemia. Bone Marrow Transplantation, 18, 235–236. Borgna-Pignatti, C., De Rugolotto, S.S.P., Di Piga, A.G.F., Gamberini, M.R., Sabato, V., Melevendi, C., Cappellini, M.D. & Verlato, G. (1998) Survival and disease complications in thalassemia major. Annals of the New York Academy of Science, 850, 227–231. Boulad, F., Giardina, P., Gillio, A., Kernan, N., Small, T., Van Brochstein, J.S.K., George, D., Szabolcs, P. & O’Reilly, R.J. (1998) Bone marrow transplantation for homozygous beta-thalassemia. The Memorial Sloan–Kettering Cancer Center experience. Annals of the New York Academy of Science, 850, 498–502. Clift, R.A. & Johnson, F.L. (1997) Marrow transplants for thalassaemia: the USA experience. Bone Marrow Transplantation, 19, 57–59. Davis, B.A., O’Sullivan, C., Eliahoo, J. & Porter, J.B. (2001) Survival in b-thalassaemia major: a single centre study. British Journal of Haematology, 113, 53. De, S.V., Galimberti, M., Lucarelli, G., Polchi, P., Ruggiero, L. & Vullo, C. (1991) Gonadal function after allogenic bone marrow transplantation for thalassaemia. Archives of Diseases of Children, 66, 517–520. Galimberti, M., Angelucci, E., Baronchiani, D., Giardini, C., Polchi, P., Erer, B., Gaziev, D., Pazzaglia, C., Ciaroni, A., Baldassarri, M., Martinelli, F. & Lucarelli, G. (1997) Bone marrow transplantation in thalassaemia. The experience of Pesaro. Bone Marrow Transplantation, 19, 45–47. Gaziev, J., Galimberti, M., Giardini, C., Baronciani, D. & Lucarelli, G. (1993) Growth in children after bone marrow transplantation for thalassemia. Bone Marrow Transplantation, 12, 100–101. Gaziev, D., Polchi, P., Galimberti, M., Angelucci, E., Giardini, C., Baronciani, D., Erer, B. & Lucarelli, G. (1997) Graft-versus-host disease after bone marrow transplantation for thalassemia: an analysis of incidence and risk factors. Transplantation, 63, 854– 860. Ghavamzadeh, A., Nasseri, P., Eshraghian, M.R., Jahani, M., Baybordi, I., Nateghi, J., Khodabandeh, A., Sadjadi, A.R.,

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