Allogeneic and autologous transplantation for haematological diseases, solid tumours and immune disorders: definitions and current practice in Europe

SPECIAL REPORT

Allogeneic and autologous transplantation for haematological diseases,

solid tumours and immune disorders: current practice in Europe 2009

P Ljungman1, M Bregni2, M Brune3, J Cornelissen4, T de Witte5, G Dini6, H Einsele7, HB Gaspar8,A Gratwohl9, J Passweg10, C Peters11, V Rocha12, R Saccardi13, H Schouten14, A Sureda15, A Tichelli9,A Velardi16 and D Niederwieser17, for the European Group for Blood and Marrow Transplantation

1Department of Haematology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden; 2Unit of MedicalOncology, San Giuseppe Hospital, Milan, Italy; 3Section of Haematology, Department of Medicine, Sahlgren’s University Hospital,Goteborg, Sweden; 4Department of Hematology, Erasmus MC-Daniel den Hoed Cancer Centre, Rotterdam, The Netherlands;5Department of Hematology, Radboud University Medical Centre Nijmegen, Nijmegen, The Netherlands; 6Department of PaediatricHaematology and Oncology, IRCCS ‘G.Gaslini’, Genoa, Italy; 7Department of Haematology and Oncology, University of Wurzburg,Wurzburg, Germany; 8Molecular Immunology Unit, UCL Institute of Child Health, London, UK; 9Haematology Division, UniversityHospital, Basel, Switzerland; 10Haematology Division, Geneva University Hospital, Geneva, Switzerland; 11BMT Unit, St AnnaKinderspital, Vienna, Austria; 12BMT Unit, Department of Haematology and Eurocord office, Hopital St Louis, Paris, France;13Department of Haematology, Careggi Hospital & University of Florence, Florence, Italy; 14Section of Haematology, Department ofInternal Medicine, University Hospital, Maastricht, The Netherlands; 15Clinical Haematology Division, Hospital de la Santa Creu iSant Pau, Barcelona, Spain; 16Department of Haematology, University of Perugia, Perugia, Italy and 17Department of Haematologyand Oncology, University of Leipzig, Leipzig, Germany

The European Group for Blood and Marrow Transplan-tation regularly publishes special reports on the currentpractice of haematopoietic SCT for haematologicaldiseases, solid tumours and immune disorders in Europe.Major changes have occurred since the first report waspublished. HSCT today includes grafting with allogeneicand autologous stem cells derived from BM, peripheralblood and cord blood. With reduced-intensity conditioningregimens in allogeneic transplantation, the age limit hasincreased, permitting the inclusion of older patients. Newindications have emerged, such as autoimmune disordersand AL amyloidosis for autologous HSCT and solidtumours, myeloproliferative syndromes and specific sub-groups of lymphomas for allogeneic transplants. Theintroduction of alternative therapies, such as imatinib forCML, has challenged well-established indications. Anupdated report with revised tables and operating defini-tions is presented.Bone Marrow Transplantation advance online publication,6 July 2009; doi:10.1038/bmt.2009.141Keywords: haematopoietic SCT; indications; recommen-dations; Europe

Introduction

This report is the fifth report from the European Group forBlood and Marrow Transplantation (EBMT) classifyingallogeneic and autologous haematopoietic SCT proceduresaccording to prevailing clinical practice in Europe.1–4 Sincethe first report, major changes have occurred in clinicalpractice based on new scientific and technical developmentsof new indications but also changed indications for HSCTbased on important developments in non-transplantmanagement of haematological malignancies. Limitationsfor the transplant procedures such as age and comorbiditieshave been modified because of the introduction of reduced-intensity conditioning regimens. The updated classificationsare presented below (Tables 1 and 2). As in the previousreports, we have attempted to summarize the opinions andpractices of clinicians working in transplant centres inEurope in 2008. The EBMT recommendations are based onexisting prospective clinical trials, registry data and expertopinion, but not on a formal extensive review of theliterature. Therefore, some recommendations have beenmade on the basis of analogy, inference and expertise. Eachsection of the recommendations has been discussed withinthe appropriate working party of the EBMT. The EBMTrecommendations are not meant to decide for an individualpatient whether a transplant is the correct choice ofprocedure. It is also outside the scope of this report toclassify indications on the basis of the use of a particularconditioning regimen or of a particular stem cell source.The classifications are aimed to give guidance and have tobe considered together with the risk of the disease, the riskof the transplant procedure and the results of non-transplant strategies. When the recommendations areinterpreted, it is important, besides a possible survival

Received 19 January 2009; revised 26 March 2009; accepted 24 April2009

Correspondence: Dr P Ljungman, Department of Haematology,Karolinska Institutet, Karolinska University Hospital/Huddinge, M54,Stockholm S-14186, Sweden.E-mail: [email protected]

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Table 1 Proposed classification of transplant procedures for adults—2009

Disease Disease status Sibling donor Allogeneic Autologous

Well-matchedunrelated

mm unrelated41 Ag mmrelated

LeukaemiaAML CR1 (low riska) CO/II D/II GNR/II CO/I

CR1 (intermediatea) S/II CO/II D/II S/ICR1 (high riska) S/II S/II CO/II CO/ICR2 S/II S/II CO/II CO/IICR3, incipient relapse S/III CO/III D/III GNR/IIIM3 molecular persistence S/II CO/II GNR/III GNR/IIIM3 molecular CR2 S/II CO/II GNR/III S/IIRelapse or refractory CO/II D/II D/II GNR

ALL CR1 (standard/intermediatea) D/II GNR/II GNR/III D/IIICR1 (high riska) S/II S/II CO/II D/IICR2, incipient relapse S/II S/II CO/II GNR/IIRelapse or refractory CO/II D/II D/II GNR/III

CML First chronic phase (CP), failing imatinib S/II S/II CO/III D/IIAccelerated phase or 4first CP S/II S/II CO/II D/IIIBlast crisis CO/II CO/II CO/II GNR/III

Myelofibrosis Primary or secondary with an S/II S/II D/III GNR/IIIintermediate or high Lille score

Myelodysplastic syndrome RA, RAEB S/II S/II CO/II GNR/IIIRAEBt, sAML in CR1 or CR2 S/II S/II CO/II CO/IIMore advanced stages S/II CO/II D/III GNR/III

CLL Poor-risk disease S/II S/II D/III CO/II

LymphomasDiffuse large B-cell lymphoma CR1 (intermediate/high IPI at dx) GNR/III GNR/III GNR/III CO/I

Chemosensitive relapse; XCR2 CO/II CO/II GNR/III S/IRefractory D/II D/II GNR/III GNR/II

Mantle cell lymphoma CR1 CO/II D/III GNR/III S/IIChemosensitive relapse; XCR2 CO/II D/II GNR/III S/IIRefractory D/II D/II GNR/III GNR/II

Lymphoblastic lymphoma andBurkitt’s lymphoma

CR1 CO/II CO/II GNR/III CO/II

Chemosensitive relapse; XCR2 CO/II CO/II GNR/III CO/IIRefractory D/III D/III GNR/III GNR/II

Follicular B-cell NHL CR1 (intermediate/high IPI at dx) GNR/III GNR/III GNR/III CO/IChemosensitive relapse; XCR2 CO/II CO/II D/III S/IRefractory CO/II CO/II D/II GNR/II

T-cell NHL CR1 CO/II D/II GNR/III CO/IIChemosensitive relapse; XCR2 CO/II CO/II GNR/III D/IIRefractory D/II D/II GNR/III GNR/II

Hodgkin’s lymphoma CR1 GNR/III GNR/III GNR/III GNR/IChemosensitive relapse; XCR2 CO/II CO/II CO/II S/IRefractory D/II D/II GNR/II CO/II

Lymphocyte predominantnodular HL

CR1Chemosensitive relapse; XCR2

GNR/IIIGNR/III

GNR/IIIGNR/III

GNR/IIIGNR/III

GNR/IIICO/III

Refractory GNR/III GNR/III GNR/III CO/III

Other diseasesMyeloma CO/I CO /II GNR/III S /IAmyloidosis CO/II CO/II GNR/III CO/IISevere aplastic anaemia Newly diagnosed S/II CO/II GNR/III GNR/III

Relapsed/refractory S/II S/II CO/II GNR/IIIPNH S/II CO/II CO/II GNR/III

Breast cancer Adjuvant high risk GNR/III GNR/III GNR/III CO/IBreast cancer Metastatic responding D/II D/II GNR/III D/CO/IIGerm cell tumours Sensitive relapses GNR/III GNR/III GNR/III CO/II

Indications for SCT in EuropeP Ljungman et al

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Bone Marrow Transplantation

gain, to assess issues of quality of life and late effects intothe risk assessment strategy. Such effects are especiallyimportant in children.

Definitions

Haematopoietic SCTHSCT refers to any procedure where haematopoietic stemcells of any donor type and any source are given to arecipient with the intention of repopulating and replacingthe haematopoietic system in total or in part. Stem cells canbe derived from BM, peripheral blood or cord blood (CB).For allogeneic HSCT, repopulation can be measured bydetermining chimerism in the peripheral blood and/or BM.The goal of the procedure should be defined beforehandand a documented informed consent of the patient (anddonor) obtained before the procedure.

Donor categoriesDonor type is categorized as autologous, syngeneic, HLA-identical sibling donor, other family donor or unrelateddonor. A well-matched unrelated donor is defined as a 9/10or 10/10 identical donor based on HLA high-resolutiontyping for class I (HLA-A, -B, -C) and II (HLA-DRB1, -DQB1). Allelic-matched unrelated BM donor 10/10 trans-plants have been compared with HLA-identical siblingHSCT and give similar outcomes.5 A mismatched unrelateddonor is defined as a 6–8/10 matched donor based on theabove definition or a less than 8/8 match (not includingDQB1.6 A haploidentical donor is defined as a full HLAhaplotype-mismatched family member. A good collabora-

tion with the HLA typing laboratory is essential for theselection of the best available donor.

Donor lymphocyte infusionsDonor lymphocyte infusions are defined as the infusion oflymphocytes (or subsets) obtained from the HSCT donor ofan allogeneic HSCT with the aim to enhance engraftment,shift the balance between the donor and recipienthaematopoiesis in favour of donor type, prevent rejection,treat or prevent relapse. It is not considered a secondallogeneic transplant. The goal of the procedure should bedefined beforehand and a documented informed consent ofthe patient and donor should be obtained before theprocedure.

Risk factors for outcomeThe main risk factors for outcome are the stage of thedisease, the age of the patient, the time interval fromdiagnosis to transplant and, for allogeneic HSCT, thedonor/recipient histocompatibility and the donor/recipientsex combination. The risk factors add up and can bequantified as illustrated in Table 3. TRM increases andsurvival rates decrease with advanced disease stage,increasing age, increasing time from diagnosis to trans-plant, increase in HLA disparities, and for male recipientshaving a female donor. All components should beintegrated into risk assessment and decision making for atransplant. These factors are never absolute. Generally,HSCT in children gives better results than in adults but agecannot be seen as a single risk factor. It must be consideredtogether with other factors in decision making.7 It should,however, be recognized that biological rather than chron-ological age is the more important determining factor for

Table 1 Continued




Germ cell tumours Third-line refractory GNR/III GNR/III GNR/III S/IOvarian cancer CR/PR GNR/III GNR/III GNR/III D/IOvarian cancer Platinum-sensitive relapse D/III GNR/III GNR/III GNR/IIIMedulloblastoma Post-surgery GNR/III GNR/III GNR/III D/COSmall-cell lung cancer Limited GNR/III GNR/III GNR/III D/IRenal cell carcinoma Metastatic, cytokine-refractory CO/II CO/II GNR/III GNR/IIISoft cell sarcoma including Metastatic, responding D/III GNR/III GNR/III D/IIImmune cytopenias CO/II D/III D/III CO/IISystemic sclerosis D/III GNR/III GNR/III CO/IIRheumatoid arthritis GNR/III GNR/III GNR/III CO/IIMultiple sclerosis D/III GNR/III GNR/III CO/IISLE D/III GNR/III GNR/III CO/IICrohn’s disease GNR/III GNR/III GNR/III CO/IICIDP GNR/III GNR/III GNR/III D/III

Abbreviations: CIDP¼ chronic inflammatory demyelinating polyradiculoneuropathy; CO¼ clinical option; can be carried after careful assessment of risksand benefits; CR1, 2, 3¼first, second and third CR; D¼ developmental; further trials are needed; GNR¼ generally not recommended; IPI¼ internationalprognostic index; mm¼mismatched; MRD¼minimal residual disease; PNH¼ paroxysmal nocturnal haemoglobinuria; RA¼ refractory anaemia;RAEB¼ refractory anaemia with excess blasts; S¼ standard of care; generally indicated in suitable patients; sAML¼ secondary AML; SLE¼ systemiclupus erythematosus.aCategories are based mainly on number of white blood cells, cytogenetics at diagnosis and molecular markers, and time to achieve remission according tointernational trials.This classification does not cover patients for whom a syngeneic donor is available.


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outcome with reduced-intensity conditioning regimens inallogeneic transplantation. According to the EMEA Guide-lines on Clinical Investigation of Medicinal Products,patients up to the age of 18 years are for the purpose ofthis document classified as children and adolescents.

Stem cell sourcesToday, there are three commonly used sources ofhaematopoietic stem cells: BM, G-CSF mobilized PBSCsand CB stem cells. For autologous HSCT, PBSC hasbecome the preferred choice because of a more rapid

Table 2 Proposed classification of transplant procedures for children—2009




Haematological malignanciesAML CR1 (low risk) GNR/II GNR/II GNR/III GNR/II

CR1 (high risk) S/II CO/II GNR/III S/IICR1 (very high risk) S/II S/II CO/II CO/IIICR2 S/II S/II S/II S/II4CR2 CO/II D/II D/II GNR/II

ALL CR1 (low risk) GNR/II GNR/II GNR/III GNR/IICR1 (high risk) S/II S/II CO/II GNR/IICR2 S/II S/II CO/II CO/II4CR2 S/II S/II CO/II CO/II

CML Chronic phase S/II S/II D/II GNR/IIIAdvanced phase S/II S/II D/II GNR/III

NHL CR1 (low risk) GNR/II GNR/II GNR/II GNR/IICR2 (high risk) CO/II CO/II GNR/II CO/IICR2 S/II S/II CO/II CO/II

Hodgkin’s disease CR1 GNR/II GNR/II GNR/II GNR/IIFirst relapse, CR2 CO/II D/III GNR/III S/II

Myelodysplastic syndromes S/II S/II D/III GNR/III

Non-malignant diseases; solid tumoursPrimary immunodeficiencies S/II S/II S/II NA

Thalassaemia S/II CO/II GNR/III NASickle cell disease (high risk) S/II CO/III GNR/III NAAplastic anaemia S/II S/II CO/II NAFanconi anaemia S/II S/II CO/II NABlackfan–Diamond anaemia S/II CO/II GNR/III NACGD S/II S/II CO/III NAKostman’s disease S/II S/II GNR/III NA

MPS-1H Hurler S/II S/II CO/II NAMPS-1H Hurler Scheie (severe) GNR/III GNR/III GNR/III NAMPS-VI Maroteaux- Lamy CO/II CO/II CO/II NAOsteopetrosis S/II S/II S/II NAOther storage diseases GNR/III GNR/III GNR/III NA

Autoimmune diseases GNR/II GNR/II GNR/II CO/II

Germ cell tumour GNR/II GNR/II GNR/II CO/IIEwing’s sarcoma(high risk or 4CR1)

D/II GNR/III GNR/III S/II

Soft tissue sarcoma(high risk or 4CR1

D/II D/II GNR/III CO/II

Neuroblastoma (high risk) CO/II GNR/III GNR/III S/IINeuroblastoma 4CR1 CO/II D/III D/III S/IIWilms’ tumour 4CR1 GNR/III GNR/III GNR/III CO/IIOsteogenic sarcoma GNR/III GNR/III GNR/III D/IIBrain tumours GNR/III GNR/III GNR/III CO/II

Abbreviations: CO¼ clinical option; can be carried out after careful assessment of risks and benefits; CR1, 2, 3¼ first, second and third CR;D¼ developmental; further trials are needed; GNR¼ generally not recommended; mm¼mismatched; NA¼ not applicable; S¼ standard of care; generallyindicated in suitable patients.This classification does not cover patients for whom a syngeneic donor is available.


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haematopoietic reconstitution. For allogeneic HSCT, allthree stem cell sources are used and have their specificadvantages and disadvantages. PBSCs are associated withmore rapid engraftment but are also associated with anincreased risk of chronic GVHD compared with BMT.8

The higher risk for chronic GVHD might therefore makeperipheral blood SCT a less attractive option for children,or for some patients with early stage disease. Whetherpaediatric donors should be considered for G-CSFmobilization and PBSC donation is also debatable. Thoughthere may be a specific advantage in collecting PBSCs fromchildren in the case of considerable disparity with therecipient’s body weight, this practice should be discouragedin standard allogeneic transplants. Furthermore, the addi-tional graft-versus-malignancy effect seen in patients withchronic GVHD is not applicable for patients with non-malignant conditions such as severe aplastic anaemia(SAA). BM is therefore seen as the preferred choice inthese indications.9 The donor’s preferences must also betaken into account as there are differences in the side effectsexperienced by the donors from a BM or PBSC harvest.Cord blood stem cells may be used in the context of HLA

genotypically identical allogeneic HSCT. As this is quite arare situation, unrelated CB cells are more commonly usedwhen patients lack an HLA-identical sibling or a well-matched unrelated donor. An additional advantage is thatCB cells can be obtained rapidly and may therefore be thebest option when a patient needs an urgent HSCT. Theindications for the use of CB as a source for stem cells inchildren are identical to the indications listed in Table 1.CB units should be selected by HLA matching and celldose. The most important factor influencing outcome is thecell dose, and a minimum dose of 2.5–3� 107 nucleatedcells/kg at collection or 2� 107 nucleated cells/kg atinfusion is recommended. HLA disparity should not exceed

two of six defined by HLA-A, -B Ag and HLA-DRB1 alleletyping. Outcomes of unrelated CB HSCT in children andadults with acute leukaemias are comparable with well-matched unrelated BM transplants.10,11 The use of doubleCB units is under investigation with promising results.12,13

The requirements of cell dose and the number of HLAdisparities for the double units are the same as for singleunits. Thus, no more than two of six HLA disparitiesshould exist between each CB unit and the patient. The useof CB in the context of reduced-intensity conditioningHSCT is under investigation but currently follows the samerecommendations as for myeloablative conditioning regi-men (Eurocord, unpublished data).Reports of haploidentical HSCT have shown promising

results in patients with high-risk diseases. The use ofhaploidentical donors can therefore be indicated when noother donor can be found and another curative approach isnot available.14 Such procedures should be performed inspecialized centres capable of managing the high risk forinfectious complications because of delayed immunereconstitution. Furthermore, standardized protocols forgraft processing (CD34þ selection, T-/B-cell depletion)must be used.15 In addition, certain HLA-C and HLA-Bmismatches have been observed to give rise to donor vsrecipient natural killer (NK) cell alloreactivity affectingbeneficially on outcome.16–19

Reduced-intensity conditioning regimenConditioning regimens vary in their intensity and can beclassified as standard intensity, reduced intensity or intensi-fied regimens. A wide variety of reduced-intensity condition-ing (RIC) regimens have been described and the resultsclearly show that RIC-HSCT can decrease the risk for earlyTRM, thereby making transplants for older patients and forpatients with comorbidities possible. Follow-up of RIC-HSCT shows that long-term disease control can be obtained.In many patients, an RIC-HSCT is the only alternativeavailable as a myeloablative transplant would be associatedwith a very high risk of early mortality. Results have beenpublished for related donor HSCT older than 75 years andfor unrelated donor HSCT up to 70 years. The experiencewith unrelated donors is comparable with those with relateddonors. No prospective or retrospective study has, however,shown superior long-term results with RIC-HSCT comparedwith standard HSCT. A conventional transplant remains thetherapy of choice for younger patients without comorbiditiesin the absence of results from prospective controlled trials.However, reports also suggest that in children the aggressivepretransplant conditioning might be replaced by milder andless toxic regimens if there are comorbidities or othercontraindications for conventional transplant or for a secondor subsequent transplant. RIC transplants are discouraged inpatients with progressive or refractory disease.

Categorization of transplant procedures

An important aim of the EBMT indication documentshas been to classify indications and to give advice aboutthe settings where these types of transplants ought to

Table 3 Quantification of risk of TRM

Disease stageEarly (for example, AML first CR) 0Intermediate (for example, AML second CR) 1Advanced (for example, refractory disease) 2

Age of patiento20 years 020–40 years 1440 years 2

Time interval diagnosis to transplanto12 months 0412 months (does not apply for patients in first CR) 1

HistocompatibilityHLA-identical sibling 0Other donor 1

Gender combinationOther 0Female donor for male recipient 1

Additional elementsComorbidity/Karnofsky 480 1Donor 450 years 1CMV not �/� 1Identical twin (syngeneic) �1Unrelated donor 10/10 high-resolution matched �1


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be performed. These have been classified as ‘standard ofcare (S)’, ‘clinical option (CO)’, ‘developmental (D)’ or‘generally not recommended (GNR)’.

Standard of careIndications categorized as ‘standard of care ’ are reason-ably well defined and results compare favourably (or aresuperior) to those of non-transplant treatment approaches.Obviously, defining an indication as the standard of caredoes not mean that an HSCT is necessarily the optimaltherapy for a given patient in all clinical circumstances.‘Standard of care’ transplants may be performed in aspecialist centre with experience with HSCT proceduresand an appropriate infrastructure as defined by the JACIEguidelines.

Clinical optionThe ‘CO’ category is based on the fact that, for manyindications, the number of patients will be low andtherefore randomized studies comparing conventionaltreatment and HSCT are difficult to perform. Results ofsmall patient cohorts treated for this disease by HSCTshow efficacy and acceptable toxicities of the procedure.The broad range of available transplant techniquescombined with the variation of patient factors such asage and comorbidity makes interpretation of these datadifficult. Our current interpretation of existing data forindications placed in this category supports the fact thatHSCT is a valuable option for individual patients after acareful discussion of risks and benefits with the patient, butthat for groups of patients the value of HSCT needs furtherevaluation. Transplants for indications under this headingshould be performed in a specialist centre with majorexperience with HSCT procedures, with an appropriateinfrastructure as defined by EBMT guidelines and opti-mally meeting JACIE standards.

DevelopmentalIndications have been classified as developmental if there islittle experience with this indication in combination withthe type of transplant and when additional research isneeded to define the role of HSCT. These transplantsshould be performed within the framework of a clinicalprotocol. Such a protocol can either be a randomizedcomparison of two or more approaches to treatment or asmall pilot series undertaken by transplant units withacknowledged expertise in the management of thatparticular disease or that type of HSCT. Patients aretherefore offered the opportunity to undergo HSCT in thecontext of a study that has been designed specifically tocover a series of patients who satisfy defined diagnosticcriteria. The category also covers fundamentally newapproaches to the management of a disease that, in adifferent stage, may already be classified under the standardof care or CO. Protocols for ‘developmental’ transplantswill have been approved by local research ethics committeesand must be according to current international standards.It is implied that the results of the study are intended forpresentation to and/or publication for the medical com-munity at large. Centres performing transplants under the

category of ‘developmental’ should meet JACIE stan-dards. The document for Rules and Regulations forEBMT Clinical Trials could also be used as a guideline(http://www.ebmt.org/1WhatisEBMT/Op_Manual/OPMAN16_Clinical%20Trials%20Guidelines.pdf).

Generally not recommendedThe GNR category can include early disease stages whenresults of conventional treatment do not normally justifythe additional risk of TRM, or when the disease is soadvanced that the chance of success is so small that the riskof the harvest procedure for the normal donor is difficult tojustify. ‘GNR’ may not apply to specific situations where asyngeneic donor exists. This category also includes HSCTfor a disease in a phase or status in which patients areconventionally not treated by HSCT. Therefore, there willbe some overlap between ‘GNR’ and ‘developmental’ andfurther research might be warranted within prospectiveclinical studies for some of these indications. ‘GNR’ doesnot exclude the fact that centres with a focus on a certaindisease can investigate HSCT in these situations.

Data reportingReporting of transplant data is mandatory for EBMTmembers and the minimum amount of data to be reportedis contained in the MED-A form. To fully assess the impactof certain transplant strategies for specific indications,reporting of data on a larger case record form (MED-Bdata) is encouraged. Reporting on MED-B forms should bestandard practice for transplants classified as CO anddevelopmental and especially if transplants for ‘GNR’indications are performed.

Evidence gradingThere has been no attempt to perform a formal evidencereview as the basis for the indication classification, but abroad classification has been made as described below. Inthis classification, results from therapeutic strategies otherthan HSCT have also been taken into account.

i Evidence from at least one well-executed randomizedtrial;

ii Evidence from at least one well-designed clinical trialwithout randomization; cohort or case-controlledanalytic studies (preferably from more than one centre);multiple time-series studies; or dramatic results fromuncontrolled experiments;

iii Evidence from opinions of respected authorities basedon clinical experience, descriptive studies or reportsfrom expert committees.

Status of transplants in specific diseases in adults

The updated classification of HSCT procedures in adults isshown in Table 1.

AMLAdults with AML in first remission may be treated byHSCT. HSCT can be used as planned consolidation in first


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http://www.ebmt.org/1WhatisEBMT/Op_Manual/OPMAN16_Clinical%20Trials%20Guidelines.pdf

http://www.ebmt.org/1WhatisEBMT/Op_Manual/OPMAN16_Clinical%20Trials%20Guidelines.pdf

CR, as rescue for patients refractory to standard inductionchemotherapy, at first relapse, or in second CR. Thedecision depends on the risk of the disease and the risk ofthe transplant procedure. Allogeneic HSCT is not recom-mended for patients in first CR with cytogenetically‘favourable’ subtypes ((t(8;21); inv(16); t(15;17)). However,in patients with acute promyelocytic leukaemia notachieving a molecular response after consolidation infrontline or after salvage treatment, an allogeneic HSCTis a CO. Patients in first CR with other cytogeneticabnormalities or normal karyotype (including those withFLT-3 mutations) are candidates for HLA-identical siblingdonor HSCT. Analyses of other molecular markers asindicators of AML subsets with distinct prognosis are stillunder validation. Patients in first CR considered as highrisk because of to specific cytogenetic abnormalities orspecific molecular markers, such as FLT-3 and MLL, arecandidates for an allogeneic HSCT from either an HLA-identical sibling or unrelated donor. Patients failing toachieve CR after one course of induction chemotherapymay be treated by allogeneic HSCT. Patients withadvanced AML, defined as in an early relapse or in secondor later remission, may also be treated by allogeneic HSCT.Patients with AML in first CR may be treated by auto-HSCT with or without purging of the graft when a suitabledonor is not available. Results of HSCT for AML must becompared with results of contemporary chemotherapyregimens. Recently, promising results have been reportedwith unrelated CB and T-cell-depleted haploidenticalHSCT for patients with AML. Those strategies are stillunder investigation in CR1 but should be considered forpatients in CR2 lacking an HLA-identical sibling or well-matched unrelated donor. In the haploidentical setting,HSCT from donors who mount donor vs recipient NK cellalloreactivity is associated with a significantly lower relapserate and better EFS, particularly when patients aretransplanted in CR.17–19

ALLAdults with ALL with poor prognostic features, forexample, t(9;22) or t(4;11), or slow response to inductionchemotherapy, are candidates for allogeneic HSCT fromeither an HLA-identical sibling or an unrelated donor.Allogeneic HSCT for standard risk patients in CR1 shouldbe performed within a clinical protocol. Patients relapsingafter chemotherapy and achieving CR2 are candidates forallogeneic HSCT from an HLA-identical sibling, anunrelated donor or other alternative donors such as CBor haploidentical donor.

CMLHSCT remains the only curative treatment for CML.However, after the advent of tyrosine kinase inhibitors(TKIs), allogeneic HSCT can rarely be recommended tochronic phase patients as first-line therapy, except in caseof patient’s preference or, in regions where access to TKIis limited because of economic reasons, where earlyHSCT may be considered in young patients with anEBMT score 0–2.

Adults with suboptimal responses to or failing imatinibaccording to the European Leukaemia Net guidelinesshould have a search for a suitable donor initiated as earlyas possible. Second-line therapy for patients with a donorshould be based on the risk of HSCT and the likelihood ofresponse to second generation TKI. The EBMT risk score(Gratwohl score) might be used to identify patients at lowrisk for TRM. The EBMT score might also be used incombination with the Sokal or Hasford score for identify-ing patients who could undergo HSCT with an increasedrisk for disease progression without HSCT.Patients with ABL mutations that are resistant to second

generation TKI may proceed directly to HCT. In patientswithout ABL mutations resistant to second generationTKI, the second generation TKI should be started andHSCT considered as preferential therapy at the time of bestresponse if (a) the EBMT score is 0–2 and one of thefollowing: additional clonal evolution, failure to achieve atleast minor cytogenetic response with imatinib, high Sokalscore at diagnosis or loss of haematological response toimatinib, or (b) if the EBMT score is 0–5 and there is one ofthe following during treatment with second generationTKI: failure or insufficient response or intolerance to ormutations resistant to second generation TKI.Patients should proceed to HSCT, regardless of the

EBMT score, if there is progression to accelerated or blastphase at presentation or during imatinib or secondgeneration TKI therapy.Patients in the advanced phase at diagnosis should be

referred for HSCT as soon as possible. While preparing forHSCT, initial therapy with imatinib or intensive thera-py±imatinib might be an option. HSCT should beperformed as soon as possible after achieving the secondchronic phase.Patients with controlled accelerated phase and blast crisis

after treatment with chemotherapy and/or TKI arecandidates for allogeneic HSCT from an HLA-identicalsibling, an unrelated donor or other alternative donors suchas CB or haploidentical family donors. A patient with asyngeneic donor is always a candidate for HSCT withstandard conditioning.Autologous HSCT should only be recommended in the

context of clinical studies.

Myeloproliferative disorders other than CMLAllogeneic HSCT is today the only curative option forpatients with myeloproliferative disorders. Polycythaemiavera (PV) and essential thrombocythaemia (ET) are ingeneral not indications for allogeneic HSCT unless thedisease has progressed to myelofibrosis or secondaryleukaemia. Owing to the lack of alternative therapeuticoptions, allogeneic HSCT is a reasonable treatment forprimary myelofibrosis with intermediate and high riskaccording to the Lille score or myelofibrosis post-ET or PVand should be considered for all patients younger than60 years of age.20,21 The experience of allogeneic HSCTin young patients with low-risk Lille score is limitedand remains controversial. The available data do notsupport splenectomy before HSCT. Autologous HSCT caninduce responses in patients with primary myelofibrosis,


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but this procedure cannot be recommended outsideclinical protocols.

MDSAllogeneic HSCT is considered the treatment of choice foradult patients with myelodysplastic syndrome (MDS) orAML evolved fromMDS and offers a good chance of long-term disease-free survival, if the treatment is performedbefore progression of the disease or if the patient istransplanted in CR after chemotherapy. The internationalprognostic score is a valuable tool to assess a patient’sprognosis without HSCT. Additional prognostic factors,such as multilineage dysplasia and transfusion requirement,may be considered as well.22 The results seem to be better inallogeneic HSCT if the blast count does not exceed 5% atthe time of transplant. The practice in Europe is to treatMDS patients with excess of marrow blasts with remissioninduction therapy, but this approach has not beensubstantiated by prospective clinical trials. Treatment withazacytidine before HSCT is another option to reduce therisk for relapse. The decision to proceed with allogeneicHSCT should be based on the risk of the disease and therisk of the transplant procedure as estimated by the EBMTrisk score. The results of a large European study show thatautologous HSCT can be recommended in patients withgood-risk cytogenetic characteristics.23

CLLAllogeneic HSCT from an HLA-identical sibling or well-matched unrelated donor is a treatment option for youngpatients having previously been treated with and progres-sing after fludarabine-containing regimens and have poor-risk disease as defined by clinical and cytogenetic/molecularassessments.24 Mature phase II studies and registry analyseshave shown that allogeneic HSCT is the only therapy withproven curative potential. In contrast to conventionaltreatment, it can provide long-term disease control even ingenetically unfavourable and refractory cases, and is clearlysuperior to any other salvage regimen despite an increasedTRM when used with myeloablative conditioning. Auto-logous HSCT could be considered for patients with poor-risk disease in complete or good PR able to withstand high-dose therapy, but should preferably be performed in thecontext of a clinical protocol.

Hodgkin’s lymphoma

Classical Hodgkin’s lymphomaAutologous HSCT is the standard therapy for patients withHodgkin’s lymphoma (HL) in first chemosensitive relapseor second CR as shown by two prospective randomizedclinical trials.25,26 There is currently no indication forautologous HSCT in first CR, even in patients with badprognostic features at diagnosis.27,28 Patients with diseaserefractory to first-line therapy but sensitive to salvagetherapy might benefit from an autologous HSCT.29 Fortruly primary refractory patients or for patients inchemorefractory relapse, autologous HSCT has only asmall likelihood to induce long-term remission30,31 but can

be considered in some patients as other therapeuticstrategies do not seem to offer better results. As part of aclinical protocol for patients with resistant Hodgkin’sdisease, autologous HSCT might be considered as an initialdebulking therapy to be followed by an allogeneic HSCT asconsolidation therapy.32

Allogeneic HSCT has mainly been used as salvagetherapy for multiply relapsed or refractory HL patients.Allogeneic HSCT with myeloablative conditioning carries ahigh risk for TRM.33,34 The use of RIC is able tosignificantly decrease TRM in these relapsed/refractorypatients as indicated by a retrospective analysis of theEBMT.35 A myeloablative conditioning regimen shouldtherefore be considered only for selected young patients.The role of RIC in relapsed/refractory HL needs to bedefined. Nowadays, more than 50% of the patients whoundergo an RIC have previously failed an autologousHSCT.36,37 A retrospective analysis indicates that RIC canimprove the outcome of HL patients relapsing after anautologous HSCT.38 Nevertheless, its impact in the long-term outcome of these patients has still to be prospectivelyevaluated. HSCTs from HLA-identical sibling donors andwell-matched unrelated donors give a similar outcome.36,37

Lymphocyte-predominant nodular HLLymphocyte-predominant nodular HL has to be consid-ered a complete separate entity and there is almost noinformation in the literature regarding the impact of SCT inthe long-term outcome of these patients. Nevertheless,autologous HSCT can be considered a therapeutic optionfor those patients in advanced stages and relapsing afterconventional chemotherapy protocols.

Non-Hodgkin’s lymphoma—adults

Diffuse large B-cell non-Hodgkin’s lymphomaAutologous HSCT is still considered the standard therapyfor patients with chemosensitive relapse of diffuse largeB-cell lymphoma (DLBCL) as indicated by the only phaseIII randomized prospective clinical trial that addresses thisissue, the Parma trial.39 Nevertheless, the exact role ofautologous HSCT is being re-evaluated with the advent ofmonoclonal antibodies and the widespread use of che-moimmunotherapy as first-line treatment for all thesepatients. The role of autologous HSCT as first-line therapyin DLBCL patients with intermediate-high or high inter-national prognostic index at diagnosis is still controversial.Although there are many phase III randomized prospectiveclinical trials that have analyzed this question, the designand the results of these trials are profoundly heteroge-neous.40–42 Two recent meta-analyses summarizing thesestudies showed heterogeneous results and no OS bene-fit.43,44 Autologous HSCT is not an option for refractorypatients with DLBCL. New and innovative approachesshould be sought for these patients.Patients relapsing after or resistant to first-line therapy

have a very poor prognosis especially if relapse occurso12months after primary treatment. Such patients along withthose failing multiple treatment modalities, including an


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autologous HSCT, might be considered candidates for anallogeneic HSCT, although the role of such a strategy is notdefined. There are no direct comparisons between the use ofmyeloablative conditioning and RIC. Nevertheless, morethan 50% of the patients in the EBMT registry havereceived an RIC. Results of RIC mainly come frommulticentre trials including a small number of patients,heterogeneous regarding disease status, conditioning regi-men and GVHD prophylaxis and with a short follow-up.45,46 Only prospective clinical trials including a sufficientnumber of patients will be able to adequately address thispoint.

Follicular lymphomaTherapies for follicular lymphoma (FL) patients arechanging because of the use of chemoimmunotherapy asfirst-line treatment, the introduction of radioimmunother-apy and the quickly evolving concept of maintenance withmonoclonal antibodies. Patients with FL are normally notconsidered candidates for an autologous HSCT as first-linetherapy, although three phase III prospective clinicaltrials47–49 performed before the ‘rituximab era’ suggesteda role in some subgroups of high-risk patients. AutologousHSCT remains the standard approach for early relapsingpatients with FL.50 New prospective trials analyzing therole of autologous HSCT in recurrent FL are needed andshould include rituximab and other new modalities. Resultsof autologous HSCT in truly refractory patients are poor.These patients should probably be offered alternativeapproaches.Allogeneic HSCT has mainly been performed in patients

with multiple relapses, including a prior autologous HSCT.RIC was used in more than 50% of the cases both in theUnited States51 and in Europe (EBMT registry), althoughthere is no prospective randomized trial comparing theapproaches. From the information derived from retro-spective registry analyses45 and from single centre prospec-tive phase II trials52 as well as multicentre prospectiveanalyses,45,46,53 the TRM and relapse rate are low and thelong-term outcome seems favourable. The impact of the useof alternative donors (for example, MUD) in relation toHLA-sibling donors is under evaluation. Prospectivestudies need to be performed.

Mantle cell lymphomaAlthough most patients with mantle cell lymphoma (MCL)are offered an early intensification with an autologousHSCT owing to the inherent bad prognosis of the disease,the only phase III prospective clinical trial showing thesuperiority of an autologous HSCT was published beforethe introduction of anti-CD20 monoclonal antibodies.54

Most of the information on autologous HSCT as first-linetherapy in MCL comes from phase II prospective trials.Autologous HSCT is considered standard therapy forpatients with MCL relapsing after a first-line treatment.Nevertheless, information from retrospective analysisindicates that the results of autologous HSCT beyond firstCR are inferior. Autologous HSCT does not provide anyclinical benefit in patients with refractory disease.

Suitable patients with relapsed disease after an adequatefirst-line therapy could be considered candidates for anallogeneic HSCT despite the fact that data are onlyavailable from very small phase II clinical trials andretrospective registry analyses. Therefore, allo-HSCTshould be considered an experimental procedure.

T-cell lymphomasPeripheral T-cell non-Hodgkin’s lymphomas (PTL) usuallyhave a very poor prognosis. Results exist from phase IItrials55 and multicentre retrospective analyses, suggesting apositive effect of autologous HSCT. These patients shouldbe included in prospective clinical trials. Phase II prospec-tive trials56 and retrospective studies57 indicate thepotential benefit of RIC allogeneic HSCT in patients witha PTL in second response. There is almost no infor-mation on allo-HSCT as early consolidation therapy forpatients with PTL.

Burkitt’s lymphoma, lymphoblastic lymphomaLittle information exists regarding the impact of HSCT inboth Burkitt’s lymphoma and lymphoblastic lymphomapatients. Patients with lymphoblastic lymphomas can beconsolidated with an autologous HSCT in first CR, asindicated by some phase II trials.58 Allogeneic HSCT caneventually be considered in young adults in first CR.59

Burkitt’s lymphoma patients with bad prognostic featuresat diagnosis can also be consolidated with an autologousHSCT.58 Allogeneic HSCT can be considered for patientsin CR2.

MyelomaAutologous HSCT is clearly indicated for patients o70years of age who respond to first-line treatment. Age shouldbe considered in conjunction with the patient’s generalhealth and fitness. New agents such as the proteasomeinhibitors (bortezomib) or the immunomodulating agents,such as lenalidomide, may change the place of autologousHSCT. Best results are seen in patients achieving goodresponses before HSCT, but some non-responding patientsalso benefit from this approach. Double autologous HSCTshave been shown to be superior to one autologous HSCT,although the benefit of the second transplant seems to berestricted to patients not achieving CR or very good PRwith the first transplant; consolidation and maintenancewith agents such as thalidomide may be an alternative forthese patients. However, the vast majority of patients stillrelapse. The use of a further transplant after reinductiontherapy is an option and may be of particular benefit inpatients achieving a long treatment-free interval after theirfirst transplant(s). TBI should not be used in theconditioning regimen owing to increased toxicity withoutappreciable benefit. Allogeneic HSCT is a treatment withcurative potential, but it is associated with considerableTRM and might be used in selected high-risk patients. Theresults of the combination of auto HSCT followed by RIC-HSCT are inconsistent. One study reported a superioroutcome compared with double autologous HSCT60 and asecond study shows a trend for better outcome.61 However,two other studies have so far not shown any benefit. However,


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longer follow-up is needed. The combination of auto HSCTand unrelated RIC-HSCT is currently being investigated.

AL amyloidosisPatients with AL (amyloid in systemic Ig-light-chain)amyloidosis have been treated by autologous HSCT.A study with matched controls showed that amyloidosispatients without severe heart failure benefited fromhigh-dose therapy and auto-HSCT, but this was notconfirmed in a recently published study.62 AllogeneicHSCT might be considered as a CO in patients withprogressive disease.

Acquired severe aplastic anaemia adultsAllogeneic BMT from an HLA-identical sibling is thetreatment of choice in patients with SAA under the age of30. The choice in patients between 30 and 45 years of age ismore difficult, and both BMT and immunosuppression givegood results. In older patients, or in the absence of anHLA-matched sibling, an initial course of a combination ofATG and CYA should be given. The median time forresponse after this treatment is 2–3 months. One shouldtherefore wait at least 4 months for assessment of responsebefore a transplant is undertaken, especially if it is from anunrelated donor. The conditioning regimen for siblingtransplants should not include irradiation because of thehigh risk of secondary tumours. Unrelated donor andmismatched family donor transplants are still associatedwith significant morbidity but are the standard of carewhen other therapies have failed.

Constitutional SAA, including Fanconi anaemiaAllogeneic HSCT is the only curative treatment for patientswith constitutional SAA. For patients lacking an HLA-identical sibling donor, transplantation from an unrelateddonor may be considered. The conditioning regimen shouldpreferably not include radiation, and the dosage of thechemotherapy is to be reduced as appropriate for patientswith Fanconi anaemia.

Paroxysmal nocturnal haemoglobinuriaSmall numbers of patients with paroxysmal nocturnalhaemoglobinuria have been treated with allogeneic HSCT,which seems to be the only curative approach. Therefore,an allogeneic HSCT is a CO for patients with high-riskdisease who have a well-matched donor.

Solid tumours—adultsThe existence of a dose-response effect in epithelial tumours(breast, ovarian, small cell lung cancer) is still a matter ofinvestigation. However, the benefit of high-dose che-motherapy (HDCT) in selected subgroups of patients hasbecome clearer. The role of autologous HSCT for primarybreast cancer at high risk of recurrence (at least fourinvolved axillary lymph nodes) has been assessed in a meta-analysis of individual patient data from 15 knownrandomized trials comparing HDCT with standard-dosechemotherapy.63 It was shown that HDCT prolongeddisease-free survival when used as adjuvant therapy, and

showed a benefit on breast cancer-specific survival and OS.Whether HDCT has benefit in the context of contemporarytaxane-based regimens and targeted therapies is unknown.In the context of metastatic breast cancer, HDCT seems tobe effective in stage IV patients rendered free of macro-scopic disease by previous therapy and in patients witholigometastatic disease.High-dose chemotherapy for germ cell tumours is

considered a CO for sensitive relapse and as standardtherapy for refractory disease. A tandem transplantcomprising high-dose carboplatin and high-dose etoposidefollowed by an infusion of autologous PBSC should beconsidered the standard of care as third-line or latertherapy or in patients with platinum-refractory disease,excluding primary mediastinal disease.64 Conversely, datado not support the use of HDCT as first-line treatment inpatients with metastatic germ cell tumour and poorprognostic clinical features.65

A randomized phase III study for first-line treatmentof advanced ovarian cancer in which high-dosesequential chemotherapy with PBSC support wascompared with standard-dose chemotherapy was pub-lished. No statistically significant difference in progres-sion-free survival or OS was observed.66 Small-celllung cancer (SCLC) is a chemosensitive tumour.A randomized phase III trial in patients with limited orextensive SCLC compared conventional-dose vs HDCT.No difference in the median progression-free survival andOS was noted among the two arms.67 Some limitationsof the study may have accounted for the lack of favour-able results.Allogeneic HSCT is considered a CO for renal cancer

relapsed/resistant to cytokine therapy, a developmentaltherapy for breast and ovarian cancer, that is notrecommended for other solid tumours with the possibleexception of colorectal cancer. The number of allogeneicHSCTs has decreased in recent years. The reasons for thisdecrease have been: (i) the introduction in clinical trials ofmolecularly targeted agents, especially for renal cancer,(ii) the lack of well-designed phase II studies, (iii) the highTRM owing to accrual of rapidly progressing, high tumourburden patients. Attempts to improve the therapeutic indexof allogeneic HSCT in solid tumours by innovative clinicalstrategies are underway. Currently, allogeneic HSCTshould only be considered in the context of prospectiveclinical trials.

Autoimmune disorders—adultsAutologous HSCT after appropriate conditioning tomaximize immunosuppression is being considered inclinical protocols for selected patients with severe multiplesclerosis,68 rheumatoid arthritis,69 systemic lupus erythro-matosus,70 systemic sclerosis,71 immune cytopenias andCrohn’s disease.72 Autologous HSCT for other autoim-mune disorders is being considered on a developmentalbasis. Dependency of high steroid doses above the ‘Cushingthreshold’ and causing skeletal damage could be anindication. Allogeneic HSCT is being considered on adevelopmental basis in patients selected for very poorprognosis.


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Status of transplants in specific diseases in children and

adolescents (Table 2)

AMLIn paediatric AML, the role of allo-HSCT in CR1 isdeclining because of the better outcome with modernmultiagent chemotherapy. Hence, HSCT is not recom-mended as frontline therapy for good-risk patients withAML.73 Allogeneic HSCT from an HLA-identical siblingin CR1 remains an option for children defined as high riskas it was proven to be more efficient than chemotherapy insome comparative studies, with vent-EFS ranging from 55to 72%. Infant AML and children with FAB M0, M6 orM7 AML, who stand very poor chances of cure bychemotherapy or by autologous HSCT, are indicationsfor unrelated donor HSCT. Results in children with AMLundergoing haploidentical HSCT have shown some effectof NK alloreactivity, suggesting that haploidentical HSCTmay have a role in early phase very high-risk AMLpatients.74

Autologous HSCT has been used as consolidation inchildren with AML, in CR1 after induction therapy andrepresents a valid alternative for high-risk children lackinga matched sibling donor. Nevertheless, results of paediatricstudies comparing autologous HSCT with chemotherapyare conflicting. The use of PBSCs in children with AMLgiven autologous HSCT is infrequent. Further prospectiveclinical trials are needed to address the pivotal clinicalquestion of whether autologous HSCT is better thanchemotherapy or allograft as consolidation treatment forchildhood AML in first CR.75

In children with relapsed AML, allogeneic HSCT isindicated either from a sibling or an unrelated donor.

ALLThe indication for HSCT in children with ALL in CR1 islimited to the subpopulation of high-risk ALL. Most studygroups define these patients as having estimated an EFS ofo50%. The risk factors indicating the usefulness of HSCTare known molecular biological markers or chromosomalabnormalities, biological factors including poor prednisoneresponse, and resistance to initial chemotherapy includingpersistence of minimal residual disease.76 For thesepatients, allogeneic HSCT from matched sibling donorsor a well-matched unrelated donor, and for the highest riskcategory a mismatched donor is also an option.77

ALL patients, who experience an early marrow relapse,still have a dismal prognosis when treated with conven-tional chemotherapy. Although nearly 90% achieve asecond remission, most of them subsequently developprogressive disease. Both matched sibling donor HSCTand unrelated donor HSCT are clearly indicated in thesepatients as the outcomes are similar.78,79 If a matchedsibling or a well-matched unrelated donor cannot beidentified, other types of donors such as CB, mismatchedunrelated donors or haploidentical family donors, particu-larly when they exert NK alloreactivity, can be indi-cated.19,80 The indication for autologous transplantation islimited to a small subset of patients with either a late BM oran extramedullary relapse.81

CMLCML is a rare disease in children. Since the approval ofTKI also for children and adolescents, HSCT is no longerthe first treatment for patients with early phase CML.However, as lifelong medication with TKI is necessary,there are treatment failures and continuous contraception ismandatory. HSCT still remains an important treatmentoption, especially for younger patients with CML depend-ing on national, physician and patient preferences. HSCTmight be postponed for patients achieving a haematologicalresponse at 3 months, followed by a minor cytogeneticresponse at 6 months and followed by a completecytogenetic response at 12 months after start of imatinibat a dose of 300mg/m2. Once imatinib refractorinessdevelops, patients should undergo HSCT. However, pro-spective cooperative studies are needed to address thiscomplex issue in young patients with CML.

Malignant lymphomaChildren suffering from lymphomas have a good prognosiswhen treated with first-line chemo- and radiotherapy.Patients,who fail to respond or those with chemosensitiverecurrent diseases can achieve long-term disease-freesurvival after autologous HSCT. The impact of allogeneicHSCT in children with lymphomas has not been clarified.Allogeneic HSCT in children and adolescents with recur-ring lymphomas may be beneficial, especially in childrenwith a good performance status and available matcheddonor; this strategy should be carefully considered at anearly time point in children failing standardized primaryand salvage treatment.

MDSAllogeneic HSCT from a sibling donor or a well-matchedunrelated donor is the treatment of choice for childrenwith primary MDS, including juvenile myelomono-cytic leukaemia, and secondary AML. The role of auto-logous HSCT in children with MDS remains contro-versial and is GNR.

Inherited diseases: primary immunodeficiencies

Primary immunodeficiencies are inherited disorders char-acterized by impairment of innate or adoptive immunity,commonly leading to lethal complications. AllogeneicHSCT can cure most of the lethal forms of immunodefi-ciencies, including SCIDs, several T-cell immunodeficien-cies, Wiskott-Aldrich syndrome, phagocyte disorders suchas leukocyte adhesion deficiency and chronic granuloma-tous diseases, haemophagocytic syndromes such as familiallymphohistiocytosis, Chediak-Higashi syndrome, Griscel-li’s disease and X-linked lymphoproliferative syndrome.Treatment by HSCT is increasingly successful. Owing tothe clinical heterogeneity of the patients, the several existingvariants for each primary immunodeficiency associatedwith the need to carefully evaluate the patient’s clinicalconditions, and the fact that drugs are used in differentdosages, combinations and time schedules according to thedisease, the age and the clinical condition of the patient,


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HSCT for primary immunodeficiency should be performedin a centre regularly performing such transplants and thatactively participates within EBMT’s inherited diseasesworking party. The guidelines for each particular inheritedcondition are published on the EBMT’s website andreviewed regularly by the Inherited Disease working partymembers. Allogeneic HSCT is indicated for severe primaryimmunodeficiencies from both HLA-identical and alter-native donors.

SCIDA patient with SCID needs to be grafted as soon aspossible. An allogeneic HSCT results in a survival rate ofmore than 90% when carried out shortly after birth.Prognostic factors are the age, the type of SCID (B(þ ) vsB(�)), the clinical state at the time of diagnosis, inparticular the presence of a lung infection, and thedegree of HLA histocompatibility. In the presence of anHLA-identical family donor (20–30% of SCID patients),HSCT can be performed in certain SCID forms withoutany conditioning regimen and its course is characterizedby the remarkable rarity of acute and chronic GVHDwithout any prophylaxis and by the rapid development ofthe T-cell function after transplant. The restoration ofthe B-cell function nearly always occurs in patients withthe B(þ ) form of SCID, but is absent in 40% of those witha B(�) form. In the absence of an HLA-identical familydonor, HSCT from a partially HLA-compatible donor isproposed. In this respect, the use of a conditioning regimenhas a positive effect on survival in the B(�) SCID groupbut not in the other SCID groups. HSCT from unrelatedHLA-compatible donors, and unrelated umbilical CB andhaploidentical HSCT from related donors (that is, one ofthe two parents) are alternative options.

Inherited diseases: metabolic diseases

Most of the metabolic diseases are lysosomal storagediseases that rely on transfer of enzyme from donor-derivedblood cells to the reticuloendothelial system and solidorgans. The success of the HSCT can be affected by thelack of engraftment (secondary rejection is comparativelycommon), the enzyme levels of the donor, the degree ofsustained donor chimerism and possibly by the immuneprocesses directed against the normal donor enzyme.In disease with the central nervous system involvement,amelioration is dependent on the replacement of microglialcells by cells of donor origin. This process is slow and thetime taken to process abnormal storage material produces adelay between transplant and disease stabilization. This canlast up to 15 months, making it necessary to best guess howthe quality of life will be 18 months on from firstconsideration of HSCT (allowing for a donor search,workup and conditioning).

Aplastic anaemia, pure red cell aplasia (Blackfan-Diamond) and Fanconi anaemia—childrenAn allogeneic HSCT with an HLA-identical family donor isthe treatment of choice for children with acquired SAA.

A course of intensive immunosuppressive therapy (ATGand CYA) is indicated for patients who lack an HLA-compatible family donor. The search for an unrelateddonor should be initiated while they receive the immuno-suppressive therapy. For children who fail their first courseof immunosuppression, if a well-matched unrelated donoris identified, the transplant or a second course ofimmunosuppression should be given according to theclinical status. Children with Blackfan–Diamond anaemiahaving a matched sibling should be transplanted if they donot respond to steroids or if they do not becomeindependent of these drugs. Children with Fanconi anaemiashall be transplanted if they have an HLA-identical siblingdonor or a well-matched unrelated donor. For patients wholack a well-matched donor, HSCT should be consideredwith a mismatched unrelated donor or with CB stem cells inthe context of a clinical protocol.

Haemoglobinopathies—childrenThe outcome of HSCT for thalassaemia has progressivelyimproved with identification of the Pesaro classes of riskand the development of new conditioning regimens andsupportive therapies. Allogeneic HSCT from a healthyrelated sibling donor or a related CB represents thetreatment of choice for young patients with homozygousthalassaemia. For patients who lack a sibling donor, atransplant from a well-matched unrelated donor is apossibility. Extended haplotype matching seems to have apositive impact on prognosis after unrelated donor HSCT.Developments of conventional therapy have improved boththe quality and the duration of life for patients with sicklecell disease. For this reason, HSCT from an HLA-identicalsibling is offered only to a subset of patients at high, life-threatening risk or to patients who cannot receive adequatesupport. The experience of well-matched unrelated donorHSCT for sickle cell disease is still very limited andadditional studies are needed.

Solid tumours—childrenNeuroblastoma (stage IV beyond the age of 1 year, or high-risk factors in lower stages) is still the only indication wherethe benefit of high-dose therapy with autologous HSCT hasbeen shown by randomized trials.82,83.Although to date thepublished results do not show an unequivocal benefit forconsolidation with high-dose therapy, children and adoles-cents with solid tumours might undergo autologous HSCTafter high-dose chemotherapy within clinical research trials,preferably as part of first-line treatment strategies in thefollowing situations:

� Neuroblastoma (high risk, 4CR1).� Ewing’s sarcoma (high risk or 4CR1).� Brain tumours: children with medulloblastoma andhigh-grade gliomas responsive to chemotherapy in anattempt to avoid or postpone radiotherapy.

� Soft tissue sarcoma: stage IV or in responding relapse.� Germ cell tumours: after a relapse or with progressivedisease.

� Wilms’ tumour: relapse.� Osteogenic sarcoma: the value of HSCT is not yet clear.


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� Generally, allogeneic HSCT cannot be recommended inchildren with solid tumours. Allogeneic HSCT may beundertaken in the context of a clinical protocol inspecialized centres.

Autoimmune disordersSelected patients with poor prognostic juvenile idiopathicarthritis are currently considered for autologous HSCTthat has been proven as effective in providing aprolonged drug-free remission in a significant percentage ofpatients.84 Other diseases can be considered as develop-mental. The dependency of high steroid doses and impairedgrowth could be an indication.

Allogeneic HSCT with reduced conditioning in childrenFor patients otherwise not treatable (for example, severeinfections, heavy burden of chemotherapy, second trans-plants) allogeneic HSCT with reduced or minimal con-ditioning may be carried out within prospective clinicalprotocols. Developmental protocols, in particular indica-tions (for example, solid tumours), may be undertaken aspilot protocols in specialized centres.

Conflict of interest

The authors declare no conflict of interest.

Acknowledgements

We are grateful for the advice and helpful comments receivedfrom a number of individuals across Europe specializing inthe use of haematopoietic stem cell transplantation. Specialthanks to C Morris, M Mohty, C Schmid, R Willemze, J Esteve,A Nagler, S Giebel, P Corradini, P Dreger, E Olavarria,D Farge, C Gisselbrecht, H Greinix, Y Beguin, CG Steward,A Fischer, A Cant, L Notarangelo, W Friedrich, I Yaniv,R Ladenstein, N Schmitz, S Montoto, O Hermine andN Wulffraat.

References

1 Schmitz N, Gratwohl A, Goldman JM. Allogeneic andautologous transplantation for haematological diseases, solidtumours and immune disorders. Current practice in Europe in1996 and proposals for an operational classification. Accred-itation Sub-Committee of the European Group for Blood andMarrow Transplantation (EBMT). Bone Marrow Transplant1996; 17: 471–477.

2 Goldman JM, Schmitz N, Niethammer D, Gratwohl A.Allogeneic and autologous transplantation for haematologicaldiseases, solid tumours and immune disorders: current practicein Europe in 1998. Accreditation Sub-Committee of theEuropean Group for Blood and Marrow Transplantation.Bone Marrow Transplant 1998; 21: 1–7.

3 Urbano-Ispizua A, Schmitz N, de Witte T, Frassoni F, RostiG, Schrezenmeier H et al. Allogeneic and autologoustransplantation for haematological diseases, solid tumoursand immune disorders: definitions and current practice inEurope. Bone Marrow Transplant 2002; 29: 639–646.

4 Ljungman P, Urbano-Ispizua A, Cavazzana-Calvo M,Demirer T, Dini G, Einsele H et al. Allogeneic and autologoustransplantation for haematological diseases, solid tumours andimmune disorders: definitions and current practice in Europe.Bone Marrow Transplant 2006; 37: 439–449.

5 Yakoub-Agha I, Mesnil F, Kuentz M, Boiron JM, Ifrah N,Milpied N et al. Allogeneic marrow stem-cell transplantationfrom human leukocyte antigen-identical siblings versus humanleukocyte antigen-allelic-matched unrelated donors (10/10) inpatients with standard-risk hematologic malignancy: a pro-spective study from the French Society of Bone MarrowTransplantation and Cell Therapy. J Clin Oncol 2006; 24:5695–5702.

6 Lee SJ, Klein J, Haagenson M, Baxter-Lowe LA, Confer DL,Eapen M et al. High-resolution donor-recipient HLA match-ing contributes to the success of unrelated donor marrowtransplantation. Blood 2007; 110: 4576–4583.

7 Matthes-Martin S, Potschger U, Bergmann K, Frommlet F,Brannath W, Bauer P et al. Risk-adjusted outcome measure-ment in pediatric allogeneic stem cell transplantation. BiolBlood Marrow Transplant 2008; 14: 335–343.

8 Champlin RE, Schmitz N, Horowitz MM, Chapuis B, ChopraR, Cornelissen JJ et al. Blood stem cells compared with bonemarrow as a source of hematopoietic cells for allogeneictransplantation. IBMTR Histocompatibility and Stem CellSources Working Committee and the European Group forBlood and Marrow Transplantation (EBMT). Blood 2000; 95:3702–3709.

9 Schrezenmeier H, Passweg JR, Marsh JC, Bacigalupo A,Bredeson CN, Bullorsky E et al. Worse outcome and morechronic GVHD with peripheral blood progenitor cells thanbone marrow in HLA-matched sibling donor transplants foryoung patients with severe acquired aplastic anemia. Blood2007; 110: 1397–1400.

10 Rocha V, Labopin M, Sanz G, Arcese W, Schwerdtfeger R,Bosi A et al. Transplants of umbilical-cord blood or bonemarrow from unrelated donors in adults with acute leukemia.N Engl J Med 2004; 351: 2276–2285.

11 Eapen M, Rubinstein P, Zhang MJ, Stevens C, Kurtzberg J,Scaradavou A et al. Outcomes of transplantation of unrelateddonor umbilical cord blood and bone marrow in children withacute leukaemia: a comparison study. Lancet 2007; 369: 1947–1954.

12 Barker JN, Weisdorf DJ, DeFor TE, Blazar BR, McGlave PB,Miller JS et al. Transplantation of 2 partially HLA-matchedumbilical cord blood units to enhance engraftment inadults with hematologic malignancy. Blood 2005; 105:1343–1347.

13 Ruggeri A, de Latour RP, Rocha V, Larghero J, Robin M,Rodrigues CA et al. Double cord blood transplantation inpatients with high risk bone marrow failure syndromes. Br JHaematol 2008; 143: 404–408.

14 Aversa F, Tabilio A, Velardi A, Cunningham I, Terenzi A,Falzetti F et al. Treatment of high-risk acute leukemia withT-cell-depleted stem cells from related donors with onefully mismatched HLA haplotype. N Engl J Med 1998; 339:1186–1193.

15 Handgretinger R, Klingebiel T, Lang P, Gordon P, Nietham-mer D. Megadose transplantation of highly purified haplo-identical stem cells: current results and future prospects.Pediatr Transplant 2003; 7(Suppl 3): 51–55.

16 Ruggeri L, Capanni M, Casucci M, Volpi I, Tosti A, PerruccioK et al. Role of natural killer cell alloreactivity in HLA-mismatched hematopoietic stem cell transplantation. Blood1999; 94: 333–339.

17 Ruggeri L, Capanni M, Urbani E, Perruccio K, ShlomchikWD, Tosti A et al. Effectiveness of donor natural killer cell


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alloreactivity in mismatched hematopoietic transplants.Science 2002; 295: 2097–2100.

18 Ruggeri L, Mancusi A, Capanni M, Urbani E, Carotti A,Aloisi T et al. Donor natural killer cell allorecognition ofmissing self in haploidentical hematopoietic transplantationfor acute myeloid leukemia: challenging its predictive value.Blood 2007; 110: 433–440.

19 Stern M, Ruggeri L, Mancusi A, Bernardo ME, de Angelis C,Bucher C et al. Survival after T cell-depleted haploidenticalstem cell transplantation is improved using the mother asdonor. Blood 2008; 112: 2990–2995.

20 Guardiola P, Anderson JE, Bandini G, Cervantes F, Runde V,Arcese W et al. Allogeneic stem cell transplantation foragnogenic myeloid metaplasia: a European Group for Bloodand Marrow Transplantation, Societe Francaise de Greffe deMoelle, Gruppo Italiano per il Trapianto del Midollo Osseo,and Fred Hutchinson Cancer Research Center CollaborativeStudy. Blood 1999; 93: 2831–2838.

21 Kroger N, Badbaran A, Holler E, Hahn J, Kobbe G,Bornhauser M et al.Monitoring of the JAK2-V617F mutationby highly sensitive quantitative real-time PCR after allogeneicstem cell transplantation in patients with myelofibrosis. Blood2007; 109: 1316–1321.

22 Malcovati L, Porta MG, Pascutto C, Invernizzi R, Boni M,Travaglino E et al. Prognostic factors and life expectancy inmyelodysplastic syndromes classified according to WHOcriteria: a basis for clinical decision making. J Clin Oncol2005; 23: 7594–7603.

23 Oosterveld M, Suciu S, Verhoef G, Labar B, Belhabri A, Aul Cet al. The presence of an HLA-identical sibling donor has noimpact on outcome of patients with high-risk MDS orsecondary AML (sAML) treated with intensive chemotherapyfollowed by transplantation: results of a prospective study ofthe EORTC, EBMT, SAKK and GIMEMA LeukemiaGroups (EORTC study 06921). Leukemia 2003; 17: 859–868.

24 Dreger P, Corradini P, Kimby E, Michallet M, Milligan D,Schetelig J et al. Indications for allogeneic stem cell transplan-tation in chronic lymphocytic leukemia: the EBMT transplantconsensus. Leukemia 2007; 21: 12–17.

25 Linch DC, Winfield D, Goldstone AH, Moir D, Hancock B,McMillan A et al. Dose intensification with autologous bone-marrow transplantation in relapsed and resistant Hodgkin’sdisease: results of a BNLI randomised trial. Lancet 1993; 341:1051–1054.

26 Schmitz N, Pfistner B, Sextro M, Sieber M, Carella AM,Haenel M et al. Aggressive conventional chemotherapycompared with high-dose chemotherapy with autologoushaemopoietic stem-cell transplantation for relapsed chemo-sensitive Hodgkin’s disease: a randomised trial. Lancet 2002;359: 2065–2071.

27 Federico M, Bellei M, Brice P, Brugiatelli M, Nagler A,Gisselbrecht C et al. High-dose therapy and autologous stem-cell transplantation versus conventional therapy for patientswith advanced Hodgkin0s lymphoma responding to front-linetherapy. J Clin Oncol 2003; 21: 2320–2325.

28 Proctor SJ, Mackie M, Dawson A, White J, Prescott RJ,Lucraft HL et al. A population-based study of intensive multi-agent chemotherapy with or without autotransplant for thehighest risk Hodgkin0s disease patients identified by theScotland and Newcastle Lymphoma Group (SNLG) prognos-tic index. A Scotland and Newcastle Lymphoma Group study(SNLG HD III). Eur J Cancer 2002; 38: 795–806.

29 Moskowitz CH, Kewalramani T, Nimer SD, Gonzalez M,Zelenetz AD, Yahalom J. Effectiveness of high dose chemor-adiotherapy and autologous stem cell transplantation forpatients with biopsy-proven primary refractory Hodgkin’sdisease. Br J Haematol 2004; 124: 645–652.

30 Sweetenham JW, Carella AM, Taghipour G, Cunningham D,Marcus R, Della Volpe A et al. High-dose therapy andautologous stem-cell transplantation for adult patients withHodgkin0s disease who do not enter remission after inductionchemotherapy: results in 175 patients reported to the EuropeanGroup for Blood and Marrow Transplantation. LymphomaWorking Party. J Clin Oncol 1999; 17: 3101–3109.

31 Lazarus HM, Rowlings PA, Zhang MJ, Vose JM, ArmitageJO, Bierman PJ et al. Autotransplants for Hodgkin’s disease inpatients never achieving remission: a report from the Auto-logous Blood and Marrow Transplant Registry. J Clin Oncol1999; 17: 534–545.

32 Carella AM, Cavaliere M, Lerma E, Ferrara R, Tedeschi L,Romanelli A et al. Autografting followed by nonmyeloablativeimmunosuppressive chemotherapy and allogeneic peripheral-blood hematopoietic stem-cell transplantation as treatment ofresistant Hodgkin’s disease and non-Hodgkin’s lymphoma.J Clin Oncol 2000; 18: 3918–3924.

33 Milpied N, Fielding AK, Pearce RM, Ernst P, Goldstone AH.Allogeneic bone marrow transplant is not better thanautologous transplant for patients with relapsed Hodgkin’sdisease. European Group for Blood and Bone MarrowTransplantation. J Clin Oncol 1996; 14: 1291–1296.

34 Gajewski JL, Phillips GL, Sobocinski KA, Armitage JO, GaleRP, Champlin RE et al. Bone marrow transplants from HLA-identical siblings in advanced Hodgkin’s disease. J Clin Oncol1996; 14: 572–578.

35 Sureda A, Robinson S, Canals C, Carella AM, Boogaerts MA,Caballero D et al. Reduced-intensity conditioning comparedwith conventional allogeneic stem-cell transplantation inrelapsed or refractory Hodgkin’s lymphoma: an analysis fromthe Lymphoma Working Party of the European Group forBlood and Marrow Transplantation. J Clin Oncol 2008; 26:455–462.

36 Anderlini P, Saliba R, Acholonu S, Giralt SA, Andersson B,Ueno NT et al. Fludarabine-melphalan as a preparativeregimen for reduced-intensity conditioning allogeneic stem celltransplantation in relapsed and refractory Hodgkin’s lympho-ma: the updated M.D. Anderson Cancer Center experience.Haematologica 2008; 93: 257–264.

37 Peggs KS, Hunter A, Chopra R, Parker A, Mahendra P,Milligan D et al. Clinical evidence of a graft-versus-Hodgkin’s-lymphoma effect after reduced-intensity allogeneic transplan-tation. Lancet 2005; 365: 1934–1941.

38 Thomson KJ, Peggs KS, Smith P, Cavet J, Hunter A, Parker Aet al. Superiority of reduced-intensity allogeneic transplanta-tion over conventional treatment for relapse of Hodgkin’slymphoma following autologous stem cell transplantation.Bone Marrow Transplant 2008; 41: 765–770.

39 Philip T, Guglielmi C, Hagenbeek A, Somers R, Van der LelieH, Bron D et al. Autologous bone marrow transplantation ascompared with salvage chemotherapy in relapses of chemo-therapy-sensitive non-Hodgkin’s lymphoma. N Engl J Med1995; 333: 1540–1545.

40 Haioun C, Lepage E, Gisselbrecht C, Salles G, Coiffier B,Brice P et al. Survival benefit of high-dose therapy in poor-riskaggressive non-Hodgkin’s lymphoma: final analysis of theprospective LNH87-2 protocol—a groupe d’Etude des lym-phomes de l’Adulte study. J Clin Oncol 2000; 18: 3025–3030.

41 Gianni AM, Bregni M, Siena S, Brambilla C, Di Nicola M,Lombardi F et al. High-dose chemotherapy and autologousbone marrow transplantation compared with MACOP-Bin aggressive B-cell lymphoma. N Engl J Med 1997; 336:1290–1297.

42 Santini G, Salvagno L, Leoni P, Chisesi T, De Souza C, SertoliMR et al. VACOP-B versus VACOP-B plus autologous bonemarrow transplantation for advanced diffuse non-Hodgkin’s


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lymphoma: results of a prospective randomized trial by thenon-Hodgkin’s Lymphoma Cooperative Study Group. J ClinOncol 1998; 16: 2796–2802.

43 Strehl J, Mey U, Glasmacher A, Djulbegovic B, Mayr C,Gorschluter M et al. High-dose chemotherapy followed byautologous stem cell transplantation as first-line therapy inaggressive non-Hodgkin’s lymphoma: a meta-analysis.Haematologica 2003; 88: 1304–1315.

44 Greb A, Bohlius J, Trelle S, Schiefer D, De Souza CA,Gisselbrecht C et al. High-dose chemotherapy with autologousstem cell support in first-line treatment of aggressive non-Hodgkin lymphoma—results of a comprehensive meta-analy-sis. Cancer Treat Rev 2007; 33: 338–346.

45 Robinson SP, Goldstone AH, Mackinnon S, Carella A,Russell N, de Elvira CR et al. Chemoresistant or aggressivelymphoma predicts for a poor outcome following reduced-intensity allogeneic progenitor cell transplantation: an analysisfrom the Lymphoma Working Party of the European Groupfor Blood and Bone Marrow Transplantation. Blood 2002;100: 4310–4316.

46 Morris E, Thomson K, Craddock C, Mahendra P, Milligan D,Cook G et al. Outcomes after alemtuzumab-containingreduced-intensity allogeneic transplantation regimen forrelapsed and refractory non-Hodgkin lymphoma. Blood 2004;104: 3865–3871.

47 Deconinck E, Foussard C, Milpied N, Bertrand P, Michenet P,Cornillet-LeFebvre P et al. High-dose therapy followed byautologous purged stem-cell transplantation and doxorubicin-based chemotherapy in patients with advanced follicularlymphoma: a randomized multicenter study by GOELAMS.Blood 2005; 105: 3817–3823.

48 Lenz G, Dreyling M, Schiegnitz E, Forstpointner R, Wandt H,Freund M et al. Myeloablative radiochemotherapy followedby autologous stem cell transplantation in first remissionprolongs progression-free survival in follicular lymphoma:results of a prospective, randomized trial of the GermanLow-Grade Lymphoma Study Group. Blood 2004; 104:2667–2674.

49 Sebban C, Mounier N, Brousse N, Belanger C, Brice P,Haioun C et al. Standard chemotherapy with interferoncompared with CHOP followed by high-dose therapy withautologous stem cell transplantation in untreated patients withadvanced follicular lymphoma: the GELF-94 randomizedstudy from the Groupe d’Etude des Lymphomes de l’Adulte(GELA). Blood 2006; 108: 2540–2544.

50 Schouten HC, Qian W, Kvaloy S, Porcellini A, Hagberg H,Johnson HE et al. High-dose therapy improves progression-free survival and survival in relapsed follicular non-Hodgkin’slymphoma: results from the randomized European CUP trial.J Clin Oncol 2003; 21: 3918–3927.

51 Hari P, Carreras J, Zhang MJ, Gale RP, Bolwell BJ, BredesonCN et al. Allogeneic transplants in follicular lymphoma: higherrisk of disease progression after reduced-intensity compared tomyeloablative conditioning. Biol Blood Marrow Transplant2008; 14: 236–245.

52 Khouri IF, McLaughlin P, Saliba RM, Hosing C, Korbling M,Lee MS et al. Eight-year experience with allogeneic stem celltransplantation for relapsed follicular lymphoma after non-myeloablative conditioning with fludarabine, cyclophospha-mide, and rituximab. Blood 2008; 111: 5530–5536.

53 Faulkner RD, Craddock C, Byrne JL, Mahendra P, HaynesAP, Prentice HG et al. BEAM-alemtuzumab reduced-intensityallogeneic stem cell transplantation for lymphoproliferativediseases: GVHD, toxicity, and survival in 65 patients. Blood2004; 103: 428–434.

54 Dreyling M, Lenz G, Hoster E, Van Hoof A, Gisselbrecht C,Schmits R et al. Early consolidation by myeloablative

radiochemotherapy followed by autologous stem cell trans-plantation in first remission significantly prolongs progression-free survival in mantle-cell lymphoma: results of a prospectiverandomized trial of the European MCL Network. Blood 2005;105: 2677–2684.

55 Reimer P, Rudiger T, Geissinger E, Weissinger F, Nerl C,Schmitz N et al. Autologous stem-cell transplantation asfirst-line therapy in peripheral T-cell lymphomas: resultsof a prospective multicenter study. J Clin Oncol 2009; 27:106–113.

56 Corradini P, Dodero A, Zallio F, Caracciolo D, Casini M,Bregni M et al. Graft-versus-lymphoma effect in relapsedperipheral T-cell non-Hodgkin’s lymphomas after reduced-intensity conditioning followed by allogeneic transplantationof hematopoietic cells. J Clin Oncol 2004; 22: 2172–2176.

57 Le Gouill S, Milpied N, Buzyn A, De Latour RP, Vernant JP,Mohty M et al. Graft-versus-lymphoma effect for aggressiveT-cell lymphomas in adults: a study by the Societe Francaisede Greffe de Moelle et de Therapie Cellulaire. J Clin Oncol2008; 26: 2264–2271.

58 van Imhoff GW, van der Holt B, MacKenzie MA, Ossenkop-pele GJ, Wijermans PW, Kramer MH et al. Short intensivesequential therapy followed by autologous stem cell transplan-tation in adult Burkitt, Burkitt-like and lymphoblasticlymphoma. Leukemia 2005; 19: 945–952.

59 Labar B, Suciu S, Zittoun R, Muus P, Marie JP, Fillet G et al.Allogeneic stem cell transplantation in acute lymphoblasticleukemia and non-Hodgkin0s lymphoma for patientsoor¼ 50years old in first complete remission: results of the EORTCALL-3 trial. Haematologica 2004; 89: 809–817.

60 Bruno B, Rotta M, Patriarca F, Mordini N, Allione B,Carnevale-Schianca F et al. A comparison of allografting withautografting for newly diagnosed myeloma. N Engl J Med2007; 356: 1110–1120.

61 Rosinol L, Perez-Simon JA, Sureda A, de la Rubia J, de ArribaF, Lahuerta JJ et al. A prospective PETHEMA study oftandem autologous transplantation versus autograft followedby reduced-intensity conditioning allogeneic transplantationin newly diagnosed multiple myeloma. Blood 2008; 112:3591–3593.

62 Jaccard A, Moreau P, Leblond V, Leleu X, Benboubker L,Hermine O et al. High-dose melphalan versus melphalan plusdexamethasone for AL amyloidosis. N Engl J Med 2007; 357:1083–1093.

63 Ueno NT, Berry DA, Johnson MM, Lei X, Lopez VT,Caputo JA, Bregni M, Demirer T. High-dose chemotherapywith autologous stem-cell support versus standard-dosechemotherapy for high-risk breast cancer: Meta-analysis ofindividual patient data from 15 randomized adjuvant trials.Biol Blood.

64 Einhorn LH, Williams SD, Chamness A, Brames MJ, PerkinsSM, Abonour R. High-dose chemotherapy and stem-cellrescue for metastatic germ-cell tumors. N Engl J Med 2007;357: 340–348.

65 Motzer RJ, Nichols CJ, Margolin KA, Bacik J, RichardsonPG, Vogelzang NJ et al. Phase III randomized trial ofconventional-dose chemotherapy with or without high-dosechemotherapy and autologous hematopoietic stem-cell rescueas first-line treatment for patients with poor-prognosis meta-static germ cell tumors. J Clin Oncol 2007; 25: 247–256.

66 Mobus V, Wandt H, Frickhofen N, Bengala C, Champion K,Kimmig R et al. Phase III trial of high-dose sequentialchemotherapy with peripheral blood stem cell supportcompared with standard dose chemotherapy for first-linetreatment of advanced ovarian cancer: intergroup trial ofthe AGO-Ovar/AIO and EBMT. J Clin Oncol 2007; 25:4187–4193.


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67 Leyvraz S, Pampallona S, Martinelli G, Ploner F, Perey L,Aversa S et al. A threefold dose intensity treatment withifosfamide, carboplatin, and etoposide for patients with smallcell lung cancer: a randomized trial. J Natl Cancer Inst 2008;100: 533–541.

68 Mancardi G, Saccardi R. Autologous haematopoietic stem-celltransplantation in multiple sclerosis. Lancet Neurol 2008; 7:626–636.

69 Snowden JA, Kapoor S, Wilson AG. Stem cell transplantation inrheumatoid arthritis.Autoimmunity 2008; 1 (e-pub ahead of print).

70 Marmont AM, Burt RK. Hematopoietic stem cell transplanta-tion for systemic lupus erythematosus, the antiphospholipidsyndrome and bullous skin diseases. Autoimmunity 2008; 1(e-pub ahead of print).

71 Farge D, Nash R, Laar JM. Autologous stem cell transplanta-tion for systemic sclerosis. Autoimmunity 2008; 1 (e-pub aheadof print).

72 Cassinotti A, Annaloro C, Ardizzone S, Onida F, Della VolpeA, Clerici M et al. Autologous haematopoietic stem celltransplantation without CD34+ cell selection in refractoryCrohn’s disease. Gut 2008; 57: 211–217.

73 Gibson BE, Wheatley K, Hann IM, Stevens RF, Webb D,Hills RK et al. Treatment strategy and long-term results inpaediatric patients treated in consecutive UK AML trials.Leukemia 2005; 19: 2130–2138.

74 Marks D, Khattry N, Cummins M, Goulden N, Green A,Harvey J et al. Haploidentical stem cell transplantationfor children with acute leukaemia. Br J Haematol 2006; 134:196–201.

75 Miano M, Labopin M, Hartmann O, Angelucci E, Cornish J,Gluckman E et al. Haematopoietic stem cell transplantationtrends in children over the last three decades: a survey by thepaediatric diseases working party of the European Group forBlood and Marrow Transplantation. Bone Marrow Transplan-tation 2007; 39: 89–99.

76 Schrauder A, Reiter A, Gadner H, Niethammer D, KlingebielT, Kremens B et al. Superiority of allogeneic hematopoieticstem-cell transplantation compared with chemotherapy alonein high-risk childhood T-cell acute lymphoblastic leukemia:results from ALL-BFM 90 and 95. J Clin Oncol 2006; 24:5742–5749.

77 Balduzzi A, Valsecchi MG, Uderzo C, De Lorenzo P,Klingebiel T, Peters C et al. Chemotherapy versus allogeneictransplantation for very-high-risk childhood acute lympho-blastic leukaemia in first complete remission: comparison bygenetic randomisation in an international prospective study.Lancet 2005; 366: 635–642.

78 Locatelli F, Zecca M, Messina C, Rondelli R, Lanino E,Sacchi N et al. Improvement over time in outcome for childrenwith acute lymphoblastic leukemia in second remission givenhematopoietic stem cell transplantation from unrelated do-nors. Leukemia 2002; 16: 2228–2237.

79 Borgmann A, von Stackelberg A, Hartmann R, Ebell W,Klingebiel T, Peters C et al. Unrelated donor stem celltransplantation compared with chemotherapy for childrenwith acute lymphoblastic leukemia in a second remission: amatched-pair analysis. Blood 2003; 101: 3835–3839.

80 Peters C, Schrauder A, Schrappe M, von Stackelberg A,Stary J, Yaniv I et al. Allogeneic haematopoietic stem celltransplantation in children with acute lymphoblastic leukae-mia: the BFM/IBFM/EBMT concepts. Bone Marrow Trans-plant 2005; 35 (Suppl 1): S9–S11.

81 Balduzzi A, Gaipa G, Bonanomi S, Dassi M, Perseghin P,Buscemi F et al. Purified autologous grafting in childhoodacute lymphoblastic leukemia in second remission: evidence forlong-term clinical and molecular remissions. Leukemia 2001;15: 50–56.

82 Ladenstein R, Potschger U, Hartman O, Pearson AD,Klingebiel T, Castel V et al. 28 years of high-dose therapyand SCT for neuroblastoma in Europe: lessons from morethan 4000 procedures. Bone Marrow Transplant 2008; 41

(Suppl 2): S118–S127.83 Matthay KK, Reynolds CP, Seeger RC, Shimada H, AdkinsES, Haas-Kogan D et al. Long-term results for children withhigh-risk neuroblastoma treated on a randomized trial ofmyeloablative therapy followed by 13-cis-retinoic acid: achildren’s oncology group study. J Clin Oncol 2009; 27:1007–1013.

84 Wulffraat NM, van Rooijen EM, Tewarie R, Brinkman D,Prakken B, Kuis W. Current perspectives of autologous stemcell transplantation for severe juvenile idiopathic arthritis.Autoimmunity 2008; 41: 632–638.


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Allogeneic and autologous transplantation for haematological diseases, solid tumours and immune disorders: definitions and current practice in Europe

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