Outcome of children with high-risk acute myeloid leukemia given

Bone Marrow Transplantation (2015) 50, 181–188
© 2015 Macmillan Publishers Limited All rights reserved 0268-3369/15
www.nature.com/bmt
ORIGINAL ARTICLE
Outcome of children with high-risk acute myeloid
leukemia given autologous or allogeneic hematopoietic cell
transplantation in the aieop AML-2002/01 study
This article has been corrected since Advance Online Publication and an erratum is also printed in this issue.
F Locatelli1,2, R Masetti3, R Rondelli3, M Zecca4, F Fagioli5, A Rovelli6, C Messina7, E Lanino8, A Bertaina1, C Favre9, G Giorgiani4,
M Ripaldi10, O Ziino11, G Palumbo1, M Pillon7, A Pession3, S Rutella1,12 and A Prete3 on behalf of AIEOP BMT Working Group
We analyzed the outcome of 243 children with high-risk (HR) AML in first CR1 enrolled in the AIEOP-2002/01 protocol, who were
given either allogeneic (ALLO; n = 141) or autologous (AUTO; n = 102) hematopoietic SCT (HSCT), depending on the availability
of a HLA-compatible sibling. Infants, patients with AML-M7, or complex karyotype or those with FLT3-ITD, were eligible to be
transplanted also from alternative donors. All patients received a myeloablative regimen combining BU, Cyclophosphamide and
Melphalan; AUTO-HSCT patients received BM cells in most cases, while in children given ALLO-HSCT stem cell source was BM in 96,
peripheral blood in 19 and cord blood in 26. With a median follow-up of 57 months (range 12–130), the probability of disease-free
survival (DFS) was 73% and 63% in patients given either ALLO- or AUTO-HSCT, respectively (P = NS). Although the cumulative
incidence (CI) of relapse was lower in ALLO- than in AUTO-HSCT recipients (17% vs 28%, respectively; P = 0.043), the CI of TRM was
7% in both groups. Patients transplanted with unrelated donor cord blood had a remarkable 92.3% 8-year DFS probability.
Altogether, these data confirm that HSCT is a suitable option for preventing leukemia recurrence in HR children with CR1 AML.
Bone Marrow Transplantation (2015) 50, 181–188; doi:10.1038/bmt.2014.246; published online 10 November 2014
INTRODUCTION
The outcome of children with AML has significantly improved
over the past two decades.1–3 Besides better risk stratification,
use of repeated course of intensive consolidation therapy
and amelioration of supportive therapy, a remarkable contribution
to this improvement has been given by the wide use of
hematopoietic SCT (HSCT).4–7 In particular, for children achieving
first CR1, allogeneic (ALLO) HSCT from an HLA-identical sibling
has been shown to be the most effective post-remission
therapy for preventing leukemia recurrence.5,7 Nowadays, large
cooperative groups consider AML children with high-risk (HR)
features, such as unfavorable cytogenetic/molecular characteristics or poor minimal residual disease clearance, eligible
to be offered an allograft from an HLA-compatible sibling in
CR1.2,8 In the past few years, several studies have documented
that transplantation of unrelated CB cells in children with CR1
AML is associated with a favorable outcome, particularly in
patients aged less than 1 year at time of diagnosis.9–11 The
use of high-resolution molecular typing techniques for selecting
an unrelated donor (UD) has also dramatically reduced the
risk of immune-mediated complications and TRM, thus
widening the indications for HSCT from an unrelated volunteer,
which now are in part coincident with those for matched-related
HSCT.12,13
Although largely used in the past,14,15 more recently the role of
autologous (AUTO) HSCT has been questioned, especially in view
of similar efficacy to repeated courses of intensive high-dose
cytarabine (HD-AraC)-based consolidation chemotherapy for
prevention of disease recurrence.5,16
We recently reported that risk-oriented treatment and broad
use of HSCT in children with CR1 AML resulted in a long-term
outcome, which compares favorably with that reported in other
patient series.17 In this study, we thoroughly analyze the results of
the 243 HR children enrolled in the AIEOP AML 2002/01 protocol,
who were given either AUTO or ALLO HSCT for consolidating
remission after achievement of CR1.
PATIENTS AND METHODS
Patients
Included in this study were 243 HR children in CR1, aged 0–18 years,
affected by de novo AML other than acute promyelocytic leukemia, who
were treated according to the AIEOP AML 2002/01 protocol, which was
approved by the Ethical Committee of each participating Institution (listed
1
Department of Pediatric Hematology-Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Bambino Gesù Children's Hospital, Roma, Italy; 2Department of
Pediatric Science, University of Pavia, Pavia, Italy; 3Pediatric Oncology and Hematology Unit ‘Lalla Seragnoli’, Department of Pediatrics, University of Bologna Sant’Orsola-Malpighi
Hospital, Bologna, Italy; 4Department of Pediatric Onco-Hematology, IRCCS, Policlinico San Matteo Foundation, Pavia, Italy; 5Pediatric Onco-Hematology, Stem Cell
Transplantation and Cellular Therapy Division, Regina Margherita Children's Hospital, Torino, Italy; 6Department of Pediatric Hematology, San Gerardo Hospital, Monza, Italy;
7
Department of Pediatric Hematology and Oncology, University of Padova, Padova, Italy; 8Department of Pediatric Hematology Oncology, IRCCS G. Gaslini Institute, Genova, Italy;
9
Department of Pediatrics, University of Pisa, Pisa, Italy; 10BMT Unit, Department of Pediatric Hemato-Oncology, Santobono-Pausilipon Hospital, Napoli, Italy; 11Pediatric
Hematology/Oncology, ARNAS Ospedale Civico di Palermo, Palermo, Italy and 12Department of Medical Sciences, Catholic University Medical School, Rome, Italy.
Correspondence: Professor F Locatelli, Department of Pediatric Hematology and Oncology, IRCCS Ospedale Pediatrico Bambino Gesù, Piazza S. Onofrio, 4, Rome 00165, Italy.
E-mail: franco.locatelli@opbg.net
Received 15 July 2014; revised 6 September 2014; accepted 11 September 2014; published online 10 November 2014
Autologous and allogeneic HSCT in childhood AML
F Locatelli et al
182
before references). Either parents or legal guardians provided written
informed consent to patient treatment. Patients with a previous
myelodysplastic phase, with Down's syndrome or who had received
previous treatment with either cytotoxic agents or steroids in the 2 weeks
preceding diagnosis were deemed not to be eligible for inclusion into the
study. Details on demographics and clinical or biological characteristics of
these HR patients are shown in Table 1, which also includes a separate
analysis of children who received either AUTO- or ALLO-HSCT.
Table 1.
Donor selection
In the AIEOP AML 2002/01 protocol, patients with isolated anomalies of
CBF-β and in morphologic CR after the first induction course were
allocated to the standard-risk (SR) group; the remaining children were
assigned to the HR group and, thus, eligible to be treated with HSCT. All
these HR children with an available HLA-compatible sibling were
transplanted using this type of donor. Infants, patients with AML-M7,
those with a complex karyotype or FLT3-internal tandem duplication (ITD)
Patients and donor characteristics
Whole population
%
AUTO-HSCT (%)
ALLO-HSCT (%)
P-value
107
136
44
56
43 (40)
57 (42)
64 (60)
79 (58)
ns
ns
Age
Median age at HSCT, years (range)
o1 year
1–2 year
2–10 year
410 year
7.2 (0.6–17.5)
46
27
92
78
19
11
38
32
7
10
44
40
39
17
48
38
WBC count (x109/L)
WBC at diagnosis, median (range)
o10
10–99
4100
23.9 (0.9–475)
96
112
35
39
46
15
37 (39)
45 (40)
19 (54)
59 (61)
67 (60)
16 (46)
16
40
45
39
67
4
25
7
7
16
18
16
28
2
10
3
5
24
17
20
33
0
0
3
11
16
28
19
34
4
25
4
33
192
18
4
45
24
4
14
79
7
2
19
10
2
10 (30)
23 (70)
0
0
20
4
0
18
2
25
20
4
243
%
102
58
75
45
30
15
7
8
8
42
24
31
19
12
6
3
3
3
141
93
26
22
102
87
15
58
66
18
16
42
85
15
Patients
Gender
F
M
FAB
M0
M1
M2
M4
M5
M6
M7
Unclassifiable/not known
Subgroups
CNS leukemia at diagnosis
Available cytogenetic data
Complex karyotype
Monosomal karyotype
11q23 abnormalities
FLT3-ITD-positive
FLT3-TKD-positive
Donor
Type of donor
AUTO
MFD
UD
Fully matched
Mismatched
1 antigen
1 allele
4 1 antigen/allele
HAPLO
Stem cell source
Allogeneic
BM
Cord
PBSC
Autologous
BM
PBSC
(15)
(37)
(48)
(51)
(31)
(60)
(38)
(51)
(49)
(0)
(0)
(43)
(0)
(0)
(44)
(17)
(0)
(85)
(63)
(52)
(49)
(69)
(40)
(62)
(49)
(51)
(100)
(100)
(57)
(100)
(100)
(56)
(83)
(100)
ns
o0.001
ns
ns
ns
ns
ns
ns
0.002
ns
ns
ns
ns
o0.001
o0.001
ns
0.001
ns
o0.001
o0.001
ns
o0.001
o0.001
Abbreviations: AUTO = autologous; CNS = central nervous system; F = female; HAPLO = HLA-haploidentical; HSCT = hematopoietic SCT; M = male;
MFD = matched family donor; pts = patients; UD = unrelated donor.
Bone Marrow Transplantation (2015) 181 – 188
© 2015 Macmillan Publishers Limited
Autologous and allogeneic HSCT in childhood AML
F Locatelli et al
183
or achieving CR1 only after the second course of induction therapy were
considered eligible to be transplanted from an alternative donor, namely an
UD, or an unrelated CB donor or an HLA-partially matched family donor.
Eligible for AUTO-HSCT were those HR children without an HLA-identical
sibling who did not qualify for receiving an allograft from an alternative
donor. As far as children transplanted from either an HLA-identical sibling
or using CB cells are concerned, in both donor and recipient, histocompatibility was determined by serology for HLA-A and HLA-B antigens and by
DNA typing for the HLA-DRB1 locus. In all children transplanted from an UD,
both class I and class II HLA alleles (that is, HLA-A, HLA-B, HLA-C, DRB1 and
DQB1) of the donor/recipient pair were typed by high-resolution, 4-digit
DNA technique. All UD ALLO-HSCT recipients were transplanted using a
donor with complete identity or a single-locus mismatch. The transplant
centers preferentially required BM as the stem cell source; however, the
final choice was left to the UD. Of the 26 CB transplant recipients, 10 were
transplanted from an HLA-identical donor, 11 from a 1-antigen disparate
donor, and 5 using a unit with 2 HLA disparities. For patients candidate to
receive an UD ALLO-HSCT, the search for locating a suitable unrelated
volunteer or a CB unit started simultaneously. CB transplantation was
performed whenever a donor with an HLA compatibility of at least 4/6 and
a pre-thawing number of total nucleated cells/kg of recipient’s body weight
of at least 3.5 × 107 was available.
Pre-transplant treatment
Before transplantation, all patients had been given two courses of
induction chemotherapy, including idarubicin, cytarabine and etoposide
(ICE, see Ravindranath et al.16 for details). After having achieved CR1, two
consolidation courses including HD-Ara-C, combined with either etoposide
in the first course (AVE) or mitoxantrone in the second course (HAM) were
administered. BM harvesting and in vitro purging with mafosfamide for
patients given AUTO-HSCT was recommended after the first consolidation
course.14 Purging was performed for 78 AUTO-HSCT.
Conditioning regimen and GVHD prophylaxis
The conditioning regimen was homogenous in all the patients and it
consisted of a combination of Busulfan (BU, 16 mg/Kg over 4 days),
Cyclophosphamide (CY, 120 mg/Kg divided in two doses) and Melphalan
(L-PAM, 140 mg/m2).18 Seventy-five percent of patients received oral BU,
the remaining being treated with the i.v. formulation of the drug. In 221
out of the 243 patients (91%), BU dosage was adjusted based on the
pharmacokinetic study performed in a centralized laboratory in Pavia
following the first administration, in order to maintain a steady-state
concentration comprised between 600 and 900 ng/mL.
GVHD prophylaxis consisted of CsA alone for 95% of matched family
donor recipients, and of a combination of CsA, short-term MTX and rabbit
anti-thymocyte globulin (ATG, 2.5–3.75 mg/kg/day from day − 4 to day − 2)
for 85% of UD recipients. Children transplanted with unrelated CB units
received a GVHD prophylaxis based on the combination of CsA and
steroids.11
Definitions
Patients were considered in morphological CR if they had o5% blast cells
in a BM smear, no extramedullary disease and normal neutrophil and
platelet counts. All the patients had a lumbar puncture before HSCT to
document cerebrospinal fluid CR.
Neutrophil and platelet engraftment were defined as the first of the
three consecutive days with a neutrophil count 40.5 × 109/L and an
unsupported platelet count 420 × 109/L, respectively.
Acute and chronic GVHD (aGVHD and cGVHD) were diagnosed and
graded according to established criteria.19,20 Children surviving more than
14 days and 100 days post transplantation and with evidence of donor
engraftment were evaluated for the occurrence of aGVHD and cGVHD,
respectively. Relapse was defined on the basis of morphological evidence
of leukemia in BM, or at other extramedullary sites. TRM was defined as all
causes of non-leukemia death occurring after HSCT. OS was defined as the
interval between HSCT and either death or date of last follow-up. Diseasefree survival (DFS) was defined as the interval between HSCT and either
relapse, or death, or date of last follow-up, whichever occurred first.
Statistical analysis
Patient-, disease- and transplantation-related variables were expressed as
median and ranges, or as percentages, as appropriate. The following
© 2015 Macmillan Publishers Limited
patient- or transplantation-related variables were analyzed for their
potential impact on outcome: gender, age, WBC at diagnosis, FrenchAmerican-British subgroups, donor type, stem cell source, abnormalities
involving MLL, FLT3-ITD, aGVHD and cGVHD occurrence. Patients were
censored at the time of relapse, death or last follow-up. Probability of OS
and DFS was estimated by the Kaplan-Meier product-limit method and
expressed as percentage ± s.e. aGVHD and cGVHD occurrence, as well as
TRM and relapse incidence (RI), were expressed as cumulative incidence
(CI) curves ± s.e., in order to adjust the analysis for competing risks.21 Death
from any cause and graft rejection were competing risks to estimate the CI
of aGVHD and cGVHD. Death in remission was treated as a competing
event to calculate the cumulative RI. Relapse was considered to be the
competing event for calculating the CI of TRM.
The significance of differences between the DFS curves was estimated
by the log–rank test (Mantel–Cox), whereas in the univariate analyses,
Gray’s test was used to assess differences between RI and TRM. All
variables having a p-value o .05 in univariate analysis were included in a
multivariate analysis on DFS performed using the Cox proportional
regression model,22,23 while the proportional sub-distribution hazard
regression model was used to perform multivariate analyses of CI of
relapse and death in continuous CR. Computations were performed using
SAS (Statistical Analysis System, Version 8.2, SAS Institute Inc., Cary, NC,
USA). Analysis used 31 March 2013 as the reference date.
RESULTS
The median observation time for the surviving patients, considering the whole study population, was 57 months (range: 12–130).
The median follow-up did not differ according to the type of
transplantation received by the patient (data not shown). The
patient flowchart is depicted in Figure 1. The median time from
achievement of CR to transplantation was 139, 125 and 136 days
for AUTO-HSCT, HLA-identical sibling ALLO-HSCT and UD ALLOHSCT, respectively (P = ns). The stem cell source employed did not
significantly influence the median time elapsing from achievement of CR and transplantation (data not shown).
Hematopoietic recovery
Neutrophil engraftment was reached in 240 out of 243 children
and the median time to neutrophil recovery was 13 days (range 9–
61) and 17 days (range 9–52), for AUTO- and ALLO-HSCT
recipients, respectively (P = 0.11). Platelet recovery was reached
in 235 children, the median time for obtaining an unsupported
platelet count more than 20 × 109/L being 21 days (range 12–119)
and 25 days (range 10–132), for AUTO- and ALLO-HSCT recipients,
respectively (P = 0.12).
Chimerism analysis during 100 days was available for 135 out of
the 141 patients receiving an allograft. Of those patients reaching
neutrophil recovery, 99% had full donor chimerism and 1% were
mixed chimera.
Acute and chronic GVHD
Eighty-two out of the 141 patients given an allograft developed
grade I–IV aGvHD, the median time of onset being 14 days (range
8–70); 53 and 19 of them had grade II–IV and grade III–IV acute
GvHD, respectively. The CI of grade II–IV and grade III–IV acute
GVHD was 38.1% (s.e. 4.1) and 13.7% (s.e. 2.9), respectively
(Figure 2a). The CI of grade II–IV aGVHD in children transplanted
from either an HLA-identical sibling or an adult UD or with UD CB
cells was 35.1% (s.e. 6.3), 45.1% (s.e. 7.2) and 38.5% (s.e. 9.5),
respectively (P = ns).
Thirty-three patients developed cGVHD, the median time of
onset being 165 days (range 100–426). In 22 of them, cGVHD was
of limited severity, while the remaining 11 children experienced
the extensive form of the disease. In 27 patients, cGVHD was
preceded by aGVHD. The overall CI of cGVHD was 25.3% (s.e. 3.8),
while that of extensive cGVHD was 8.6% (s.e. 2.5; Figure 2b).
Bone Marrow Transplantation (2015) 181 – 188
Autologous and allogeneic HSCT in childhood AML
F Locatelli et al
184
AML 2002/01 study:
421 patients in CR after induction
96 SR patients treated with
chemotherapy only
325 HR
patients
113 AUTO-HSCT
candidates
77 with an available
MFD donor
135 eligible to UD
52 patients lost due to:
toxic death/relapse
during consolidation
or refusal of HSCT
11 patients lost due to:
toxic death/relapse
during consolidation
or refusal of HSCT
19 patients lost due to:
toxic death/relapse
during consolidation
or refusal of HSCT
8 patients
without a MUD
102 AUTO
Figure 1.
8 HAPLO
75 MUD
58 MFD
Consolidated Standards for Reporting of Trials (CONSORT) diagram.
100
CI of chronic GvHD (%; SE)
CI of grade II-IV
acute GvHD (%; SE)
100
75
50
Grade II-IV = 38.1%(4.1)
25
Grade III-IV = 13.7%(2.9)
75
50
Chronic GvHD = 25.3% (3.8)
25
Extensive chronic GvHD = 8.6%(2.5)
0
0
0
2
4
6
8
10
12
14
16
0
Weeks from HSCT
1
3
2
Years from HSCT
Figure 2. (a) Cumulative incidence (s.e.) of grade II–IV and of grade III–IV aGVHD in the whole population of children given allogenic HSCT
(ALLO-HSCT). (b) Cumulative incidence ( ± s.e.) of overall and extensive cGVHD in the whole population of children given ALLO-HSCT.
Transplantation-related mortality
Sixteen patients died from transplantation-related causes, seven
after AUTO- and nine after ALLO-HSCT. Five of the seven patients
who died after AUTO-HSCT had the fatal event before 2006. The CI
of TRM in AUTO- and AUTO-HSCT was 7.1% (s.e. 2.8) and 7.4% (s.e.
2.5), respectively (P = ns). Neither type of donor nor stem cell
source employed influenced the risk of TRM in the 141 patients
given an allograft. Table 2 enlists the causes of death in patients
given either ALLO- or AUTO-HSCT. Only one of the four children
who died because of sinusoidal obstruction syndrome had a
steady-state BU concentration higher than the recommended
range (data not shown). The CI of TRM of the 82 patients who
experienced GVHD was 8.9% (s.e. 3.6), whereas that of patients
who did not develop GVHD was 7.0% (s.e. 3.4; P = ns). Likewise,
occurrence of cGVHD did not influence the risk of dying for
transplantation-related complications (data not shown).
Bone Marrow Transplantation (2015) 181 – 188
Table 2. Causes of death in patients given either allogeneic or
autologous HSCT
Causes of death
Autologus HSCT
Allogeneic HSCT
4
—
—
1
2
—
3
4
1
—
Sinusoidal obstruction syndrome
aGVHD
cGVHD
Pulmonary aspergillosis
Bacterial sepsis
Abbreviation: HSCT = hematopoietic SCT.
Leukemia relapse
Fifty-one patients experienced leukemia relapse: 29 after AUTOand 22 after ALLO-HSCT; the CI of leukemia recurrence was 28.3%
© 2015 Macmillan Publishers Limited
Autologous and allogeneic HSCT in childhood AML
F Locatelli et al
185
100
Table 3.
% (SE)
75
P=0.043
50
AUTO 8-year C.I. of relapse (SE) = 28.3% (4.5)
25
ALLO 8-year C.I. of relapse (SE) =17.4% (3.3)
0
0
2
6
4
8
10
Years from HSCT
Figure 3. Cumulative incidence ( ± s.e.) of leukemia relapse in
children with CR1 AML given either an autologous or an
allogeneic HSCT.
100
ALLO 8-year DFS (SE) = 73% (4.0)
% (SE)
75
AUTO 8-year DFS (SE) = 63% (4.9)
50
25
0
0
2
4
6
8
10
Years from HSCT
Figure 4. Eight-year probability of disease-free survival (DFS, ± s.e.)
for children with CR1 AML given either an allogeneic or an
autologous HSCT.
100
CORD 8-year DFS = 92.3 (5.2)
BM 8-year DFS = 75.5 (4.6)
% (SE)
75
PBSC 8-year DFS = 53.0 (12.6)
50
P = 0.0035
25
0
0
2
4
6
8
10
Probability of 8-year EFS by subgroups
Variable
Cases
8-Year EFS
s.e.
Gender
F
M
107
136
63.3
74.0
5.4
3.9
46
27
92
78
58.2
61.2
65.4
69.8
7.6
9.4
6.8
5.0
96
112
35
76.2
67.0
57.9
4.6
5.2
8.7
16
40
45
39
67
4
25
7
68.7
55.4
76.2
69.8
71.9
100
63.3
85.7
11.6
9.4
6.6
9.1
5.6
−
9.8
13.2
24
219
73.3
70.2
11.8
3.5
4
239
50
65.8
25
4.8
45
198
72.6
68.6
6.8
3.7
18
225
55.0
70.9
11.9
3.4
102
141
62.8
73.1
4.9
4.0
58
45
30
8
73.8
84.0
73.5
49.6
6.3
5.5
9.2
18.6
180
26
37
67.2
92.3
62.7
3.8
5.2
9.1
P-value
0.14
0.81
Age
o 1 year
1–2 year
2–10 year
4 10 year
WBC count (x109/L)
o 10
10–99
4 100
0.12
FAB
M0
M1
M2
M4
M5
M6
M7
Unclassifiable/not known
Subgroups
FLT3-ITD
Yes
No
FLT3-TKD
Yes
No
11q23 abnormalities
Yes
No
Complex karyotype
Yes
No
0.71
0.51
0.54
0.86
0.13
0.06
Type of transplant
AUTO
ALLO
0.12
Type of donor
MFD
MUD
MMUD
HAPLO
0.06
Stem cell source
BM
Cord blood
PBSC
Years from HSCT
0.0035
Figure 5. Eight-year probability of DFS ( ± s.e.) for children with CR1
AML given allogeneic HSCT according to the stem cell source used.
Stem cell source only for ALLO
BM
Cord blood
PBSC
95
26
20
75.5
92.3
53.0
4.6
5.2
12.6
(s.e. 4.5) and 17.4% (s.e. 3.3) after AUTO- and ALLO-HSCT,
respectively (P = 0.043, Figure 3). The median time to leukemia
recurrence was 6.3 months (range 1.1–49.5). Relapse involved BM
only in 42 patients, while either combined or isolated extramedullary relapse occurred in 6 and 3 patients, respectively. In the
subgroup of patients given an allograft, the stem cell source
employed did not influence the risk of leukemia recurrence (data
not shown). Notably, only 2 out of the 26 children given CB
transplantation experienced leukemia relapse, this translating into
a CI of recurrence of only 7.7% (s.e. 5.2). By contrast, the CI of
relapse in children transplanted from an HLA-identical sibling or
Stem cell source only for UD
BM
Cord blood
PBSC
39
26
10
74.5
92.3
50.0
6.7
5.2
21.2
aGVHD
Yes
No
82
59
74.8
76.1
5.1
5.9
aGVHD, grade II-IV
Yes
No
53
88
78.3
73.3
6.4
4.9
© 2015 Macmillan Publishers Limited
0.18
0.79
0.42
Bone Marrow Transplantation (2015) 181 – 188
Autologous and allogeneic HSCT in childhood AML
F Locatelli et al
186
Table. 3.
(Continued )
Variable
Cases
8-Year EFS
s.e.
aGVHD, grade III-IV
Yes
No
19
122
72.3
75.7
12.6
4.0
cGVHD
Yes
No
33
106
81.9
74.6
7.6
4.4
Extensive cGVHD
Yes
No
11
128
61.4
78.3
15.3
3.8
P-value
0.87
0.23
0.31
Abbreviations: ALLO = allogeneic; AUTO = autologous; CNS = central nervous system; F = female; HAPLO = HLA-haploidentical HSCT; HSCT = hematopoietic SCT; M = male; MFD = matched family donor; MMUD = mismatched unrelated donor; MUD = matched unrelated donor; pts =
patients.
an adult UD was 18.6% (s.e. 5.3) and 17.2% (s.e. 5.6), respectively
(P = ns). While there was no difference in terms of leukemia
recurrence for children who did or did not experience aGVHD
(data not shown), only 2 out of the 33 patients who experienced
cGVHD relapsed, as compared to 19 of the 106 patients who did
not develop this complication, the CI of relapse in patients with or
without cGVHD being 6.1% (s.e. 4.1) and 19.4% (s.e. 4.0),
respectively (P = 0.09).
Overall and event-free survival
The 8-year probability of OS for the whole cohort of patients was
75.1% (s.e. 3.0); it was 75.5% (s.e. 4.4) and 74.7% (s.e. 4.0) for
patients given either AUTO- or ALLO-HSCT, respectively (P = ns).
The 8-year DFS, calculated from the date of HSCT, for the 102
patients given an AUTO-HSCT was 63% (s.e. 4.9); it was 73% (s.e.
4.0) for the 141 patients given an allograft (P = ns; Figure 4). The 8year DFS for AUTO-HSCT recipients who did or did not receive
in vitro purging was comparable (data not shown).
The 8-year probability of DFS for patients transplanted from an
HLA-identical sibling was 73.8% (s.e. 6.3); it was 75.5% (s.e. 4.6),
53% (s.e. 12.6) and 92.3% (s.e. 5.2) for patients given either BM, or
PBSC from an unrelated volunteer or CB cells, respectively (overall
P = 0.0035; Figure 5).
Table 3 reports details on the influence of the different variables
analyzed on the probability of 8-year DFS. None of the variables
analyzed resulted to be significantly associated with DFS in
multivariate analysis.
Notably, out of the 29 patients who experienced relapse after
AUTO-HSCT 11 are alive and disease-free after having received an
ALLO-HSCT in CR2; in 5 out of these 11 patients, the donor was an
HLA-haploidentical relative.
DISCUSSION
We report the outcome of children with HR-AML in CR1, who were
given either AUTO- or ALLO-HSCT in the AIEOP AML 2002/01
study. We have previously demonstrated that a broad use of HSCT
in this HR population is able to lower the CI of relapse to an extent
comparable to that of SR children,17 suggesting that transplantation can abolish the detrimental impact mainly imparted by
specific molecular lesions and poor response to therapy.
More than 75% of the patients in CR1 enrolled in this study
became long-term survivors, leukemia recurrence being the most
important cause of treatment failure. The strength of our results
lies on the fact that: (i) children were prospectively allocated to the
Bone Marrow Transplantation (2015) 181 – 188
HR group according to consistent criteria of stratification; (ii) all
patients received the same chemotherapy treatment for inducing
and consolidating remission before transplantation; and (iii) they
were given a homogenous conditioning regimen.
Our data argue that, despite being used in children with more
adverse prognostic features (see also Tables 1 and 3), ALLO-HSCT
is more effective than AUTO-HSCT in preventing leukemia
recurrence, without this positive effect being obscured by an
increased risk of TRM. Indeed, both in AUTO- and in ALLO-HSCT
the CI of TRM was 7%, a value which compares favorably with
previously reported data on ALLO-HSCT,4,5,7,10 while it was worse
than expected in AUTO-HSCT. In this regard, it has to be
emphasized that more than a half of the fatal events were due
to sinusoidal obstruction syndrome, a complication known to
occur with increased incidence in patients given BU as part of the
conditioning regimen.24 However, there is no obvious explanation
why sinusoidal obstruction syndrome occurred only in AUTOHSCT recipients, although more Centers perform this type of
transplantation in comparison to those involved in the ALLO-HSCT
procedure.
The final outcome of our patients transplanted from an UD did
not differ from that of patients given HSCT from an HLA-identical
sibling and the 8-year DFS of 73% observed in our cohort of UD
HSCT recipients compares favorably with results reported in
previously published studies.10,25,26 The outcome of children
transplanted from UDs acquires particular value in light of the
fact that this type of allograft was employed in patients either with
poor-prognosis molecular lesions, such as FLT3-ITD, or in infants,
or in children with M7-AML or complex karyotype or in those
patients not responding to the first course of induction therapy,
these subgroups notoriously predicting a grim prognosis.2,8,17,27,28
We and others have previously provided evidence that the
outcome of children with acute lymphoblastic leukemia given
HSCT from an UD has improved over time,12,13,26 and the present
results confirm that currently, thanks to the improvements in HLA
typing obtained through the use of high-resolution molecular
techniques and the optimization of GVHD prevention and
treatment, post-transplantation outcome is not influenced by
the type of donor used, either related or unrelated.
The outcome of children transplanted with CB cells is
particularly remarkable, as the probability of DFS in this subgroup
of patients overcomes 90%. Our data confirm and strengthen the
data reported by Michel et al.11 on children with AML receiving
single-unit CB transplantation after a myeloablative preparation.
These data were recently updated by Ruggeri and Colleagues9 for
the subgroup of infants with AML, in whom the reported 4-year
DFS was 82% for those patients who were transplanted in CR1.
The favorable outcome of children transplanted with CB cells was
both due to a particularly low risk of TRM and to a CI of recurrence
of only 7.7%.
Previously published studies have reported that FLT3-ITD is an
adverse prognostic factor in childhood AML.27,28 In particular,
Meshinchi et al.27 reported that children with FLT3-ITD had a 4year progression-free survival and a CI of leukemia recurrence of
31% and 65%, respectively. The probability of OS in children with
FLT3-ITD given an allograft from a matched family donor
increased to 64%, thanks to reduced risk of leukemia recurrence.
The 74% probability of 8-year DFS in our cohort confirms and
extends the data by Meshinchi et al., as well as those of other
published studies,29,30 documenting that ALLO-HSCT can supersede the negative prognostic impact of FLT3-ITD in AML.
The 72% probability of 8-year DFS observed in our patients with
11q23 abnormalities mimics that reported by the I-BFM group in a
recently published paper (71% at 5 years),7 this finding confirming
that the subgroup of children with CR1 AML and MLL rearrangement has a high probability of benefiting from HSCT. In particular,
the 17 children with t(9;11) had a DFS probability of 82%, while
© 2015 Macmillan Publishers Limited
Autologous and allogeneic HSCT in childhood AML
F Locatelli et al
187
the 28 children carrying MLL rearrangements with other partner
genes had a DFS probability of 65% (P = ns).
The choice of adopting a preparative regimen consisting of 3
alkylating agents was inspired by studies demonstrating the safety
and efficacy of this therapy in both AML and juvenile myelomonocytic leukemia.18,31 Since we transplanted patients in CR1, the
risk of TRM and of leukemia recurrence in our allograft recipients
(7% and 17%, respectively) are in line with those (12% and 33%,
respectively) reported by Beier et al.32 in children with AML in CR2,
after the same conditioning regimen. Moreover, preparative
regimens before the allograft which do not include TBI are
particularly attractive for children, since radiation-induced late
effects may be especially deleterious for very-young children.33–35
The merits of using HSCT, in particular the autograft procedure,
as consolidation therapy for pediatric patients with CR1 AML have
been contested vigorously in the past years in light of the
progress achieved with chemotherapy, and the risks inherent to
the procedure have been advocated in support of restricting the
use of transplantation.2,4 Moreover, growing attention has been
paid to the emergence of the potentially severe side effects,
including also cGVHD, correlated to the transplant procedure.
These considerations must certainly be put forward also in our
cohort of patients, which, however, did not include any child with
acute promyelocytic leukemia or core-binding factor anomalies.
As we previously reported,17 37 HR patients (11% of the whole HR
population included in the AIEOP-2002/01 protocol) received
neither AUTO- nor ALLO-HSCT at the end of consolidation therapy.
These patients had a significantly worse outcome in comparison
with those given HSCT.
In the successor protocol, the AIEOP group will not use AUTOHSCT and will restrict the indications to ALLO-HSCT to a
population of patients (40–45% of the total number of children
with AML other than acute promyelocytic leukemia instead of the
75–80% of patients who were given HSCT in the protocol AIEOP
2002/01) with biological and treatment-related characteristics
predicting poor outcome if treated with chemotherapy only (see
Pession et al.17 and Hasle36 for details).
In conclusion, our data document that both AUTO- and ALLOHSCT, after a preparative regimen consisting of BU, CY and
melphalan, offer a chance of cure for a large proportion of
children with AML in CR1. Disease recurrence remains the major
cause of treatment failure, and strategies to reduce the risk of
relapse are warranted. In the future, the role of HSCT in the
treatment of children and adolescents with AML in CR1 will need
to be reassessed as the field evolves. In this regard, a more refined
selection of children candidate to receive transplantation in CR1
based on genetic parameters, such as monosomy 7, complex
karyotype, FLT3-ITD, so on1,2,36–39 and response to initial
treatment through the use of flow cytometry for measuring
minimal residual disease36,40 can contribute to further improve
patient’s outcome and to spare long-term side effects associated
with the transplant procedure.
CONFLICT OF INTEREST
The authors declare no conflict of interest.
ACKNOWLEDGEMENTS
This study was supported by research grants awarded by Associazione Italiana per la
Ricerca sul Cancro (5 x 1000 Special Grant #9962 to FL), by PRIN (Progetti di Rilevante
Interesse Nazionale) 2010 to FL and 2012 to SR, by Ospedale Bambino Gesù, Roma,
(Progetto di Ricerca Corrente 2012–2013) to AB and FL, and FILAS (Adult Stem Cells) to SR.
LIST OF PARTICIPATING CENTERS AND INVESTIGATORS
Department of Pediatric Onco-Hematology, Istituto di Ricovero e
Cura a Carattere Scientifico (IRCCS), Policlinico San Matteo
© 2015 Macmillan Publishers Limited
Foundation, Pavia. Franco Locatelli (till January 2010), Marco
Zecca, Giovanna Giorgiani [38 HSCT].Department of Pediatric
Hematology-Oncology, Istituto di Ricovero e Cura a Carattere
Scientifico (IRCCS), Bambino Gesù Children's Hospital, Roma.
Franco Locatelli (since January 2010), Alice Bertaina, Maurizio
Caniglia, Giuseppe Palumbo, Sergio Rutella [30 HSCT]. Department
of Pediatric Hematology and Oncology, University of Padova,
Padova. Chiara Messina, Marta Pillon [29 HSCT]. Department of
Pediatric Hematology, San Gerardo Hospital, Monza. Adriana
Balduzzi, Attilio Rovelli [27 HSCT]. BMT Unit, Department of
Pediatric Hemato-Oncology, Santobono-Pausilipon Hospital,
Napoli. Mimmo Ripaldi [24 HSCT]. Department of Pediatric
Hematology Oncology, IRCCS G. Gaslini Institute, Genova. Edoardo
Lanino, Giorgio Dini [23 HSCT]. Pediatric Onco-Hematology, Stem
Cell Transplantation and Cellular Therapy Division, Regina
Margherita Children's Hospital, Torino. Franca Fagioli [15 HSCT].
Pediatric Oncology and Hematology Unit ‘Lalla Seragnoli’,
Department of Pediatrics, University of Bologna Sant’OrsolaMalpighi Hospital, Bologna. Riccardo Masetti, Arcangelo Prete,
Andrea Pession [12 HSCT]. Department of Pediatrics, University of
Pisa, Pisa. Claudio Favre [9 HSCT]. Pediatric Hematology/Oncology,
ARNAS Ospedale Civico di Palermo. Ottavio Ziino, Paolo D’Angelo
[8 HSCT]. Pediatric Hematology/Oncology, University Hospital,
Catania. Luca Lo Nigro [8 HSCT]. BMT Unit, Ospedale di Pescara.
Paolo Di Bartolomeo [6 HSCT]. BMT Unit, Ospedale Pediatrico
Burlo Garofalo, Trieste. Marco Rabusin [6 HSCT]. BMT Unit,
Department of Pediatric Hematology/Oncology, Ospedale Pediatrico Meier, Florence. Desiree Caselli [5 HSCT]. BMT Unit, Pediatric
Hematology/Oncology, Ospedale Silvestrini, Perugia. Franco
Aversa [3 HSCT].
AUTHOR CONTRIBUTIONS
FL designed the study, interpreted data, performed transplantation and wrote
the article; RM designed the study, checked data and performed transplantation; RR analyzed data; MZ, FF, AR, CM and EL designed the study, performed
transplantation and followed patients; AB, CF, GG, MR, GP, MP and OZ
performed transplantation and followed patients; AP designed the study,
performed transplantation and interpreted the data; SR interpreted the data
and wrote the paper; ArPr contributed to study design, interpreted the data and
performed transplantation.
REFERENCES
1 Pui CH, Carroll WL, Meshinchi S, Arceci RJ. Biology, risk stratification, and therapy
of pediatric acute leukemias: an update. J Clin Oncol 2011; 29: 551–565.
2 Creutzig U, van den Heuvel-Eibrink MM, Gibson B, Dworzak MN, Adachi S,
de Bont E et al. Diagnosis and management of acute myeloid leukemia in children
and adolescents: recommendations from an international expert panel. Blood
2012; 120: 3187–3205.
3 Kaspers GJ, Zwaan CM. Pediatric acute myeloid leukemia: towards high-quality
cure of all patients. Haematologica 2007; 92: 1519–1532.
4 Niewerth D, Creutzig U, Bierings MB, Kaspers GJ. A review on allogeneic stem cell
transplantation for newly diagnosed pediatric acute myeloid leukemia. Blood
2010; 116: 2205–2214.
5 Woods WG, Neudorf S, Gold S, Sanders J, Buckley JD, Barnard DR et al. A
comparison of allogeneic bone marrow transplantation, autologous bone marrow
transplantation, and aggressive chemotherapy in children with acute myeloid
leukemia in remission. Blood 2001; 97: 56–62.
6 Amadori S, Testi AM, Arico M, Comelli A, Giuliano M, Madon E et al. Prospective
comparative study of bone marrow transplantation and postremission chemotherapy for childhood acute myelogenous leukemia. The Associazione Italiana
Ematologia ed Oncologia Pediatrica Cooperative Group. J Clin Oncol 1993; 11:
1046–1054.
7 Klusmann JH, Reinhardt D, Zimmermann M, Kremens B, Vormoor J, Dworzak M
et al. The role of matched sibling donor allogeneic stem cell transplantation in
pediatric high-risk acute myeloid leukemia: results from the AML-BFM 98 study.
Haematologica 2012; 97: 21–29.
8 Horan JT, Alonzo TA, Lyman GH, Gerbing RB, Lange BJ, Ravindranath Y et al.
Impact of disease risk on efficacy of matched related bone marrow
Bone Marrow Transplantation (2015) 181 – 188
Autologous and allogeneic HSCT in childhood AML
F Locatelli et al
188
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
transplantation for pediatric acute myeloid leukemia: the Children's
Oncology Group. J Clin Oncol 2008; 26: 5797–5801.
Ruggeri A, Volt F, Michel G, Diaz de Heredia C, Abecasis M, Zecca M et al.
Unrelated cord blood transplantation for infant acute leukemia diagnosed within
1 year of age: outcomes and risk factor analysis on behalf of Eurocord and
PDWP-EBMT. Blood 2013; 122: 160-.
Eapen M, Rubinstein P, Zhang MJ, Stevens C, Kurtzberg J, Scaradavou A et al.
Outcomes of transplantation of unrelated donor umbilical cord blood and bone
marrow in children with acute leukaemia: a comparison study. Lancet 2007; 369:
1947–1954.
Michel G, Rocha V, Chevret S, Arcese W, Chan KW, Filipovich A et al. Unrelated
cord blood transplantation for childhood acute myeloid leukemia: a Eurocord
Group analysis. Blood 2003; 102: 4290–4297.
Locatelli F, Zecca M, Messina C, Rondelli R, Lanino E, Sacchi N et al. Improvement
over time in outcome for children with acute lymphoblastic leukemia in second
remission given hematopoietic stem cell transplantation from unrelated donors.
Leukemia 2002; 16: 2228–2237.
Dini G, Zecca M, Balduzzi A, Messina C, Masetti R, Fagioli F et al. No difference in
outcome between children and adolescents transplanted for acute lymphoblastic
leukemia in second remission. Blood 2011; 118: 6683–6690.
Bonetti F, Zecca M, Pession A, Messina C, Montagna D, Lanino E et al. Total-body
irradiation and melphalan is a safe and effective conditioning regimen for
autologous bone marrow transplantation in children with acute myeloid leukemia
in first remission. The Italian Association for Pediatric Hematology and OncologyBone Marrow Transplantation Group. J Clin Oncol 1999; 17: 3729–3735.
Zittoun R A, Mandelli F, Willemze R, de Witte T, Labar B, Resegotti L et al. Autologous or allogeneic bone marrow transplantation compared with intensive
chemotherapy in acute myelogenous leukemia. European Organization for
Research and Treatment of Cancer (EORTC) and the Gruppo Italiano Malattie
Ematologiche Maligne dell'Adulto (GIMEMA) Leukemia Cooperative Groups. N
Engl J Med 1995; 332: 217–223.
Ravindranath Y, Yeager AM, Chang MN, Steuber CP, Krischer J, Graham-Pole J
et al. Autologous bone marrow transplantation versus intensive consolidation
chemotherapy for acute myeloid leukemia in childhood. Pediatric
Oncology Group. N Engl J Med 1996; 334: 1428–1434.
Pession A, Masetti R, Rizzari C, Putti MC, Casale F, Fagioli F et al. Results of the
AIEOP AML 2002/01 multicenter prospective trial for the treatment of children
with acute myeloid leukemia. Blood 2013; 122: 170–178.
Locatelli F, Pession A, Bonetti F, Maserati E, Prete L, Pedrazzoli P et al. Busulfan,
cyclophosphamide and melphalan as conditioning regimen for bone marrow
transplantation in children with myelodysplastic syndromes. Leukemia 1994; 8:
844–849.
Glucksberg H, Storb R, Fefer A, Buckner CD, Neiman PE, Clift RA et al. Clinical
manifestations of graft-versus-host disease in human recipients of marrow from
HL-A-matched sibling donors. Transplantation 1974; 18: 295–304.
Storb R, Prentice RL, Sullivan KM, Shulman HM, Deeg HJ, Doney KC et al. Predictive factors in chronic graft-versus-host disease in patients with aplastic anemia treated by marrow transplantation from HLA-identical siblings. Ann intern
Med 1983; 98: 461–466.
Gooley TA, Leisenring W, Crowley J, Storer BE. Estimation of failure probabilities in
the presence of competing risks: new representations of old estimators. Stat Med
1999; 18: 695–706.
Zhang X, Zhang MJ, Fine J. A proportional hazards regression model for the
subdistribution with right-censored and left-truncated competing risks data. Stat
Med 2011; 30: 1933–1951.
Reeves GK, Cox DR, Darby SC, Whitley E. Some aspects of measurement error in
explanatory variables for continuous and binary regression models. Stat Med
1998; 17: 2157–2177.
Bone Marrow Transplantation (2015) 181 – 188
24 Dignan FL, Wynn RF, Hadzic N, Karani J, Quaglia A, Pagliuca A et al. BCSH/BSBMT
guideline: diagnosis and management of veno-occlusive disease (sinusoidal
obstruction syndrome) following haematopoietic stem cell transplantation. Brit J
Haematol 2013; 163: 444–457.
25 Kelly MJ, Horan JT, Alonzo TA, Eapen M, Gerbing RB, He W et al. Comparable
survival for pediatric acute myeloid leukemia with poor-risk cytogenetics following chemotherapy, matched related donor, or unrelated donor transplantation. Pediatri Blood Cancer 2014; 61: 269–275.
26 Eapen M, Rubinstein P, Zhang MJ, Camitta BM, Stevens C, Cairo MS et al.
Comparable long-term survival after unrelated and HLA-matched sibling donor
hematopoietic stem cell transplantations for acute leukemia in children younger
than 18 months. J Clin Oncol 2006; 24: 145–151.
27 Meshinchi S, Arceci RJ, Sanders JE, Smith FO, Woods WB, Radich JP et al. Role of
allogeneic stem cell transplantation in FLT3/ITD-positive AML. Blood 2006; 108:
400.
28 Staffas A, Kanduri M, Hovland R, Rosenquist R, Ommen HB, Abrahamsson J et al.
Presence of FLT3-ITD and high BAALC expression are independent prognostic
markers in childhood acute myeloid leukemia. Blood2011; 118: 5905–5913.
29 Levis M, Small D. FLT3: ITDoes matter in leukemia. Leukemia 2003; 17: 1738–1752.
30 DeZern A E, Sung A, Kim S, Smith B D, Karp J E, Gore S D et al. Role of allogeneic
transplantation for FLT3/ITD acute myeloid leukemia: outcomes from 133 consecutive newly diagnosed patients from a single institution. Biol Blood Marrow
Transplant 2011; 17: 1404–1409.
31 Locatelli F, Nollke P, Zecca M, Korthof E, Lanino E, Peters C et al. Hematopoietic
stem cell transplantation (HSCT) in children with juvenile myelomonocytic
leukemia (JMML): results of the EWOG-MDS/EBMT trial. Blood 2005; 105:
410–419.
32 Beier R, Albert MH, Bader P, Borkhardt A, Creutzig U, Eyrich M et al. Allo-SCT using
BU, CY and melphalan for children with AML in second CR. Bone Marrow Transplant 2013; 48: 651–656.
33 Giorgiani G, Bozzola M, Locatelli F, Picco P, Zecca M, Cisternino M et al. Role of
busulfan and total body irradiation on growth of prepubertal children receiving
bone marrow transplantation and results of treatment with recombinant human
growth hormone. Blood 1995; 86: 825–831.
34 Michel G, Gluckman E, Esperou-Bourdeau H, Reiffers J, Pico JL, Bordigoni P et al.
Allogeneic bone marrow transplantation for children with acute myeloblastic
leukemia in first complete remission: impact of conditioning regimen without
total-body irradiation—a report from the Societe Francaise de Greffe de Moelle. J
Clin Oncol 1994; 12: 1217–1222.
35 Parth P, Dunlap WP, Kennedy RS, Ordy JM, Lane NE. Motor and cognitive testing
of bone marrow transplant patients after chemoradiotherapy. Percept Mot Skills
1989; 68: 1227–1241.
36 Hasle H. A critical review of which children with acute myeloid leukaemia need
stem cell procedures. Brit J Haematol 2014; 166: 23–33.
37 Masetti R, Pigazzi M, Togni M, Astolfi A, Indio V, Manara E et al. CBFA2T3-GLIS2
fusion transcript is a novel common feature in pediatric, cytogenetically normal
AML, not restricted to FAB M7 subtype. Blood 2013; 121: 3469–3472.
38 von Neuhoff C, Reinhardt D, Sander A, Zimmermann M, Bradtke J, Betts DR et al.
Prognostic impact of specific chromosomal aberrations in a large group of
pediatric patients with acute myeloid leukemia treated uniformly according to
trial AML-BFM 98. J Clin Oncol 2010; 28: 2682–2689.
39 Balgobind BV, Van den Heuvel-Eibrink MM, De Menezes RX, Reinhardt D, Hollink
IH, Arentsen-Peters ST et al. Evaluation of gene expression signatures predictive of
cytogenetic and molecular subtypes of pediatric acute myeloid leukemia. Haematologica 2011; 96: 221–230.
40 Rubnitz JE, Inaba H, Dahl G, Ribeiro RC, Bowman WP, Taub J et al. Minimal residual
disease-directed therapy for childhood acute myeloid leukaemia: results of the
AML02 multicentre trial. Lancet Oncol 2010; 11: 543–552.
© 2015 Macmillan Publishers Limited

Download Report