CURRENT STATUS OF ALLOGENEIC TRANSPLANTATION FOR HAEMOGLOBINOPATHIES

Review

CURRENT STATUS OF ALLOGENEIC TRANSPLANTATION FOR HAEMOGLOBINOPATHIES

The dilemma of selecting the best treatment for youngpatients who suffer from one of the major haemoglobino-pathies remains a difficult one. On the one hand, extensiveexperience of bone marrow transplantation (BMT) forchildren with b-thalassaemia major confirms the value ofthis procedure for the majority of transplanted children(Lucarelli et al, 1995; Galimberti et al, 1997); on the otherhand, BMT carries considerable risks for such children, evenafter extremely careful patient selection, and these must bebalanced against recent and forseeable advances in medicaltreatment (Olivieri, 1996; Olivieri & Brittenham, 1997). Forthe other major haemoglobinopathies which have beentreated by BMT (sickle cell disease, HbE thalassaemia, andthe a-thalassaemia syndromes) the dilemma is often evenmore acute since outcome data are relatively sparse andthere is often marked intra- and inter-individual variabilityin disease severity (Vermylen et al, 1991; Walters et al,1996b; Issaragrisil et al, 1997; Li et al, 1997).

BMT for b-thalassaemia majorBMT programmes for b-thalassaemia major have now beenestablished in most parts of the world where the disease isprevalent, although in many countries it is only a tinyminority of affected patients who have access to suchspecialized care. At the Third International Symposium onBMT in Thalassaemia (1997) held recently in Pesaro, Italy,outcome on more than 1000 patients was presented fromcentres in Europe, north America and Asia. Overall around80% of patients survive long-term and of these nearly 90%are cured of their disease.

Prognostic factors for outcome after BMT. The largest seriesof transplanted patients is that from Professor Lucarelli’sgroup in Pesaro. Multivariate analysis of the outcome of thefirst 222 patients showed that the risks of BMT using anHLA-identical sibling donor could be predicted according tothe presence or absence of only three criteria: hepatomegaly,biopsy-evidence of portal fibrosis in the liver, and irregularcompliance with iron chelation therapy (Lucarelli et al,1990). Patients were grouped according to whether theyhad none of these risk factors (class I), any one or two of therisk factors (class II), or all three risk factors (class III). In thisanalysis disease-free survival was 94%, 77% and 53%respectively in class I, II and III (Lucarelli et al, 1990). Thisled to them to investigate less toxic conditioning regimens(see below) for class III patients. Their recent analysis of the

class III outcome data showed not only that this approach wasassociated with improved survival (74% 5-year survival), butalso that in such high-risk patients both age (<17 years) andthe intensity of conditioning were also predictive of survival(Lucarelli et al, 1996). These data are of practical help both byproviding guidelines for selecting patients for BMT and also fordetermining the most appropriate conditioning for individualpatients.

Conditioning regimens. Most BMT centres use a combina-tion of busulphan and cyclophosphamide, with cyclosporin6 methotrexate as GVHD prophylaxis. The dose of busul-phan has been the subject of some controversy in view of therecognized interindividual variability in busulphan pharma-cokinetics, particularly in very young children (Grochowet al, 1990; Vassall et al, 1992). The most widely usedregimen (the standard ‘Pesaro regimen’ for class I and IIpatients) is a total dose of busulphan of 14 mg/kg given over4 d, followed by 200 mg/kg of cyclophosphamide over thenext 4 d (Galimberti et al, 1997; Lucarelli et al, 1990). In ourexperience this is very well tolerated with minimal mucositisand neither opiates nor total parenteral nutrition (TPN) arerequired (Roberts et al, 1995). Other centres use either16 mg/kg, 600 mg/m2 (Issaragrisil et al, 1997) or, in a fewcases, tailor the dose in each patient according to plasmabusulphan levels (Yeager et al, 1992). For BMT forthalassaemia, there is no good evidence that plasmabusulphan levels correlate either with the efficacy ofmyeloablation or with toxicity (Lucarelli et al, 1990,1995). It is clear, however, that doses of busulphan of>16 mg/kg are associated with more toxicity and also thatconditioning regimens containing lower than standard dosesof busulphan and cyclophosphamide significantly increasethe risk of graft rejection (Lucarelli et al, 1996; Galimbertiet al, 1997; Slattery et al, 1995). In the recent analysis ofclass III patients transplanted by the Pesaro group, theprobability of graft rejection in children <17 years was 0·35when doses of cyclophosphamide <200 mg/kg were usedcompared to 0·13 with the standard 200 mg/kg regimen(Lucarelli et al, 1996).

The recognition that graft rejection is a commoncomplication of BMT for haemoglobinopathies when lowerdoses of conditioning therapy are employed has led a numberof groups to add either antilymphocyte globulin (ALG) orCampath to the pre-BMT preparative regimen (Galimbertiet al, 1997; Roberts et al, 1995; Li et al, 1997; Souillet et al,1995). The toxicity appears to be acceptable and, althoughno controlled trials have been carried out, the rate of graftrejection following the introduction of ALG/ATG (antithymo-cyte globulin) or Campath has fallen substantially (Roberts

British Journal of Haematology, 1997, 98, 1–7

1q 1997 Blackwell Science Ltd

Correspondence: Dr Irene Roberts, Department of Haematology,Royal Postgraduate Medical School, Hammersmith Hospital,DuCane Road, London W12 0NN.

et al, 1995; Li et al, 1997; Souillet et al, 1995). Takentogether, the data suggest that, at least for class I and IIpatients, i.e. those without major organ damage, aconditioning regimen of busulphan 14 mg/kg and cyclo-phosphamide 200 mg/kg 6 ALG or Campath is the mostappropriate. For those higher risk patients still beingconsidered for BMT, particularly for patients >17 years, alower dose of cyclophosphamide could be considered (120–160 mg/kg) in order to reduce transplant-related mortality,although this is likely to be at the expense of an increasedchance of graft rejection.

Outcome. The largest series of transplants for b-thalassae-mia major (n ¼ 802) remains that of Lucarelli’s group inPesaro, in which current overall survival for class I, II and IIIpatients respectively is 95%, 84% and 79% and disease-freesurvival is 90%, 82% and 57% (Galimberti et al, 1997).These data reflect the impact of reducing the intensity ofconditioning in high-risk patients; the major complicationbeing graft rejection with recurrent thalassaemia ratherthan transplant-related fatal events. Acute GVHD, despiteprophylaxis with cyclosporin (and methotrexate in class IIIpatients), remains the cause of death in a small proportion ofthese patients (<5%), but is not more common than seenfollowing BMT for other conditions.

In the U.K. around 60 children with b-thalassaemia majorhave been transplanted since 1991; data on 50 of these fromthree centres have recently been analysed (Roberts et al,1997). The children were predominantly of Indian orPakistani origin and >50% admitted to poor compliancewith desferrioxamine. All the transplants were from HLA-identical family members and all employed conditioningwith a combination of busulphan and cyclophosphamide.Overall survival for the whole group of 50 patients was 90%,and of the 45 surviving patients 38 (76%) are alive and freeof thalassaemia. Although in these patients the Pesaro classdid not predict survival (95%, 83% and 91% in class I, II andIII respectively), it did correlate with the chance of curewhich was 81%, 78% and 64% in class I, II and IIIrespectively. The most common complication seen in the U.K.patients was graft rejection (8/50; 16%), which, as in otherseries, was almost always associated with autologous marrowrecovery and recurrence of transfusion-dependent thalassae-mia major. However, since the introduction of modest protocolmodifications in 1993 the rate of graft rejection has fallendramatically (to <5% in the last 25 patients) (Roberts et al,1995, 1997). Severe extensive chronic GVHD was the othercomplication associated with a poor outcome in the U.K.patients. Although uncommon (<5%), chronic GVHD is aparticularly difficult problem to manage in thalassaemiapatients for whom improved quality of life, rather thanprolongation of life, is a major factor in their decision toundergo BMT.

Second BMT. The role of a second BMT following graftrejection is unclear. The numbers of patients undergoing arepeat procedure are still too small to identify the bestconditioning regimen in this setting (Polchi et al, 1997). Therisks of rejection and death appear to be considerably higherthan for the first transplant; it should probably be reservedfor two circumstances: firstly, the small number of cases

where there is rejection to aplasia and, secondly, for specialcases where there is autologous marrow recovery and forwhom medical management of thalassaemia major isextremely difficult.

Long-term consequences. Management of patients who haveundergone BMT (‘ex-thalassaemics’) must encompass diag-nosis and treatment of complications secondary both to thetransplant itself and to the underlying disease. Virtually all‘ex-thalassaemic’ patients have moderate-severe iron over-load (Giardini et al, 1995). It is now clear that although thisimproves after transplant, the rate of iron removal from thetissues, particularly the liver and the heart, is very slow(Giardini et al, 1995). Persistence of iron overload islikely to be associated with ongoing tissue damage; indeed‘ex-thalassaemics’ have been compared to patients withhaemachromatosis. In order to prevent progressive cardiacdamage and hepatic fibrosis, it is now recommended that all‘ex-thalassaemic’ patients should have their total ironburden reduced towards normal levels by a programme ofregular venesection or desferrioxamine beginning 1–2 yearspost-BMT. This is particularly important for patients withconcomitant chronic hepatitis, who may also benefit frominterferon if this is hepatitis C associated. Encouragingly,reduction in liver iron in ‘ex-thalassaemics’ does result inmarked improvement in liver histology in the majority ofpatients suggesting that normal long-term life expectancyafter BMT is a realistic hope (Giardini et al, 1995, 1997;Angelucci et al, 1997).

The effects of BMT on growth and development, particu-larly on fertility, in ‘ex-thalassaemics’ are still not clear, sincethe majority of patients were transplanted in early childhood.Most of the available data derive from the Pesaro group andshow that children transplanted early in the history of theirdisease (<8 years) regain a normal growth rate after BMT(Gaziev et al, 1993; De Sanctis et al, 1997). At the otherextreme, older children and children in class III, especiallythose who develop chronic GVHD, often have severelyimpaired growth (Gaziev et al, 1993; De Simone et al,1995). These data have to be balanced against the recog-nized problem of growth failure even in non-transplantedthalassaemic patients (De Sanctis et al, 1994; Kattamis &Kattamis, 1995). Similarly, there is a high prevalence ofgonadal failure both in medically-treated patients withthalassaemia (De Sanctis et al, 1988) and following BMT(De Sanctis et al, 1991, 1997). Increased gonadotrophins,reflecting gonadal damage, are found in the majority ofpatients transplanted before puberty (De Sanctis et al, 1991);nevertheless, 40% of such patients still enter pubertyspontaneously. Indeed, successful pregnancy following BMTfor thalassaemia, as well as following BMT for otherhaematological disorders using busulphan/cyclophosphamideconditioning, has been reported, and no increase incongenital anomalies of the resultant offspring has yet beenseen (Borgna-Pignatti et al, 1996; Sanders et al, 1996). It isnot possible at present to accurately predict the effects of BMTon fertility for individual patients, and patients need to becounselled accordingly, including the risks of transmittingthalassaemia to their offspring should they become parents.

BMT for adults. The success of BMT for children with

2 Review

q 1997 Blackwell Science Ltd, British Journal of Haematology 98: 1–7

thalassaemia has led some groups to extend this option tocarefully selected adults with the disease (Lucarelli et al,1992; Di Bartolomeo et al, 1997). In Pesaro, 106 adults(17–35 years) have been transplanted (Galimberti et al,1997). Virtually all are class II and III and this is reflected inthe outcome: overall survival is 68% and event-free survival65% (Galimberti et al, 1997). Interestingly, the rejection rateis only 3%, considerably lower than in the younger class IIIpatients. However, the high mortality rate suggests thatadults with thalassaemia should be selected for BMT withgreat caution and that such transplants ought to be carriedout only in centres with considerable experience of BMT forthalassaemia.

Cord blood transplantation for thalassaemia. The first cordblood transplant for thalassaemia major has recently beenreported and resulted in successful durable engraftment(Issaragrisil et al, 1995). For haemoglobinopathies, transplan-tation of stem cells from cord blood has several theoreticaladvantages, including the feasibility of prenatal HLA typing(in tandem with prenatal diagnosis of thalassaemia) enablingdirected donation of only those cord bloods which arecompatible. In addition, the availability of a suitable cordblood collection may allow the transplant to be carried out 1–2 years earlier and spares the donor the discomfort and risksof bone marrow donation.

In the largest single-centre experience reported, cord bloodtransplants were carried out on six young children (2–7years) with thalassaemia major, five of whom survive free ofdisease (Issagrisil et al, 1997). The place of cord bloodtransplants has not yet been established; too few have beenperformed in thalassaemia to allow assessment of the relativemerits of cord blood versus marrow-derived stem cells.However, preliminary data suggest that the principal draw-back of cord blood is the increased risk of graft rejectionwhich has now been reported by several groups (Wagneret al, 1995; Chik et al, 1996; Gluckman, personal commu-nication), and this may in part reflect the limited number ofcells available for transplantation.

Recommendations and future prospects. For the majority ofchildren with b-thalassaemia major, and an HLA-identicalsibling donor, BMT results in cure and is likely to restore theirlife expectancy to normal. This suggests that BMT should beoffered to all such children, even where optimal medical careis available. It is, nevertheless, essential that the risks anddisadvantages of BMT are carefully explained to all familiesconsidering this option. Uncertainty over fertility remains,and even young children in class I may experience severechronic GVHD or fatal transplant-related complications. Forchildren in class III the choices are particularly difficult;children with recurrent prolonged periods of poor chelation,who are known to have a poor prognosis with medicalmanagement, should therefore be identified promptly byexperienced clinicians and transplanted early before majororgan damage makes the risks of BMT too high.

The role of BMT for adults with thalassaemia major is farfrom clear, since transplant-related mortality is significantlyhigher than during childhood. One approach, not yetexplored in clinical trials, may be to offer it to highly selectedpatients willing to undergo 12–18 months of intensive

intravenous iron chelation therapy prior to BMT with theaim of improving iron-mediated liver and cardiac damage.An alternative approach for future consideration would beto combine a less-intensive myeloablative regimen withrepeated infusions of donor peripheral blood stem cells and/or lymphocytes at intervals soon after the original transplantas suggested by Slavin’s group (Or et al, 1996; Kapelushniket al, 1997). A similar approach was used by this group tosuccessfully restore 100% donor haemopoiesis in a childwho had manifest only 4–7% donor haemopoiesis for 5years following allogenic BMT from the same donor (Or et al,1996). The persistence of apparently small numbers of donorcells over a prolonged period raises the prospect of developingless toxic submyeloablative conditioning protocols for genetherapy of haemoglobin disorders. Until then, BMT remainsthe only cure for thalassaemia major; it is therefore likely toretain an important role in its management for at leastanother 5 years and the lessons learnt from allogeneictransplantation will be essential in the planning andexecution of gene therapy protocols.

BMT for sickle cell diseaseAlthough the first BMT in sickle cell disease was carriedout in 1984 (Johnson et al, 1984), the total number oftransplants carried out worldwide is less than 150, a farlower number than undertaken during the same period forthalassaemia major (Vermylen et al, 1991; Walters et al,1996b; Bernaudin et al, 1997). There are likely to be severalreasons for this. One of the main ones is that the disease, incontrast to thalassaemia, tends to be heterogenous in itsmanifestations and impact on affected patients and theirfamilies. At least in childhood, mortality and morbidity isfairly low for the majority of those with the disease, althougha subset of children experience major life-threateningdisease-related complications (Platt et al, 1994). In addition,although BMT remains the only cure for sickle cell disease,recent advances in medical treatment (e.g. using HbF-inducing drugs) have now been shown to reduce some of thecomplications of the disease as well as improve quality of lifein children as well as adults (Charache et al, 1995; Fersteret al, 1996), leading some to question the role of BMT whereless-aggressive treatment shows promise (Piomelli, 1991;Roberts & Davies, 1993). Nevertheless, even with optimalmedical care the majority of patients with sickle cell diseasewill have sustained some major organ or tissue damage bythe age of 30, including stroke, sickle lung disease, asepticnecrosis or nephropathy. This has led several groups to offerBMT to a subset of selected chidren with sickle cellsyndromes who are at high risk of major morbidity orpremature death either as a consequence of seriouscomplications sustained early in childhood or because theylive in parts of the world with poor access to good-qualitymedical care (Vermylen et al, 1991; Walters et al, 1996b).

Selection of patients. Although cogent arguments foroffering BMT to all patients with sickle cell disease havebeen presented (performing the procedure early to minimizemortality and complications) (Piomelli, 1991), most clin-icians are rigorous in selecting those patients most likely tobenefit from this approach. The first groups to transplant

3Review


significant numbers of patients, in Belgium and France, didoffer BMT to children with recurrent vaso-occlusive criseswithout other major complications of their disease wheresuch children were returning to Africa (Vermylen et al,1991). In contrast, the international study with centres inthe U.S.A. and Europe, including the U.K., focuses onchildren with symptomatic sickle cell disease who haveexperienced major disease-related complications (Walterset al, 1996b). The principal entry (and exclusion) criteria forthis study have been adopted by the HaemoglobinopathySubcommittee of the Paediatric Haematology Forum in theU.K. (Davies, 1993; Davies & Roberts, 1996) as reasonableindications for BMT (Table I). The aim of these criteria is toidentify the subset of children most likely to experiencefurther complications of their disease (e.g. a fatal or disablingstoke) and to transplant such children before irreversibleorgan damage makes the risks of BMT unacceptably high.In this respect it is essential to carry out a comprehensiveassessment of the extent of any pre-existing organ damagein all patients prior to being accepted for the BMT pro-gramme, including mandatory detailed neurological andneuropsychometric evaluation.

Conditioning regimens. Most patients have received con-ditioning regimens very similar to those used for transplanta-tion of thalassaemia, employing a combination of busulphanand cyclophosphamide. Oral busulphan (14–16 mg/kg or485 mg/m2) together with cyclophosphamide (200 mg/kg)have been shown to be effective as a myeloablative regimen(Vermylen et al, 1991; Walters et al, 1996b; Bernaudin et al,1997), although, as for thalassaemia, the rate of graftrejection with autologous reconstitution approaches 10%and may be reduced by the inclusion of ALG or Campath forseveral days prior to transplant. GVHD prophylaxis in mostcentres has been with cyclosporine 6 short-course metho-trexate (two to four doses in the first 2 weeks after BMT). The

high incidence of neurological complications (Walters et al,1995) seen during BMT for sickle cell disease (see below) hasled to the introduction of a number of additional guidelinesincluding the use of anticonvulsant prophylaxis duringconditioning and for at least 6 months thereafter, themaintenance of strict control of blood pressure, throughoutthe first post-transplant year, and aiming to keep plateletcounts >50 × 109/l at all times (Walters et al, 1995, 1996b).

Outcome. The relatively small number of transplantscarried out to date means that a prognostic classificationcomparable to that for thalassaemia has not been reported.Given that the Pesaro classification is largely derived from theconsequences of long-term transfusion/iron overload, itseems unlikely that it would be predictive for sickle celldisease. The largest series of patients transplanted remainsthat from the Belgian centres reported by Vermylen et al(1991, 1997). Although many of the earlier patients hadfairly uncomplicated histories prior to transplant, the seriesnow includes many children who have experienced majordisease-related complications. Nevertheless, the results arevery encouraging, with 95% overall survival and 86% event-free survival, the difference in the two figures being largelyaccounted for by graft rejection with autologous reconsti-tution. The results from the international study, recentlyupdated (Walters et al, 1996b; Sullivan et al, 1997), showthat even in a series of children who have all experiencedsevere complications from their disease prior to BMT (almosthalf had had a previous stroke) the majority benefit from thisapproach to treatment. The overall survival in the 32children transplanted so far is just over 90%, with event-freesurvival of 76%. In the U.K., 14 children known to theHaemoglobinopathy Subcommittee of the Paediatric Hae-matology Forum have been transplanted for sickle celldisease. Overall survival is 93% (one patient died from severeacute GVHD) and to date no cases of graft rejection havebeen seen, although many patients have evidence of stablemixed chimaerism with <20% residual host cells.

It seems likely that these encouraging results have largelybeen achieved because of careful patient selection; in par-ticular, excluding those patients who already have majororgan damage. In addition, strict adherence to protocolsdesigned to minimize neurological complications may havecontributed to the reduced incidence of fatal CNS events inrecent years. Nevertheless, for most patients with sickle celldisease transplantation remains a hazardous procedure whenbalanced against the risks associated with the disease itself. Aswell as neurological complications (currently affecting about20% of patients), a small number of patients experience fatalor extensive acute or chronic GVHD and the overall risk ofgraft rejection can be estimated at around 10% (Vermylen et al,1991, 1997; Walters et al, 1996b; Bernaudin et al, 1997).The counselling of sickle cell disease patients and their familiesabout these risks is particularly difficult, since, unliketransplantation for haematological malignancies, many donot perceive it as an immediately life-threatening diseasewhereas others find the unpredictability of the diseaseintolerable and worth accepting a BMT-associated mortalityrisk of 50% or more (Kodish et al, 1991; Roberts & Davies,1993).

4 Review


Table I. Selection of patients with sickle cell disease for BMT: BritishPaediatric Haematology Forum criteria.

Acceptance1. <16 years with HLA-identical sibling and informed consent

2. One or more of these sickle-cell disease-related complications:CNS diseaseRecurrent acute or stage I/II chronic sickle lung diseaseRecurrent, severe, debilitating pain (>3 hospital admissions/year in 3–4 years)

3. Problems respecting future care

Exclusions1. Donor with a major haemoglobinopathy

2. One or more of the following:Karnofsky performance <70%Portal fibrosis (moderate or severe)Renal impairment (GFR <30%)Major intellectual impairmentStage III and IV chronic sickle lung diseaseCardiomyopathyHIV infection

Long-term effects. It is still too early to be able to evaluatethe long-term effects of BMT for sickle cell disease in detail.They can, however, be considered in three main areas:those related to the transplant itself (conditioning toxicity/immunosuppression); the effects on the pre-existing organdamage secondary to sickle cell disease; and the psychosocialimpact of BMT on children with sickle cell disease and theirfamilies, about which almost nothing is known.

Measurable long-term toxicity of the BMT conditioningregimen appears to be fairly low. One patient in the Belgianseries has developed AML; the association between this eventand BMT is unclear at present since there are no otherreports of malignancy following BMT for sickle cell disease(Vermylen et al, 1997). Recent evidence from other studies inchildren of the effects of busulphan/cyclophosphamideconditioning on growth suggest that although initialgrowth velocity may be reduced, growth returns to normalin the vast majority of cases (Wingard et al, 1992; Gaziev etal, 1993; Huma et al, 1995). Data from the Belgian andinternational series (Vermylen et al, 1997; Sullivan et al,1997), as well as anecdotal experience in the U.K., indicatethat the same is true following BMT for sickle cell disease. Incontrast, impaired gonadal function following busulphan/cyclophosphamide conditioning appears to be very common(De Sanctis et al, 1991, 1997). Although recovery in girlstransplanted before puberty occurs quite frequently, in thosetransplanted after puberty gonadal recovery is much lesslikely (Sanders et al, 1996). Data from studies of thalassae-mic children would, however, suggest that there is somepreservation of fertility in children transplanted beforepuberty (De Sanctis et al, 1991, 1997), particularly inboys, and, in general, the endocrine problems associatedwith iron overload/desferrioxamine would be anticipated toaffect a smaller proportion of the children transplanted forsickle cell disease.

Data on improvement of organ damage following BMT forsickle cell disease are of great interest. Certainly, BMTabolishes vaso-occlusive crises, as would be expected(Vermylen et al, 1991; Walters et al, 1996b). However, thereare also now reports of improved splenic function (Ferster et al,1993; Vermylen et al, 1997), of the reversibility of impairedlung function secondary to chronic sickle lung disease, ofresolution of osteonecrosis and of the stabilization andoccasional improvement of sickle-related CNS disease (Walterset al, 1996b; Vermylen et al, 1997; Bernaudin et al, 1997).These encouraging results suggest that successfully trans-planted patients with sickle cell disease can reasonably expectboth a vastly improved quality of life and a normal lifespan.

Recommendations and future prospects. The results of BMTfor sickle cell disease represent a major advance for the smallsubset of children who have experienced significant butnot irreversible sickle cell disease-related organ damage andwho have an HLA-identical sibling donor. Recent estimatessuggest that such patients represent only 5–10% of thetotal number of affected children (Davies & Roberts, 1996;Walters et al, 1996a). Given that medical treatment isslowly improving and that gene therapy is not yet anoption, what should be the role of BMT in the near future?Possibilities include offering BMT to all affected children with

HLA-identical donors, extending the programme to youngadults, and the use of volunteer marrow or cord blood donors.

The available data suggest that the risks of BMT are likelyto outweigh the benefits for ‘well’ children with sickle celldisease who have a 97% chance of reaching adulthood andthat targetting the subset of ‘complicated’ children remainsappropriate, although the numbers of transplanted patientsin the U.K. indicate that many children are still not beingoffered this opportunity. The question of transplantingyoung adults is a more difficult one; if we are to pursuethis possibility it seems prudent to confine BMT for adultswith sickle cell disease to a very small number of centres withspecialist expertise in BMT for sickle cell disease and to useselection criteria as rigorous as those currently employed forchildren with the disease. The use of unrelated donor stemcells for children with sickle cell disease who fulfil the criteriafor transplantation but have no suitable family donor is areasonable prospect for the future, as advances in donormatching and extending of the donor ‘pool’ via cord bloodbanks are already leading to improved results in haemato-logical malignancies. Such improvements may well precedethe clinical application of gene therapy; BMT for sickle celldisease is therefore likely remain the best option for themanagement of children with complicated sickle cell diseasefor the forseeable future.

ACKNOWLEDGMENTS

I thank Drs P. Darbyshire, A. Will, S. Ball and P. Veys forsharing the data on children in the U.K. transplanted in theirUnits for haemoglobinopathies.

Department of Haematology, I R E N E RO B E RT S

Royal Postgraduate Medical SchoolHammersmith Hospital,London

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Keywords: bone marrow transplantation, thalassaemiamajor, sickle cell disease.

7Review


Documents

CURRENT STATUS OF ALLOGENEIC TRANSPLANTATION FOR HAEMOGLOBINOPATHIES