forpatientswiththalassaemia - esh360-377).pdf · history of regular iron chelation therapy •...

* CHAPTER 14

Franco Locatelli, Maria Ester Bernardo

Haematopoietic stem celltransplantation

* 14.1For patients with thalassaemia

IRON2009_CAP.14.1(360-377):IRON2009 4-12-2009 16:29 Pagina 360

1. IntroductionThe b-thalassaemias are congenital haemolytic anaemias which are due to mutationsthat either reduce or abolish the production of the b-globin chain of adulthaemoglobin (HbA, a2b2). Caused by over 200 different mutations, the b-thalassaemias are amongst the most common inherited blood disorders worldwide.Allogeneic haematopoietic stem cell transplantation (HSCT) still remains the onlypotentially curative treatment for patients with thalassaemia (1). Since the firstsuccessful allogeneic HSCT, performed in Seattle more than 20 years ago by Thomasand colleagues on an Italian child (2), hundreds of patients with thalassaemia havebeen cured of their original disorder after receiving an allograft, in most cases froman HLA-identical family donor (3-5). In view of this result, allogeneic HSCTrepresents a most attractive therapeutic alternative, especially for those patients,and their families who do not accept the prospective of a lifelong disease requiringcontinuing treatment with blood transfusion and drugs (5).

2. HLA- identical sibling transplant

2.1 Transplant outcome and prognostic factorsThe extensive experience accumulated in the field of HSCT from an HLA-identicalsibling for patients with thalassaemia has allowed the identification of clinicalparameters influencing post-transplantation outcome, thus permitting more refinedprognostic counselling for patients considering the option of HSCT or their parents(3-7). In particular, the risk of dying of transplantation-related complications hasbeen clearly shown to be mainly dependent on patient age, iron overload andinfection with hepatitis viruses. Adults, especially when affected by chronic activehepatitis, have a worse outcome than children, the probability of survival withtransfusion independence having been reported to be 58% (7). Among children belowthe age of 17, three classes of risk have been identified, on the basis of regularityof previous iron chelation, liver enlargement and presence of portal fibrosis (seealso Table 1) (3). In the most recent update of the Pesaro group’s experience, theprobability of thalassaemia-free survival for patients younger than 17 years at timeof HSCT, who received the allograft from an HLA-identical relative, was 87% and 85%,respectively, in patients belonging to class I and II (8). Worse results have beenreported in paediatric patients who had low compliance with iron chelation,especially those in class III, favouring the occurrence of iron-induced organdamage; in these patients the probability of thalassaemia-free survival was initiallyreported to be 53%, mainly due to transplantation-related mortality. By reducingthe dosage of cyclophosphamide, used together with busulfan in the preparative

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CHAPTER 14.1 • HSCT in thalassaemia


regimen of these patients, it has been possible to document a lower incidence oftransplantation-related mortality for children in class III, in the order of 25% (6).A most recent survey, reporting on a limited number of class III patients, mainlyfrom Middle-East Countries, has suggested that the adoption, during the 2 monthspreceding HSCT, of a hypertransfusion regimen, intended to reduce the expansionpressure on the erythron, together with the use of azathioprine and hydroxyureato suppress haematopoiesis and fludarabine for reducing the risk of rejection, maylower the probability of treatment failures and improve post-transplant outcome inthis subgroup of patients (9). These encouraging preliminary results need to beconfirmed in larger cohorts of patients, including those of Caucasian origin.The results obtained by the Pesaro team in patients transplanted from an HLA-compatible relative have been substantially reproduced by other groups, whose studieshave confirmed that the majority of patients with thalassaemia given HSCT froman HLA-identical sibling can be cured of their disease and that both an heavy ironoverload and old age unfavourably affect post-transplant outcome (10, 11).

2.2 Reasons for treatment failureBoth transplant-related mortality (TRM) and lack of sustained donor engraftmentcontribute to treatment failure in patients with haemoglobinopathies. In particular,the incidence of graft rejection in patients given HSCT for thalassaemia is considerablyhigher than that observed in patients transplanted for leukaemia (6, 8). Severalfactors may explain the high incidence of graft failure after an allograft in patientswith haemoglobinopathies, including previous sensitisation to alloantigens throughrepeated transfusions, no chemotherapy treatment before HSCT and large spleen size,

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Table 1: Stratification of patients with thalassaemia under the age of 17undergoing haematopoietic stem cell transplantation in 3 different classes ofrisk according to the presence or absence of regular iron chelation therapy,portal fibrosis and hepatomegaly

• Class INo hepatomegalyNo portal fibrosis at liver biopsyHistory of regular iron chelation therapy

• Class IIOne or two of the risk factors

• Class IIIHepatomegaly (>2 cm below the costal margin)Portal fibrosis at liver biopsyHistory of irregular iron chelation therapy


especially in older patients. Notably, in patients transplanted from an HLA-identicalsibling, the incidence of rejection is directly correlated with the patient’s class ofrisk, an incidence of 4%, 8% and 12% being observed in patients belonging to riskclass I, II and III, respectively (6, 8).Stable mixed chimerism is also not uncommon among patients transplanted forthalassaemia from a compatible sibling (12), as seen also in patients with acquiredaplastic anaemia following HSCT. Patients with thalassaemia developing stablechimerism, even with a low percentage of donor marrow progenitors (20-30%), havebeen reported to experience marked enrichment of donor cells in the mature redblood cell compartment, which makes them transfusion-independent (12). However,a not negligible proportion of thalassaemia patients given HSCT with mixedchimerism develop secondary graft failure, in particular when increasing proportionsof recipient’s cells are observed in serial monitoring.

2.3 Reduced intensity allograftsThe observation that sustained mixed chimerism is frequently observed inthalassaemia patients has provided a strong biological and clinical rationale forconsidering the use of reduced-intensity preparative regimens in patients withthalassaemia. This novel approach has been extensively investigated for thetreatment of patients with malignancies who are not eligible for an allograft usingstandard conditioning regimens, either because of age or poor medical condition(14, 15). In fact, non-myeloablative conditioning regimens, mainly based on theuse of purine analogues like fludarabine, can reduce or eliminate toxic effectsassociated with conventional HSCT allowing a wider applicability of the procedure.In the context of non-malignant disorders, the use of a reduced intensity preparativeregimen could also allow engraftment of donor cells. Once T and NK cells of the donorhave engrafted, they can either completely eliminate residual host cells, or favourthe induction of a state of stable mixed chimerism, which, as mentioned before,may be sufficient to cure the patient. Post-transplant donor lymphocyte infusion(DLI) may help eradicate host residual host haematopoiesis. Thalassaemia patientswith liver/heart damage could represent the ideal candidates for well-controlled,clinical trials of less toxic conditioning regimens carried out in centres experiencedin HSCT. Such regimens may also help reduce the incidence of late effects, in particularthose concerning growth and fertility, resulting from high-dose chemotherapyused for conventional HSCT) for treating patients with haemoglobinopathies (16-18). So far, only a few reports have demonstrated the feasibility of using reduced-intensity preparative regimens. Although transplant-related toxicity was mild in allcases reported, a significant proportion of these patients did not have sustainedengraftment of donor erythropoiesis. This finding indicates that, stable donor

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engraftment is more difficult to achieve with non-myeloablative strategies inpatients with haemoglobinopathies than in adults with malignancy, and it does notencourage the use of this approach in young and fit patients who can tolerate moreintensive myeloablative treatment. Reduced intensity preparative regimens may findmore appropriate application in older patients or in those with poor performancestatus and/or organ dysfunction, predicting a high risk of life-threateningcomplications if a fully myeloablative regimen is employed. In the perspective ofidentifying conditioning regimens displaying both immune-suppression and myelo-suppression, able to prevent host-versus-graft reaction and promote engraftment,while devoid of relevant extra-medullary toxicity, a recent study has reportedencouraging results (19). In this phase I-II trial, a novel conditioning regimenincluding thiotepa, treosulfan and fludarabine was utilised in patients withthalassaemia given an allogeneic HSCT; it was associated mild extra-medullary toxicity,and proved to be effective. Indeed, in 20 patients with thalassaemia given anallogeneic HSCT, 9 of whom were adults or belonged to the class III of the Pesaroclassification, the 2-year probability of survival and thalassaemia-free survivalwas 95% and 85%, respectively. An update of this study, analysing 32 patients,substantially confirms the results obtained in the initial cohort of patients (see alsoFigure 1 for details). Altogether, these results render the use of a treosulfan-basedpreparative regimen attractive in patients with thalassaemia eligible for an allograft,in order to reduce the risk of life-threatening complications and increase thenumber of patients successfully cured. In particular, treosulfan-based myeloablationmight find elective application in adult patients or in those with poor performancestatus and/or organ dysfunction, all predicting a high risk of life-threateningcomplications if busulfan is employed.It is possible that in order to increase the chance of successful transplantation whenreduced-intensity regimens are employed, stem cell doses higher than thoseattainable with marrow harvest may be needed. This means a preferential use ofcytokine-mobilised, peripheral blood haematopoietic stem cells, a practice whichraises concerns for the donor when the donor is a minor, and for the recipient becauseof the increased risk of chronic graft-versus-host disease (GvHD) suggested by somestudies (20). Also the use of DLI for obtaining a stable chimerism may trigger thedevelopment of severe, life-threatening or invalidating, GvHD.

2.4 Complications of HSCTChronic GvHD is considered one of the most severe and feared complications of HSCT;it has been reported to occur in between 8% and 27%.of patients with thalassaemia,given HSCT from a compatible relative (11, 21). In fact, although only a minorityof patients with chronic GvHD have the extensive form of the disease, the quality



of life of patients with extensive chronic GvHD may be certainly worse than thatof patients with thalassaemia treated with supportive therapy (i.e. regular erythrocytetransfusions and iron-chelating drugs). Thus, the most effective strategy ofpharmacological prophylaxis must be employed to reduce the incidence of both acuteand chronic GvHD in patients with thalassaemia.In terms of long-term side effects associated with HSCT in patients with thalassaemia,available data (22, 23) suggest that HSCT probably does not lead to more adverseendocrine consequences (i.e. growth impairment, delayed puberty, hypothyroidism)than conservative therapy, with the exception perhaps of patients who maintain anexcellent compliance with iron chelation for the crucial years before and aroundpuberty. Effects on fertility are more worrying as, despite anecdotal report ofsuccessful pregnancy after transplantation (24), the vast majority of patients givenstandard preparative regimens (namely those containing busulfan) before HSCT losefertility, whereas a significant number of successful pregnancies in women with



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Figure 1: Treosulfan as conditioning regimen

Survival and thalassaemia-free survival. Two-year Kaplan-Meier estimates of the overall survival ( )and survival with transfusion independence ( ) in 32 patients with thalassaemia transplantedafter a conditioning regimen including thiotepa, treosulfan and fludarabine.

Thalassaemia-free survival = 86% (72-99)

Survival = 93% (84-100)

SUR: N = 39; E = 3

TFS: N = 39; E = 6

1.00

0.75

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thalassaemia treated with conservative therapy have been reported in recent years(25, 26). Due to the recent introduction of regimens including treosulfan insteadof busulfan, it is still unknown whether treosulfan-based conditioning may beassociated with a greater chance of preserving patient’s fertility.As liver fibrosis, cirrhosis and cardiac failure are well-known complications of ironoverload in thalassaemia patients, a program of serial phlebotomies post-transplantation is employed in many centres to reduce iron overload in patients whohave successfully undergone HSCT and it has been demonstrated that throughregular phlebotomy or even chelation therapy, it is possible to prevent or reverseorgan damage due to pre-existing iron overload in the liver (27). Likewise, regardingcardiac function, a recent report documented that subclinical left ventriculardiastolic dysfunction and impaired left ventricular contractility in transplantedthalassaemia patients with may be reversed with an effective regimen of ironreduction such as phlebotomy (28). A phlebotomy programme can be started even


Figure 2: Kaplan-Meier estimates

Kaplan-Meier estimates of the overall survival ( ) and survival with transfusion independence( ) in 50 paediatric patients belonging to the class I and II of the Pesaro classification transplantedfrom an unrelated volunteer. Additional estimation of survival with transfusion independence wasperformed considering patients with graft rejection and subsequent sustained engraftment after secondtransplantation from the same donor as non-failures ( ).

Overall survival

Survival with transfusion independence

Survival with transfusion independence after 2nd BMT

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0.9

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0.6

0.5

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in the first months after HSCT, whenever the patient reaches a sustained haemoglobinvalue greater than 10.5 g/dL.

3. Cord blood transplantation for patients with thalassaemiaOver the past decade, cord blood haematopoietic stem cells have been usedincreasingly, in place of bone marrow progenitors, for transplanting paediatricpatients with either malignant or non-malignant disorders (29). In comparison withBMT, the main clinical advantage associated with cord blood transplantation (CBT)from an HLA-identical sibling is the lower risk of both grade II-IV acute andchronic GvHD (29-31). The low incidence of GvHD in CBT recipients renders this typeof transplant particularly appealing for patients with thalassaemia, also for otherpatients affected by a non-malignant disorder. After a few anecdotal reports ofsuccessful CBT for patients with thalassaemia (32, 33), a study from the Eurocordcooperative group has analysed the outcome of 33 patients with thalassaemia,belonging to class I and class II in the Pesaro classification, given CBT from a sibling,HLA-identical in 30 cases and with a single HLA-disparity in the 3 remainingdonor/recipient pairs (34). No patient died for transplant-related complications,suggesting that related CBT for haemoglobinopathies is a safe procedure (34). Sevenout of these 33 patients did not have sustained engraftment of donor cells,although two of them obtained sustained engraftment after subsequent BMT fromthe same donor. A better probability of thalassaemia-free survival was observed inpatients belonging to class I as compared to those assigned to class II of the Pesaroclassification, (89% vs. 62%, respectively, p=0.05). Patients who did not receivemethotrexate as part of GvHD prophylaxis and who were given thiotepa during thepreparative regimen had a remarkably better outcome, this indicating that, in optimalconditions, CBT offers a probability of success at least as good as that of BMT. Arecent update of this analysis on 38 patients confirmed the absence of transplant-related mortality, with a thalassaemia-free survival in the order of 80% (LocatelliF, unpublished results). A recent report addressed the issue of donor/recipientchimerism in patients with thalassaemia given CBT from an HLA-identical relativein a longitudinal study (35). The study showed that mixed chimerism sustained overtime in circulating leukocytes was found in a large proportion of these patients,without, however, predicting the occurrence of graft failure (35). In particular, attime of haematological engraftment, all 27 children given CBT, who were studied,displayed mixed chimerism, with co-existence of donor and host haematopoieticcells. Subsequently, 13 of them converted to full donor chimerism, while theremaining 14 children are maintaining a stable mixed chimerism after a medianfollow-up time of 42 months. This study also demonstrates that mixed chimerism



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is associated with a favorable transplantation outcome, as all the 27 patientsinvestigated are alive and transfusion independent, without having experiencedneither acute nor chronic GvHD (35).The possibility of using cord blood cells for curing thalassaemia may tempt acouple who has an affected child to conceive a new compatible, healthy sibling.This raises some bioethical issues (36). Pre-natal diagnosis of thalassaemia iswidely available and, besides determining whether a foetus is healthy, makes itpossible also to evaluate HLA-compatibility with the affected child. Pre-natalknowledge of lack of HLA-compatibility between the affected child and the foetusmight induce the parents to decide to terminate the pregnancy also in the case thefoetus results to be healthy, an attitude that is questionable from an ethicalstandpoint. Moreover, the recent demonstration that in vitro fertilisation and pre-implantation selection of compatible, healthy embryos is feasible (37) mayencourage a couple with an affected child to initiate a pregnancy with the certaintythat a source of stem cells will be available for transplantation (36). Reduced toits essential ethical-bioethical problematic issues, this attitude of selecting the “HLAcompatible and not sick” embryo entails weighing the desirable saving of a life (withoptimum quality of success) against the choice of discarding other (equally not sick)embryos just because they are not HLA-compatible with the candidate recipient (thus,not “usable” for transplantation purposes) (36).Discussing in utero HLA typing performed early in the pregnancy offers also theopportunity to mention that there is another, more innovative, way to perform geneticcounselling for beta thalassaemia: in fact, it has been recently reported thatcouples at risk diagnosed with an affected embryo may decide against terminationof the pregnancy if the prospect of BMT from a family member (namely an HLA-identical living sibling) is available (38).

4. A strategy to increase the applicability of HSCT: the use of unrelatedvolounteersOnly 25-30% of patients with diseases potentially curable by HSCT have a suitableHLA-compatible sibling. Thus, the vast majority of patients who can benefit froman allograft lack a family donor. During the past 15 years, with the establishmentof bone marrow donor registries, which now include more than 12 million volunteersworld-wide, many patients who need allogeneic HSCT have been able to locate asuitable unrelated donor. However, mainly because of HLA polymorphism and thelimitations of serological techniques for HLA-typing, increased difficulties withengraftment and augmented incidence of both acute and chronic GvHD have beenreported in recipients of an unrelated donor allograft (39, 40). Recently, it has been



demonstrated that more precise characterisation of HLA alleles using high-resolutiontyping for both class I and class II molecules can reduce the risk of developingimmune-mediated complications and fatal events after transplantation (41). Theseachievements have provided the rationale for considering the possibility ofperforming HSCT from unrelated volunteers in patients with haemoglobinopathies.Thus, it has been hypothesised that with accurate selection of the donor, the outcomeof patients given an allograft from an unrelated volunteer could become comparableto that of patients transplanted from an HLA-identical family donor. Some anecdotalreports have initially shown that unrelated donor HSCT is able to cure patients withthalassaemia major (42, 43). The Italian co-operative group for BMT (GITMO)activated a protocol of transplantation from an unrelated donor for patients withthalassaemia major, the results of which have been published in different reports(44-46). In all cases, the unrelated volunteer donor was selected using high-resolution molecular typing for both HLA class I and II loci and stringent criteriaof compatibility in the donor recipient pair (namely allelic identity for HLA loci A,B, C and DRB1 or single allelic disparity for class I loci). Altogether, the resultsobtained with this protocol in the different classes of risk for paediatric patients(44, 45), as well as in adults (46), demonstrate that, when donor selection is basedon stringent compatibility criteria, it is possible to reproduce the results alreadyreported using a compatible family donor. As an example, Figure 2 shows theKaplan-Meier estimates of survival and of survival with transfusion-independencein 50 children with thalassaemia belonging to the class I and II of the Pesaroclassification. In the same cohort of patients, the cumulative incidences oftransplant-related mortality and of extensive chronic GvHD were 6% and 7%,respectively.Thus, the experience of transplantation using unrelated volunteer shows that boththe risk of death and that of developing severe chronic GvHD are limited and donot exceed the level already largely accepted when using a family donor providedthat stringent criteria of compatibility be employed for selecting the donor.The main limitation of the Italian experience is that, using such criteria,approximately only one third of thalassaemia patients who started the search founda suitable donor in a median time of 3-4 months. In order to further widen theapplicability of HSCT, it is theoretically possible to select the donor according toless strict matching criteria and to use some sort of in vivo serotherapy, which hasrecently been proven to reduce the incidence of both acute and chronic GvHD ina dose-dependent manner, after an allograft from an unrelated donor (47). However,it remains to be proved whether the results achievable with HSCT from unrelateddonors selected using less stringent criteria of compatibility with the recipients canfavourably compare with those reported using an HLA-identical sibling as donor.



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This concern is highlighted by an analysis on the role of DPB1 disparity betweendonor and recipient in the Italian cohort of patients with thalassaemia transplantedfrom an unrelated volunteer (48). In that study, in fact, the risk of graft rejectionwas found to be significantly increased in patients with a non-permissive disparity(defined according to the rules of functional immunogenetics) at locus DPB1 in thehost-versus-graft direction. Other relevant immunogenetic aspects influencing theoutcome of thalassaemia patients transplanted from an unrelated donor refer to therole played by the 14-basepair (bp) deletion-insertion polymorphism located in the3'-untranslated region of the HLA-G gene and to the interaction between killerimmunoglobulin-like receptors (KIRs) and their ligands. Indeed, a recent study hasdemonstrated that thalassaemia patients given BMT from an unrelated donor whowere homozygous for the 14-bp deletion had a significantly higher risk of developingacute GvHD as compared to patients homozygous or heterozygous for the 14-bpinsertion (49). As far as the interaction between KIRs and their HLA ligands,another report has suggested that patient HLA C1/C2 heterozygosity may favour thedevelopment of donor alloreactivity and thereby increase the risk of GvHD.Conversely, HLA C1/C1 and C2/C2 homozygosity of the patient seems to reduce therisk of GvHD, but may increase the incidence of graft rejection (50). The data derivingfrom these studies (49, 50) may be helpful in tailoring the intensity of GvHDprophylaxis and conditioning regimens in thalassaemia patients receiving HSCT froman HLA-identical volunteer donor.Finally, it must be mentioned that, for the time being, the use of T-cell depletedHSCT from an HLA-partially matched relative is not routinely advisable for patientswith thalassaemia, due to the high risk of serious, often fatal, infectiouscomplications. Haploidentical, T-cell depleted HSCT can be considered in extremesituations, such as that of a patient completely not compliant with any type ofchelation therapy and/or with immunisation to allogeneic or autologous erythrocyteantigens that renders transfusion either impossible or life-threatening.

5. The choice between transplantation and conventional treatmentSafe blood transfusion and effective iron-chelating drugs have dramatically improvedboth survival and quality of life of patients with thalassaemia over the last twodecades, and have changed a previously fatal disease with early death, to a chronic,although progressive, disease compatible with prolonged survival. In the developedworld, the life expectancy of patients with thalassaemia is now in the order of 40-55 years, mainly depending on compliance with medical treatment (1, 51-53). Infact, when compliance with chelation therapy is good and consistent, 90% of patientssurvive well into their 30s, whereas, where compliance is poor, fewer than 10% willreach their 40th birthday (54). In the developing world, by contrast, most children



with this disease die before the age of 20 years because of the unavailability of safeblood products in adequate amounts and/or of expensive iron-chelating drugs.In view of all these considerations the evaluation of the benefit/risk balance of whatHSCT can offer profoundly differs for patients with thalassaemia living in differentsocio-economic contexts. As mentioned before, HSCT has the great appeal of beingthe only treatment able to definitively cure thalassaemia, although it is associatedwith a consistent risk of complications that can dramatically shorten the lifeduration of some patients. The best results can be obtained in younger patients withlimited iron overload and without severe organ damage. These patients are the “ideal”candidates for an allograft, whereas older, heavily iron-overloaded patients,especially when affected by liver complications, run a considerable risk of transplant-related, life-threatening complications. It is possible, however, that the latterpatients, whenever the transplant is successful, are those who receive the maximumbenefit from it, given the much reduced life expectancy, associated, in thalassaemia,with continuing transfusions in the presence of reduced compliance with ironchelation.Looking at the option of HSCT for treating thalassaemia from the point of view ofa health system will show that this procedure for thalassaemia is highly costeffective. In fact the cost of medical treatment for this disease is considerable: recentcalculations estimated the lifetime treatment cost in the UK at £803,002, whereasthe cost of HSCT ranges between approximately £50,000 and £100,000, dependingon the country in which it is performed. In view of this finding, there is no doubtthat, for countries with limited economic resources, HSCT can be a convenient option,provided that the resources needed for performing the transplant are immediatelyavailable.

AcknowledgementsThis work has been partly supported by grants from European Union (ITHANET project), CNR(Consiglio Nazionale delle Ricerche), MIUR (Ministero dell’Istruzione, Università e della Ricerca)and Fondazione IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico) Policlinico S.Matteo to F.L.

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Multiple Choice Questionnaire

To find the correct answer, go to http://www.esh.org/iron-handbook2009answers.htm

1. Which are the “ideal” thalassaemia patient candidates for anallograft?a) Older, heavily iron-overloaded patient . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

b) Patients affected by liver complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

c) Young patients with limited iron overload and without severeorgan damage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

d) Young patients with heavy iron overload . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2. Which of the following explains the high incidence of graft failureafter an allograft in patients with haemoglobinopathies:a) Previous sensitisation to alloantigens through repeated transfusions . . . .

b) No chemotherapy treatment before HSCT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

c) Large spleen size . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

d) All the above. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3. Which of the following measures have been recently reported to becapable of lowering the probability of treatment failures and improvingpost-transplant outcome in thalassaemia patients fromMiddle-Eastern countries?a) A hypertransfusion regimen during the 2 months preceding HSCT . . . . . . . .

b) The use of azathioprine and hydroxyurea before HSCT . . . . . . . . . . . . . . . . . . . . .



375


c) The use of fludarabine as part of the preparative regimen . . . . . . . . . . . . . . . . .

d) All of the above . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

4. What is the main clinical advantage associated with cord bloodtransplantation (CBT) from an HLA-identical sibling, in comparisonwith BMT, for patients with thalassaemia:a) Lower risk of both grade II-IV acute and chronic GvHD. . . . . . . . . . . . . . . . . . . .

b) Absence of risks for the donor. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

c) Reduced risk of transmitting infections. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

d) Rapid availability of the cryopreserved cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

5. When safe blood transfusion is applied and compliance with chelationtherapy is good, what is the proportion of thalassaemia patients whoat present can survive well into their 30s?a) 50% of patients. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

b) 30% of patients. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

c) 90% of patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

d) 100% of patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .



NOTES

DISORDERS OF ERYTHROPOIESIS, ERYTHROCYTES AND IRON METABOLISM377


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