ORIGINAL ARTICLE

Outcome of Children and Adolescents With a Second or

Third Relapse of Acute Lymphoblastic Leukemia (ALL):
A Population-based Analysis of the Austrian ALL-BFM
(Berlin-Frankfurt-Munster) Study Group
Bettina Reismuller, MD,* Christina Peters, MD,* Michael N. Dworzak, MD,*w
Ulrike Potschger, MSc,w Christian Urban, MD,z Bernhard Meister, MD,y Klaus Schmitt, MD,8
Karin Dieckmann, MD,z Helmut Gadner, MD,*w Andishe Attarbaschi, MD,* and Georg Mann,
MD,* on behalf of the Austrian ALL-BFM (Berlin-Frankfurt-Munster) Study Group

Summary: We analyzed outcome of a population-based cohort of

74 children with second and third acute lymphoblastic leukemia
(ALL) relapse and aimed to identify prognostic factors. Duration
of previous remission and site of relapse appeared of prognostic
relevance as patients with a second remission duration >1.5 years
and isolated extramedullary relapse did better. Neither patient with
a second bone marrow relapse who underwent previous allogeneic
transplantation nor patients with T-cell ALL survived. Overall, 7 of
74 (9%) patients are in long-term remission. Stem cell transplantation seemed to be the only curative option for systemic
relapse of B-cell precursor ALL as all 4 surviving patients with a
second/third relapse involving the bone marrow received a transplant. Conclusively, patients with a second ALL relapse are ideal
candidates for phase I/II trials exploring new innovative drugs.
Key Words: relapsed acute lymphoblastic leukemia, outcome, stem
cell transplantation

(J Pediatr Hematol Oncol 2013;35:e200e204)

uring the last 3 decades outcome of children with acute

lymphoblastic leukemia (ALL) has substantially
improved by using standardized risk-adapted protocols
ending up with cure rates of 85% to 90%.1 Nevertheless,
relapse still is the most common cause of treatment failure
in this disease with long-term remission rates of only 40%
to 50%.25 Several study groups have repeatedly shown
that by using prognostic criteria such as rst remission
duration, site and immunophenotype of relapse, genetic
alterations, and initial response to relapse therapy, distinct
subgroups of relapsed ALL can be identied that may
Received for publication November 20, 2012; accepted March 2, 2013.
From the *Pediatric Hematology and Oncology, Department of
Pediatrics, St Anna Childrens Hospital, Medical University of
Vienna; wChildrens Cancer Research Institute (CCRI), St. Anna
Kinderkrebsforschung; zDepartment of Radiotherapy, Medical
University of Vienna, Vienna; zDepartment of Pediatric and
Adolescent Medicine, Division of Pediatric Hematology and
Oncology, Medical University of Graz, Graz; yDepartment of
Pediatrics, University of Innsbruck, Innsbruck; and 8Department
of Pediatrics, Landeskinderklinik Linz, Linz, Austria.
A.A. and G.M. contributed equally.
The authors declare no conict of interest.
Reprints: Andishe Attarbaschi, MD, Pediatric Hematology and
Oncology, Department of Pediatrics, St Anna Childrens Hospital,
Medical University of Vienna, Kinderspitalgasse 6, 1090 Vienna,
Austria (e-mail: andishe.attarbaschi@stanna.at).
Copyright r 2013 by Lippincott Williams & Wilkins

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either be treated with chemoradiotherapy only or by additional allogeneic stem cell transplantation (SCT).314
About 50% of relapsed ALL patients do not respond
to salvage therapy or suer a second relapse with no
standardized treatment concepts existing for them so
far.3,4,1012,15 Prognosis is extremely poor with survival
rates below 10%; however, comprehensive data on this
particular cohort of patients are scarce, probably as a
negative reporting bias. Herein, we review the characteristics, management, and outcome of children and adolescents with a second or further ALL relapse diagnosed in
Austria within the last 30 years and retrieved from a population-based cohort of initially uniformly treated patients.
Moreover, we aimed to identify prognostic factors for
potential cure and future treatment approaches.

PATIENTS AND METHODS

Between 1981 and 1999, 896 children diagnosed with
ALL in Austria received rst-line ALL-BFM treatment.16
A total of 203/896 (23%) patients had a rst relapse before
February 2006.11 A total of 126/203 (62%) were enrolled
into contemporary ALL-REZ BFM trials, 6/203 (3%)
received no treatment, and 71/203 (35%) patients received
other intensive therapy due to relapse in a period before
standardized relapse studies or due to the choice of the local
treatment center.11 Of note, almost all children with primary and relapsed ALL diagnosed in Austria are usually
transferred to specialized pediatric institutions only,
thereby giving us the unique opportunity to analyse population-based and reliable data sets representative for
children with ALL relapse.17
A total of 74/203 (36%) and 18/74 (24%) patients had
a second and third relapse, respectively, before September
1, 2012. All cases were reviewed by the National Study
Centre in Vienna and treated according to the respective
protocols with informed consent from the patients,
patients parents or legal guardians.11 Studies were conducted in accordance with the declaration of Helsinki and
approval was delivered by the ethic committees. Denition
of relapse according to the site of involvement and time
point has been described in detail previously.11 Event-free
survival (EFS) rates were estimated with Kaplan-Meier
curves. Statistical analysis was done with log-rank tests and
Cox regression. To adjust for waiting time to transplant in
the evaluation of SCT in third complete remission (CR),
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Cox regression with time-dependant covariates and landmark analysis was performed.

Outcome of Second and Third ALL Relapse

TABLE 1. Characteristics of the 74 Patients With Second and 18

Patients With Third Relapse of ALL

RESULTS
Characteristics for the 74 patients with second and 18
patients with third relapse are shown in Table 1 and their
course of disease in Figure 1. Median duration of second
CR for the 74 patients was 7.5 months (range, 18 d to 4.4 y).
Treatment for second relapse followed a curative intention
according to ALL-REZ BFM protocols in 38 (51%) and
other individually designed therapy regimens in 16 (22%)
of the 74 children. Fifteen/74 (20%) patients received palliation and for 5 (7%) patients detailed data on their treatment
was not available. Treatment for third relapse followed ALLREZ BFM therapy components in 4/18 (22%) patients, 5/18
(28%) received other intensive treatment, 7/18 (39%) were
treated with a palliative intention, and there were no data
available for 2/18 (11%) patients. Fourteen/74 (19%) children with a second relapse underwent previous SCT (4 in rst
CR and 10 in second CR). After second relapse, SCT was
given to 19/74 (26%) patients (10 in third CR, 7 in second
relapse, 1 in third relapse, and 1 in fth relapse). Neither of
the patients transplanted without CR except for the one in
third relapse survived.
In total, 67/74 (91%) children died, 39 (58%) from
secondary disease itself, 11 (16%) from second-line therapy-related complications, and 17 (25%) after third relapse.
Seventeen/18 (94%) patients with a third relapse died, 13
(76%) from the disease and 4 (24%) from therapy-related
events. Accordingly, 7/74 (9%) patients with a second
relapse are in continuous complete remission (CCR)
including one after a third relapse. Treatment included SCT
in 4 [all with bone marrow (BM) relapse] and chemoradiotherapy only in 3 (all with isolated extramedullary
relapse) patients. With a median follow-up time for surviving patients of 11.6 years (range, 7.4 to 22.2 y) and 16.6
years, respectively, 10-year probabilities of EFS (pEFS)
were 9% 3% and 6% 6% after second and third
relapse, respectively (Fig. 2).
Concerning prognostic factors (Table 2), duration of
second CR seemed to have an inuence on EFS
(P = 0.008). In 50/74 (68%) patients, duration of second
CR was <1.5 years with 3/50 (6%) in CCR. In contrast,
duration of second CR was >1.5 years for 19/74 (26%)
children with 4/19 (21%) in CCR. In 5/74 (6%) patients,
the exact date of second CR was not available. The only
other prognostic factors that proved to be statistically signicant were site of rst and second relapse with isolated
extramedullary relapses faring better than isolated and
combined BM relapses (P = 0.020; 0.034) and duration of
rst CR (P = 0.045). Multivariable analysis revealed rst
CR duration and site of second relapse to maintain their
signicance (P = 0.016; 0.045) and a trend to signicance
for second CR duration (P = 0.078). Outcome of patients
who did or did not undergo SCT in third CR/second
relapse were compared adjusting for waiting time to SCT
and did not show an EFS advantage for SCT over
chemotherapy.

DISCUSSION
Because of the fact that almost 100% of all pediatric
patients diagnosed with ALL in Austria are initially uniformly treated and reported to and followed up by the
ALL-BFM study centre in Vienna, incidence rates, clinical
r

2013 Lippincott Williams & Wilkins

No. patients
Sex
Male
Female
Immunophenotype
B cell
T cell
Not available
Age at rst relapse
1-10 y
Z10 y
Genetics
Available
TEL-AML1
MLL-ENL
TCF3-PBX1
BCR-ABL1
High hyperdiploid
Hypodiploid
Other
Not available
Site of rst relapse
Isolated BM
Combined BM
Isolated extramedullary
Time of rst relapse (mo)
< 18
18-30
Z30
Therapy for rst relapse
ALL-REZ BFM
Other therapy
Palliation
Not available
Stem cell transplantation
Before second/third relapse
First CR
Second CR
Third CR
Site of second/third relapse
Isolated BM
Combined BM
CNS
Testicle(s)
Other
Isolated extramedullary
CNS
Testicle(s)
Other
Time of second/third relapse
< 18 mo
Z18 mo
Not available
Therapy for second/third relapse
ALL-REZ BFM
Other therapy
Palliation
Not available
Third/fourth CR achieved by reinduction
chemotherapy
Stem cell transplantation
Third/fourth CR
Second/third relapse

Second
Relapse

Third
Relapse

74

18

47 (64%)
27 (36%)

14 (78%)
4 (22%)

57 (77%)
7 (9%)
10 (14%)

14 (78%)
2 (11%)
2 (11%)

49 (66%)
25 (34%)

12 (67%)
6 (33%)

33 (45%)
3
1
1
3
6
2
17
41 (55%)

6 (33%)
1
0
0
1
0
0
4
12 (67%)

43 (58%)
14 (19%)
17 (23%)

8 (44%)
4 (22%)
6 (33%)

32 (43%)
20 (27%)
22 (30%)

6 (33%)
5 (28%)
7 (39%)

42 (57%)
32 (43%)
0
0

10 (56%)
8 (44%)
0
0

14 (19%)
4
10
/

5 (28%)
1
2
2

54 (73%)
9 (12%)
7
1
1
11 (15%)
5
5
1

13 (72%)
2 (11%)
2
0
0
3 (17%)
3
0
0

50 (68%)
19 (26%)
5 (6%)

15 (83%)
3 (17%)
0

38
16
15
5
30

(51%)
(22%)
(20%)
(7%)
(41%)

10 (14%)
7 (9%)

4
5
7
2
6

(22%)
(28%)
(39%)
(11%)
(33%)

0
1 (6%)

ALL indicates acute lymphoblastic leukemia; BM, bone marrow; CNS,

central nervous system; CR, complete remission.

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primary ALL: n=896

1st relapse: n=203

death: n=44 (100%)

incl. 2 after 3rd relapse

2nd relapse: n=74

no 3rd CR: n=44 (59%)

allo-SCT: n=7 (16%)

3rd CR: n=30 (41%)

allo-SCT: n=10 (31%)

in CCR: n=6 (3 with allo-SCT), n=1 after 3rd relapse

death: n=23

3rd relapse: n=18

no 4th CR: n=12 (67%)

allo-SCT: n=1 (8%)

4th CR: n=6 (33%)

allo-SCT: n=1 (17%)

(in 5th relapse)

in CCR: n=1 (with allo-SCT)

death: n=11

death: n=6 (100%)

incl. 3 after 4th and 1 after 5th relapse

FIGURE 1. Flow chart for the disease course of the 74 patients with second and 18 patients with third ALL relapse. ALL indicates acute
lymphoblastic leukemia; allo-SCT, allogeneic stem cell transplantation; CCR, continuous complete remission; CR, complete remission.

characteristics, and therapy results of patients with a second or third relapse can be considered reproducible and
gained on a population-based scale. Our analysis shows
that three quarters of the patients with a second and half of
the patients with a third ALL relapse were treated with a
curative intention. However, not unexpectedly, outcome
was poor with EFS rates of only 9% 3% and 6% 6%
for the 2 groups, respectively. Similar results have been
reported for children with a rst relapse nonresponding to
ALL-REZ BFM salvage protocols and second relapses of
the ALL-REZ BFM 87 trial [13/106 (12%) in third
CR].10,18 Thus far, only the Nordic Society of Pediatric
Hematology and Oncology (NOPHO), the Medical
Research Council (MRC) United Kingdom (UK) ALL
(UKALL) Study Group and the US. Therapeutic Advances
in Childhood Leukemia (TACL) Consortium presented
comprehensive data for children with second or further
ALL relapse.3,19,20 Although the NOPHO study showed
that patients in Zthird CR did better with allogeneic SCT
than with chemotherapy only with long-term overall survival rates of 37% 7% compared with 12% 3%, the
MRC UKALL study did not nd such a prominent difference in 10-year overall survival (approximately 20% vs.
10%).3,20 The TACL Consortium demonstrated 5-year
disease-free survival rates of 15% 7% for patients in
third CR and, most importantly, a signicant survival
advantage for patients who underwent allogeneic SCT,
regardless of the number of prior relapses.19 However,
reliable intergroup comparisons are dicult to perform due
to dierent patient cohorts, number of patients, and, particularly, dierent end points (overall survival, EFS, disease-free survival, CCR rates).3,10,19,20

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The data presented herein add some additional information to children with second/third ALL relapse: (1) As
established for rst relapse situation, duration of previous
remission and site of relapse are prognostically important
for children with second relapse with patients having a
second CR duration >1.5 years and isolated extramedullary relapse doing better. Chessells and colleagues
also found length of second CR and relapse site to be signicantly relevant and the NOPHO study demonstrated
that patients who never achieved third CR had shorter
previous remission durations and more BM relapses.3,20
(2) We also observed that neither patient with a BM
relapse who underwent previous SCT nor patients without
a third CR after reinduction chemotherapy or patients with
T-cell ALL survived. Four patients received a SCT in rst
CR, and whereas the 3 cases with rst BM relapse died
from following relapses, 1 patient with a rst isolated
extramedullary relapse survived the second relapse with
having received chemoradiotherapy only. Eight patients
experienced a second BM relapse after SCT in second CR;
none of them survived. Moreover, 4 children who relapsed
in the BM after SCT in third CR/second relapse died, all in
all pointing at the dismal prognosis of children with BM
relapse after SCT. The poor prognosis of children with a
second relapse of T-cell ALL was mainly due to the fact
that only one of 7 patients entered a third CR and all died
from the disease itself. This latter observation suggests that
remission rates might only be improved by the addition of
novel targeted non-cross-resistant drugs such as nelarabine
or forodesine, thereby transferring as many as possible
patients into third CR for successive SCT as the only
potential chance for cure.18
r

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J Pediatr Hematol Oncol

Probability of event-free survival

Volume 35, Number 5, July 2013

Outcome of Second and Third ALL Relapse

TABLE 2. Analysis of the Factors Influencing 10-year EFS of the

74 Patients With Second Relapse of ALL

1
0.9
0.8

No.
Patients

0.7
0.6
0.5
censored

0.4
0.3
0.2
0.1
0
0

10
15
Years after diagnosis

20

25

No. of patients: n=74: 10-year pEFS: 9%3%

Probability of event-free survival

1
0.9
0.8
0.7
0.6
0.5
censored

0.4
0.3
0.2
0.1
0
0

10
15
Years after diagnosis

20

No. of patients: n=18: 10-year pEFS: 6%6%

FIGURE 2. Ten-year probability of event-free survival (pEFS) of
the 74 patients with second (A) and 18 patients with third (B)
relapse of acute lymphoblastic leukemia.

(3) Allogeneic SCT seemed as the only curative option

for children with a systemic relapse of B-cell precursor ALL
as all 4 surviving patients with a second/third relapse
involving the BM received SCT (3/7 had an isolated
extramedullary relapse and none of them underwent SCT).
However, as the overall number of patients with second
relapse surviving is extremely low, we also argue the view
that patients, who have been oered chemotherapy only in
second CR and suer a further relapse, could be easily
rescued later on with allogeneic SCT in third CR. This is
also partly corroborated by the fact that there was no
survival advantage for SCT over chemotherapy for patients
who did or did not undergo SCT in third CR when compared by adjusting for waiting time to transplant.
Conclusively, only a very small group of patients with
second ALL relapse has a realistic chance for cure with still
chemosensitive leukemia and tolerability of remission
induction treatment followed by SCT. Thus, patients with a
second ALL relapse are ideal candidates for phase I/II trials
exploring new innovative drugs such as novel nucleoside
analogues (ie, clofarabine, nelarabine), monoclonal antibodies (ie, blinatumomab, epratuzumab), proteasome
inhibitors (ie, bortezomib), and targeted therapies with
tyrosine (multi) kinase inhibitors.4,19,2124
r

2013 Lippincott Williams & Wilkins

Eventfree
Survival

Sex
Male
47
9% 4%
Female
27
11% 6%
0.617
Immunophenotype
B cell
57
9% 4%
T cell
7
0%
Not available
10
20% 13% 0.113
Age at rst relapse (y)
1-10
49
10% 4%
Z10
25
8% 5%
0.842
Site of rst relapse
Isolated BM
43
5% 3%
Combined BM
14
0%
Isolated extramedullary
17
29% 11% 0.020
Time of rst relapse (mo)
< 18
32
6% 4%
18-30
20
10% 7%
Z30
22
14% 7%
0.045
Therapy of rst relapse
ALL-REZ BFM
42
10% 5%
Other therapy
32
9% 5%
0.947
SCT before second relapse
Yes (rst CR/second CR)
14
7% 7%
No
60
10% 4%
0.643
Site of second relapse
Isolated BM
54
6% 3%
Combined BM
9
11% 10%
Isolated extramedullary
11
27% 13% 0.034
Time of second relapse (mo)
< 18
50
4% 3%
Z18
19
26% 10%
Not available
5
/
0.008
Therapy for second relapse
ALL-REZ BFM
38
8% 4%
Other therapy
16
19% 10%
Palliation
15
7% 6%
Not available
5
0%
0.250
SCT* in third CR/second relapse adjusted for waiting time to SCT
SCT performed at 2.5 mo
8
14% 13%
No SCT performed at
52
16% 7%
0.659
2.5 mo
SCTw in third CR adjusted for waiting time to SCT
SCT performed at 3 mo
5
20% 18%
No SCT performed at 3 mo
30
27% 11% 0.372
*Patients with SCT in rst and second CR (n = 14) were excluded from
this analysis.
wPatients with SCT in rst CR, second CR, and in second relapse
(n = 21) as well as patients without a curative intention (n = 18) were
excluded from this analysis. In a landmark analysis (landmark time 3 mo),
the conditional 10-year pEFS is 20% 18% for 5 patients (4 events) with
SCT within 3 months and 27% 11% for 30 patients (27 events) without
SCT within 3 months. The latter group includes 4 patients with SCT after
landmark time. For this comparison, it needs to be taken into account that
events happen very soon after the second relapse. Thus, in addition to the
small sample size the number at risk for late time-points is extremely small.
In addition, for the interpretation it needs to be considered that these EFS
rates are conditional on having survived 3 months; the 3-month pEFS in the
entire group of 35 patients is with 22% 8% poor.
ALL indicates acute lymphoblastic leukemia; BM, bone marrow; CR,
complete remission; EFS, event-free survival pEFS, probability of event-free
survival; SCT, stem cell transplantation.

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ACKNOWLEDGMENTS
The authors thank all participating institutions and
physicians and nurses for their support of the study as well as
Nora Muhlegger, MSc, and Dasa Janousek, MSc, for collection and management of the data.
Participating institutions and investigators: Krankenhaus (KH) Dornbirn, B. Ausserer; Landeskrankenhaus
(LKH) Feldkirch, U. Busch, G. Muller; Medical University
of Graz, R. Kurz, Ch. Urban; Medical University of Innsbruck, H. Berger, F.-M. Fink, B. Meister; LKH Klagenfurt,
W. Kaulfersch, H. Messner; LKH Leoben, I. Mutz; Allgemeines oentliches KH der Barmherzigen Schwestern Linz,
O. Stollinger; Landeskinderklinik Linz, W. Tulzer, K.
Schmitt; LKH Salzburg, H. Grienberger, N. Jones, J.
Rucker; Kardinal Schwarzenbergsches KH Schwarzach, H.
Haas; LKH Steyr, R. Ploier; St. Anna Childrens Hospital:
H. Gadner, E.R. Grumayer-Panzer, P. Krepler, G. Mann, M.
Dworzak, A. Attarbaschi, Ch. Peters, W. EmmingerSchmidmeier; Medical University of Vienna: E. Pichler, O.
Jurgenssen, I. Slavc.
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