VOLUME 28 NUMBER 14 MAY 10 2010

JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T

Long-Term Outcome in Children With Relapsed Acute

From the Departments of Pediatric
Oncology/Hematology and of General
Pediatrics, Charite-Universitatsmedizin
Berlin; Department of Pediatric Oncolo-
gy/Hematology, University Hamburg-
Eppendorf, Hamburg; Department of
General Pediatrics, University of
Schleswig-Holstein, Kiel; Department
of Pediatric Oncology/Hematology,
Johann-Wolfgang-Goethe-University,
Frankfurt, Germany; Department of
Oncology/Hematology and Tumour-
Immunology, Helios Klinikum Berlin-
BuchRobert-Rossle-Klinik, Department
of Pediatric Oncology/Hematology, St
Anna Spital, Vienna, Austria; VU Univer-
sity Medical Center, Amsterdam, the
Netherlands; Department of Pediatric
Oncology/Hematology, University Chil-
drens Hospital Zurich, Switzerland; and
Department of Pediatric Oncology/He-
matology of the Republic Childrens
Hospital, Moscow, Russia.
Submitted July 17, 2009; accepted
January 28, 2010; published online
ahead of print at www.jco.org on April
12, 2010.
Written on behalf of the ALL-REZ BFM
(Acute Lymphoblastic Leukemia
Relapse Berlin-Frankfurt-Munster) Study
Group.
Supported by Deutsche Krebshilfe e. V
Deutsche Jose Carreras Leukmie Stif-
tung (A 09/01).
Authors disclosures of potential con-
flicts of interest and author contribu-
tions are found at the end of this
article.
Lymphoblastic Leukemia After Time-Point
and Site-of-Relapse Stratification and Intensified
Short-Course Multidrug Chemotherapy: Results of Trial
ALL-REZ BFM 90
Gesche Tallen, Richard Ratei, Georg Mann, Gertjan Kaspers, Felix Niggli, Alexandr Karachunsky,
Wolfram Ebell, Gabriele Escherich, Martin Schrappe, Thomas Klingebiel, Ruediger Fengler, Gunter Henze,
and Arend von Stackelberg
A B S T R A C T
Purpose
The multicenter trial ALL-REZ BFM (ie, Acute Lymphoblastic Leukemia Relapse Berlin-Frankfurt-
Munster) 90 was designed to improve prognosis for children with relapsed acute lymphoblastic
leukemia (ALL) by time-to-relapse and site-of-relapseadapted stratification and by introduction of
novel chemotherapy elements and to evaluate new prognostic parameters in a large, population-
based cohort.
Patients and Methods
Five hundred twenty-five patients stratified into risk groups A (early bone marrow [BM] relapses),
B (late BM relapses), and C (isolated extramedullary relapses) received alternating short-course
intensive polychemotherapy (in blocks R1, R2, or R3) and cranial/craniospinal irradiation followed
by maintenance therapy. Block R3 (high-dose cytarabine and etoposide) was introduced to
improve the outcome compared with historical controls. Patients with early BM or T-ALL relapse
(poor prognosis group [PPG]) were eligible for experimental regimens. One hundred seventeen
patients received stem-cell transplantation (SCT).
Results
The probabilities (and standard deviations) of event-free survival (pEFS) and overall survival (pOS)
at 10 years were 0.30 .02 and 0.36 .02, respectively. Significant differences existed between
strategic groups (pEFSA .17 .03; pEFSB .43 .04; pEFSC .54 .06; pEFSPPG .15 .03;
log-rank P .001). Patients of high-risk groups A plus PPG did better with SCT than with
chemotherapy (pEFS .33 .05 v 0.20 .05; P .005). The pEFS was similar to trials ALL-REZ
BFM 85/87 (.36 .03. v 0.37 .03; P .419; PPG excluded). Time point, site of relapse,
immunophenotype, and SCT were significant predictors of pEFS in multivariate analyses.
Conclusion
More than one third of patients in this large, population-based trial were cured. Neither R3 nor
adaptation of chemotherapy intensity was capable of improving pEFS or of overcoming prognostic
factors. In high-risk patients, remission induction regimens must be improved, and allogeneic SCT
should be recommended in patients achieving second complete remission.
J Clin Oncol 28:2339-2347. 2010 by American Society of Clinical Oncology

Corresponding author: Arend von

Stackelberg, MD, PhD, Otto-Heubner-
Centrum fur Kinder- und Jugendmedizin,
Klinik fur Padiatrie m. S. Onkologie/
Hamatologie, Augustenburger Platz 1,
13353 Berlin, Germany; e-mail:
arend.stackelberg@charite.de.
2010 by American Society of Clinical
Oncology
0732-183X/10/2814-2339/$20.00
DOI: 10.1200/JCO.2009.25.1983
INTRODUCTION
Remarkable progress was made in treatment of
childhood acute lymphoblastic leukemia (ALL)
during the past two decades, during which long-
term event-free survival (EFS) rates reached greater
than 80%.1,2 However, compared with newly diag-
nosed ALL, prognosis is still substantially reduced in
cases of relapse. Since 1983, EFS was improved by
protocols of the ALL-relapse-Berlin/Frankfurt/
Munster-Study-Group (ALL-REZ BFM 83, 85,
87),3-5 for which intensive-treatment phases in-
cluded alternating short-course (approximately 1
week), multiagent chemotherapy courses (R1 and
R2). Stem-cell transplantation (SCT) was an alter-
native postsecond-remission therapy for high-risk
(HR) patients.6,7 Time point, site of relapse, and ALL
immunophenotype have been identified as most

2010 by American Society of Clinical Oncology 2339

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 Tallen et al
important risk factors. Second complete remission (CR) rates of 85%
and EFS rates of 30% to 40% were reported.4,5,8,9 Treatment failure
was most frequent in HR subgroups, and subsequent relapse was the
most common adverse event.10-12 Therefore, treatment optimization
and additional prognostic factors are required to improve prognosis
for children with relapsed ALL.
Here, we present the complete analysis of trial ALL-REZ BFM 90,
designed to improve prognosis through an additional chemotherapy
block, R3, which contained high-dose (HD) cytarabine and etoposide
for all strategic groups on the basis of promising effects of epipodo-
phyllotoxins and HD cytarabine, which was reported on earlier for
treatment of childhood relapsed ALL and acute myeloid leukemia
(AML).5,13,14 Additional aims of this study were to confirm established
and to evaluate new prognostic factors on the basis of standardized,
uniform treatment of a large population-based cohort, to provide
intensification of postremission therapy by using SCT for selected
subgroups, and to involve experimental approaches for patients with
poor prognoses. The prognostic impact of randomly administered
HD or intermediate-dose methotrexate (MTX) in this trial was re-
ported earlier.15
PATIENTS AND METHODS
Patients
Between 1990 and 1995, 525 patients younger than 19 years of age with
first relapse of T- or B-cellprecursor ALL were enrolled on trial ALL-REZ
BFM 90 (Table 1), which was conducted in 80 hospitals that recruited all
children with relapsed ALL in Germany, Austria, and selected centers in
Switzerland, the Netherlands, Denmark, and Russia after approval by each
local ethics committee. Informed consent was obtained from guardians and/or
patients according to the Declaration of Helsinki. Almost all patients who had
received first-line treatment as per ALL-BFM and protocols of the Cooperative
Study Group for Childhood Acute Lymphoblastic Leukemia (COALL) and of
the German Democratic Republic (GDR)-ALL study groups were included in
ALL-REZ BFM trials. Immunophenotyping and cytology were performed as
described15,16 and were centrally reviewed. Relapses were defined as very early
(ie, within 18 months after initial diagnosis), early (ie, more than 18 months
from initial diagnosis and less than 6 months after cessation of frontline
therapy), and late (ie, after 6 months of cessation of frontline treatment).
Patients were stratified into group A (ie, early isolated bone marrow [BM],
with 25% blast cells in the BM without extramedullary disease, or combined
BM with 5% blast cells in the BM and extramedullary disease relapses)
group B (ie, late isolated or combined BM relapses), group C (isolated ex-
tramedullary relapses, regardless of time point of relapse), and a poor progno-
sis group (PPG) with very early BM or any relapse of T-lineage ALL.
Treatment
The cytoreductive prephase included prednisone 100 mg/m2/day intra-
venously (IV) for 5 days. Induction and consolidation consisted of nine alter-
nating short courses of intensive polychemotherapy (three each of R1, R2, and
R3; for groups A and B) or a total of six courses (two each of R1, R2, and R3; for
group C; Fig 1). The newly introduced R3 block consisted of dexamethasone,
L-asparaginase, triple intrathecal therapy (IT), HD cytarabine (four rounds of
2 g/m2 IV) and etoposide (three rounds of 150 mg/m2 IV; Table 2). All patients
received maintenance therapy with daily thioguanine 50 mg/m2 orally and
MTX 50 mg/m2 IV every other week for 1 (group C) or 2 (groups A, B) years.
Randomization. Groups A, B, and C were randomly assigned to treat-
ment with either intermediate-dose (1 g/m2/36 hours IV) or HD MTX (5g/
m2/24 hours IV) in each R1 and R2 course, as reported previously.15
CNS-directed regimens. All patients received triple IT (12 mg MTX, 30
mg cytarabine, 10 mg prednisolone) during each course. Children with overt
meningeal leukemia initially received one to three doses of IT until the cere-
2340 2010 by American Society of Clinical Oncology
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Copyright 2010 American Society of Clinical Oncology. All rights reserved.
brospinal fluid was free of leukemic cells and received additional triple IT at the
end of each R2 course. Craniospinal irradiation was recommended for all
patients with CNS involvement, and the recommended spinal dose was 18 Gy,
which was reduced to 15 Gy in children younger than 2 years of age. For
patients with CNS relapse, the recommended cranial dose was 18 Gy, which
was reduced to 15 Gy in case of prior cranial irradiation ( 20 Gy). In children
younger than 2 years of age who were preirradiated ( 8 Gy), dose reduction
was from 18 to 15 Gy. Patients with hematologic relapse received prophylactic
cranial irradiation (12 Gy).17
Testicular-relapse regimens. Any affected testis was subjected to orchi-
ectomy or local radiotherapy (24 Gy). Contralateral, noninvolved testes re-
ceived reduced doses (18 Gy or 15 Gy after biopsy and exclusion of subclinical
leukemic involvement).
PPG regimens. In some centers, treatment was according to regimens A,
B, or C; however, in those participating in ALL-REZ BFM pilot protocols
P91/92, courses were individually designed according to in vitro resistance
profiles. In addition to established antileukemic agents, these tailored-therapy
courses also contained less common drugs, like mitoxantrone, aclarubicin,
hydroxyurea, thiotepa, and cisplatinum. At the end of ALL-REZ BFM 90,
patients in PPG were recruited to protocol P94, piloting the I and S courses for
HR patients of the subsequent trial ALL-REZ BFM 95/96.18,19 I courses con-
sisted of dexamethasone (6 mg/m2 orally, days 1 through 14), thioguanine
(100 mg/m2 orally, days 1 through 14), vincristine (1.5 mg/m2 IV, days 1, 8,
and 15), and idarubicin (10 mg/m2, day 1), and triple IT. S courses included
dexamethasone (6 mg/m2 orally, days 1 through 6), vincristine (1.5 mg/m2 IV,
days 1 and 6), idarubicin (8 mg/m2 IV, days 1 and 2), etoposide (100 mg/m2 IV,
days 3 through 5), thiotepa (30 mg/m2 IV, day 3), L-asparaginase (10.000 U/m2
IV, day 6), and triple IT.
SCT. SCT from HLA-matched family donors (MFDs) was recom-
mended for patients with isolated or combined BM relapse occurring within 4
yearsfrominitialdiagnosisinsecondCRafterthreetofivecoursesofpolychem-
otherapy. For increased-risk patients without MFD or matched unrelated
donors (MUDs), autologous or grafts from HLA-mismatched family (MMF)
or HLA-unrelated donors (UDs) were considered as experimental alterna-
tive sources. The preferred conditioning regimen was total-body irradia-
tion (TBI; 12 Gy) and etoposide (60 mg/kg). Children age 1 to 3 years
received busulfan-containing regimens without TBI. Graft-versus-host
disease (GVHD) prophylaxis included a short course of MTX, cyclospor-
ine A daily, and corticosteroids.
Statistical Analyses
Differences in the distribution of categoric variables among patient
groups were assessed by the 2 test, continuous variables by the Mann-
Whitney U or Kruskal-Wallis tests. Probabilities of EFS (pEFS) or overall
survival (pOS) from the start of salvage therapy until death in remission,
second relapse, or secondary malignant neoplasm (SMN), or until any death,
respectively, were estimated as described.20 Nonresponders to therapy and
deaths during induction were censored at time point zero for calculation of
EFS probabilities. Patients lost to follow-up were censored at the date of last
contact. Subgroups were compared by the two-sided log-rank test. In all tests,
two-sided P values at .05 or higher were regarded as not significant. Multivar-
iate Cox stepwise forward conditional regression analysis and forward Wald
test were performed to determine statistically significant and independent
indicators of outcome.
RESULTS
Total Cohort
Table 3 demonstrates that 440 patients (84%) achieved second
CR, 25 patients (5%) died during induction, and 60 patients (11%)
were nonresponders. Thirty-one patients (6%) died in second CR as a
result of treatment-related adverse effects. Of those patients who
achieved second CR, 246 patients (56%) suffered subsequent relapse,
and six patients (1%) experienced SMN. Including four patients lost
JOURNAL OF CLINICAL ONCOLOGY
 Results of Trial ALL-REZ BFM 90

Table 1. Frequencies of Clinical and Prognostic Parameters of Children With Relapsed ALL Treated According to Trial ALL-REZ BFM 90 by Strategic Groups, of
Patients in PPG by Strategic Groups and Pilot Protocols, and of Patients Treated According to ALL-REZ BFM 85/87 Compared With 90
ALL-REZ BFM 90
Comparison R3
Frequencies Among PPG Frequencies
Subgroups Survival Frequencies Among Subgroups Among Trials
Total No.
Variable of Patients A B C PPG P pEFS SE Log-Rank P A/B C P91/92 P94 P 85/87 90 P
Overall 525 126 183 64 152 0.30 0.02 74 17 39 22 252 373
Sex .001 .774 .076 .243
Male 353 73 114 48 118 0.30 0.02 56 17 27 18 147 235
Female 172 53 69 16 34 0.29 0.03 18 12 4 105 138
Age at relapse, years .001 .001 .346 .950
5 89 28 9 9 43 0.17 0.04 25 1 11 6 33 46
5 to 10 244 61 100 31 52 0.32 0.03 21 7 15 9 130 192
10 192 37 74 24 57 0.33 0.03 28 9 13 7 89 135
Time point of relapse .001 .001 .001 .030
Very early 136 13 123 0.14 0.03 66 7 33 17 10 13
Early 172 126 30 16 0.20 0.03 4 3 5 4 79 156
Late 217 183 21 13 0.47 0.03 4 7 1 1 163 204
Site .001 .001 .001 .436
BM isolated 324 88 135 101 0.23 0.02 57 29 15 145 223
BM combined 117 38 48 31 0.35 0.04 15 1 9 6 69 86
EM isolated 84 64 20 0.50 0.06 2 16 1 1 38 64
EM sites (combined and isolated) .001 .002 .176 .216
CNS 95 26 20 27 22 0.39 0.05 10 6 3 3 66 73
Testes 71 12 20 32 7 0.53 0.06 5 1 1 33 64
Other EM sites 29 5 4 20 0.28 0.08 5 6 6 3 6 9
Combined EM 6 3 1 2 2 2 4
PBCs,/L .001 .001 .001 .624
1 174 29 39 59 47 0.40 0.04 18 16 8 5 77 127
1 to 10,000 278 85 110 1 82 0.25 0.03 45 1 24 12 138 196
10,000 63 11 34 18 0.24 0.05 8 5 5 34 45
No data 10 1 4 5 3 2 3 5
Immunophenotype .001 .001 .001 .004
Pro-B ALL 36 12 12 3 9 0.17 0.06 3 5 1 12 27
Common ALL 303 80 132 43 48 0.33 0.03 32 10 6 206 255
Pre-B ALL 89 31 29 10 19 0.27 0.05 13 3 3 22 70
Pre-T ALL 17 17 0.18 0.09 6 4 6 1
Cortical-T ALL 17 17 0.05 0.06 4 2 6 5
Mature-T ALL 39 39 0.21 0.07 14 11 9 5
Biphenotypic 2 1 1 3 2
No data 22 3 9 7 3 0.61 0.11 1 9 19

NOTE. PPG is excluded in the comparison of trials BFM 85/87 and 90, because there is no PPG in BFM 90.
Abbreviations: ALL, acute lymphoblastic leukemia; ALL-REZ BFM, Acute Lymphoblastic Leukemia Relapse Berlin-Frankfurt-Munster Study Group; PPG, poor
prognostic group; R3, polychemotherapy course 3; pEFS, probability of event-free survival; SE, standard error; BM, bone marrow; EM, extramedullary; PBC,
peripheral blast cells.

Missing values; frequencies and survival probabilities are given but are not included into 2 and log-rank tests.
B-cellprecursor ALL.

to follow-up, 153 (29%) of 521 patients remained in complete contin-
uous remission (CCR) at a median follow-up of 12 years. The pEFS
and pOS and standard deviations at 10 years were 0.30 .02 and
0.36 .02, respectively (Fig 2A).
Groups A, B, and C
Group A consisted of 126 patients; group B, 183 patients; and
group C, 64 patients (Table 1). The majority of patients in each group
(A, 105 [83%] of 126 patients; B, 172 [94%] of 183 patients; and C, all
64 patients) achieved second CR (Table 3). Most SCTs were per-
formed in group A (45 [43%] of 105 patients), followed by B (30
[17%] of 172 patients) and C (three [5%] of 64 patients). The number
of events including nonresponse, treatment-related deaths, and sub-
sequent relapses was considerably higher in A than in B and C. The
pEFS at 10 years was significantly lower in A than in B and C (Fig 2B).
PPG
Table 3 shows that 74 (49%) of 152 patients in PPG were treated
according to regimens A or B. Sixteen patients with isolated, and one
with combined extramedullary T-lineage ALL received regimen C.
Thirty-nine patients (26%) received pilot protocol P91/92, and 22
patients (14%) received P94. For postremission therapy, chemoradio-
therapy was performed in 60 (61%) of 99 patients in second CR,
whereas 39 (39%) of 99 patients received SCT. Twenty-two (22%) of
the 99 patients who achieved second CR also attained CCR. Overall,
pEFS of the PPG and group A were comparable and were lowest

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 Tallen et al

Fig 1. Treatment design of trial Acute

R R R R R R R R R Lymphoblastic Leukemia Relapse Berlin-
A/B 1 2 3 1 2 3 1 2 3
M24 //
Frankfurt-Munster Study Group 90. Strate-
gic groups: A, B, and C. Chemotherapy
R R R R R R courses: R1, R2, and R3. Arrows indicate
C 1 2 3 1 2 3
M12 // time point of craniospinal irradiation for pa-
tients with bone marrow (not CNS) relapse.
M12, maintenance therapy 12 months;
Week 1 5 10 15 20 25 // 70 // 130 M24, maintenance therapy 24 months.

compared with groups B and C (Fig 2B). Most patients in PPG treated Effects of the Additional R3 Block
according to regimens A/B, P91/92, or P94 with very early BM or Tables 1 and 3 list patient and treatment characteristics of trial
T-lineage BM relapses only achieved comparably poor pEFS rates. In ALL-REZ BFM 85/87 (no R3 courses, n 252) and the current study
contrast, those with isolated extramedullary disease allocated to regi- (n 373). For appropriate analysis, patients in PPG have been ex-
men C had a significantly better outcome (Fig 2C). cluded from historical comparison. Although sex, age, site of relapse,
Overall, probability of EFS of the PPG was lower than of and peripheral-blood cell count (PBC) were equally distributed, rela-
groups B and C. Conversely, the EFS rates of the PPG and group A tively more patients with early and fewer with late relapses, pro or
were comparable (p[ 2] .640), the PPG achieved a lower second preB-cellprecursor ALL were registered on ALL-REZ BFM 90. Fur-
CR rate, leading to a significantly lower EFS probability in log-rank thermore, the SCT rates were higher in the current trial. No significant
test (Fig 2B). differences in second CR rates or pEFS could be observed. In trials
85/87, 235 (93%) of 252 patients attained second CR compared with
341 (91%) of 373 in this study. Also, the rates of subsequent relevant
events were not significantly different. The pEFS at 10 years was
comparable between trials ALL-REZ BFM 90 and 85/87 (Fig 2D).
Table 2. Drugs and Dosages of Alternating Polychemotherapy Courses R1
Through R3 According to Protocol ALL-REZ BFM 90
Comparison by strategic subgroups (A, B, C) did not reveal any
significant differences, either (data not shown).
Drug by Course Dose Route Days
R1
SCT
Dexamethasone 20 mg/m2/day PO 1-5
Mercaptopurine 100 mg/m2/day PO 1-5
SCT was given to 117 patients in second CR (Table 3). Sixty-one
Vincristine 1.5 mg/m2/day PO 1, 6 received grafts from MFD, 19 from MUD, and seven from MMF/UD,
Methotrexate 1 g/m/36 hours or 5 g/m/24 hours IV 1 and 30 underwent autologous SCTs. Median time to SCT was 144
Cytarabine 2 2 g/m2/day IV 5 days. The pEFS at 10 years was higher after SCT from MFD (n 61;
L -Asparaginase 25,000 U/m2/day IM 6 pEFS .43 .06) and MUD (n 19; pEFS .42 .11) than after
Prednisolone Age-dependent IT 1 autologous (n 30; pEFS .27 .08) or MMF/UD-SCT (n 7;
Cytarabine Age-dependent IT 1
pEFS .14 .13). Neither comparison of pEFS in patients in second
Methotrexate Age-dependent IT 1
R2
CR after chemoradiotherapy alone, nor comparison of the chemother-
Dexamethasone 20 mg/m2/day PO 1-5 apy group adjusted to median time to transplantation (omitting pa-
Thioguanine 100 mg/m2/day PO 1-5 tients with events within 144 days after relapse diagnosis: n 276;
Vindesine 3 mg/m2/day IV pEFS .41 .03) with the total SCT group (P .585 or .185,
Methotrexate 1 g/m/36 hours or 5 g/m/24 hours IV 1 respectively) or with those patients who received allogeneic HLA-
Daunorubicin 50 mg/m2/day IV 5
compatible grafts (excluding experimental SCT with mismatched or
Ifosfamide 400 mg/m2/day IV 1-5
autologous grafts; P .131 or .989, respectively) revealed any signifi-
L -Asparaginase 25,000 U/m2/day IM 6
Prednisolone Age-dependent IT 1 (5) cant differences. SCT did not improve pEFS for intermediate-risk
Cytarabine Age-dependent IT 1 (5) patients (groups B and C: n 33; pEFS .46 .09) or for those who
Methotrexate Age-dependent IT 1 (5) received allogeneic HLA-compatible grafts (n 25; pEFS .52 .10).
R3 When compared with the chemoradiotherapy group adapted to
Dexamethasone 20 mg/m2/day PO 1-5 time to transplantation (n 199; pEFS .49 .04; P .304 or
Cytarabine 2 2 g/m2/day IV 1, 2
.847, respectively), pEFS was significantly higher after SCT in HR
Etoposide 150 mg/m2/day IV 3-5
L -Asparaginase 25,000 U/m2/day IM 6
patients (groups A and PPG: n 84; pEFS .33 .05; and
Prednisolone Age-dependent IT 5 HLA-compatible allogeneic grafts only: n 53; pEFS .40 .07)
Cytarabine Age-dependent IT 5 than after chemoradiotherapy alone (n 76; pEFS .20 .05;
Methotrexate Age-dependent IT 5 P .005 or .001, respectively).
Abbreviations: ALL-REZ BFM, Acute Lymphoblastic Leukemia Relapse
Berlin-Frankfurt-Munster Study Group; PO, orally; IV, intravenously; IM, intra- Prognostic Factors
muscularly; IT, itrathecally.

As per randomization criteria.
Univariate analysis confirmed site of relapse (P .001), time
In case of CNS involvement. point of relapse (P .001), ALL immunophenotype (P .001), age
at relapse (P .001), PBC (P .001), initial treatment protocol

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 Results of Trial ALL-REZ BFM 90

Table 3. Frequencies of Therapeutic Parameters and Events of Children With Relapsed ALL Treated According to Trial ALL-REZ BFM 90 by Strategic Groups,
of Patients in PPG by Strategic Groups and Pilot Protocols, and of Patients Treated According to ALL-REZ BFM 85/87 Compared With 90
ALL-REZ BFM 90
Comparison R3
Frequencies Among PPG Frequencies Among
Subgroups Survival Frequencies Among Subgroups Trials
Total No.
Variable of Patients A B C PPG P pEFS SE Log-Rank P A/B C P91/92 P94 P 85/87 90 P
First-line protocol .001 .094 .001 .001
ALL-BFM 342 89 103 39 111 0.26 0.02 48 11 37 15 176 231
NHL-BFM 12 4 1 7 0.42 0.14 3 2 2 2 5
COALL 62 14 31 5 12 0.29 0.06 6 2 4 44 50
GDR ALL 28 7 14 1 6 0.43 0.09 3 3 1 22
Western Europe other 33 5 19 4 5 0.36 0.08 3 1 1 22 28
Eastern Europe other 44 9 11 13 11 0.42 0.09 11 2 33
No data/other 4 2 1 1 5 4
First-line cranial irradiation, Gy .003 .008 .171 .001
None 186 38 70 25 53 0.36 0.04 29 4 12 8 69 133
12 190 55 50 15 70 0.23 0.03 27 8 23 12 13 120
18 111 27 47 17 20 0.27 0.04 13 2 3 2 92 91
24 34 4 14 7 9 0.38 0.08 5 3 1 21 25
No data 4 2 2 57 4
Relapse protocol ALL-REZ BFM .001 .001 .001 .033
Group A 196 126 70 0.14 0.03 70 65 126
Group B 187 183 4 0.43 0.04 4 150 183
Group C 81 64 17 0.53 0.06 17 37 64
P91/92 39 39 0.03 0.03 39
P94 22 22 0.18 0.08 22
Postremission therapy .001 .585 .687 .014
Chemoradiotherapy 323 60 142 61 60 0.35 0.03 33 7 11 9 201 263
Total SCT 117 45 30 3 39 0.37 0.05 19 8 7 5 34 78
No second CR achieved 85 21 11 53) 22 2 21 8 17 32
SC source/donor .199 .002 .135 .022
MFD 61 23 21 1 16 0.43 0.06 9 2 3 2 29 45
MUD 19 7 3 9 0.42 0.11 6 1 2 10
MMF/UD 7 5 2 0.14 0.13 1 1 2 5
Autologous 30 10 6 2 12 0.27 0.08 4 5 3 3 18
Event .001 .001 .680
Induction death 25 7 6 12 8 1 3 9 13
NR 60 14 5 41 14 2 20 5 8 19
TRD 31 13 6 3 9 4 4 1 9 22
Subsequent relapse 246 69 85 25 67 39 7 13 8 131 179
SMN 6 2 3 1 1 2 5
Lost to follow up 4 1 3 2 4
CCR 153 21 77 33 22 9 8 1 4 91 131

NOTE. PPG is excluded in the comparison of trials BFM 85/87 and 90, because there is no PPG in BFM 90.
Abbreviations: ALL-REZ BFM, Acute Lymphoblastic Leukemia Relapse Berlin-Frankfurt-Munster Study Group; PPG, poor prognosis group; R3, polychemotherapy
course 3; pEFS, probability of event-free survival; SE, standard error; NHL-BFM, Non-Hodgkins Lymphoma Study Group; COALL, Cooperative ALL Study Group;
GDR ALL, German Democratic Republic Study Group; SCT, stem-cell transplantation; CR, complete remission; SC, stem-cell; MFD, matched family donor; MUD,
matched unrelated donor; MMF, mismatched family donor; UD, unrelated donor; NR, nonresponse; TRD, treatment-related death; SMN, secondary malignant
neoplasm; CCR, continuous complete remission.

Missing values; frequencies and survival probabilities are given but are not included into 2 or log-rank tests.

(P .001), and SCT in HR patients (group A, PPG) to have significant
impact on pEFS (Table 1). In multivariate Cox regression analysis,
time point (risk ratio for subsequent event at late, early, and very early
time point of relapse, 1, 2.4, and 2.9, respectively; P .001) and site of
relapse (risk ratio for subsequent event at isolated extramedullary v
combined and isolated bone marrow site of relapse, 1, 1.7, and 2.3,
respectively; P .001), immunophenotype (risk ratio for B-cell
precursor v T-lineage ALL, 1 v 1.9; P .001), and SCT as time-
dependent covariate (risk ratio for subsequent event after SCT v
chemoradiotherapy alone, 1 v 1.8; P .001) proved to be independent
predictors of EFS (Wald 2 for total model, 207.5; P .001). The
parameters of sex, PBC at relapse diagnosis, age, first-line treatment
protocol, and cranial irradiation dose at first-line treatment did not
significantly improve the model.
Thirty-nine of 84 patients with isolated extramedullary dis-
ease also had isolated testicular relapse, and 35 of 84 patients had
isolated CNS relapse. Among the latter, no clinical risk factor was
prognostically significant in univariate analyses (Table 4). For 39
patients who had isolated testicular relapse, age at relapse and time
point of relapse revealed significantly different pEFS in univariate

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 Tallen et al

A 1.0 B 1.0

0.8 0.8
Survival (probability)

Survival (probability)
C: N = 64; cens. = 36; pEFS = .54 .06
0.6 0.6

N = 525; cens. = 187; pOS = .36 .02

0.4 0.4
B: N = 183; cens. = 78; pEFS = .43 .04

A: N = 126; cens. = 21; pEFS = .17 .03

N = 525; cens. = 157; pEFS = .30 .02
0.2 0.2

PPG: N = 152; cens. = 22; pEFS = .15 .03

0 5 10 15 20 0 5 10 15 20

Time (years) Time (years)

C 1.0 D 1.0

0.8 0.8
Survival (probability)

Survival (probability)
0.6 0.6
C: N = 17; cens. = 8; pEFS = .47 .12

85/87: N = 252; cens. = 92; pEFS = .37 .03

0.4 0.4

90: N = 373; cens. = 135; pEFS = .36 .03

P94: N = 22; cens. = 4; pEFS = .18 .08
0.2 0.2
A/B: N = 74; cens. = 9; pEFS = .12 .04

P91/92: N = 39; cens. = 1; pEFS = .03 .03

0 5 10 15 20 0 5 10 15 20

Time (years) Time (years)

Fig 2. (A) Event-free and overall survival probabilities (pEFS and pOS, respectively) at 10 years for children with first relapse of acute lymphoblastic leukemia (ALL)
treated according to ALL-REZ BFM 90. (B) pEFS at 10 years by strategic groups A, B, and C and poor prognosis group (PPG) within protocol ALL-REZ BFM 90 (log-rank
P, total group, .001; P, groups A and B, .001; P, groups B and C, .327; P, group A and PPG, .001). (C) pEFS of patients in PPG by treatment strategies A,
B, and C or pilot protocols P91/92 and P94. (D) pEFS of patients treated according to ALL-REZ BFM 90 v 85/87 (PPG excluded) to assess the prognostic impact of the
R3 course. Vertical bar indicates censored (cens) observations.

analysis, whereas only time point of relapse showed independent
prognostic significance in multivariate analysis (P .019; com-
pared with patients who had late relapses as a reference parameter,
the risk ratio for adverse events was 20.5 in children with very early
relapse and was 16.2 in patients with early relapse).
DISCUSSION
We report the results of the prospective multicenter trial ALL-REZ
BFM 90 for treatment of childhood relapsed ALL in Germany, Aus-
tria, and selected centers in Switzerland, the Netherlands, Denmark,
and Russia. The data revealed that more than one third of this large,
population-based cohort can be considered cured by a mainly
chemoradiotherapy-based regimen. Since 1983, the ALL-REZ BFM
Study Group performed consecutive investigator-driven, prospective,
controlled trials with curative approach for pediatric patients with
relapsed ALL, most of whom had received well-described, largely
homogenous, intensive, first-line therapies according to ALL-BFM
and COALL protocols.10,21 Initial intensive treatment according to
ALL-REZ BFM protocols was based on alternating short-course in-
tensive polychemotherapy (R courses) to overcome resistance.22 R
courses initially formed the basis for the BFM-HR courses for patients
with HR features at initial diagnosis,10 and these are now widely
adapted internationally.
A major aim of this study was to improve outcome through a
third intensive chemotherapy course (R3) containing HD cytarabine
and etoposide. Other differences between the previous and current
trial that harbor a potentially manipulative impact on historical com-
parison were the omission of the induction course F for group A in
trial 87 (prednisone 100 mg/m2 IV, days 1 through 7 and days 15

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 Results of Trial ALL-REZ BFM 90

binations without convincing results.13,26-29 Hence, agents providing

Table 4. Frequencies, EFS Probabilities, and Univariate P Values in Patients
With Isolated CNS or Testicular Relapse by ClinicalRisk Parameters more targeted mechanisms of antileukemic action, such as monoclo-
Patient Data by Relapse Site
nal antibodies, proteasome, and kinase inhibitors, are currently being
tested as a potential treatment option.30
CNS Testicular
In this study, MUD-SCT was individually considered for exper-
Variable No. % pEFS SE P No. % pEFS SE P imental postremission treatment for HR patients (group A and PPG).
Total 35 100 39 100 The finding that second CR rates and pEFS were significantly higher
Sex .29
after allogeneic SCT than after chemoradiotherapy alone in HR, but
Male 22 63 0.36 0.10 39 100
Female 13 37 0.56 0.15
not in intermediate-risk patients (groups B and C), confirms previous
Age at .32 .05 reports.31-34 For patients without suitable unrelated donors, autolo-
relapse, gous SCT was considered as experimental postremission treatment in
years
5 6 17 0.33 0.19 4 10 0.25 0.22
both HR patients and in patients with isolated extramedullary ALL
5 to 10 15 43 0.58 0.13 21 54 0.46 0.11 relapse in this trial. Although autologous SCT did not provide any
10 14 40 0.31 0.13 14 36 0.79 0.11 advantage over allogeneic SCT or chemoradiotherapy alone in retro-
Time point of .39 .01 spective analyses of patients with BM relapse,35-38 it was efficient in
relapse
Very early 12 34 0.33 0.14 9 23 0.33 0.16
patients with extramedullary disease.39,40
Early 19 54 0.47 0.12 14 36 0.29 0.12 Among patients with isolated CNS relapse, no significant prog-
Late 4 11 0.50 0.25 16 41 0.93 0.06 nostic factor could be determined. This observation might be due to
Lineage .11 .14 the small cohort and must be re-evaluated in a larger group by merg-
BCP 26 79 0.44 0.10 29 83 0.55 0.09 ing the data of several trials or by performing international meta-
T-cell 7 21 0.29 0.17 6 17 0.33 0.19
analyses. Among patients with isolated testicular relapse, those with
No data 2 6 None 4 10 None
late relapses have a remarkably good prognosis, which has been ad-
Abbreviations: EFS, event-free survival; pEFS, probability of EFS; BCP,
B-cell precursor. dressed in future trials by stratifying patients with this risk profile to a
standard-risk group receiving less-intense treatment.
Time point, site of relapse, ALL immunophenotype, and SCT as
time-dependent covariate proved to be independently associated with
through 21; vincristine 1.5 mg/m2 IV, days 1, 8, 15, and 22; MTX 1 EFS in this trial. These data confirm previous reports.9,11,12,41,42 How-
g/m2/36 hours IV, day 1; cytarabine, two courses of 3 g/m2 IV, days 15 ever, although these established prognostic factors provided the basis
and 16; and L-asparaginase 10,000 U/m2 IV, days 3, 4, 17, and 18)5; a for defining strategic groups A, B, and C and PPG, risk-adapted and
total of nine instead of eight R courses in groups A and B; and six intensified treatment for HR patients did not result in improved
instead of four R courses in group C. Also, some minor changes outcome. Another important consequence of this study is, in accor-
(modification of R1 by substituting prednisone with dexamethasone dance with previous reports, the establishment of a novel stratification
and cytarabine/teniposide with higher cumulative doses of cytara- system. Use of the significant parameters disclosed in the Cox regres-
bine) were made. Overall, ALL-REZ BFM 90 involved higher cumu- sion analysis made it possible to create four prognostically different
lative doses of cytarabine and etoposide, lower cumulative doses of strategy groups, S1 through S4,1 which were applied to all patients in
daunorubicin, and lower numbers of HD or medium-to-high doses of all subsequent ALL-REZ BFM trials to individually adjust treatment
MTX courses. The historical comparison did not reveal a significantly intensity.23-25 Because diverse chemotherapy regimens failed to
better outcome of either the total cohort (PPG excluded) or any of the achieve acceptable EFS in patients in PPG, allogeneic SCT has been
subgroups A, B, or C in this trial. The validity of this comparison is
recommended as a treatment option for these patients in subsequent
limited by several factors. Historical comparisons may be generally
and ongoing trials.
biased because of varying experience of the different centers. Also, a
In intermediate-risk patients, second CR rates and EFS
different distribution of prognostic factors may affect outcome. Nev-
greater than 40% were achieved in this trial. However, to addition-
ertheless, on the basis of the results presented here, the ALL-REZ BFM
ally improve prognosis, special risk factors must be evaluated to
Study Group decided not to maintain the R3 but to keep the modified
R1 course in subsequent trials.23-25 identify those patients with high risk of subsequent relapse who are
Analyses of trials ALL-REZ-BFM 85/874,5 revealed that patients thus eligible for SCT. Potential prognostic and biologically impor-
in PPG treated with conventional chemoradiotherapy had a low tant parameters, such as BCR/ABL and TEL-AML1 fusion tran-
chance of cure. Excluded from the regular study population, but scripts,43,44 may be considered for future stratification. Also, the
treated according to experimental approaches18,19 in ALL-REZ BFM dynamics of treatment response assessed by minimal residual dis-
90, the high rates of nonresponders and subsequent relapses among ease quantification is a promising prognostic tool being validated
PPG patients treated according to P91/92 or P94 suggest that those in ongoing trials.45,46
tailored therapies were not efficient for this HR group. However,
patients with late extramedullary relapse of T-lineage ALL treated as
per the C regimen revealed better results. Therefore, these patients AUTHORS DISCLOSURES OF POTENTIAL CONFLICTS
were no longer regarded as a very high risk group in subsequent trials. OF INTEREST
Many attempts to improve prognosis of patients in PPG have been
reported by different groups by using new substances and drug com- The author(s) indicated no potential conflicts of interest.

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Copyright 2010 American Society of Clinical Oncology. All rights reserved.
 Tallen et al

Collection and assembly of data: Gesche Tallen, Ruediger Fengler,

AUTHOR CONTRIBUTIONS
Conception and design: Martin Schrappe, Thomas Klingebiel, Ruediger
Fengler, Gunter Henze, Arend von Stackelberg
Administrative support: Richard Ratei, Georg Mann, Gertjan Kaspers,
Felix Niggli, Alexandr Karachunsky, Wolfram Ebell, Gabriele Escherich,
Martin Schrappe, Thomas Klingebiel, Ruediger Fengler, Gunter Henze,
Arend von Stackelberg
Provision of study materials or patients: Richard Ratei, Georg Mann,
Gertjan Kaspers, Felix Niggli, Alexandr Karachunsky, Wolfram Ebell,
Gabriele Escherich, Martin Schrappe, Thomas Klingebiel, Ruediger
Fengler, Gunter Henze, Arend von Stackelberg
Gunter Henze, Arend von Stackelberg
Data analysis and interpretation: Gesche Tallen, Richard Ratei, Georg
Mann, Gertjan Kaspers, Felix Niggli, Alexandr Karachunsky, Wolfram
Ebell, Gabriele Escherich, Martin Schrappe, Thomas Klingebiel, Ruediger
Fengler, Gunter Henze, Arend von Stackelberg
Manuscript writing: Gesche Tallen, Gunter Henze,
Arend von Stackelberg
Final approval of manuscript: Gesche Tallen, Richard Ratei, Georg
Mann, Gertjan Kaspers, Felix Niggli, Alexandr Karachunsky, Wolfram
Ebell, Gabriele Escherich, Martin Schrappe, Thomas Klingebiel, Ruediger
Fengler, Gunter Henze, Arend von Stackelberg

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