research paper

Long-term outcome of initially homogenously treated

and relapsed childhood acute lymphoblastic leukaemia in
Austria – A population-based report of the Austrian
Berlin-Frankfurt-Münster (BFM) Study Group

Bettina Reismüller,1 Andishe Summary

Attarbaschi,1 Christina Peters,1 Michael
N. Dworzak,1,2 Ulrike Pötschger,2 Relapsed acute lymphoblastic leukaemia (ALL) is the most common cause for
Christian Urban,3 Franz-Martin Fink,4 a fatal outcome in paediatric oncology. Although initial ALL cure rates have
Bernhard Meister,4 Klaus Schmitt,5 Karin improved up to 80%, the prognosis of recurrent ALL remains dismal with
Dieckmann,6 Günter Henze,7 Oskar A. event-free-survival (EFS) rates about 35%. In order to analyse a population-
Haas,1 Helmut Gadner1,2 and Georg based cohort with uniform treatment of initial disease, we examined the
Mann1 on behalf of the Austrian Berlin- outcome of children suffering from relapsed ALL in Austria for the past
Frankfurt-Münster (BFM) Study Group 20 years and the validity of the currently used prognostic factors (e.g. time to
1
Department of Paediatric Haematology and and site of relapse, immunophenotype). Furthermore, we compared survival
Oncology, St Anna Children’s Hospital, Vienna,
rates after chemotherapy alone with those after allogeneic stem cell
Austria, 2Children’s Cancer Research Institute
transplantation (SCT). All 896 patients who suffered from ALL in Austria
(CCRI), St Anna Children’s Hospital, Vienna,
between 1981 and 1999 were registered in a prospectively designed database
Austria, 3Division of Paediatric Haematology and
Oncology, Department of Paediatric and
and treated according to trials ALL-Berlin-Frankfurt-Münster (BFM)-Austria
Adolescent Medicine, Medical University of Graz, (A) 81, ALL-A 84 and ALL-BFM-A 86, 90 and 95. Of these, 203 (23%)
Graz, Austria, 4Department of Paediatrics, suffered from recurrent disease. One-hundred-and-seventy-two patients
Innsbruck Medical University, Innsbruck, Austria, (85%) achieved second complete remission. The probability of 10-year EFS
5
Department of Paediatrics, Landeskinderklinik for the total group was 34 ± 3%. Clinical prognostic markers that
Linz, Linz, Austria, 6Department of Radiotherapy, independently influenced survival were time to relapse, site of relapse and
Medical University of Vienna, Vienna, Austria, the immunophenotype. Additionally, a Cox regression model demonstrated
and 7Department of Paediatric Oncology/ that allogeneic SCT after first relapse was associated with a superior EFS
Haematology, University of Berlin (Charité compared with chemo/radiotherapy only (hazard ratio = 0Æ254; P = 0Æ0017).
Universitätsmedizin Berlin), Berlin, Germany
Keywords: acute lymphoblastic leukaemia, relapse, risk factors, stem cell
transplantation, chemotherapy.
Received 17 July 2008; accepted for publication
18 September 2008
Correspondence: Georg Mann, MD,
Department of Paediatric Haematology and
Oncology, St. Anna Children’s Hospital,
Kinderspitalgasse 6, A-1090 Vienna, Austria.
E-mail: georg.mann@stanna.at

About 20% of children and adolescents with acute lympho- over, death after ALL relapse is the most common cause for a
blastic leukaemia (ALL) suffer from recurrent disease. In fact, fatal outcome in paediatric oncology and improving the results
relapsed ALL as an entity itself is a frequent malignancy for relapsed ALL therefore would be a major step towards
diagnosed in childhood (0Æ93 cases per year per 100 000 raising the overall survival (OS) rates in paediatric cancer.
children <15 years old), being even more common than solid In children with primary ALL, international multi-centre
tumours, such as neuroblastoma, rhabdomyosarcoma or trials using constantly improved and standardised treatment
osteosarcoma (Young et al, 1986; Gaynon et al, 1998). More- protocols have led to first remission rates above 95% and

ª 2008 The Authors First published online 10 December 2008

Journal Compilation ª 2008 Blackwell Publishing Ltd, British Journal of Haematology, 144, 559–570 doi:10.1111/j.1365-2141.2008.07499.x
B. Reismüller et al

10-year event-free survival (EFS) rates exceeding 80% (Schr- leukaemic blast cells. CNS involvement was also diagnosed if a
appe et al, 2000). However, the outcome of relapsed ALL is leukaemic mass was found on cranial computed tomography
comparably worse, with long-term survival rates around 30– or magnetic resonance imaging. Testicular relapse was diag-
35% (Gaynon et al, 1998; Chessells et al, 2003; Einsiedel et al, nosed in case of uni- or bilateral painless enlargement of the
2005). testicles. Relapse at any other site was established by biopsy
In the present study, the outcome of a population-based and histological or cytomorphological confirmation of leukae-
cohort of initially uniformly pretreated children suffering from mic blast cells. The diagnosis of combined BM relapse was
relapsed ALL in Austria within the last twenty years will be made if any extramedullary site was involved and ‡5% blast
reported. Patients were treated for initial disease according to cells were found in the BM. Complete remission (CR) was
the contemporarily used ALL-BFM (Berlin-Frankfurt-Mün- characterised by a non-aplastic BM with <5% blasts, absence of
ster) protocols and registered at a national study centre. The blasts in peripheral blood and no evidence of any extra-
particular aims of the study were to reflect the epidemiology of medullary leukaemic disease spread. Testicular remission was
recurrent ALL in Austria and to assess the validity of currently either achieved at the time of orchidectomy or if the size of the
used prognostic factors. Furthermore, we compared survival involved testicle had returned to normal.
rates following chemotherapy alone with those after allogeneic
stem cell transplantation (SCT).
Immunophenotypic and genetic analyses
Immunological marker studies were performed at the time of
Patients and methods
diagnosis of the disease and leukaemic cases were classified as
pro-B ALL, common ALL, pre-B ALL and T-cell ALL
Patients
according to the immunological classification of acute leukae-
Between April 1981 and July 1999, 896 children in Austria were mias as proposed by the European Group for the Immuno-
diagnosed with ALL and received front-line treatment accord- logical Characterization of Leukaemias (Bene et al, 1995).
ing to the protocols ALL-BFM-Austria (A) 81 (n = 141), ALL- Conventional metaphase cytogenetics have successfully been
A 84 (n = 127), ALL-BFM-A 86 (n = 142), ALL-BFM-A 90 performed in 100 of the 118 patients who received front-line
(n = 256) and ALL-BFM-A 95 (n = 230) (Gadner et al, 1985; treatment from 1986 onwards (ALL-BFM-A 86, 90, 95; no data
Attarbaschi et al, 2002). Two-hundred-and-three/896 (23%) for 18 patients because of lack of BM samples). In addition,
patients suffered from relapse of a B-cell precursor [BCP, fluorescence in situ hybridisation (FISH) and polymerase chain
n = 152/203 (75%)] and T-cell ALL [n = 28/203 (14%)] reaction (PCR)-based investigations were available from 1986
before February 2006 [for 23 patients (11%) no immunophe- onwards. Conventional and molecular genetic analyses were
notypic data were available]. All relapsed cases were reviewed performed according to standard procedures and described in
by the national study centre in Vienna and patients were detail elsewhere (Attarbaschi et al, 2007).
treated according to the respective protocols after informed
consent was obtained from the patients, patient’s parents or
Relapse treatment
legal guardians. Studies were conducted in accordance with the
declaration of Helsinki and approval was delivered by the For treatment of relapsed ALL, 126/203 patients (62%) were
relevant ethic committees. Patient’s characteristics for all 203 enrolled into contemporary and regular ALL-REZ BFM
patients are shown in Table I. studies (ALL-REZ BFM 87, n = 25; ALL-REZ BFM 90,
n = 46; ALL-REZ BFM 95/96, n = 46; ALL-REZ BFM 2002,
n = 9). Six/203 (3%) cases received palliative treatment for
Definition and diagnosis of relapse
first relapse, and 71/203 (35%) patients received other
Relapse within 18 months from diagnosis of ALL was defined intensive therapy because of relapse in an era before the
as a very early relapse. Relapse after 18 months from initial availability of standardised relapse studies or because of the
diagnosis and up to 6 months after cessation of front-line choice of the local treatment centre. The composition of this
treatment was classified as an early relapse. Relapse occurring miscellaneous intensive therapy was based on an individual
later than 6 months after cessation of front-line therapy was decision of the treating physician and mainly consisted of
defined as a late relapse. Furthermore, recurrent disease was elements which were already used in first-line therapy,
classified according to the involved site as isolated bone however, including few chemotherapeutic intensifications
marrow (BM) relapse, isolated extramedullary relapse (central (data not shown).
nervous system [CNS], testicles, and other sites) and combined Chemotherapy according to the ALL-REZ BFM protocols
BM and extramedullary relapse. Isolated BM relapse was started with a prephase of prednisone or dexamethasone
defined by ‡25% blast cells within the BM and no manifes- followed by alternating multi-drug chemotherapy courses (R1
tation of recurrent leukaemia at any other site. The diagnosis and R2). Regimens ALL-REZ BFM 87, 95/96 and 2002 also
of CNS relapse required more than five leucocytes per ll comprised additional induction protocols (F, F1, F2). Treat-
cerebrospinal fluid (CSF) and the unequivocal presence of ment outlines of studies ALL-REZ BFM 87, 90, and 95/96 are

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560 Journal Compilation ª 2008 Blackwell Publishing Ltd, British Journal of Haematology, 144, 559–570
 Long-term Outcome of ALL Relapse in Austria

Table I. Patients characteristics and survival of the different prognostic subgroups with ALL relapse.

No. of patients (%) 10-year EFS (%) P-value 10-year OS (%) P-value

Total group 203 (100) 34 ± 3 – 37 ± 4 –

Sex
Male 124 (61) 34 ± 4 NS 37 ± 5 NS
Female 79 (39) 32 ± 5 36 ± 5
Time of relapse
Very early 84 (41) 23 ± 5 25 ± 5
Early 44 (22) 23 ± 6 <0Æ001 26 ± 7 <0Æ001
Late 75 (37) 52 ± 6 57 ± 6
Age at relapse
<1 year 5 (2) 20 ± 19 20 ± 19
‡1 and <10 years 127 (63) 35 ± 4 NS 40 ± 4 NS
‡10 years 71 (35) 32 ± 6 32 ± 6
Site of relapse
Isolated BM 127 (63) 28 ± 4 30 ± 4
Combined BM 32 (16) 33 ± 9 0Æ03 30 ± 9 0Æ0017
Isolated extramedullary 44 (22) 50 ± 8 60 ± 8
CNS 27 (13) (48 ± 10) 53 ± 10
Testicular 14 (7) (50 ± 13) 64 ± 13
Mediastinal 0 (0) – –
Other 3 (1) – –
Immunophenotype*
B-cell precursor ALL 150 (74) 37 ± 4 40 ± 4
Pro-B 15 (7) (27 ± 11) (33 ± 12)
Common 104 (51) (37 ± 5) 0Æ0022 (39 ± 5) 0Æ0009
Pre-B 31 (16) (42 ± 9) (45 ± 9)
T-cell ALL 28 (14) 21 ± 8 21 ± 8
No data 23 (11) 30 ± 10 39 ± 10
Peripheral blast cell count at relapse
<0Æ001 · 109/l 57 (28) 38 ± 7 44 ± 7
‡0Æ001 and <10 · 109/l 92 (45%) 40 ± 5 0Æ002 43 ± 5 0Æ0034
‡10 · 109/l 20 (10) 24 ± 10 23 ± 10
No data 34 (17) 15 ± 6 18 ± 7
Front-line treatment
ALL-BFM A 81 45 (22) 22 ± 6 29 ± 7
ALL-A 84 40 (20) 23 ± 7 25 ± 7
ALL-BFM A 86 23 (11) 35 ± 10 0Æ039 39 ± 10 0Æ0758
ALL-BFM A 90 55 (27) 45 ± 7 49 ± 7
ALL-BFM A 95 40 (20) 43 ± 8 43 ± 8
Initial risk group
Standard risk 81 (40) 35 ± 5 40 ± 6
Intermediate risk 70 (34) 38 ± 6 0Æ0047 42 ± 6 0Æ012
High risk 52 (26) 25 ± 6 26 ± 6
Treatment of relapse
Palliative therapy 6 (3%) 17 ± 15 17 ± 15
BFM relapse study 126 (62%) 43 ± 5 47 ± 5
ALL-REZ BFM 87 + 90 71 (35) (34 ± 6) <0Æ001 41 ± 6 <0Æ001
ALL-REZ BFM 95/96 + 02 55 (28) (58 ± 7) 59 ± 7
Other intensive therapy 71 (35) 18 ± 5 22 ± 5
Cytogenetics
Diploid 37/100 (37) 38 ± 6 48 ± 11
Pseudodiploid 30/100 (30) 46 ± 9 36 ± 11
Hypodiploid 6/100 (6) 33 ± 19 NS 33 ± 27 NS
Hyperdiploid (47–50 chromosomes) 9/100 (9) 56 ± 17 40 ± 15
Hyperdiploid (>50 chromosomes) 18/100 (18) 58 ± 12 20 ± 12

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B. Reismüller et al

Table I. (Continued).

No. of patients (%) 10-year EFS (%) P-value 10-year OS (%) P-value

Fusion genes
ETV6/RUNX1 16/118 (13Æ5) 67 ± 12 73 ± 12
BCR/ABL1 10/118 (8Æ5) 30 ± 14 50 ± 16
TCF3/PBX1 4/118 (3Æ5) 40 ± 22 0Æ004 40 ± 22 0Æ005
MLL/AFF1 5/118 (4) 60 ± 22 60 ± 22
MLL/MLLT1 3/118 (2Æ5) 33 ± 27 33 ± 27

A, Austria; ALL, acute lymphoblastic leukaemia; BFM, Berlin-Frankfurt-Münster; BM, bone marrow; CNS, central nervous system; EFS, event-free
survival; NS, not significant. OS, overall survival.
*Two/203 patients had an acute undifferentiated leukaemia and died of the disease.

Fig 1. Design of studies ALL-REZ BFM 87, 90 and 95/96. A, B, C, S1-S4, treatment stratification groups; BM, bone marrow; EM, extramedullary; P,
cyto-reductive prophase with prednisolone (PRED, 100 mg/m2; ALL-REZ BFM 87, 90, 95/96) or dexamethsone (DEXA, 6 mg/m2; ALL-REZ BFM
2002); F1, induction protocol including DEXA/vincristine (VCR) methotrexate (MTX)/L-asparaginase (ASP); F2, induction protocol including
DEXA/VCR/cytarabine (ARA-C)/ASP; I, induction protocol including DEXA/6-thioguanine (6-TG)/VCR/idarubicin (IDA); R1, treatment course
including DEXA/6-mercaptopurine (6-MP)/VCR/MTX/ARA-C/ASP; R2, treatment course including DEXA/6-TG/vindesine (VDS) MTX/dauno-
rubicin (DNR)/ifosfamide (IFO)/ASP; R3, treatment course including DEXA/ARA-C/teniposide (VM-26)/ASP (only in ALL-REZ BFM 87 and 90); S,
treatment course including DEXA/VCR/IDA/VP-16/THIOTEPA/ASP; SCT, stem cell transplantation; G, doses of G-CSF (G?, randomised); D12/24,
duration therapy for 12 or 24 months, including oral 6-TG and i.v. MTX (in ALL-REZ BFM 95/96); all treatment protocols include at least one
intrathecal dose of MTX/ARA-C/PRED.

shown in Fig 1. As the study ALL-REZ BFM 2002 is an

Central nervous system-directed therapy
ongoing randomised trial, treatment design cannot be shown
here. Patients were stratified to treatment groups according to All chemotherapeutic blocks contained intrathecal therapy.
site of relapse, duration of first remission and immunophe- Prophylactic CNS-directed therapy in trial ALL-REZ BFM 87
notype (Fig 1). primarily consisted of intrathecal methotrexate (MTX) only.

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562 Journal Compilation ª 2008 Blackwell Publishing Ltd, British Journal of Haematology, 144, 559–570
 Long-term Outcome of ALL Relapse in Austria

During the course of the study, a significant increase in subsequent third relapse. Twenty-eight/172 children (16%)
subsequent CNS relapses was found in patients with first died in second CR. The probability of 10-year EFS (pEFS) for
isolated BM relapse of the ongoing and preceding ALL-REZ the total group was 34 ± 3% and the probability of 10-year OS
BFM 85 study. Thus, prophylactic cranial irradiation was (pOS) was 37 ± 4% (Fig 2A). Survival of the different
introduced from 1989 onwards for all cases with an isolated prognostic subgroups is listed in Table I.
BM relapse. If the CNS was involved at the time of relapse,
patients received more intense intrathecal triple chemotherapy
Time to relapse and site of relapse (Tables I and II)
with MTX, cytarabine and prednisone. In addition, cranial or
cranio-spinal radiation was delivered in an age-dependent Time to relapse was very early in 84 patients (41%), early in 44
manner to all patients (Einsiedel et al, 2005). patients (22%) and late in 75 patients (37%). Ten-year pEFS
In trials ALL-REZ BFM 90, 95/96 and 02, intrathecal for very early relapse was 23 ± 5%, for early relapse 23 ± 6%,
triple chemotherapy was included in therapy courses F1, F2, and for late relapse 52 ± 6% (P < 0Æ001; Fig 2B). Isolated BM
R1, R2, and R3 for all patients. Patients with a BM relapse relapse was diagnosed in 127 (63%), isolated CNS relapse in 27
without CNS involvement received cranial irradiation with (13%) and isolated testicular relapse in 14 children (7%). One
12 Gy. If the CNS was involved, the cranial irradiation dose patient suffered from an isolated relapse of the ovary and
was augmented to 18 Gy. Children with CNS relapse, who another one from an isolated relapse in the peripheral lymph
already had received cranial irradiation with more than nodes (each 0Æ5%). In one patient, the site of extramedullary
18 Gy in previous therapy, underwent radiation with only relapse was the femur (0Æ5%). Combined relapse of the BM
15 Gy. and an extramedullary site occurred in 32 patients (16%). In
19/32 children (60%) combined BM and CNS relapse
occurred. Twelve/32 patients (38%) suffered from combined
Treatment of testicular relapse
BM and testicular relapse and one patient (3%) from
Orchidectomy was the treatment of choice for the involved combined relapse of the BM and bones of the lower extremities
testicle. In unilateral testicular disease the clinically affected on both sides. Ten-year pEFS for isolated BM relapse,
testis was removed and the remaining testis irradiated (15– combined BM and extramedullary relapse and isolated extra-
18 Gy according to the results of biopsy). In case of clinical medullary relapse was 28 ± 4%, 33 ± 9%, and 50 ± 8%,
unilateral or bilateral testicular involvement and no resection respectively (P = 0Æ03; Fig 2C).
24 Gy local irradiation was recommended.
Immunophenotype
Statistical methods
The immunophenotypic profile of the leukaemic cells was
Overall survival (OS) was calculated as the interval between available for 180 patients (no data for 23 patients). One-
diagnosis of first relapse and death from any cause. EFS was hundred-and-fifty children had a B-cell precursor ALL (pro-B
defined as the time between diagnosis of first relapse and the ALL, n = 15; common ALL, n = 104; pre-B ALL, n = 31) 28
day of the first adverse event (further relapse, secondary children suffered from a T-cell ALL and in two children
malignancy, death from any cause). Survival probabilities were leukaemia was classified as acute undifferentiated leukaemia.
analysed by the method of Kaplan and Meier (1958). Outcome Ten-year pEFS was 37 ± 4% in B-cell precursor ALL, 21 ± 8%
of different subgroups was compared by the log-rank test. in T-cell ALL and for the patients with no data available pEFS
Multivariate risk factor analysis was performed according to was 30 ± 10% (P = 0Æ0022; Fig 2D). Within the group of B-
the Cox regression model. To calculate the influence of cell precursor ALL, 10-year pEFS for pro-B ALL was 27 ± 11%,
allogeneic stem cell transplantation (SCT) on prognosis, we for common ALL 37 ± 5% and for pre-B ALL 42 ± 9%.
included allogeneic SCT in a Cox regression model to adjust
for time to transplant and known prognostic factors (Klein
Multivariate risk factor analysis
et al, 2001). P values < 0Æ05 were considered significant.
The Cox regression analysis revealed time to relapse, site of
relapse, immunophenotype and treatment of relapse to be
Results
factors that significantly influenced EFS and OS (Table III).
EFS was shorter in very early and early relapse than in late
Complete remission and survival
relapse [hazard ratio (HR)=4Æ53; P < 0Æ0001 and HR = 2Æ24;
Out of the 203 patients with recurrent ALL, 172 (85%) P = 0Æ0128, respectively). Patients with BM involvement at
achieved second CR. Thirty-one/203 (15%) children never relapse had an inferior EFS when compared with patients with
achieved second CR. Seventy/172 patients (41%) still are isolated extramedullary relapse (HR = 2Æ82; P = 0Æ0109 for
surviving in second continuous CR with a median duration of isolated BM relapse and HR = 2Æ40; P = 0Æ0410 for combined
8Æ8 years (range from 0Æ8 to 18Æ9 years). Seventy-four/172 BM and extramedullary relapse, respectively). The immuno-
(43%) patients suffered a second relapse, and 17/74 (23%) a phenotype also significantly influenced prognosis (HR = 2Æ61;

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B. Reismüller et al

(A) 1 (B) 1
Censored
0·9 0·9
Very early relapse: n = 84 (41%): 23 ± 5%
0·8 0·8
Event-free survival

Early relapse: n = 44 (22%): 23 ± 6%

Event-free survival
Censored
0·7 Total group of relapsed ALL: n = 203: 34 ± 3% 0·7 Late relapse: n = 75 (37%): 52 ± 6%
0·6 0·6
0·5 0·5
0·4 0·4
0·3 0·3
0·2 0·2
0·1 0·1
0 0
0 5 10 15 20 0 5 10 15 20
Years after diagnosis Years after diagnosis
(C) (D)
1 Censored 1 Censored
0·9 Isolated BM relapse: n = 127 (63%): 28 ± 4% 0·9 Relapsed B-cell precursor ALL:
0·8 Combined BM relapse: n = 32 (16%): 33 ± 9% 0·8 n = 150 (74%): 37 ± 4%

Event-free survival
Event-free survival

Relapsed T-cell ALL: n = 28 (14%): 21 ± 8%

0·7 Isolated extramedullary relapse: 0·7
n = 44 (22%): 50 ± 8% Relapsed ALL with no phenotypic data:
0·6 0·6 n = 23 (11%): 30 ± 10%
0·5 0·5
0·4 0·4
0·3 0·3
0·2 0·2
0·1 0·1
0 0
0 5 10 15 20 0 5 10 15 20
Years after diagnosis Years after diagnosis

Fig 2. (A), 10-year probability of event-free survival (pEFS) of the total group of 203 patients with ALL relapse; (B), pEFS according to time of
relapse; (C), pEFS according to site of relapse; (D), pEFS according to immunophenotype.

Table II. Probability of 10-year event-free and

No. of overall survival according to time and site of
patients EFS P- OS P- relapse of the 203 patients with ALL relapse.
(%) (%) value (%) value

Isolated marrow relapse n = 127

Very early 55 (43) 20 ± 5 20 ± 5
Early 21 (17) 10 ± 6 <0Æ001 10 ± 6 <0Æ001
Late 51 (40) 44 ± 7 50 ± 7
Combined marrow relapse n = 32
Very early (5: CNS, 2: testis, 1: other) 8 (25) 13 ± 12 13 ± 12
Early (7: CNS, 2: testis) 9 (28) 11 ± 10 0Æ0016 22 ± 14 <0Æ001
Late (7: CNS, 8: testis) 15 (47) 57 ± 13 57 ± 14
Isolated extramedullary n = 44
Very early (18: CNS, 3: testis) 21 (48) 33 ± 10 43 ± 11
Early (7: CNS, 6: testis, 1: other) 14 (32) 50 ± 13 0Æ0144 63 ± 13 0Æ019
Late (2: CNS, 5: testis, 2: other) 9 (20) 89 ± 10 100

EFS, event free survival; OS, overall survival; CNS, central nervous system.

P = 0Æ0047 for patients with T-cell ALL versus non-T-cell

Genetic characteristics
ALL). EFS in patients who received palliative therapy and other
intensive therapy than ALL-REZ BFM protocols was poorer A normal karyotype was found in 37/100 patients for whom
than therapy with regular ALL-REZ BFM protocols cytogenetic results were available. The 10-year pEFS in this
(HR = 11Æ64; P = 0Æ0003 and HR = 2Æ049; P = 0Æ0257, respec- group was 36 ± 8%. A pseudodiploid karyotype was seen in
tively). 30/100 (pEFS 46 ± 9%), a hypodiploid in 6/100 (pEFS

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564 Journal Compilation ª 2008 Blackwell Publishing Ltd, British Journal of Haematology, 144, 559–570
 Long-term Outcome of ALL Relapse in Austria

Table III. Multivariate risk factor analysis according to the Cox Front-line treatment
regression model.
The 10-year pEFS was analysed according to treatment of first
95% Hazard occurrence of ALL. In children who were initially treated in
Hazard ratio confidence trial ALL-BFM-A 81 (n = 45) 10-year pEFS was 22 ± 6%, in
ratio limits P-value
trial ALL-A 84 (n = 40) 23 ± 7%, in trial ALL-BFM-A 86
Time to relapse versus late (n = 23) 35 ± 10%, in trial ALL-BFM-A 90 (n = 55) 45 ± 7%
Early 4Æ530 2Æ527–8Æ123 <0Æ0001 and in trial ALL-BFM-A 95 (n = 40) 10-year pEFS was
Very early 2Æ241 1Æ187–4Æ229 0Æ0128 43 ± 8% (P = 0Æ039). Patients who were initially treated in
Site of relapse versus isolated extramedullary trials ALL-BFM-A 81 and ALL-BFM 84 (pEFS 22 ± 5%) had a
Isolated BM 2Æ819 1Æ270–6Æ259 0Æ0109 worse outcome than those included in trials ALL-BFM-A 86,
Combined BM 2Æ408 1Æ037–5Æ593 0Æ0410 90 and 95 (pEFS 42 ± 5%; P = 0Æ0052).
Immunophenotype versus BCP
T-cell 2Æ613 1Æ342–5Æ090 0Æ0047
Treatment of relapse versus ALL-REZ BFM Treatment of relapse
Palliative 11Æ639 3Æ095–43Æ764 0Æ0003
All six/203 (3%) patients who received palliative treatment
Other 2Æ049 1Æ091–3Æ849 0Æ0257
subsequently died. All of them suffered from a very early
ALL, acute lymphoblastic leukaemia; BFM, Berlin-Frankfurt-Münster; isolated BM relapse. The median survival time was 2 months
BM, bone marrow; BCP, B-cell precursor ALL. (range from 0 to 3Æ6 month).
Seventy-one/203 (35%) patients received no study treatment
33 ± 19%), a low hyperdiploid (47–50 chromosomes) in 9/100 but other intense relapse treatment. The time to relapse was
(pEFS 56 ± 17%), and a high hyperdiploid karyotype (>50 very early in 47/71 (66%), early in 15/71 (21%) and late in
chromosomes) in 18/100 children (pEFS 58 ± 12%). nine/71 (13%) patients. The site of relapse was isolated BM in
In all cases with a t(12;21)/ETV6-RUNX1, t(9;22)/BCR- 42/71 (59%), isolated extramedullary in 23/71 (32%) (CNS,
ABL1, t(1;19)/TCF3-PBX1, t(4;11)/MLL-AFF1 or t(11;19)/ n = 14; testicles, n = 9), and combined BM in six/71 (9%)
MLL-MLLT1 a respective clone recurred at relapse. The children (CNS, n = 4; testicles, n = 1; bones, n = 1). Thirty-
incidence of cases with ETV6-RUNX1 was 13Æ5% (n = 16/ two/71 (45%) patients suffered from second relapse. Twenty-
118), with BCR-ABL1 8Æ5% (n = 10/118), and with TCF3- nine of these 32 patients and 26 other patients died [in total
PBX1 3Æ5% (n = 4/118) (Table IV). MLL-involving rearrange- 55/71 (77%)]. Thirteen/71 (18%) children still are in second
ments [MLL-AFF1, n = 5/118 (4%) and MLL-MLLT1 n = 3/ CR and three children are in third CR. Ten-year pEFS in
118 (2Æ5%)] were present in 8/118 cases (7%). The 10-year patients who received no standardised study treatment but
pEFS for the four groups was 67 ± 12%, 30 ± 14%, 40 ± 22% other intense relapse treatment was 18 ± 5%.
and 38 ± 17%, respectively. In patients with ETV6-RUNX1 + The number of patients who received treatment according to
ALL, relapse occurred rather later (median 4Æ4 years, range 1Æ5 ALL-REZ BFM studies was 126/203 (62%). Fifty-seven/126
to 10Æ1 years) than in other groups (TCF3-PBX1 + : median (45%) patients are surviving in second continuous CR. Forty-
0Æ4 years, range 0Æ2 to 2Æ4 years; BCR-ABL1 + : median two/126 (33%) and nine/42 (21%) children suffered from a
1Æ3 years, range 0Æ5 to 7Æ2 years). In particular, patients with second and third relapse, respectively, and overall, 64/126
MLL-rearrangements most often presented with a very early (51%) patients died. Probability of 10-year EFS was 43 ± 5%
relapse (median 0Æ8 years, range 0Æ5 to 3Æ1 years). for the total group of patients treated in ALL-REZ BFM

Table IV. Characteristics of 38 patients with

ALL relapse according to their molecular-genetic ETV6/RUNX1 BCR/ABL1 TCF3/PBX1 MLL
results. (n = 16/118) (n = 10/118) (n = 4/118) (n = 8/118)

Time of relapse
Very early 1 4 3 6
Early 4 3 1 1
Late 11 3 0 1
Median (years) 4Æ4 1Æ3 0Æ4 0Æ8
Range (years) 1Æ5–10Æ1 0Æ5–7Æ2 0Æ2–2Æ4 0Æ5–3Æ1
Site of relapse
Isolated BM 9 6 3 7
Combined BM 4 1 1 0
Isolated Extramedullary 3 3 0 1

Total number of patients with molecular-genetic data available n = 118; MLL, includes all
patients with MLL/MLLT1+ or MLL/AFF1+ ALL.
BM, bone marrow.

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Journal Compilation ª 2008 Blackwell Publishing Ltd, British Journal of Haematology, 144, 559–570 565
B. Reismüller et al

studies. Outcome differed according to the different ALL-REZ n = 1; mother, n = 2), one from a mismatched unrelated
BFM studies, as shown in Table I. donor, and eight children underwent autologous SCT. The
conditioning regimen consisted of total body irradiation (TBI)
in combination with VP-16 in 29/62 patients and TBI together
Causes of death
with VP-16 and cyclophosphamide in 17/62 patients. Nine/62
One-hundred-and-twenty-five/203 (61Æ5%) children died patients received a conditioning regimen without TBI and in
before February 2006, including 50 (40%) who underwent six/62 the conditioning procedure did not follow any protocol.
SCT and 75 (60%) who were treated with chemotherapy alone. One out of the 62 patients received a reduced-intensity
After SCT, 19/50 children (38%) died from the underlying conditioning regimen.
disease (persistent leukaemia or relapse), 25/50 (50%) from an Ten-year pEFS for patients who received SCT in second CR
infection, four/50 (8%) from other therapy-related complica- was 55 ± 7% as compared with 33 ± 5% for patients who
tions (haemolytic anaemia, coma hepaticum, cardiovascular received chemotherapy only (P = 0Æ005). If only patients with
failure, n = 1; bleeding, n = 1; multi organ failure, n = 1; an isolated BM relapse are included in the analysis, 10-year
encephalopathy, n = 1), and in two/50 patients (4%) cause of pEFS after SCT in second CR was 55 ± 8% as compared with
death was unknown. 22 ± 6% after chemotherapy only (P < 0Æ001). For patients
Following chemotherapy alone, 53/75 patients (71%) died with a combined BM, 10-year pEFS was 39 ± 15% after SCT in
from the underlying disease (persistent leukaemia or relapse), second CR and 31 ± 12% after chemotherapy only (P = not
20/75 (27%) from an infection, one/75 (1%) from a therapy- significant). When outcome of patients who received SCT in an
related complication (cardiomyopathy, pericardial effusion), earlier era (before 1995) was compared with SCT in a more
and one/75 (1%) from a bleeding event. recent period (from 1995 until 2005), no differences were found
(56 ± 10% vs. 53 ± 9%, respectively; P = not significant).
In a Cox regression analysis, allogeneic SCT was included as
Second and further relapse
a time-dependent covariate to regulate biases for waiting time
A second relapse occurred in 74/203 children (36%). The site to transplant and prognostic factors (patients who did not
of second relapse was isolated BM in 54/74 patients (73%). reach second CR as well as patients who received SCT previous
Nine of the 74 patients (12%) suffered from combined second to second CR were excluded from analysis). Thereby, it was
relapse of the BM and an extramedullary site (CNS, n = 7; found that allogeneic SCT significantly influenced prognosis.
testicles, n = 1; mediastinum, n = 1) and 11/74 patients (15%) The risk to experience a following adverse event (further
suffered from isolated extramedullary second relapse (CNS, relapse, death, secondary malignancy) after first relapse was
n = 5; testicles, n = 5; kidney/para-aortal lymph nodes, lower after SCT (HR = 0Æ245; P = 0Æ0017). Results were
n = 1). Fifty/74 patients (68%) died after second relapse, 17/ similar if only cases with relapse including the BM were taken
74 patients (23%) suffered from third relapse, and 7/74 (9%) into account (HR = 0Æ237; P = 0Æ0011). For combined BM
are still in third CR. In patients who had a second relapse, the relapse only, SCT reduced the risk of further adverse events
median duration of second CR was 13 months. The longest even more (HR = 0Æ078; P = 0Æ0137).
second CR duration preceding second relapse was 4Æ4 years.
Ten-year EFS for the total group of patients with a second
Discussion
relapse was 9 ± 3%.
Out of the 17 patients who suffered from third relapse, the This population-based retrospective study, comprising 896
site of third relapse was isolated BM in 12 patients, isolated children with newly diagnosed ALL, analysed the outcome of
CNS in three patients and combined BM and CNS relapse in 203 patients (23%) suffering from a first recurrence. With the
two patients. All patients except one died. Ten-year EFS within relapse therapy reported herein and used in Austria over the
the total group with a third relapse was 6 ± 6%. Further fourth last 20 years, the vast number of patients (85%) included in
and fifth relapse occurred in four and two patients before our analysis achieved second CR. Nevertheless, only 34%
death, respectively. maintained long-term (10-year) EFS. The influence of clinical
features at the time of relapse diagnosis on prognosis has been
repeatedly described (Gaynon et al, 1998; Arico et al, 2000;
Stem cell transplantation
Buchanan et al, 2000; Lawson et al, 2000; Chessells et al,
Out of 203 patients treated for relapse, a total of 62 patients 2003). With regard to our study population, the Cox
underwent SCT in second CR. Thirty-one received SCT at regression model revealed the time to relapse, the site of
another time or disease status (1st CR, n = 6; 3rd CR, n = 10; relapse and the immunophenotype to be consistent factors that
1st relapse, n = 13; 2nd relapse, n = 1; 5th relapse, n = 1). Out independently influenced both EFS and OS. Furthermore,
of the 62 patients who were transplanted in second CR, 25 regular ALL-REZ BFM therapy protocols compared with
received a graft from a human leucocyte antigen (HLA)- intensive therapy other than ALL-REZ BFM protocols, which
matched sibling donor, 25 from an HLA-matched unrelated were given because of relapse in the time period before the
donor, three from a haploidentical related donor (father, availability of BFM-relapse studies or because of the choice of

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566 Journal Compilation ª 2008 Blackwell Publishing Ltd, British Journal of Haematology, 144, 559–570
 Long-term Outcome of ALL Relapse in Austria

the local treatment centre (mainly due to initial treatment in maintained long-term remission. Five out of the six survivors
the high risk group), was significantly associated with suffered from a very early relapse and one from a late relapse.
improved survival. The influence of sex and age at relapse on The site of relapse was isolated BM in 3/6 and isolated CNS in
outcome was statistically not significant. 3/6 children. It is noteworthy that four of these six survivors
Intriguingly, 10-year EFS was similar for very early and early underwent a SCT after first relapse (in total, nine/28 patients
relapses, at around 23%. The comparable outcome for very with T-cell ALL received a SCT after first relapse), suggesting
early and early relapses is in contrast to the results of other that SCT may be an important curative option in relapsed
groups, who found differing survival rates for the two T-cell ALL.
subgroups. Studies performed by the Children’s Cancer Study In our analysis, prognosis for children with a peripheral
Group (CCG) usually discriminated between early (0– blast cell (PBC) count <0Æ001 · 109/l and a PBC count 0Æ001–
17 months from diagnosis), intermediate (18–35 months from 10 · 109/l at the time of relapse was significantly better than in
diagnosis) and late relapses (‡36 months from diagnosis). children with PBC ‡10 · 109/l. The lacking superior outcome
Although this classification system is slightly different, it may for children with a PBC count <0Æ001 · 109/l (n = 57) as
be compared with the classification scheme used in the ALL- compared to those with a PBC count 0Æ001–10 · 109/l
REZ BFM studies. Gaynon et al (1998), found that outcome (n = 92) may be explained by a high percentage of very early
was significantly better for intermediate than for early relapses. relapses in the group with no blast cells [very early, n = 27/57
Moreover, Roy et al (2005), on behalf of the British Study (47%); early, n = 15/57 (26%); late n = 15/57 (26%)].
Group that used the regular BFM classification system for time Accordingly, we observed a high percentage of late relapses
to relapse, demonstrated that the 5-year pEFS was 16% for very in the group with a PBC count 0Æ001–10 · 109/l [very early,
early and 29% for early relapses (P < 0Æ0001). These n = 23/92 (25%); early, n = 23/92 (25%); late, n = 46/92
discrepancies to our results may be explained by the fact that (50%)]. A further possible explanation may be that children
patients who had been treated with front-line ALL-BFM with a very early relapse who are still on front-line therapy are
protocols usually received therapy up to a total treatment more intensively observed and blood counts are measured
duration of 24 months, so that disease recurrence at 18– regularly. Therefore, their relapse is detected in an earlier phase
24 months after diagnosis still occurred during therapy. ALL- than in children off therapy when relapse is not noticed until
REZ BFM protocols were created at a time when initial distinct symptoms become apparent.
treatment was given for 18 months, and therefore the time The traditional prognostic markers used for risk assessment
point for discriminating very early from early relapse was in ALL relapse have been recently complemented by new
defined to be 18 months after primary diagnosis. Thus, it prognostic factors such as genetic rearrangements. Fusion
might be not that surprising that the prognosis in our genes, including the ETV6/RUNX1, BCR/ABL1, and MLL-
population was not different between very early and early rearrangements as well as high hyperdiploid karyotypes are
relapses. In addition, when calculating the 10-year EFS for reported to have am impact on prognosis in primary disease
patients studied herein who relapsed within (23 ± 4%) and (Heerema et al, 1994; Borkhardt et al, 1997; Harrison &
after 24 months (44 ± 5%) from initial diagnosis, the results Foroni, 2002; Loh & Rubnitz, 2002; Pui et al, 2002; Yeoh et al,
were significantly different (P < 0Æ001). 2002; Attarbaschi et al, 2004). We confirmed that ETV6/
Isolated CNS relapse was diagnosed in 27/203 (13%) RUNX1 was a good prognostic factor at the time of relapse
children. Eleven/27 patients (41%) experienced a second with a 10-year pEFS of 67 ± 12%. This is in line with other
relapse following isolated CNS relapse, and the BM was studies reporting EFS rates exceeding 60% for this group of
included in 6 of these (54%). Other authors also reported a ALL relapse (Seeger et al, 1998, 2001). Although the number of
high percentage of secondary relapse after isolated CNS relapse patients with other fusions genes was rather small, some
(Behrendt et al, 1989). It is notable that all the six patients who conclusions may be drawn. In our study, patients carrying a
suffered from a subsequent relapse that included the BM, died. BCR/ABL1 fusion gene and MLL-rearrangements had surpris-
Thus, this observation underlines the importance of intensive ing 10-year EFS rates of 30 ± 14% and 38 ± 17%, respectively,
systemic therapy for apparently isolated leukaemia. Fourteen/ which were in the range of the overall group of ALL relapses.
203 (7%) patients suffered from an isolated testicular relapse However, whereas children with TCF3/PBX1+ ALL are
with nine/14 children in continuous second CR. Five/14 reported to have a good prognosis at initial disease, outcome
patients died, including all patients with a very early isolated after relapse was relatively poor (10-year pEFS 25 ± 22%),
testicular relapse (n = 3/14). On the other hand, all patients which might be due to adverse prognostic markers, such as
with a late isolated testicular relapse (n = 5/14) are alive, very early and isolated BM relapses in three of four patients.
demonstrating that the time to relapse is an important marker It is generally thought that more intense front-line therapy
for this subgroup. enhances relapse-free survival but on the other hand reduces
A T-cell immunophenotype is a well-known predictor of an EFS rates for those patients who relapse. In our analysis,
unfavourable outcome in relapsed ALL, as it has been survival after relapse constantly increased during the last
demonstrated in other reports (Henze et al, 1991). It was 20 years, while front-line therapy also concomitantly improved
present in 28/203 patients (14%) and only six of them dramatically. This observation may indicate that refinement of

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Journal Compilation ª 2008 Blackwell Publishing Ltd, British Journal of Haematology, 144, 559–570 567
B. Reismüller et al

relapse stratification and treatment also improved during the In summary, we have shown that the traditionally known
past decades. Concerning relapse treatment, children who were clinical prognostic markers are still important, although we
treated for their relapse with ALL-REZ BFM protocols had a questioned the often reported difference between very early and
notably better prognosis than patients who received other early relapses and between isolated and combined BM relapses
intensive treatment. with respect to a possible differential benefit of SCT in these
A central question in relapsed childhood ALL is the value of groups. Moreover, our data strongly suggest that children in
SCT in relapse therapy. While some authors emphasised the second remission may profit from SCT. However, the outcome
importance and need of a matched SCT by a related or of relapsed childhood ALL is still unsatisfactory and is even
unrelated donor, especially for high-risk relapsed ALL patients worse in children who suffer from second or further relapse.
(Dopfer et al, 1991; Barrett et al, 1994; Uderzo et al, 1995; New treatment strategies, such as targeted therapies (i.e., BCR-
Torres et al, 1999; Borgmann et al, 2003; Gaynon et al, 2006), ABL tyrosine kinase inhibitors, like imatinib, dasatinib or
others found similar results after SCT and after chemotherapy/ rituximab, an anti-CD20 antibody, for B-cell precursor ALL) or
radiotherapy alone (Wheeler et al, 1998; Harrison et al, 2000; innovative agents (i.e., aplidin or clofarabine) (Erba et al, 2003;
Chessells et al, 2003). In our analysis, patients who received Zwaan et al, 2003; deVries et al, 2004; Jeha et al, 2006), need to
SCT in second CR did significantly better than patients given be investigated to keep patients after first relapse in continuous
chemotherapy only (10-year pEFS 55 ± 7% vs. 33 ± 5%, remission and thus improve long-term survival.
P = 0Æ005). This was even more obvious following an isolated
BM relapse (10-year pEFS 55 ± 8% for SCT in second CR vs.
Participating centres and investigators
22 ± 6% for chemotherapy only, P < 0Æ001).
Because of practical reasons, no randomised studies com- Krankenhaus (KH) Dornbirn: B. Ausserer; Landeskrankenhaus
paring SCT and chemotherapy in relapsed ALL are yet (LKH) Feldkirch: U. Busch, G. Müller; Universitäts-Kinderkli-
available. Therefore, some uncertainty remains with respect nik Graz: R. Kurz, Ch. Urban; Universitäts-Kinderklinik
to the value of stratifying criteria. Different approaches Innsbruck: H. Berger, F-M. Fink, B. Meister; LKH Klagenfurt:
concerning the retrospective comparison of SCT and chemo- W. Kaulfersch, H. Messner; LKH Leoben: I. Mutz; Allgemeines
therapy/radiotherapy are reported, for example case–control öffentliches KH der Barmherzigen Schwestern Linz: O.
studies performed by matched pair analysis (Barrett et al, Stöllinger; Landeskinderklinik Linz: W. Tulzer, K. Schmidt,
1994; Borgmann et al, 2003). As already described by the T. Ebetsberger; LKH Salzburg: H. Grienberger, N. and R.
Gruppo Italiano Trapianto Di Midollo Osseo (GITMO) and Jones, J. Rücker; Kardinal Schwarzenberg’sches KH Schwar-
the Associazione Italiana di Ematologia e Oncologia Pediatrica zach: H. Haas; LKH Steyr: R. Ploier; St. Anna Kinderspital
(AIEOP), we included allogeneic SCT as a time-dependent Wien: H. Gadner, E. R. Grümayer-Panzer, P. Krepler, G.
covariate in a Cox regression model to adjust for waiting time Mann; Universitäts-Kinderklinik Wien: E. Pichler, O. Jürgen-
bias and to consider prognostic factors that were demonstrated ssen, I. Slavc; Universitätskinderklinik für Blutgruppenserolo-
to influence outcome (Uderzo et al, 1995; Lawson et al, 2000; gie und Transfusionsmedizin Wein: P. Höcker.
Klein et al, 2001). We found that the use of SCT significantly
improved prognosis. When the total group (excluding patients
Immunophenotyping
who did not reach second CR and patients who received SCT
previous to second CR) was considered, EFS after SCT was Institute of Immunology, Centre for Physiology, Pathophy-
superior to EFS following chemotherapy/radiotherapy alone, siology and Immunology, Medical University of Vienna,
with a four times lower risk to experience a subsequent adverse Austria: W. Knapp, W. F. Pickl.
event. Analogous results were obtained for all patients with a
relapse involving the BM and for patients with combined BM
Cytogenetic analyses
relapse only. Notably, the benefit of SCT in the group with very
early and early combined BM relapse was not statistically Children’s Cancer Research Institute, St. Anna Children’s
significant (possibly because of a low number of patients). Hospital, Vienna, Austria: O. A. Haas.
Additionally, we observed that no patient who underwent
SCT in second remission survived further BM relapse. Six
Molecular-genetic analyses
patients received a SCT in first CR. The four of them with
BM relapse died but both patients with an isolated Children’s Cancer Research Institute, St. Anna Children’s
extramedullary relapse survived. Treatment was chemother- Hospital, Vienna, Austria: Th. Lion.
apy/radiotherapy only in both of them. Seventeen patients
experienced a further second relapse after SCT in first relapse
Radiotherapy
or in second CR; none of them survived. Moreover, both
children who relapsed a third time after SCT in third CR Department of Radiation Oncology, Medical University of
died, leading to the conclusion that children who suffer from Vienna, Austria: K. H. Kärcher, R. Hawlicek, R. Pötter and
BM relapse following a SCT cannot be cured at the moment. K. Dieckmann.

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568 Journal Compilation ª 2008 Blackwell Publishing Ltd, British Journal of Haematology, 144, 559–570
 Long-term Outcome of ALL Relapse in Austria

Acknowledgements Alternating drug pairs with or without periodic reinduction in

children with acute lymphoblastic leukemia in second bone marrow
We are indebted to J. Regelsberger, MSc, N. Mühlegger, remission: Pediatric Oncology Group study. Cancer, 88, 1166–1174.
MSc, and D. Janousek, MSc, for documentation and data Chessells, J.M., Veys, P., Kempsiki, H., Henley, P., Leiper, A., Webb, D.
management. & Hann, I.M. (2003) Long-term follow-up of relapsed childhood
acute lymphoblastic leukemia. British Journal of Haematology, 123,
396–405.
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ª 2008 The Authors

570 Journal Compilation ª 2008 Blackwell Publishing Ltd, British Journal of Haematology, 144, 559–570