Pediatr Blood Cancer 2011;57:210216

Outcome After First Relapse in Children With Acute Lymphoblastic Leukemia:

A Report Based on the Dutch Childhood Oncology Group (DCOG)
Relapse ALL 98 Protocol
H. van den Berg, MD, MMEd, PhD,1,2* H.A. de Groot-Kruseman, MSc,1 C.M. Damen-Korbijn, MSc,1
E.S.J.M de Bont, MD, PhD,1,3 A.Y.N. Schouten-van Meeteren, MD, PhD,1,2,4 and P.M. Hoogerbrugge, MD,
Background. We report on the treatment of children and adolescents with acute lymphoblastic leukemia (ALL) in first relapse.
The protocol focused on: (1) Intensive chemotherapy preceding
allogeneic stem cell transplantation (SCT) in early bone marrow
relapse; (2) Rotational chemotherapy in late relapse, without donor;
(3) Postponement of cerebro-spinal irradiation in late isolated CNS
relapse; and (4) Treatment in very late bone marrow relapse with
chemotherapy only. Methods. From January 1999 until July 2006
all 158 Dutch pediatric patients with ALL in first relapse were
recorded. Ninety-nine patients were eligible; 54 patients with early
and 45 with late relapse. Eighteen patients had an isolated extramedullary relapse; 69 patients had bone marrow involvement only.

Key words:

PhD

1,5

Results. Five-years EFS rates for early and late relapses were 12%
and 35%, respectively. For early relapses 5 years EFSs were 25% for
patients transplanted; 0% for non-transplanted patients. For late
relapses 5 years EFS was 64% for patients treated with chemotherapy only, and 16% for transplanted patients. For very late relapses
EFS was 58%. Conclusions. Our data suggest the superiority of SCT
for early relapse patients. For late relapses a better outcome is
achieved with chemotherapy only using the rotational chemotherapy scheme. The most important factor for survival was interval
between first CR and occurrence of the first relapse. Pediatr Blood
Cancer. 2011;57:210216. 2011 Wiley-Liss, Inc.

acute lymphoblastic leukemia; central nervous system; child; stem cell transplantation; testicular leukemia

INTRODUCTION
The introduction of multidrug chemotherapy in the treatment
of children suffering from acute lymphoblastic leukemia (ALL)
has been one of the major successes in pediatric oncology. Longterm event-free survival rates currently range from 75% upwards.
However, this means that still a substantial proportion of children
will eventually suffer from a relapse. Although most patients
achieve a second remission; maintaining this remission is often
less successful [1]. In current relapse strategies re-induction
therapy is often quite similar to induction therapy at primary
manifestation of the disease. Treatment strategies to consolidate
a second remission status are less uniform. In designing an effective treatment protocol for ALL relapse patients the duration of
the first remission is important. Chemotherapy resistance is probably the most important factor in early relapse. Considering these
factors the Dutch Childhood Leukemia Study Group (DCLSG,
currently DCOG) designed a protocol to treat all ALL patients in
first relapse, that is, Relapse Acute Lymphoblastic Leukemia
1998 Protocol (Rel-ALL98 protocol). The aims of the protocol
were: (1) to offer patients with an early isolated or combined
bone marrow relapse of ALL an intensive treatment preceding
allogeneic bone marrow transplantation using either an HLAidentical sibling donor or a matched unrelated bone marrow
donor, (2) to offer patients with a late relapse chemotherapy
followed by (if available) bone marrow from an HLA-matched
sibling donor, (3) to offer patients with an early extra-medullary
relapse without bone marrow involvement chemotherapy followed
by (if available) a bone marrow from an HLA-matched sibling
donor, (4) to offer, in order to avoid intolerance for methotrexate
chemotherapy, patients with a late isolated relapse in the central
nervous system prolonged chemotherapy and to postpone craniospinal irradiation until chemotherapy was finished, (5) to treat
patients with a very late bone marrow relapse with chemotherapy
only. The protocol was based on the most favorable treatment
results, published by that time: St. Jude Protocol R11 [2]. In the
Rel-ALL98 Protocol, the following modifications were introduced: ( 1) Substitution of prednisone by the more effective

2011 Wiley-Liss, Inc.

DOI 10.1002/pbc.22946
Published online 18 February 2011 in Wiley Online Library
(wileyonlinelibrary.com).

dexamethasone during re-induction treatment; (2) All children

in 2nd complete remission were eligible for stem cell transplantation (SCT) with marrow from an HLA identical sibling donor if
available, except patients with a very late bone marrow relapse
and patients with a late isolated CNS or testicular relapse. If an
HLA-matched sibling donor was not available, patients with an
early bone marrow relapse were eligible for transplantation with a
matched unrelated donor or haplo-identical donor; (3) For patients
with early extramedullary relapse without an HLA identical
donor, maintenance treatment of Protocol R11 was substituted
by the more intensive maintenance treatment of the POG
Simal9 Pilot Protocol; (4) Boys with testicular relapse received
high-dose methotrexate before the start of re-induction treatment
and during maintenance treatment. Testicular irradiation was only
used in patients with early relapse and no suitable donor; (5) For
patients with late isolated CNS relapse, cranio-spinal irradiation
was postponed until the end of maintenance treatment, in order to
avoid intolerability for chemotherapy. In this manuscript, we
report on the treatment results of this protocol.

Dutch Childhood Oncology Group, The Hague, the Netherlands;

Emma Children Hospital Academic Medical Centre, University
of Amsterdam, Amsterdam, the Netherlands; 3University Medical
Centre Groningen, University of Groningen, Groningen, the
Netherlands; 4VU University Medical Centre, Amsterdam, the
Netherlands; 5Radboud Medical Centre St Radboud, Nijmegen,
the Netherlands
2

Conflict of interest: Nothing to declare.

*Correspondence to: H. van den Berg, MD, MMEd, PhD, Department
of Pediatric Oncology, Emma Children Hospital Academic Medical
Centre, University of Amsterdam, Room F8-242, P.O. Box 22700,
1100 DD Amsterdam, the Netherlands.
E-mail: h.vandenberg@amc.uva.nl
Received 6 July 2010; Accepted 8 November 2010

DCOG ALL Relapse Study 98

METHODS
All patients up to the age of 18 years experiencing a first
relapse in the period from January 1999 until July 1, 2006 were
eligible for the Rel-ALL98 protocol. In the protocol early relapse
was defined as a relapse within 30 months after attaining the first
complete remission (CR1); late and very late relapses were
defined as relapses between 3060 months and more than
60 months duration of CR1, respectively. CR was defined as
absence of clinical signs of disease in combination with a blast
percentage <5% in a recovered bone marrow and blast negative
CSF. Recovery of the bone marrow was assumed in case the white
blood cell (WBC) count >2.0
109/L and platelets were
>50
109/L.

Patients
All patients up to the age of 18 years experiencing a first ALL
relapse in the Netherlands in the period from January 1999 until
July 1, 2006 were eligible for treatment according to the RelALL98 protocol. The relapse had to be confirmed by the DCOG
Central Laboratory. Patients were treated in the Pediatric
Oncology and the Bone Marrow Transplantation Centers of the
Academic Hospitals in the Netherlands. Informed consent was
given.

Diagnosis and Definitions

Isolated bone marrow (medullary) relapse was defined as
25% blasts in the bone marrow and/or blasts cells in the peripheral blood without evidence of ALL in the CNS or testicle(s).
Combined bone marrow (medullary) relapse was defined as:
5% blasts in the bone marrow in combination with extramedullary ALL. Isolated CNS relapse was defined as: 5 cells/mm3 in
the cerebro-spinal fluid with leukemic blasts (cytomorphological)
without major blood contamination (20 erythrocytes/mm3) in
two consecutive CSF samples taken with an interval of at least
24-hr, <5% blasts in the bone marrow, no blasts in the peripheral
blood and absence of leukemic infiltrations elsewhere. Isolated
relapse elsewhere (testicle, skin, bone orbita, mediastinum, lymph
nodes, and tonsils): leukemic infiltrations demonstrated by biopsy
(both microscopically and immunologically), with <5% blasts in
the bone marrow, no blasts in the peripheral blood and absence of
leukemic infiltrations elsewhere. Second complete remission was
defined as: <5% blasts in a recovered bone marrow (WBC
>2.0
109/L, platelets >50
109/L) and absence of leukemic
infiltrations elsewhere. Immunophenotyping, cytogenetic analysis,
and DNA index were performed as described previously [3].

Treatment
Chemotherapy in late and very late relapses was based on the
St. Judes R11 protocol 2. For early relapses the post-induction
chemotherapy was based on the POG Simal9 Pilot Protocol. Data
on the cytostatic scheme are given in Table I. In order to enable
full-dose chemotherapy, irradiation in patients with central nervous system involvement was given after finishing all chemotherapy (24 and 15 Gy to cranium and spine, respectively). This
strategy was based on the data of Mandell et al. [4] and van
den Berg et al. [5]. Patients with late testicular relapses were
treated without irradiation and without surgery, as based on the
Pediatr Blood Cancer DOI 10.1002/pbc

211

results of van den Berg et al. [6]. Patients with early testicular
relapse received 24 Gy testicular irradiation assuming primary
chemo resistance of leukemia cells in these cases. SCT was
planned for any patient with an early relapse. At the start of the
protocol only patients with HLA-matched sibling donors were
eligible for transplantation. From September 1999, also early
relapse patients with HLA-matched unrelated donors or with
haplo-identical donors were eligible for transplantation. For
patients with late relapses, SCT was still only planned in case a
matched sibling donor was available. Very late relapse patients
(i.e., a relapse >60 months after attaining first CR) were not
considered for transplantation, as based on data reported by
Niethammer et al. [7].

Evaluation Criteria and Statistical Analyses

All results were updated until July 2008. The primary endpoints were overall and event-free survival. All analyses were
performed on the basis of intention-to-treat. Survival rates were
calculated according to the KaplanMeier method. Overall survival was calculated as the time from diagnosis of first relapse to
date of death or latest follow-up (censored observations). Eventfree survival was defined as the time from first relapse to death,
re-induction failure, second relapse, or the occurrence of a second
tumor. Patients not achieving second CR (re-induction failures)
were included and considered as having an event on day 0. For
patients alive at the latest follow-up (censored observations),
event-free survival was calculated until this latest follow-up.
Event-free survival and overall distributions were compared by
using the log-rank test. Cox regression analysis was used for
univariate and multivariate analysis in relation to event-free survival. A time-dependent Cox regression analysis was applied in
order to compare transplanted versus non-transplanted patients.
Statistical analyses with time-dependent Cox regression were
performed with mstate library [8].

RESULTS
Patients
In total, 158 patients were reported. Early relapse was diagnosed in 99 patients, late relapse in 41 patients and very late
relapse in 18 cases. One hundred forty-nine patients were eligible;
9 patients were not eligible, 8 because of age (>18 years), and 1
patient due to the pre-existing Fanconi anaemia. Of these 149
relapsed patients 99; 54 (early), 32 (late), and 13 (very late) were
eligible and treated according to the protocol. Fifty of the 149
eligible patients were not treated according to the protocol; 43 of
them had an early relapse, 6 had a late relapse, and 1 had a very
late relapse. In 41 cases this was done on basis of investigators
choice. In 37 of these 41 patients an early relapse had been
diagnosed. Fifteen were treated according to a protocol of another
cooperative group, 16 according to institutional protocols, 9
received palliative treatment (among them 4 with imatinib), 3
were based on their age referred to adult hematology departments
and treated accordingly and in 7 cases no treatment was given.
Initial treatment of the 99 included patients varied and originated
from the DCOG-ALL7 [9], DCOG-ALL 8 [3], DCOG-ALL9
[10], DCOG-ALL10, and Interfant 99 [11] protocols. The
majority of the patients (81%) had initially been treated according
to the DCOG-ALL 9 protocol. Protocol DCOG-ALL10 is based

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van den Berg et al.

TABLE I. Chemotherapy in Relapse ALL 1998 Protocol

Dosage
Induction
Vincristine i.v.
1.5 mg/m2
Dexamethasone oral
6 mg/m2
TM
L-asparaginase (Paronal
) i.v.
6,000 E/m2
Teniposide i.v.
200 mg/m2
Cytosar i.v.
300 mg/m2
Methotrexate, cytosar, prednisolone intrathecally
Dosages according to age
Methotrexate
12,000 mg/m2
Maintenance/consolidation treatment courses in early relapse (given five times)
Teniposide i.v.
100 mg/m2
Cyclophosphamide BID i.v.
250 mg/m2
6-Thioguanine oral
75 mg/m2
Methotrexate QID
25 mg/m2
Methothrexate i.v.
6,000 mg/m2
Folinic acid TID
5 mg/m2
Methotrexate, cytosar, prednisolone intrathecally
Idarubicin i.v.
5 mg/m2
Cytosar i.v.
1,000 mg/m2
Vincristine i.v.
2 mg/m2
Dexamethasone oral
8 mg/m2
TM
L-asparaginase (Paronal
) i.v.
6,000 E/m2
Methotrexate, cytosar, prednisolone intrathecally
Dosages according to age
Maintenance/consolidation treatment courses in (very) late relapse (given seven times)
Etoposide i.v.
300 mg/m2
Cyclophosphamide i.v.
300 mg/m2
Methotrexate, cytosar, prednisolone intrathecally
Dosages according to age
Methotrexate oral
40 mg/m2
6-Mercaptopurin oral
75 mg/m2
Teniposide i.v.
150 mg/m2
Cytosar i.v.
300 mg/m2
Vincristine i.v.
1.5 mg/m2
Dexamethasone oral
6 mg/m2

Days of administration
Days 1, 8, 15, 22, 29, 36, 43a
Days 129, tapering to 0 at day 46
Days 1, 5, 15, 19, 29, 33
Days 8, 22, 36
Days 8, 22, 36
Days 1, 8b, 15b, 22, 29b, 36b, 43
Day 1c
Days 1, 2, 3
Days 1, 2, 3
Days 2236
Days 22, 29
Day 22d
Days 24, 31
Day 22
Days 36, 37, 38e
Days 36, 37, 38
Day 57a
Days 5770
Days 57, 60, 64, 67
Day 64
Day 1
Day 1
Day 1 (only in 1st and 3rd maintenance course)
Day 8
Days 814
Day 15
Day 15
Day 22
Days 2228

i.v., intravenous. aMaximum dosage 2 mg irrespective of body surface area. bIn case of CNS involvement. cIn case of testicular involvement.
Given in every second course in case of testicular relapse instead of oral methotrexate. eCumulative dosage maximized to prevent
cardiotoxicity.

on the current MRD-stratified BFM-protocol. Thirty-nine (50%)

of the bone marrow relapses (isolated or combined) and 12
(92.3%) of the isolated CNS relapses had occurred early.
Immune-phenotyping of the patients with an isolated or combined
bone marrow relapse revealed that the vast majority had a common-ALL or pre-B-ALL phenotype; that is, 90% of the 89
patients with reported immune-phenotyping. Immune-phenotyping was not statistically different for early versus (very) late
relapses (P 0.18; Fisher exact test). Cytogenetic data were
obtained in 55 patients. Karyotyping revealed in one case a
Philadelphia chromosome. In only a limited number of cases
(n 6) rearrangement studies were reported; one of them had a
TEL-AML1 rearrangement.

Treatment Results
Of the 99 included patients, 27 died during re-induction or
failed to reach CR. Five patients were withdrawn before achieving
CR; in four of them this was due to treatment-related toxicity and
one patient with an isolated bone marrow relapse was found
ineligible since no specimens for review of remission status after
induction therapy were centrally reviewed. Twenty-three patients
Pediatr Blood Cancer DOI 10.1002/pbc

with an early relapse were transplanted with stem cells. Twentyone patients with late and very late relapses had a stem cell
transplant, despite the fact that the protocol did not foresee a
transplant in the very late relapse patients. Stem cell sources were
in 74% bone marrow cells, in 19% stem cells originated from
peripheral blood, and in 7% they were collected from cord
blood. After achieving a 2nd CR 9 patients were treated according
other protocols as based on investigators choice. Thirty-four
patients experienced a second relapse; 28 of these patients have
died at time of analysis. Of the early relapse patients 14 out of
54 patients are alive in 2nd CR. Of the late relapse patients 11 out
of 32 patients are alive. From the 13 very late relapse cases 5
patients are alive. Figures 14 give the overall and event-free
survival curves for early, late (inclusive very) relapses; also in
relation to SCT. Figures 3 and 4 are corrected for moment of
transplantation.
From the 54 early relapse patients, 19 patients did not achieve
a complete remission after re-induction treatment or had progressed during re-induction treatment. In 7 of these 19 patients
a second remission was reached on alternative chemotherapy; 1
died due to infection, the remaining died due to a further relapses,
in 4 of them SCT had been attempted. In four early relapse

DCOG ALL Relapse Study 98

213

Fig. 1. Overall survival of early (black line) and (very) late relapses
(gray line).

patients re-induction treatment was stopped due to toxicity; three

of these four died; the single patient who survived despite severe
toxicity in conjunction with a candida esophagitis had suffered
from an early isolated testicular relapse.
From the 45 late and very late relapse patients, 7 patients did
not achieve complete remission after re-induction treatment or
had progressed during re-induction treatment. In four of these
seven patients a second remission was reached on different chemotherapy; however, all died despite SCT in two of them. In one
very late relapse patient induction treatment was stopped due to
toxicity.
From patients with late relapses, who did not receive a SCT
five died due to a re-induction failure, one died due to septicemia,
one died due to intracerebral bleeding in conjunction with a
systemic aspergillosis. From the late relapsing patients who had
a transplant 7 patients had an event after SCT ( all second

Fig. 2. Event-free survival of early (black line) and (very) late

relapses (gray line).
Pediatr Blood Cancer DOI 10.1002/pbc

Fig. 3. Event-free survival in early relapses in relation to stem cell

transplantation.

relapses); from the remaining 14 cases 3 died from infection.

The single Ph ALL cases is alive. This patient has been censored at 30 months.
The covariates employed in the multivariate analysis were
gender, age, WBC count at first relapse, immunophenotype, and
time to occurrence of relapse. Time to relapse was divided in
three categories: early, late, or very late relapse. While each of
this relapse category had a significant impact on event-free survival (P-value equal to 0.004, 0.003, and 0.031, respectively), the
remaining covariates showed no significant results. Transplanted
versus non-transplanted patients were analyzed by employing a

Fig. 4. Event-free survival in (very) late relapses in relation to stem

cell transplantation.

214

van den Berg et al.

time-dependent Cox regression model. Time to relapse was then

divided in two categories: early and late relapse. In the latter
category late and very late relapse were collapsed together. For
the category early relapse a risk factor equal to 0.466 (P-value
0.048) and 0.542 (P-value 0.12) was estimated for OS and EFS,
respectively, implying that transplanted patients perform better.
However, for the late relapse category, results do not follow the
same trend: risk factors 6.91 (P < 0.001) and 3.02 (P 0.012)
for OS and EFS, respectively. Separate assessment for non-isolated extramedullary relapses were done, but were not essentially
different.

DISCUSSION
Despite current cure rates above 75%, relapse is still considered as the most important obstacle in definite cure of children
with ALL. In case of relapse second remissions are obtained in
the vast majority of patients; for example, 95% in the UKALLR1
study [12]. However, the chance to experience a second relapse is
still high. The most important factor for a second relapse is the
duration of the first remission. A cut-off point between early and
late relapses is often made at 36 months after treatment cessation. Studies report for early relapses EFS rates ranging from 5%
to 11% and for late relapses ranges from 19% to 57% [1,13]. Our
findings are in line with these data. The exclusion of 50 patients
from our study reflects that there are generally serious doubts on
effective treatment for early relapses. The large majority of
patients not entered in our study had an early relapse. In even
one-third of these cases no treatment or palliative treatment was
given. This is weakness in our study, but it is most probable that
these patients had an even poorer chance of cure. Adding them to
our study would not have improved our bad results in this subcategory of early relapse patients.
There is some debate in the literature on the prognostic factor
of the WBC count and the presence of blasts in the peripheral
blood at the time of relapse. T-cell immunophenotype is known to
be a poor prognostic factor. A twofold rise in second relapse risk
is claimed [14,15]. Minimal residual disease of leukemia (MRD;
as measured by real-time PCR) both during second CR and after
transplantation, has been reported to be a very strong prognostic
factor for ultimate outcome [16]. An additional prognostic factor
for survival is the site of relapse and the combination with bone
marrow involvement. The outcome of isolated CNS relapses is
better than a CNS relapse combined with bone marrow involvement; whereas isolated testicular relapses even have a better
prognosis. Chessells [17] reported survival rates of about 15%,
25%, and 65% for (combined) bone marrow, isolated CNS, and
isolated testicular relapses, respectively. Our strategy for the various types of relapse was in line with the strategies in the UK and
Germany; that is, early relapse cases are high risk, irrespective of
localization of the disease at relapse, and abstaining from transplantation in isolated late relapse [13,18].

(OS rate of 37% and EFS of 25%, vs. 0% OS and 0% EFS,

respectively). This difference (P < 0.001 for both OS and EFS)
illustrates that treatment with only chemotherapy fails in these
patients. We were not able to identify whether in all patients
qualifying for bone marrow transplantation HLA-typing had been
done; which may bias our results and conclusions. Statistical
correction was done for interval between diagnosis and transplantation in order to make comparisons with non-transplanted
patients. Unidentified differences, such as aggressiveness of the
malignancy might still bias our conclusions. In our patients with a
late relapse undergoing a transplant the outcome is poorer considering the risk factor of 6.91 and 3.02 for OS and EFS, respectively. Our data confirm reports in literature that SCT in late
relapses is not beneficial. Since the majority of these patients
die from a relapse of leukemia the benefits of the conditioning
and the possible graft-versus-leukemia effect do not outweigh the
benefit of the prolonged, rotational chemotherapy. The observed
high number of early events in the stem cell transplanted group
was in the majority of cases caused by infectious complications
(often fungal; i.e., aspergillus).
We can confirm the initial data of Rivera et al., on which our
protocol was based, claiming a 65% survival rate in cases of late
relapse treated with only chemotherapy. Although a difference in
outcome as compared with the patients in the Rivera et al. study
might have been likely due to different treatment schemes given
after initial diagnosis. Our patients were in a mix of BFM protocol-based treatment (49%) and Dutch protocol treated patients
(36%), the latter often not treated with an anthracycline [2].

Extramedullary Relapse
In extramedullary relapses, also a clear distinction has to be
made for early relapses versus late relapses. Most authors claim
that absence of bone marrow involvement is a favorable factor
[19,20]. Relapses in extramedullary sites are often considered as
relapses from malignant cells treated with suboptimal drug levels;
due to their homing in these sanctuaries. However, it was shown
that by increasing the dosages of methotrexate, outcome was not
improved [21]. In case of a testicular relapse, isolated relapse
patients fare better with an EFS of 0.58 versus 0.28 for combined
relapses. For CNS involvement, no statistical difference on outcome has been reported whether the bone marrow was involved or
not [14]. Since isolated extramedullary relapses are often late
relapses; we are reluctant to generalize such a statement for
patients with early relapse leukemia. Of note is a single report
that patients with early isolated ALL in the CNS may have a
poorer outcome than those with an early combined bone marrow/CNS relapse [13]. In our study, separate analysis on nonisolated extramedullary relapses was done, but results were not
essentially different. This is possibly explained by the fact that
since only 3 out of 18 cases were late or very late relapses.

Transplantation
Bone Marrow Relapses and Combined Relapses
According to our protocol, all patients with an HLA-identical
sibling donor were advised to have a SCT, with the exception of
patients with very late relapses and late isolated extramedullary
relapses. In patients with early relapse, SCT treatment in CR2
showed a favorable outcome compared to non-transplant patients
Pediatr Blood Cancer DOI 10.1002/pbc

Only treatment results between autologous transplantation and

chemotherapy have been reported. Results of autologous transplantation were not better than of only chemotherapy [22,23].
Some of these studies have flaws in the randomization of patients
[12]. The role of allogeneic transplantation has been reported to
be superior to chemotherapy-only treatment options in various

DCOG ALL Relapse Study 98

studies [24,25]. However, biases are not uncommon in these
studies due to, for example, selective entry in the studies, length
of interval between diagnosis and actual moment of transplantation and intervening complications. For late and very late isolated extramedullary relapses there is no indication for allogeneic
bone marrow transplantation [26]. Early relapse patients may
benefit most from the transplantation strategy probably due to
the lack of adequate chemotherapy [27,28]. Based on the similar
outcome of SCT with HLA-identical donors versus chemotherapy
in patients with a lower risk for a later relapse the role of transplantation is, however, debated [29]. From the BFM group,
Borgmann et al. [30] reported that intermediate risk patients
had EFS rates after transplantation of 0.39 for; for non-transplanted patients this was 0.49; whereas transplanted high-risk
patients had an EFS of 0.44 versus non-transplanted patients of
0.00. In line with such a statement are the data in a UK study
including 256 patients, who were analyzed on basis of HLAmatched donor availability; no statistical benefit in outcome was
seen [27].
Assessing transplantation data, the choice of the donor is of
major importance considering survival data merits full attention,
especially in relation with transplantation-related survival.
Another impediment in comparing reports is the more favorable
outcomes of non-sibling donors over the years. At the time our
protocol was designed, transplants with matched unrelated donors
were associated with severe toxicity and mortality. However,
already in the first year after starting the protocol results of
SCT with matched unrelated donors had significantly improved;
as a consequence, the protocol was amended and early relapse
patients became eligible for SCT with matched unrelated donors
[14,31]. Confirming this change in policy are data from Bunin
et al. reporting for children <15 years of age and a relapse within
6 months after CR1, the leukemia-free survival rate was 25%, for
children with a longer CR1 the leukemia-free survival rate was
39% after transplantation with stem cells from unrelated donors.
A matched-pair analysis of unrelated donor SCT versus chemotherapy revealed that only high-risk patients, defined as early
isolated T-ALL (combined) bone marrow relapse benefited from
unrelated donor transplantations [30]. Comparing the outcome
data in relation to the origin of the stem cell graft; that is,
originating from HLA-matched siblings or HLA-matched nonsibling donors, no significant differences in outcome were noted
in 124 patients with early bone marrow relapse leukemia [32].
This is in line with the survival rate in our cohort showing better
survival rates in chemotherapy only treated patients.
We conclude from our data that SCT shows improved outcomes for patients with early relapse leukemia. For patients with
late relapse leukemia patients a more advantageous outcome is
achieved for non-transplanted patients using this rotational chemotherapy scheme. Infections and relapses are the major causes
of death in patients who have undergone transplantation and then
suffered a disease relapse. The most important factor identified to
date for survival is the duration of the first remission.

ACKNOWLEDGMENT
The authors want to thank Dr. M. Fiocco and Prof. Dr. T.
Stijnen for their advise on statistical analysis and Dr. A. van
der Does-van den Berg for critical review of the manuscript.
Pediatr Blood Cancer DOI 10.1002/pbc

215

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