Stem-Cell Transplantation in Children With Acute Lymphoblastic Leukemia: A Prospective International...

Stem-Cell Transplantation in Children With AcuteLymphoblastic Leukemia: A Prospective InternationalMulticenter Trial Comparing Sibling Donors With MatchedUnrelated Donors—The ALL-SCT-BFM-2003 Trial

Christina Peters, Martin Schrappe, Arend von Stackelberg, André Schrauder, Peter Bader, Wolfram Ebell,Peter Lang, Karl-Walter Sykora, Johanna Schrum, Bernhard Kremens, Karoline Ehlert, Michael H. Albert,Roland Meisel, Susanne Matthes-Martin, Tayfun Gungor, Wolfgang Holter, Brigitte Strahm, Bernd Gruhn,Ansgar Schulz, Wilhelm Woessmann, Ulrike Poetschger, Martin Zimmermann, and Thomas Klingebiel

See accompanying article doi: 10.1200/JCO.2014.58.4631; listen to the podcast by Dr Bunin atwww.jco.org/podcasts

Author affiliations appear at the end ofthis article.

Published online ahead of print atwww.jco.org on March 9, 2015.

Written on behalf of the Berlin-Frankfurt-Muenster (BFM) Study Group,the International BFM Study Group, theChildren’s Cancer Research Institute,and the European Society for Blood andMarrow Transplantation PaediatricDiseases Working Party.

Supported by the Children’s CancerResearch Institute, Vienna, Austria;Deutsche Krebshilfe, Bonn, Germany;Deutsche Knochenmarkspenderdatei,Tübingen, Germany; Orphan Pharma-ceuticals and Amomed Pharma, Vienna,Austria; Fresenius Biotech, Gräfelfing,Germany; Gilead Sciences, Vienna,Austria; and Medac, Wedel, Germany.

Authors’ disclosures of potentialconflicts of interest are found in thearticle online at www.jco.org. Authorcontributions are found at the end ofthis article.

The supporting institutes and compa-nies had no role in study design, datacollection, data analysis, data interpreta-tion, or writing of the report. All datawere maintained by the Berlin-Frankfurt-Muenster statistics and datacenter and were reviewed by an inde-pendent data safety monitoringcommittee.

Clinical trial information: NC01423747.

Corresponding author: Christina Peters,MD, St Anna Children’s Hospital,Kinderspitalgasse 6, A-1090 Vienna,Austria; e-mail: [email protected].

© 2015 by American Society of ClinicalOncology

0732-183X/14/3399-1/$20.00

DOI: 10.1200/JCO.2014.58.9747

A B S T R A C T

PurposeAlthough hematopoietic stem-cell transplantation is widely performed in children with high-riskacute lymphoblastic leukemia (ALL), the influence of donor types is poorly understood. Thus,transplantation outcomes were compared in the prospective multinational Berlin-Frankfurt-Muenster (BFM) study group trial: ALL-SCT-BFM 2003 (Allogeneic Stem Cell Transplantation inChildren and Adolescents with Acute Lymphoblastic Leukemia).

Patients and MethodsAfter conditioning with total-body irradiation and etoposide, 411 children with high-risk ALLreceived highly standardized stem-cell transplantations during the first or later remissions.Depending on donor availability, grafts originated from HLA-genoidentical siblings or fromHLA-matched unrelated donors who were identified and matched by high-resolution allelic typingand were compatible in at least 9 of 10 HLA loci.

ResultsFour-year event-free survival (� standard deviation [SD]) did not differ between patients with transplanta-tions from unrelated or sibling donors (0.67 � 0.03 v 0.71 � 0.05; P � .405), with cumulative incidences ofnonrelapse mortality (� SD) of 0.10 � 0.02 and 0.03 � 0.02 (P � .017) and relapse rates (� SD) of 0.22 �0.02 and 0.24 � 0.04 (P � .732), respectively. Among recipients of transplantations from unrelated donors,no significant differences in event-free survival, overall survival, or nonrelapse mortality were observedbetween 9/10 and 10/10 matched grafts or between peripheral blood stem cells and bone marrow. Theabsence of chronic graft-versus-host disease had no effect on event-free survival. Engraftment was fasterafter bone marrow transplantation from siblings and was associated with fewer severe infections andpulmonary complications.

ConclusionOutcome among high-risk pediatric patients with ALL after hematopoietic stem-cell transplanta-tion was not affected by donor type. Standardized myeloablative conditioning produced a lowincidence of treatment-related mortality and effective control of leukemia.

J Clin Oncol 33. © 2015 by American Society of Clinical Oncology

INTRODUCTION

Although the majority of children and adolescentswith acute lymphoblastic leukemia (ALL) are cur-able with current chemotherapy regimens, pooroutcomes persist in some individuals.1,2 Thesehigh-risk patients require additional therapeutic ap-proaches after achieving remission. Allogeneic he-

matopoietic stem-cell transplantation (HSCT) caneffectively induce immunologic antileukemic con-trol in children with ALL by means of the graft-versus-leukemia effect.3 HSCT from allogeneicdonors has become the standard of care for suchhigh-risk patients. Only 20% to 25% of childrenwith indications for allogeneic HSCT have HLA-matched sibling donors (MSDs), but the availability

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of volunteer HLA-matched unrelated donors (MUDs) has increasedtransplantation rates over recent decades.4,5

Previous retrospective analyses demonstrated that some high-riskpatients with ALL benefitted from unrelated donor HSCT, but they hadnonrelapsemortality(NRM)ratesof25%.6,7 Inaddition,heterogeneityofavailabledataregardingpatientselection,qualityofHLAtyping,degreeofmatching, transplantation procedures, and study end points have ham-pered comparisons of different HSCT approaches. 8,9 Thus, in 2003, theBerlin-Frankfurt-Muenster (BFM) study group initiated the prospectiveinternational multicenter ALL-SCT-BFM 2003 (Allogeneic Stem CellTransplantation in Children and Adolescents with Acute LymphoblasticLeukemia)trialofallogeneicHSCTforchildrenwithALLandindicationsfor HSCT according to first-line and relapse chemotherapy protocolsduring first, second, or subsequent complete remissions (CRs). In thesestudies, all patients received pretransplantation treatments according to

Table 1. Patient Characteristics

Characteristic

Total MSD MUD

No. ofPatients % No. % No. %

Patients 411 105 306Age at SCT, years

Median 10.1 10 10.1Range 0.5-18.5 1.8-18.3 0.5-18.50-2 12 3 1 1 11 4� 2-12 249 61 68 65 181 59� 12-18 140 34 31 30 109 36� 18 10 2 5 5 5 2

SexMale 256 62 61 58 195 64Female 155 38 44 42 111 36

RemissionCR1 209 52 56 58 153 54CR2 173 42 41 42 132 46� CR2 29 8 8 8 21 7

ImmunophenotypeB 309 75 79 75 230 75T 87 21 21 20 66 22Other 15 4 5 5 10 3

BCR-ABLNegative 311 85 83 86 228 84Positive 56 15 14 14 42 16No data 44 8 36

MLL/AF4Negative 336 95 87 95 249 95Positive 17 5 5 5 12 5Not done 2 0 2No data 56 13 43

CMV (donor-patient)Negative-negative 84 22 32 33 52 18Negative-positive 56 14 8 8 48 17Positive-negative 61 16 13 13 48 17Positive-positive 186 48 45 46 141 49Incomplete data 24 7 17

Stem-cell sourceBone marrow 309 75 99 94 210 69PBSC 88 21 0 88 29CB SC 4 1 4 4 0Other 10 2 2 2 8 3

Time from indication to HSCT,months

No. of patients 408 104 304Median 4.3 4.1 4.4Range 0.3-16.6 1.1-9.9 0.3-16.6

CR1: time from initial diagnosisto HSCT, months

No. of patients 208 56 152Median 6.6 6.3 6.7Range 4.1-39.3 4.3-11.4 4.1-39.3

CR2, � CR2: time from lastrelapse to HSCT, months

Median 5.2 5.3 5.1Range 2.4-9 3.4-6.6 2.4-9

Type of relapseIsolated BM 162 80 34 69 128 84Isolated extramedullary 9 4 5 10 4 3Combined 31 15 10 20 21 14

(continued in next column)

Table 1. Patient Characteristics (continued)

Characteristic

Total MSD MUD

No. ofPatients % No. % No. %

CR2, � CR2: time from initialdiagnosis to diagnosis oflast relapse, months

No. of patients 173 41 128Median 29.9 31.8 29.3Range 3-128 8.9-86.4 3-128� 18 35 20 7 17 28 2118-30 52 30 11 27 41 31� 30 86 50 23 56 63 48

Conditioning regimenTBI and etoposide 370 90 96 90 274 90Chemotherapy conditioning 41 10 9 10 32 10

Abbreviations: BM, bone marrow; CB, cord blood; CMV, cytomegalovirus;CR1, first complete remission; CR2, second complete remission; HSCT,hematopoietic stem-cell transplantation; MSD, matched sibling donor;MUD, matched unrelated donor; PBSC, peripheral blood stem cell; SC,stem cell; SCT, stem-cell transplantation; TBI, total-body irradiation.

HSCT performed(N = 492)

MSD(n = 105)

MUD(n = 306)

MSD(n = 118)

MUD(n = 306)

Excluded MMD (n = 63) Insufficient (n = 5) donor typing

PBSC, PBSC+CB(n = 13)

Fig 1. Patient recruitment. CB, cord blood; HSCT, hematopoietic stem-celltransplantation; MMD, HLA-mismatched donor; MSD, HLA-matched siblingdonor; MUD, HLA-matched unrelated donor; PBSC, peripheral blood stem cell.

Peters et al

2 © 2015 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY

Zurich) on March 27, 2015 from 130.60.58.2Information downloaded from jco.ascopubs.org and provided by at SWISS CONSORTIUM (Hauptbibliothek Universitat

Copyright © 2015 American Society of Clinical Oncology. All rights reserved.

the ALL-BFM 2000 (Combination Chemotherapy Based on Risk of Re-lapse in Treating Young Patients With Acute Lymphoblastic Leuke-mia), the COALL (Multicenter Therapy Study of the Co-OperativeStudy Group for Childhood ALL), or the ALL-REZ BFM 2002(ALL-REZ BFM 2002: Multi-Center Study for Children With Re-lapsed Acute Lymphoblastic Leukemia) protocols.10,11 Patientswere allocated to receive HSCT from MSDs when they were avail-able or allogeneic HSCT from 9/10 or 10/10 MUDs when no MSDswere available. Hence treatment assignments were biologicallyrandomized according to the availability of donors.

Outcomes after HSCT are influenced by patient’s remission sta-tus, age, conditioning regimens, graft-versus-host disease (GVHD)prophylaxis, and supportive care and are also influenced by donorselections and stem-cell sources.12-16 Therefore, this trial aimed tostratify patients according to their remission status and age to harmo-nize the transplantation procedures (which were clearly defined ac-cording to standardized protocols) and to include patients from 29centers in Austria, Germany, and Switzerland (Data Supplement).

PATIENTS AND METHODS

Study Design

Outcomes of HSCTs from MSDs and MUDs in children with ALL whohad poor prognoses after treatment with a consistent remission inductionprotocol were prospectively compared.17,18

Patients were allocated to receive HSCT from MSDs when they wereavailable or from 9/10 or 10/10 HLA-matched MUDs. Conditioning wasperformed with total-body irradiation (TBI) and etoposide in patients olderthan age 2 years and in the absence of contraindications for TBI. Patients willbe observed indefinitely, and the median follow-up time at the time of thisanalysis was 4.2 years (see the Data Supplement for protocol outlines). Thisstudy was performed in accordance with the Declaration of Helsinki and GoodClinical Practice and was approved by the local institutional review board ateach participating site. Patients and/or their legal guardians provided writteninformed consent before enrollment.

Patient Selection

Eligible patients were treated with remission induction therapy accord-ing to the BFM or COALL trial protocol; were identified as high-risk by usingthe risk-adapted stratification criteria defined by BFM, including leukemiaphenotype, response to induction chemotherapy, and time and site of re-lapse19; had morphologic remission (� 5% bone marrow blasts) at the time ofHSCT; were age 18 years or younger at the time of initial diagnosis or relapse;and had no pregnancy, no secondary malignancy, and no previous HSCT.

Donor Selection

HLA typing was performed by using allelic typing, with a resolution offour digits per allele at HLA-A, -B, -C, -DRB1, and -DQB1 loci. Matchedsibling donors were defined as genotypically or phenotypically identical sib-lings. No 9/10 or 10/10 HLA-matched nonsibling donors were identified.Thus, in the absence of MSDs, 9/10 or 10/10 MUDs were recruited fromnational and international donor registries. The assignment to a donor group

Table 2. Secondary End Points

End Point

MSD (n � 105) MUD (n � 306)

PNo. ofEvents %

No. ofPatients

30-Day CumulativeIncidence (� SD)

No. ofEvents %

No. ofPatients

30-Day CumulativeIncidence (� SD)

Engraftment achieved (per microliter)� 1,000 leucocytes 105 0.96 � 0.02 299 0.91 � 0.02 .008� 100 lymphocytes 93 0.92 � 0.03 268 0.76 � 0.03 .002� 500 neutrophils 97 0.76 � 0.04 251 0.44 � 0.03 � .001� 20,000 platelets 93 0.64 � 0.05 225 0.33 � 0.03 � .001� 50,000 platelets 104 0.92 � 0.03 296 0.89 � 0.02 � .001

Graft failure 2 2 105 15 5 301 .259aGVHD

0 25 24 78 261 47 45 121 402 21 20 71 233 or 4 11 11 29 10 .751�

Death without aGVHD 0 0 6 2Death before day 100 1 18cGVHD

Patients at risk 104 2882-year cumulative incidence 30 0.29 � 0.05 51 0.18 � 0.02 .026†Limited 15 0.15 � 0.04 31 0.11 � 0.02 .307†Extensive 14 0.14 � 0.03 16 0.06 � 0.01 .012†Unknown extent 1 5Death without cGVHD 17 0.15 � 0.04 57 0.19 � 0.02 .377†

Grade 3 or 4 toxicityNausea and vomiting 7 7 104 42 14 291 .055Hypoxia 9 9 102 52 18 283 .026Tachypnea 4 4 93 30 11 264 .062Infection 16 16 103 111 39 287 � .001Central neurotoxicity 0 0 101 16 6 285 .016

Abbreviations: aGVHD, acute graft-versus-host disease; cGVHD, chronic GVHD; MSD, matched sibling donor; MUD, matched unrelated donor; SD, standard deviation.��2 test.†Gray test.

Comparison of Sibling and Unrelated Donors for Pediatric ALL

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determined the transplantation regimen (ie, stem-cell source, stem-cell ma-nipulation, conditioning protocol, and GVHD prophylaxis; details are pro-vided in the Protocol [online only]).

In the absence of matched donors, patients continued with conventionalchemotherapy, or other transplantation approaches were performed by usingmismatched cord blood (CB) or haploidentical HSCTs. These patients will bedescribed in a separate report.

Stem-Cell Source

For children, the preferred stem-cell source was bone marrow (BM)from either MSDs or MUDs, as indicated by a large retrospective analysis that

showed a higher incidence of chronic GVHD (cGVHD) and lower overallsurvival (OS) after peripheral blood stem cell (PBSC) transplantation.20 Re-cipients of unrelated grafts received BM or PBSCs according to donor choices.CB from MSDs or MUDs was used when sufficient cell numbers were available(� 2.5 � 107 cells per kilogram of recipient body weight).21

Conditioning Regimen

The conditioning regimen for patients older than age 2 years comprisedfractionated TBI (12 Gy in six fractions over 3 days with lung shielding at 10Gy) and intravenous etoposide 60 mg/kg (upper total dose, 3,600 mg). Chil-dren younger than age 2 years and older children with contraindications for

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10/10 HLA matches9/10 HLA matches

Peripheral-blood stem cellsBone marrow





Fig 2. Influence of (A, C, E) HLA-matched unrelated donor (MUD) and (B, D, F) stem-cell source on incidence and severity of chronic graft-versus-host disease(cGVHD v extensive cGVHD v limited cGVHD, according to Glucksberg criteria). 9/10 and 10/10, nine of 10 and 10 of 10 HLA matches defined by allelic typing on HLA-A,-B, -C, -DRB1, and -DQB1 loci.

Peters et al




TBI (eg, CNS irradiation before HSCT, history of CNS toxicities, signs ofleukoencephalopathy) were treated with chemotherapy consisting of intrave-nous busulfan without therapeutic drug monitoring according to the manu-facturer’s brochure and as described elsewhere,22 in combination withcyclophosphamide (120 mg/kg total dose) and etoposide (40 mg/kg totaldose). Details of conditioning regimens are provided in the Protocol.

GVHD Prophylaxis

GVHD prophylaxis for MSD bone marrow transplantation consisted ofinitial intravenous cyclosporine 1.5 mg/kg twice per day followed by oralcyclosporine when appropriate. MUD-HSCT patients were administered cy-closporine at the same dosage with methotrexate 10 mg/m2 on days �1, �3,and �6 after HSCT, followed by folinic acid 15 mg/m2 24 hours after eachdose. Antithymocyte globulin (ATG) was administered on days �3, �2, and�1 (ATG Fresenius 60 mg/kg total dose).

Statistics

Event-free survival (EFS) was the primary end point, taking the date ofHSCT as the starting point, and the date of first event or of the last follow-up asthe end of the interval. An event was defined as relapse, secondary malignancy,or death as a result of any cause. The null hypothesis is that MUD-HSCT isinferior to MSD-HSCT. To determine whether there was any difference in EFSbetween MSD-HSCT and MUD-HSCT, the cumulative incidence approachwas used, with a one-sided CI for the difference of the Kaplan-Meier estimateof the 4-year EFS. With the initially planned sample size of 84 MSD patientsand 228 MUD patients, 80% power can be achieved to show that MUD-HSCTis noninferior if a lower limit of the CI of 16% is used as the margin.23

Secondary end points were OS, relapse incidence (RI), NRM, engraft-ment, incidence and severity of acute GVHD (aGVHD) and cGVHD, andtoxicity. For OS, death as a result of any cause was used as an event, andsurvivors were censored at the date of the last follow-up information. For RI,NRM, engraftment, and cGVHD, cumulative incidences were estimated byusing the approach of Kalbfleisch and Prentice.24 Competing events weredefined as follows: for RI, deaths from any cause and secondary malignancies;for engraftment and cGVHD, deaths from any cause; and for NRM, relapsesand secondary malignancies.25 For the evaluation of risk factors and donortype, the comparison of cumulative incidences was done with Gray’s test andan approach based on pseudovalues,26 respectively. The pseudovalue ap-proach was also used to assess the impact of donor type on the 4-year proba-bility of EFS and probability of OS in subgroups of patients because theproportional hazard assumption was violated. The incidences of aGVHD andgrade 3 or 4 toxicity were compared by using the �2 test.

The impact of prognostic factors on EFS and OS was evaluated by usingCox regression analyses, and pseudovalue regression analyses were used toseparately evaluate the impact of donor type and of remission status on long-term event rates and survival times.

RESULTS

Characteristics of Study Patients

Between September 2003 and September 2011, 411 patientsreceived HSCT according to the protocol (105 MSDs and 306

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Patients Events 4-yr. EFS P*MSD 105 30 0.71±0.05 .405MUD 306 100 0.67±0.03

Difference in 4-year EFS 5%Upper limit of one-sided 95% CI 13%

Patients Events 4-yr. OS P*MSD 105 22 0.79±0.04 .230MUD 306 81 0.73±0.03

Patients Events 4-yr. CI P*MSD 105 24 0.24±0.04 .732MUD 306 65 0.22±0.02


Fig 3. Four-year (A) event-free survival (EFS), (B) overall survival (OS), (C) relapse incidence (RI), and (D) nonrelapse mortality (NRM). MSD, HLA-matched siblingdonor; MUD, HLA-matched unrelated donor. (*) Based on pseudovalues at 4 years.





MUDs). Patient characteristics are provided in Table 1. In additionto these patients, 81 patients were given transplantations by usingapproaches that are beyond the scope of this article (Fig 1) andwere excluded from analyses.

Patient groups had comparable proportions of patients in first orlater remissions and had similar times from initial diagnosis or relapseto HSCT (median, 4.3 months) and phenotypical risk factors. In all,90% of patients in both groups received conditioning regimens con-taining TBI and etoposide.

Among 105 patients who received MSD-HSCT, 99 received BMalone, four received CB, and two received BM and CB. The majority ofpatients with MUD transplantations (210 patients; 69%) received BM,whereas 88 patients (29%) received PBSCs and the remaining eightpatients received CB or a combination of CB and BM or PBSCs afterdelayed engraftment. At the time of analysis in November 2013, themedian follow-up from time of diagnosis until last follow-up evalua-tion was 4.2 years (range, 0.27 to 9.1 years).

Engraftment

Engraftment was significantly faster after MSD-HSCT (Table 2).The median time to neutrophil engraftment (ie, absolute neutrophilcount � 500/�L) was 17 days after MSD-HSCT and 22 days afterMUD-HSCT with a 30-day cumulative incidence of 76% versus 44%(P � .001). Lymphocyte count � 100/�L was observed in the MSD

group on day 14 compared with day 23 after MUD-HSCT with 30-daycumulative incidences of 92% versus 76% (P � .001).

Transfusion-independent platelet count � 20,000/�L wasreached on day 22 after MSD-HSCT and on day 32 after MUD-HSCTwith 30-day cumulative incidences of 64% versus 33% (P � .001).Although graft failure was generally rare, it was more frequent amongpatients who received MUD-HSCT (n � 2 v n � 15; P � .259).

aGVHD and cGVHD

No differences in incidence or severity of aGVHD were observedbetween MSD-HSCT and MUD-HSCT patients; in contrast, exten-sive cGVHD occurred more frequently after MSD-HSCT (Table 2).For the MUD group, in which more intensive immunosuppressionwas used, the 2-year cumulative incidence of extensive cGVHD wasonly 0.06 � 0.01 and did not vary between BM and PBSCs or withHLA disparities (9/10 or 10/10 matches; Fig 2). Fourteen patients(14%) developed extensive cGVHD after MSD-HSCT; 16 patients(6%) developed extensive cGVHD after MUD-HSCT. Five of thosepatients had a Karnovsky/Lansky performance status below 80% 2years after MSD-HSCT and only six of 16 MUD-HSCT patientsreached a performance status of 80% to 100%, reflecting the reducedquality of life with such complications.

After MSD-HSCT, patients older than age 12 years had a higherincidence of extensive cGVHD compared with younger patients (25%

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Fig 4. Outcomes for patients who received a transplantation in first complete remission. (A) Event-free survival (EFS), (B) overall survival (OS), (C) relapse incidence(RI), and (D) nonrelapse mortality (NRM). MSD, HLA-matched sibling donor; MUD, HLA-matched unrelated donor. (*) Based on pseudovalues at 4 years.

Peters et al




v 48%). Sex match of donor and recipient, year of HSCT, phenotype,and cytomegalovirus status did not influence the incidence and sever-ity of cGVHD after MSD-HSCT.

Toxicity

The incidenceofgrade3to4 infectionwassignificantlyhigher in theMUD group and was associated with a tendency toward pulmonarycomplications (Table 2). Other extramedullary toxicities of grade � 2were rare and were predominantly associated with oral mucositis. Thirty-threepatientsdiedasaresultofnonrelapsecomplications, includingthreeof 105 from the MSD-HSCT group and 30 of 306 from the MUD-HSCTgroup (P � .017). The main causes of death were bacterial (n � 6) andviral(n�6)infections,Epstein-Barrvirus–lymphoproliferativedisease(n�3),multiorganfailure(n�6), toxicity(n�4),andaGVHD(n�2)orcGVHD (n � 6). A total of nine patients developed secondary malignan-cies at a median of 5 years (range, 26 to 84 months) after HSCT: fivethyroid cancers, one myelodysplastic syndrome, one osteosarcoma, onerhabdomyosarcoma, and one colon carcinoma. Among these patients,three were in the MSD-HSCT group and six were in the MUD-HSCTgroup. All patients received TBI.

Outcomes

The 4-year EFS rate after MUD-HSCT was similar to that afterMSD-HSCT (0.67�0.03 v 0.71�0.05; P� .405). The upper limit of the

95% CI for the difference in 4-year EFS was 13% (Fig 3A). No significantdifferences in OS or RI were observed (4-year cumulative incidence,0.22 � 0.02 after MUD-HSCT and 0.24 � 0.02 after MSD-HSCT).

However, NRM at 4 years was 0.10 � 0.02 with transplantationsfrom MUDs and was 0.03�0.02 with transplantations from MSDs (P�.017). Patients receiving transplantations during the first CR (CR1) hadbetter outcomes than those with subsequent remissions (Fig 4 and Fig 5).No differences in patient outcomes were found between MUD-HSCTwith 9/10 and 10/10 HLA matches or between patients receiving BM andPBSCs (Fig 2). No differences in EFS, RI, or OS were identified betweenpatients with and without limited or extensive cGVHD (Data Supple-ment). Moreover, no significant influences of other prognostic factors,including immunophenotype and cytogenetic abnormalities, were iden-tified in univariable or multivariable analyses (Data Supplement).

DISCUSSION

This is the first prospective study to compare HSCT from different donortypes in well-defined cohorts of children with high-risk ALL by using astandardized transplantation and prophylaxis protocol. All patients re-ceived comparable risk-stratified chemotherapy before HSCT and wereselected for HSCT according to prognostically relevant leukemia pheno-types and response to induction chemotherapy or according to time and

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Fig 5. Outcomes for patients transplanted in second or third complete remissions. (A) Event-free survival (EFS), (B) overall survival (OS), (C) relapse incidence (RI),and (D) nonrelapse mortality (NRM). MSD, HLA-matched sibling donor; MUD, HLA-matched unrelated donor. (*) Based on pseudovalues at 4 years.





site of relapse. Donor selections were determined according to the avail-ability of suitable siblings, which produced biologically randomized treat-ment groups. The close cooperation and compliance of study centers, theprospectiveevaluation,andqualityassurancefromregularpatientconfer-ences about complications led to noticeable treatment improvementscompared with those of some previous retrospective studies.27-29 More-over, multicenter cooperation allowed stringent alignment of selectioncriteria for allogeneic HSCT according to predictions of contemporarychemotherapy outcomes. Patients with a long-term survival prognosis ofless than 50% after validated chemotherapy were selected for HSCT. Incontrast with previous trials, these criteria were defined in first-line pro-tocols and did not differ for MSD or MUD indications. Specifically,known risk factors, such as phenotype, response to prednisone, age atdiagnosis, relapse, duration of first remission, and site of relapse,were defined in the indication for allogeneic HSCT. For patientswith CR1 and second CR (CR2) HSCT indications, the minimalresidual disease level at 4 and 12 weeks after initial treatmentbecame a major selection criteria.10,12,30

EFS and OS of patients in the MUD group were superior to thosein previously published data from children with high-risk ALL whowere treated with MUD transplantations,31,32 and the quality of HLAtyping and the degree of matching may have played an important role.

When this study was designed, it was still common practice to useunrelated donors with 7/8 HLA matches, as determined by medium-resolution typing. However, the drawback of this procedure has beena high rate of transplantation-associated complications, especiallyaGVHD and cGVHD, which particularly affects the growing organs ofchildren. Petersdorf et al33 and Flomenberg et al34 demonstrated strik-ing prognostic efficacy of high-resolution typing and, consequently,only donors with 9/10 or 10/10 HLA matches (four digits per allele)were used in this study. MUDs were identified for more than 70% ofpatients who lacked MSDs, and the search for donors did not delayHSCT. Moreover, no differences in outcomes were identified betweenpatients receiving transplantations from 9/10 or 10/10 matches.

Among patients with MUD transplantations, no differences inOS were observed between recipients of BM or PBSC, probably re-flecting the protective effect of intensive GVHD prophylaxis withcyclosporine, methotrexate, and ATG Fresenius.35,36 Furthermore, nosignificant differences in outcomes were observed between patientswith various degrees of aGVHD or cGVHD. These data demonstratethat long-term relapse-free survival after MUD-HSCT can beachieved without a high incidence of cGVHD, which is a devastatingdisease for children and adolescents.37,38

Despite excellent outcomes of MUD-HSCT, our data indicate thatMSD BM transplantation remains superior, which is possibly a result offaster engraftment and more rapid immune reconstitution resulting infewer severe infections. We speculate that this is influenced by the shortand limited GVHD prophylaxis in this setting. This investigator-initiated,multicenter studyhas limitations.Becauseonly10%ofchildrenwithALLqualifyforanallogeneicHSCT,therecruitmentdurationwasmorethan7years. Although no striking differences in supportive care were observed,

some new techniques developed over time and possibly influenced thetreatment intensity of aGVHD and cGVHD; extracorporeal photophere-sis and mesenchymal stem-cell infusion were increasingly used to reducepharmacologic immunosuppression. One of the most important tools isthe evaluation of minimal residual disease before and after HSCT. Theresultsof this investigationinourstudygroupwererecentlyreported,andadditional analyses are under way.39,39a

The risk of secondary malignancies is a major concern,40-42 and ourdata demonstrate this risk with nine secondary malignancies in patientswho received TBI, with the expectation of more with longer follow-up.The long-term effects of TBI in children and adolescents also includeorgandysfunction,growthretardation,andhormonalinsufficiencies.43-45

Thus, future studies are required to develop effective alternatives to TBI.In conclusion, our data demonstrate excellent EFS and OS, and low

incidence of relapse in children with high-risk ALL after treatment withTBI and etoposide before allogeneic HSCT from HLA-matched siblingsor well-matched unrelated donors. This large, prospective, multicentertrial suggests that MUD-HSCT could be a standard of care for patientswith ALL who have a high risk of relapse and who lack MSDs.

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTSOF INTEREST

Disclosures provided by the authors are available with this article atwww.jco.org.

AUTHOR CONTRIBUTIONS

Conception and design: Christina Peters, Martin Schrappe, Arend vonStackelberg, André Schrauder, Peter Bader, Wolfram Ebell, Peter Lang,Johanna Schrum, Bernhard Kremens, Michael H. Albert, Roland Meisel,Susanne Matthes-Martin, Tayfun Gungor, Wolfgang Holter, BrigitteStrahm, Bernd Gruhn, Ansgar Schulz, Wilhelm Woessmann, UlrikePoetschger, Martin Zimmermann, Thomas KlingebielProvision of study materials or patients: Christina Peters, Martin Schrappe,Arend von Stackelberg, André Schrauder, Peter Bader, Wolfram Ebell, PeterLang, Johanna Schrum, Bernhard Kremens, Michael H. Albert, Roland Meisel,Susanne Matthes-Martin, Tayfun Gungor, Wolfgang Holter, Brigitte Strahm,Bernd Gruhn, Ansgar Schulz, Wilhelm Woessmann, Ulrike Poetschger, MartinZimmermann, Thomas KlingebielCollection and assembly of data: Christina Peters, Martin Schrappe, Arend vonStackelberg, André Schrauder, Peter Bader, Wolfram Ebell, Peter Lang, JohannaSchrum, Bernhard Kremens, Michael H. Albert, Roland Meisel, SusanneMatthes Martin, Tayfun Gungor, Wolfgang Holter, Brigitte Strahm, BerndGruhn, Ansgar Schulz, Wilhelm Woessmann, Ulrike Poetschger, MartinZimmermann, Thomas KlingebielData analysis and interpretation: Christina Peters, Martin Schrappe, Arend vonStackelberg, Peter Bader, Peter Lang, Karl-Walter Sykora, Johanna Schrum,Bernhard Kremens, Karoline Ehlert, Michael H. Albert, Roland Meisel, SusanneMatthes-Martin, Tayfun Gungor, Wolfgang Holter, Brigitte Strahm, BerndGruhn, Ansgar Schulz, Wilhelm Woessmann, Ulrike Poetschger, MartinZimmermann, Thomas KlingebielManuscript writing: All authorsFinal approval of manuscript: All authors

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Affiliations

Christina Peters, Susanne Matthes-Martin, and Ulrike Poetschger, St Anna Children’s Hospital, Vienna, Austria; Martin Schrappe,University Medical Center Schleswig-Holstein and Christian-Albrechts-University Kiel; André Schrauder, Kinderarztpraxis am Aalborgring,Kiel; Arend von Stackelberg and Wolfram Ebell, Charité–Children’s Hospital Berlin, Berlin; Peter Bader and Thomas Klingebiel, JohannWolfgang Goethe University, Frankfurt; Peter Lang, University Hospital Tübingen, Tübingen; Karl-Walter Sykora and Martin Zimmerman,Hannover Medical School, Hannover; Johanna Schrum, University Medical Center Hamburg-Eppendorf, Hamburg; Bernhard Kremens,University Hospital Essen, Essen; Karoline Ehlert, University Clinic Greifswald, Greifswald; Michael H. Albert, Dr. von Hauner UniversityChildren’s Hospital, München; Roland Meisel, University Hospital Düsseldorf, Düsseldorf; Wolfgang Holter, Children’s University HospitalErlangen, Erlangen; Brigitte Strahm, University Hospital Freiburg, Freiburg; Bernd Gruhn, University Hospital Jena, Jena; Ansgar Schulz,University Hospital Ulm, Ulm; Wilhelm Woessmann, University Clinic Giessen, Giessen, Germany; and Tayfun Gungor, UniversityChildren’s Hospital Zürich, Zürich, Switzerland.

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Peters et al




AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Stem-Cell Transplantation in Children With Acute Lymphoblastic Leukemia: A Prospective International Multicenter Trial Comparing SiblingDonors With Matched Unrelated Donors—The ALL-SCT-BFM-2003 Trial

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships areself-held unless noted. I � Immediate Family Member, Inst � My Institution. Relationships may not relate to the subject matter of this manuscript. For moreinformation about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or jco.ascopubs.org/site/ifc.

Christina PetersHonoraria: EUSA Pharma, Medac PharmaConsulting or Advisory Role: Medac Pharma, EUSA Pharma, PfizerSpeakers’ Bureau: Amgen, Novartis, Medac Pharma, Fresenius BiotechResearch Funding: Amgen (Inst), Fresenius Biotech (Inst), Genzyme(Inst), Medac (Inst), RIEMSER Pharma (Inst)Travel, Accommodations, Expenses: Pierre Fabre

Martin SchrappeNo relationship to disclose

Arend von StackelbergHonoraria: AmgenConsulting or Advisory Role: Amgen (Inst)Research Funding: EUSA Pharma (Inst)

André SchrauderNo relationship to disclose

Peter BaderTravel, Accommodations, Expenses: Medac Pharma, Novartis

Wolfram EbellNo relationship to disclose

Peter LangNo relationship to disclose

Karl-Walter SykoraTravel, Accommodations, Expenses: Medac Pharma

Johanna SchrumNo relationship to disclose

Bernhard KremensNo relationship to disclose

Karoline EhlertNo relationship to disclose

Michael H. AlbertStock or Other Ownership: Amgen, Biogen IdecTravel, Accommodations, Expenses: Neovii Biotech, Astellas Pharma

Roland MeiselNo relationship to disclose

Susanne Matthes-MartinNo relationship to disclose

Tayfun GungorNo relationship to disclose

Wolfgang HolterNo relationship to disclose

Brigitte StrahmNo relationship to disclose

Bernd GruhnConsulting or Advisory Role: Amgen, EUSA PharmaTravel, Accommodations, Expenses: EUSA Pharma, Neovii Biotech

Ansgar SchulzNo relationship to disclose

Wilhelm WoessmannNo relationship to disclose

Ulrike PoetschgerNo relationship to disclose

Martin ZimmermannNo relationship to disclose

Thomas KlingebielExpert Testimony: NovartisTravel, Accommodations, Expenses: EUSA Pharma, Medac Pharma


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http://www.asco.org/rwc

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Acknowledgment

Presented in part at the 52nd Annual Meeting of the American Society of Hematology, Orlando, FL, December 4-7, 2010; at the 7th BiannualChildhood Leukemia Symposium, Antalya, Turkey, October 4-6, 2010; and at the International European Society for Blood and Marrow

Transplantation Annual Meeting, Geneva, Switzerland, April 1-4, 2012.

Peters et al

© 2015 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY



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