Leukemia (2005) 19, 2130–2138
& 2005 Nature Publishing Group All rights reserved 0887-6924/05 $30.00
www.nature.com/leu
Treatment strategy and long-term results in paediatric patients treated in consecutive
UK AML trials
BES Gibson1, K Wheatley2, IM Hann3, RF Stevens4, D Webb3, RK Hills2, SSN De Graaf5 and CJ Harrison6, for the United Kingdom
Childhood Leukaemia Working Party, and the Dutch Childhood Oncology Group
1
Royal Hospital for Sick Children, Glasgow, UK; 2Birmingham Clinical Trials Unit, University of Birmingham, Birmingham, UK;
Great Ormond Street Hospital for Children, London, UK; 4Royal Manchester Children’s Hospital, Manchester, UK;
5
Dutch Childhood Oncology Group, The Hague, The Netherlands; and 6LRF Cytogenetic Group, Cancer Sciences Division,
University of Southampton, Southampton, UK
3
Between 1988 and 2002, 758 children with acute myeloid
leukaemia (AML) were treated on Medical Research Council
(MRC) AML 10 and AML 12. MRC AML 10 tested the role of bone
marrow transplantation following four blocks of intensive
chemotherapy and found that while both allogeneic bone
marrow transplant (allo-BMT) and autologous bone marrow
transplant (A-BMT) significantly reduced the relapse risk (RR),
this did not translate into a significant improvement in overall
survival (OS). A risk group stratification based on cytogenetics
and response to the first course of chemotherapy derived from
MRC AML 10 was used to deliver risk-directed therapy in MRC
AML 12. Allo-BMT was limited to standard and poor risk
patients and A-BMT was not employed. Instead, the benefit of
an additional block of treatment was tested by randomising
children to receive either four or five blocks of treatment in
total. While the results of MRC AML 12 remain immature, there
appears to be no survival advantage for a fifth course of
treatment. The 5 year OS, disease-free survival (DFS), eventfree survival (EFS) and RR in MRC AML 12 are 66, 61, 56 and
35%, respectively; at present superior to MRC AML 10, which
had a 5-year OS, DFS, EFS and RR of 58, 53, 49 and 42%,
respectively. MRC AML trials employ a short course of triple
intrathecal chemotherapy alone for CNS-directed treatment and
CNS relapse is uncommon. Improvements in supportive care
have contributed to improved outcomes and the number of
deaths in remission fell between trials. Anthracycline-related
cardiotoxicity remains a concern and the current MRC AML 15
trial tests the feasibility of reducing anthracycline dosage
without compromising outcome by comparing standard MRC
anthracycline-based consolidation with high-dose ara-C. MRC
studies suggest that the role of allo-BMT is limited in 1st CR
and that there may be a ceiling of benefit from current or
conventional chemotherapy.
Leukemia (2005) 19, 2130–2138. doi:10.1038/sj.leu.2403924
Keywords: acute myeloid leukaemia; children; bone marrow
transplantation; cytogenetics; prognostic factors
Introduction
The survival of children with AML treated on United Kingdom
(UK) MRC trials has improved dramatically over the past 30
years and continues to improve (Figure 1). This has been
achieved by a combination of increasingly intensive anthracycline- and cytosine-based chemotherapy and advances in
supportive care, whcih have allowed intensive chemotherapy
to be delivered with less morbidity and mortality. The role of
allogeneic bone marrow transplant (allo-BMT) and autologous
bone marrow transplant (A-BMT) in 1st complete remission
Correspondence: Dr BES Gibson, Department of Haematology, Royal
Hospital for Sick Children, Glasgow G3 8SJ, UK;
Fax: þ 44(0) 141 201 9303;
E-mail: [email protected]
Received 14 March 2005; accepted 20 April 2005
(CR 1) have been tested and a risk group stratification identified
based on cytogenetics and response to the first block of
chemotherapy. In the UK, children and adults have traditionally
been treated on the same, or very similar protocols, within a
single trial. There are approximately 70 new cases per annum of
AML in children less than 15 years of age in the UK.
Table 1 presents details of the most recent of these trials,
including the number of centres involved, their average patient
numbers and the patient numbers per trial. The protocols are
shown schematically in Figure 2a and b and given in detail in
Table 2.
Treatment strategy of MRC AML trials
Three MRC AML trials were conducted between
1978 and 1990:
MRC AML 81 (1978–1983), Joint AML study2 (1982–
1985) and MRC AML 93 (1984–1990): The recruitment of
children was limited, but these trials provided important
information (mainly from adult results), based on a combination
of randomised and historical comparisons, which were carried
forward in the design of MRC AML 10.
Firstly, MRC AML 9 found the DAT 3 þ 10 regimen
(daunorubicin, ara-C, thioguanine) to be superior to the DAT
1 þ 5 regimen of AML 8. The high remission rate for DAT 3 þ 10
(91% for children) was confirmed in the Joint AML study and the
second course modified to DAT 3 þ 8; two courses of DAT
3 þ 10 having been shown to be too toxic. Secondly, both MRC
AML 9 and the Joint AML study tested the role of high-dose
consolidation therapy and allo-BMT in maintaining remission.
New regimens, previously used in resistant disease4–10 were
piloted: MAZE (amsacrine, 5-azacytidine, etoposide) and ara-C
1 g/m2 combined with daunorubicin and thioguanine. The
former became MACE when ara-C replaced 5-azacytidine and
the latter was further modified to MidAC, when the same dose of
ara-C was combined with mitoxantrone. Thirdly, MRC AML 9
tested the value of maintenance therapy followed by late
intensification (COAP regimen) and found it to be limited.
Maintenance therapy was not employed in subsequent MRC
trials. Finally, intrathecal chemotherapy was the only form of
CNS treatment used in these studies and the CNS relapse rate
was low suggesting that intrathecal chemotherapy and/or
intensive systemic therapy were effective in preventing CNS
disease.
MRC AML 10 (1988–1995): With excellent CR rates being
achieved, MRC AML 10 concentrated on the prevention of
relapse. DAT 3 þ 10 was compared with ADE 3 þ 10 þ 5 (ara-C,
Treatment strategy and long-term results in paediatric patients
BES Gibson et al
2131
daunorubicin, etoposide) as induction therapy. These regimens
delivered the same doses of daunorubicin and ara-C and tested
the comparative benefits of thioguanine with etoposide. MRC
AML 10 delivered a total of four courses of treatment (DAT
3 þ 10 or ADE 3 þ 10 þ 5, DAT 3 þ 8 or ADE 3 þ 8 þ 5, MACE,
MidAC) and investigated the role of BMT following this
intensive chemotherapy. Allo-BMT was recommended for all
children with a matched sibling donor. Children without an HLA
compatible sibling were randomised to receive an A-BMT in 1st
CR following four blocks of intensive chemotherapy (marrow
harvested after 3rd course of chemotherapy), or no further
treatment.
While there was a reduction in relapse rate for both forms of
transplantation, this did not translate into an overall survival
advantage. MRC AML 10 identified a risk group stratification
based on karyotype and response to the 1st block of treatment.
MRC AML 12 (1995–2002): The Dutch Children’s Oncology Group joined MRC AML 12. This trial took forward the
marginally better induction regimen from MRC AML 10 (ADE)
and the standard MRC template became ADE, ADE, MACE,
MidAC. MRC AML 12, investigated whether mitoxantrone11
might be superior to daunorubicin and less cardiotoxic, by
comparing ADE (daunorubicin, ara-C, etoposide) with MAE
(mitoxantrone, ara-C, etoposide). MRC AML 10 risk group
stratification was adopted in MRC AML 12 to deliver riskdirected therapy. Allo-BMT was restricted to standard and poor
risk patients in whom relapse remained the main cause of
treatment failure. In the absence of an advantage in OS, A-BMT,
with its substantial morbidity in children, was omitted from
MRC AML 12. The reduction in relapse risk, similar for A-BMT
and allo-BMT, in MRC AML 10, suggested that the benefit might
be one of additional treatment rather than a graft-versusleukaemia effect. This was tested by the introduction of a 5th
Figure 1
Table 1
course of therapy by randomisation. HD ara-C with asparaginase was chosen to avoid further anthracycline exposure.
CNS-directed therapy in MRC AML 10 was with four courses
and in AML 12 three courses of triple intrathecal chemotherapy
(ara-C, methotrexate, hydrocortisone) at age-adjusted doses.
Patients and methods
Eligibility
The paediatric upper age limit for MRC AML 10 was 14 years
and for MRC AML 12 was 16 years, although only 22 (4%) and
two (o1%) of the children who were entered into MRC AML 12
were aged 15 and 16, respectively. De novo AML, Down
syndrome (DS), secondary AML and aggressive MDS (RAEB,
RAEB-t) patients, for whom intensive-type therapy was considered appropriate, were eligible. Written informed consent
from the patient or parent was required.
Diagnosis
The diagnosis of AML and its subtypes was established
according to the FAB classification in each local centre and
reviewed by a central morphology panel. Confirmatory immunophenotyping and cytogenetics were performed locally.
Cytogenetics were coordinated by the LRF Cytogenetics Group.
Remission marrows were not centrally reviewed. CNS disease
was defined by the presence of 45 106/l leukaemia blasts in a
CSF cytospin and/or the presence of neurological symptoms.
Definitions and statistics
Complete remission (CR) was defined as a bone marrow with
o 5% leukaemic cells and evidence of regeneration of
normal haemopoietic cells. Neutrophil and platelet parameters were not included in the definition. Partial remission
(PR) was defined as a bone marrow with between 5 and 15%
leukaemic cells and evidence of regeneration of normal
haemopoietic cells.
Resistant disease (RD) was defined as a bone marrow
containing 415% leukaemic cells.
Remission failures were classified as either induction deaths,
that is, related to treatment and/or hypoplasia, or as resistant
disease, that is, related to the failure of therapy to eliminate
the disease (including partial remissions). When the clinician’s evaluation was not available, deaths within 30 days of
entry were classified as induction deaths and deaths at more
than 30 days as resistant disease.
OS was calculated from the date of entry into the trial, or from
the date of randomisation, to death from any cause.
Disease-free survival (DFS) for patients achieving remission
was calculated from the date of remission to the date of the
MRC AML trials: OS: Age 0–14 years: 1970–1999.
Patient accrual and follow-up
Trial
MRC AML 10
MRC AML 12
Accrual of patients:
time period
Total no. of
patients (n)
Centres (n)
No. of patients/centre
(median/range)
No. of
patients/year
Follow-up (median,
range, years)
5/88–3/95
4/95–5/02
364
564
39
30
4 (1–48)
15 (1–63)
53
78
11 (5–15)
3 (1–7)
Leukemia
Treatment strategy and long-term results in paediatric patients
BES Gibson et al
2132
a
MRC AML 10
Allo BMT
DONOR
DAT
DAT
MACE
R1
ADE
M id AC
ADE
NO DONOR
ABMT
R2
NFT
Ara-C (g/ m 2 )
2
1.6
Anthracycline (mg/m2)
150
150
DAT 3 + 10
DAT 3 + 8
or
ADE 3 + 10
ADE 3 + 8
MACE
MidAC
CUMULATIVE DOSES
150
150
2
1.6
1
6
10.6
250
550
Etoposide (mg/ m2 )
500
500
500
500-1500
An anthracycline conversion factor of 1.5 (mitoxantrone 1mg/m2 is equivalent to daunorubicin 5mg/m2) has been used to
calculate cumulative anthracycline doses at the instruction of the Editor.
b
MRC AML 12
MidAC
R2
RISK GROUP
ASSIGNED
CLASP
GOOD
ADE
ADE
MACE
R1
MAE
MidAC
AlloBMT
MAE
STANDARD
+ POOR
DONOR
R2
CLASP
AlloBMT
MidAC
NO DONOR
R2
CLASP
ADE 3 + 10
ADE 3 + 8
or
MAE 3 + 10
MAE 3 + 8
MACE
MidAC
CLASP
CUMULATIVE DOSES
Anthracycline(mg/m2)
150
150
180
180
250
300 - 610
Anthracycline doses calculated as for MRC AML 10
Figure 2
Leukemia
Treatment schemas of MRC AML 10 (a) and AML 12 (b).
Ara-C(g/m2)
2
1.6
2
1.6
1
6
24
4.6 – 34.6
MidAC
Etoposide (mg/m2)
500
500
500
500
500
1500
Treatment strategy and long-term results in paediatric patients
BES Gibson et al
2133
Table 2
Treatment elements in the four AML Studies 1982–2002
MRC AML 10
Induction
Consolidation
Course 1: Randomisation: DAT vs ADE
DAT 3+10: Daunorubicin 50 mg/m2 i.v. d 1, 3, 5; Ara-C 100 mg/m2/12 h i.v. d 1–10; 6-TG 75 mg/m2 12-h orally d 1–10
ADE 10+3+5: Ara-C 100 mg/m2/12-h i.v. d 1–10; Daunorubicin 50 mg/m2 i.v. d 1, 3, 5; Etoposide 100 mg/m2 i.v. d 1–5
Course 2: DAT 3+8 vs ADE 3+8+5: Ara-C reduced to 8 days in both regimens and 6-TG to 8 days in DAT
Course 3: MACE: Amsacrine 100 mg/m2 d 1–5; Ara-C 200 mg/m2 continuous infusion d 1–5; Etoposide 100 mg/m2/day
i.v. d 1–5
Course 4: MIDAC: Mitozantrone 10 mg/m2/day i.v. d 1–5; Ara-C 1 g/m2 12-h i.v. d 1–3
Age-adjusted intrathecal chemotherapy with methotrexate, Ara-C and hydrocortisone ( 4)
Patients with a sibling donor were eligible for allo-BMT
Patients with no sibling donor were randomised between A-BMT and no further treatment
MRC AML 12
Induction
Consolidation
Course 1: randomisation: ADE vs MAE
ADE 10+3+5: Ara-C 100 mg/m2 12-h i.v. d 1–10; Daunorubicin 50 mg/m2 i.v. d 1, 3, 5; Etoposide 100 mg/m2 i.v. d 1–5
MAE 3+10+5: Mitozantrone 12 mg/m2 i.v. d 1, 3, 5; Ara-C 100 mg/m2 12-h i.v. d 1–10; Etoposide 100 mg/m2 i.v. d 1–5
Course 2: ADE 8+3+5 vs MAE 3+8+5: Ara-C reduced to 8 days in both regimens
Course 3: MACE: Amsacrine 100 mg/m2 d 1–5; Ara-C 200 mg/m2 continuous infusion d 1–5; Etoposide 100 mg/m2 d 1–5
Good risk patients randomised: MidAC vs CLASP-MidAC
Standard and poor risk patients with no sibling donor randomised for MidAC vs CLASP-MidAC
Standard and poor risk patients with sibling donor were eligible for allo-BMT and randomised for allo-BMT vs CLASP-allo-BMT
MidAC: Mitozantrone 10 mg/m2 i.v. d 15; Ara-C 1 g/m2 12 h i.v. d 1–3
CLASP: Ara-C 3 g/m2 12-h i.v. d 1, 2, 8, 9; Asparaginase 6000 U/m2 s.c. d 2, 9
Age-adjusted intrathecal therapy with methotrexate, Ara-C and hydrocortisone ( 3)
d ¼ Days.
first event (either relapse or death in CR), or from the date of
randomisation for post CR questions.
Event-free survival (EFS) was calculated from the date of entry
into the trial to the date of first event (failure to achieve CR,
relapse or death from any cause – failure to achieve CR was
considered an event on day 1).
RR for patients achieving remission was the cumulative
probability of relapse censored at death in CR.
Toxicity was assessed according to the WHO toxicity criteria.
Randomised comparison results, including the Mendelian
randomisation to assess allo-BMT, were based on an intention
to treat analysis and included all randomised patients according
to the eligibility criteria for the trial. Randomisations were
balanced by minimisation. Remission rates and reasons for
failure to achieve CR were compared using w2 tests. Kaplan–
Meier life-tables were constructed for time to event data and
were compared by means of the log-rank test. For the main
mature randomised comparisons in MRC AML 10, odds ratios
(OR) or hazard ratios (HR), with 95% confidence intervals (CI),
are given. All P-values are two-tailed. In both MRC AML 10 and
AML 12, some children were not registered at diagnosis. Such
patients cannot contribute to estimates of overall outcome, since
because they had to survive long enough to be registered, their
inclusion will inflate the estimates slightly. In MRC AML 10, 341
out of 364 children were registered at diagnosis; the corresponding figure for MRC AML 12 was 527 out of 564. Also
excluded, at the request of the editor, from analyses of overall
outcome were patients aged 15 or 16 years, patients with
secondary AML, patients with MDS and DS children. Four
children rediagnosed after entry as having ALL (n ¼ 3) or
bilineage leukaemia (n ¼ 1) were also excluded. Overall outcome data will be confined to the 758 children (MRC AML 10:
303, MRC AML 12: 455) who met the study criteria for this
publication.12 Data were analysed using a follow-up date of 1
April 2004.
Results of MRC AML 10 and 12 trials
This review will concentrate on MRC AML 10 and the
preliminary results of MRC AML 12, which are already in the
public domain because these are the only trials, that recruited
all, or most children in the UK. Patient characteristics are given
in Table 3 and results in Table 4. Overall outcome results are
restricted to patients 0–14 years of age with de novo AML while
randomised comparisons include all trial entrants. Survival, DFS
and EFS have consistently improved and, most importantly, the
improvement has been maintained between MRC AML 10 and
AML 12 (Figures 1, 3, 4 and Table 4)
MRC AML 10
In all, 93% (282 of 303) of patients achieved remission. 3% of
children had resistant disease and 4% an induction death
(Table 4). The 5-year and 10-year OS, EFS and DFS are 58, 49,
53 and 56, 48, 51%, respectively.
A total of 286 children (143 in each arm) were randomised to
DAT vs ADE; a comparison of etoposide with thioguanine.
There was no significant difference in CR rate (DAT 90% vs ADE
93%, OR ¼ 1.58, CI ¼ 0.68–3.51, P ¼ 0.3), induction deaths,
the number of courses required to achieve CR, or resistant
disease (DAT 4% vs ADE 3%, P ¼ 0.7). At 10 years, the OS, DFS
and EFS were similar (DAT 57% vs ADE 51%, HR ¼ 0.83,
CI ¼ 0.59–1.17, P ¼ 0.3; DAT 53% vs ADE 48%, HR ¼ 0.83,
CI ¼ 0.59–1.17, P ¼ 0.3; DAT 48% vs ADE 45%, HR ¼ 0.89,
CI ¼ 0.65–1.23, P ¼ 0.5, respectively). There was a nonsignificant excess of deaths in 1st CR during consolidation in the ADE
Leukemia
Treatment strategy and long-term results in paediatric patients
BES Gibson et al
2134
Table 3
Initial patient data on studies MRC AML 10 and AML 12
(0–14 years with AML)
MRC AML 10
n
%
MRC AML 12
n
172
57
241
53
Age (years)
0–1
2–9
10–14
59
136
108
19
45
36
92
203
160
20
45
35
WBC 109/l
o10
10–o99.9
X100
118
135
50
39
45
16
166
198
78
38
45
18
23
8
28
6
4
52
108
27
49
41
5
14
1
17
36
9
16
14
2
5
21
52
116
40
77
105
10
19
5
12
26
9
17
24
2
4
84
38
31
15
31
14
12
6
110
50
33
26
28
13
9
7
164
61
230
59
20
7
51
13
FAB types
M0
M1
M2
M3
M4
M5
M6
M7
Cytogenetics
Favourable
t(8;21)
t(15;17)
inv(16)
Intermediate
Adverse
7, 5, del(5q), abn(3q),
complex karyotype
564
303
455
Crude overall CNS relapse rate for both trials of 1.6% – not expected
to differ significantly from the cumulative CNS relapse rate.
Unknown values are not included.
arm (8 vs 15%, P ¼ 0.09). There was no evidence that children
with monocytic involvement (FAB type M4 or M5) did better
with ADE than with DAT. In this subgroup the CR rate with DAT
was 83% (35/42) and with ADE 94% (32/34) (P ¼ 0.2), whereas
7-year survival was 52 and 55%, respectively (P ¼ 0.9).
There was no significant OS advantage for A-BMT (A-BMT 70
vs Stop 58% at 10 years, HR ¼ 0.67, CI ¼ 0.35–1.29, P ¼ 0.2),
but there was a decrease in RR (A-BMT 31% vs Stop 52%,
HR ¼ 0.50, CI ¼ 0.27–0.92, P ¼ 0.03), with a significant improvement in DFS in the A-BMT arm (A-BMT 68% vs Stop 44%
at 10 years, HR ¼ 0.50, CI ¼ 0.28–0.90, P ¼ 0.02). The benefit of
A-BMT emerged at 2 years from diagnosis. The reduction in the
RR did not translate into a significant improvement in OS
because children who relapsed and who had not had an A-BMT
were more likely to be salvaged with second-line treatment than
those who had had an A-BMT (survival at 5 years from relapse
A-BMT 7% vs Stop 27%, P ¼ 0.05). There were no deaths in CR
after ABMT.
The results of allo-BMT were analysed on whether or not a
donor was available that is, intention to treat. Of the 85 children
Leukemia
MRC AML 10
%
Total number of patients
entered
Number of patients included in
overall outcome analysis
Gender (male)
CNS leukaemia (yes)
364
Table 4
Results in studies MRC AML 10 and 12 (0–14 years with
de novo AML)
n
Number of patients
Early deaths
Nonresponse
CR achieved
Death in 1st CR (5 years)
Relapse (5 years)
%
303
MRC AML 12
n
%
455
4
3
93
10
42
4
4
92
6
35
OS
At 5 years
At 10 years
58
56
66
F
EFS
At 5 years
At 10 years
49
48
56
F
DFS
At 5 years
At 10 years
53
51
61
F
Figure 3
MRC AML Trials: Survival from entry.
Figure 4
MRC AML Trials: EFS.
with a donor, 61 received an allo-BMT and this included 12 of
21 good risk patients with a donor. Allo-BMT was associated
with a significant reduction in RR from 45 to 30% at 10 years
(HR ¼ 0.64, CI ¼ 0.43–0.95, P ¼ 0.02). The transplant-related
Treatment strategy and long-term results in paediatric patients
BES Gibson et al
2135
mortality for children with a donor was 11%, but 15% in those
children who actually received an allo-BMT. There was no
significant difference in survival between those children with or
without a donor at 10 years (donor 68% vs no donor 59%
HR ¼ 0.79, CI ¼ 0.54–1.17, P ¼ 0.3). The fewer relapses in the
donor group were counterbalanced by procedure-related deaths
(P ¼ 0.001).
AML 10 allowed stratification of patients into a good (32%),
standard (49%) or poor (19%) risk group based on karyotype and
response to the first course of treatment. OS from CR at 10 years
for good, standard and poor risk patients was 77, 58 and 30%
(Po0.0001), respectively, while DFS at 10 years was 60, 52 and
25%, respectively, (Po0.0001). The RR for good, standard and
poor was 35, 43 and 72%, respectively, (Po0.0001). Survival
from relapse at 5 years was significantly different: survival for
good, standard and poor risk was 57, 14 and 8% (P ¼ 0.0003)
respectively, suggesting that bone marrow transplantation might
be reserved for second CR in good risk patients at least.
Results of MRC AML 12
MRC AML 12 was closed to recruitment in May 2002 and the
results remain immature. In all, 92% (420 of 455) of patients
who entered into MRC AML 12 achieved remission. Failure to
achieve remission was equally due to early deaths (4%) and
resistant disease (4%). The estimated probabilities of 5-year OS,
EFS and DFS are 66, 56 and 61%, respectively. MRC AML 12
compared mitoxantrone to daunorubicin (ADE vs MAE). In all,
251 children were randomised into each arm of the study and
compliance was 99%. The CR (ADE 92% vs MAE 90%, P ¼ 0.3)
and resistant disease (4 vs 4%) rates were similar for both
regimens. Induction deaths were slightly, but not significantly
higher for MAE than for ADE (MAE 6% vs ADE 3%); however,
the DFS and RR were both superior for MAE compared to ADE
(ADE 59%, MAE 68%, P ¼ 0.04; ADE 37%, MAE 29%, P ¼ 0.06,
respectively). The estimated probability for 5-year OS is not
significantly different (ADE 64%, MAE 70%, P ¼ 0.1).
The second randomisation compared five courses of treatment
with four; testing whether an additional course of treatment
would reduce the RR. Compliance with randomisation to four
courses was 93% and to five courses was 75%. There appears to
be no benefit from an extra course of treatment at present, but
analysis is ongoing; the estimated probability for 5-year OS for
four courses is 81%, five courses 78%, P ¼ 0.5, DFS for four
courses 65%, five courses 66%, P ¼ 0.8, and RR for four courses
33%, and five courses 32%, P ¼ 0.9. There was no difference in
the number of deaths in CR: four courses 2% vs five courses 1%,
P ¼ 0.3.
The risk group stratification derived from MRC AML 10
remains prognostically significant in MRC AML 12. For good,
standard and poor risk patients the estimated probability for
5-year survival from CR is 84, 76 and 47%; DFS 75, 62 and 41%
and RR 19, 37 and 54%, respectively (all Po0.0001). Only 35
children underwent a sibling transplant in 1st CR. However,
results from AML 10 and AML 12 can be combined to address
the question of the benefit of allo-BMT in the 1st CR in AML in
children. There was no heterogeneity for RR between the trials
(P ¼ 0.3) and combined, they showed a significant reduction in
RR (2P ¼ 0.02) which did not translate into a significant
reduction in DFS (2P ¼ 0.06) or OS (2P ¼ 0.1). The numbers of
children are too small for reliable interpretation, which will in
due course be based on the entire population aged up to 44
years in AML 10 and AML 12.
Table 5
AML 10
Results according to different risk parameters in MRC
Presenting features
Total number
of patients
OS % at 5 years
84
38
31
15
76
76
77
73
164
52
20
40
FAB classification
M0
M1
M2
M3
M4
M5
M6
M7
4
52
108
27
49
41
5
14
50
48
65
82
43
61
40
64
Status after course 1
Complete remission
Partial remission
Resistant disease
186
51
47
67
65
23
Age (years)
0–1
2–9
10–14
59
136
108
63
57
56
Risk group
Good
Standard
Poor
85
127
49
79
60
25
Cytogenetics
Favourable
t(8;21)
t(15;17)
inv(16)
Cytogenetics
Intermediate
Cytogenetics
Adverse
NB: data on status after course 1 and risk group is survival from start of
course 2.
Risk groups
The response after course 1 of treatment and diagnostic
cytogenetics were strongly predictive of outcome in MRC
AML 10.13 For children with CR, PR (5–15% blasts) and RD
(415% blasts), the 5-year survival from the start of course 2 was
67, 65 and 23% and the relapse rates were 34, 38 and 87%,
respectively (both Po0.0001), and for favourable, intermediate
and adverse karyotypic abnormalities, the survival was 76, 52
and 40% and the relapse rates were 34, 44 and 61%,
respectively (P ¼ 0.0007 and 0.006, respectively) (Table 5).
These factors combined to give three risk groups.
Good risk patients are defined as those with
t(8,21),inv(16),t(15,17) or FAB M3 morphology, irrespective of
bone marrow status after course 1 or the presence of other
genetic abnormalities; standard risk patients are those with
neither favourable nor adverse genetic abnormalities or FAB
M3, and not more than 15% blasts in the bone marrow after
course 1; poor risk patients are those with more than 15% blasts
in the bone marrow after course 1 or with adverse abnormalities
of 5, 7, del(5q), abn(3q), complex karyotype and without
favourable genetic abnormalities. The OS was intermediate for
patients with 11q23 abnormalities and similar for those with
t(9;11) compared to the other 11q23 translocations. (Harrison CJ
et al. Blood 2003; 102: 98a)
Leukemia
Treatment strategy and long-term results in paediatric patients
BES Gibson et al
2136
Toxicity
The treatment-related mortality for AML10 was 14% but
decreased in the latter half of the trial from 18 to 10%
(P ¼ 0.03) and fell to 10% in AML 12; 4% during induction in
both trials. The main cause of death was infection, with fungal
infection accounting for 23% of the infection-related deaths in
AML 10.14 Haemorrhage occurred most commonly early in
children with an initial WCC of greater than 100 109/l
(P ¼ 0.001), and M4 and M5 morphology. In AML 10, there
were nine deaths due to cardiac failure in children still receiving
treatment and in the majority (seven of nine) this occurred
during an episode of sepsis. Cardiac monitoring was not part of
the study and therefore subclinical reduction in cardiac function
may have been overlooked, and when exacerbated by infection
proved fatal. Cardiac deaths were only reported from course
3 onwards and after a cumulative anthracycline dose of 300
mg/m2. The incidence of long-term cardiac toxicity for this study
is unknown.
Acute promyelocytic leukaemia – FAB M3
APML represented 8% of children entered into MRC AML 10
and MRC AML 12. Extended-course ATRA (ATRA given during
induction chemotherapy until remission was achieved, or for
a maximum of 60 days) was found to be superior to shortcourse ATRA (ATRA given for 5 days only prior to starting
induction chemotherapy) both at a dose of 45 mg/m2 in MRC
AML 10; CR rate (Po0.001), induction deaths (P ¼ 0.02),
resistant disease (P ¼ 0.03), RR (P ¼ 0.04) and OS (P ¼ 0.005).
Extended-course ATRA became standard treatment in MRC
AML 12. The OS, DFS and RR for children with APML who
received extended ATRA in AML 10 and AML 12 are 75, 64 and
31%, respectively; 87, 79 and 18%, respectively, for those with
a WCC of o10 109/l.
Down syndrome
Treatment for children with DS in MRC AML 10 was not
modified but in MRC AML 12 they were allocated four courses
of chemotherapy only and were not eligible for BMT.
Approximately 6% of children entered into MRC AML 10 and
AML 12 had DS. In all, 34% of DS children and 4% of non-DS
children had FAB M7 morphology. There was a strikingly
different age distribution between DS and non-DS AML
children, 41 of 46 patients with DS were 1–3 years of age. In
this age group, the OS, DFS and EFS at 5 years was somewhat
better for DS compared to non-DS children for those treated
on MRC AML 10 and AML 12; 76 vs 63% (P ¼ 0.4), DFS 84
vs 59% (P ¼ 0.02) and EFS 76 vs 56% (P ¼ 0.08), respectively.
There were more induction and remission deaths in DS children;
10 vs 4% (P ¼ 0.2) and 16 vs 7% (P ¼ 0.05). The relapse rate
was significantly lower for DS children in this age group 0
vs 36% (P ¼ 0.0003). The most common additional cytogenetic
abnormality was trisomy 8 and favourable karyotypes were
absent.
Infants o1 year of age
All infants treated in MRC AML 10 and AML 12 had
chemotherapy arbitrarily reduced by 25% as a protocol
recommendation. Younger children had a high incidence
Leukemia
(35%) of 11q23 abnormalities. The favourable cytogenetic
abnormalities of t(8,21) or t(15,17) were not seen, but there
was one case of inv(16). The EFS at 5 years was 58% (56% for
normal cytogenetics, 55% for 11q23 and 64% for other
abnormalities), which was not significantly different from that
of older children (P ¼ 0.6), nor were DFS (65% at 5 years,
P ¼ 0.2) or RR (31%, P ¼ 0.3). There were more induction deaths
in infants (12 vs 3%, P ¼ 0.0008). Despite the absence of
favourable cytogenetics, the EFS is very encouraging for infants.
Discussion
While acknowledging the problems of nonrandomised comparisons, MRC AML 10 results are comparable with, or better than
those of other trial groups conducted during the same period.
The dosage, duration and total number of courses of treatment
were more intensive in MRC AML 10 than that used by most
other groups and this is the likely explanation for its superior
outcome. The hypothesis that more treatment is better was
further tested in MRC AML 12. The results of this trial are
immature, but while they suggest continuing improvement, this
cannot be explained by the benefit of additional therapy. The
reason for the observed improvement continues to be investigated, but is likely to be related to improvements in supportive
care and increased clinical experience.
The intensity of both induction and post remission treatment,
in terms of dosage and scheduling, is important in AML. The
CCG 2861 study15 compared standard timing during induction
(days 0–3 and 14–17 or later on count recovery) with intensive
timing (days 0–3 and 10–13 irrespective of count recovery). At 3
years there was no difference in CR rate (70 vs 75%), but a
significant EFS advantage for intensive timing (42 vs 27%,
Po0.0005), although at the expense of excess early deaths in
the intensive timing arm (11 vs 4%).
In MRC AML 10, A-BMT reduced relapse but did not
significantly improve long-term survival. There are three other
randomised paediatric trials that have shown no survival
advantage for A-BMT,15–18 and a meta-analysis19 concluded
that there was insufficient data to determine whether A-BMT is
superior to nonmyeloablative chemotherapy. Therefore, A-BMT
does not appear to have a major role in paediatric AML in first
remission, particularly when the acute and long-term morbidity
is considered. The lack of benefit found in MRC AML 10 for alloBMT mirrors the experience of the BFM,20 but not that of CCG
289118 who reported a significant survival advantage for alloBMT compared to A-BMT (P ¼ 0.002) and chemotherapy
(P ¼ 0.05) as postremission treatment, but no advantage for
A-BMT over intensive chemotherapy. However, the CCG
analysis was not a true intention to treat comparison since,
while all donor patients were included in the analysis whether
or not they received allo-BMT, not all patients without a donor
were included – only those who were randomised between
A-BMT and chemotherapy.21 It is possible that any benefit for
allo-BMT may be protocol dependent and may only appear
when less intensive treatment is delivered than that used by the
MRC. Whatever the benefit of allo-BMT, good and standard risk
children have a good outcome when treated with chemotherapy
alone, suggesting that BMT in CR 1, particularly with alternative
donor, with its associated morbidity and mortality, should
probably be restricted to poor risk patients. When MRC AML 10
and AML 12 are combined to increase numbers, there is no
statistically significant survival benefit for allo-BMT in 1st CR for
any risk group in children.
Treatment strategy and long-term results in paediatric patients
BES Gibson et al
2137
The BFM report that cranial irradiation not only reduces CNS
relapse, but also marrow seeding and relapse. MRC AML trials
have never employed cranial irradiation, but delivered intrathecal chemotherapy alone and the low incidence of isolated and
combined CNS relapses challenges the use of cranial irradiation
with its long-term sequelae.
The reported benefit of cranial irradiation in BFM-87 in
reducing bone marrow relapse occurred in nonrandomised
patients (randomised patients P ¼ 0.34, non randomised patients
P ¼ 0.01).22 The MRC strategy is to continue decreasing CNS
therapy in a step-wise manner. MRC protocols include high
dose ara-C, which may afford additional CNS protection.
The MRC risk group stratification has been confirmed to be
highly discriminatory in children treated in AML 10 and AML
12. In the UK, the coordination of cytogenetics facilitated a high
success rate in achieving an overall cytogenetic result of 88%
(93% of entrants with a specimen/information), with an
abnormality detection rate of 78% among successful cases.
In MRC AML 10 and AML 12, children received a relatively
high cumulative dose of anthracycline, but acute cardiotoxicity
was rare.23 However, anthracyclines are important in AML and
while it may be possible and desirable to reduce anthracycline
exposure, this must not be done at the expense of disease
control and without the safety of reduction being proven by
clinical trial.
Further improvement in outcome, particularly for poor risk
patients, requires new approaches. Monoclonal antibodies,
drugs targeted at specific fusion genes and multidrug-resistant
modifiers are being tested. MRD monitoring, gene expression
profiling and continued cytogenetic analysis may further refine
risk groups and allow treatment to be more tailored to risk and
biology of the disease. Toxicity will be limited by restricting
transplantation and reducing anthracycline dosage if the latter is
shown not to result in an increased relapse rate.
4
5
6
7
8
9
10
11
12
13
Acknowledgements
The MRC/UK Childhood Leukaemia Working Party acknowledge
the very significant contribution to MRC AML 10 and subsequent
trials of Dr Richard Stevens (Deceased). For Acknowledgements
refer to Supplementary Information.
14
15
Supplementary Information
Supplementary Information accompanies the paper on the
Leukemia website (http://www.nature.com/leu).
16
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