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CLINICAL TRIALS AND OBSERVATIONS
Outcome of treatment in children with hypodiploid acute lymphoblastic leukemia
James B. Nachman,1 Nyla A. Heerema,2 Harland Sather,3 Bruce Camitta,4 Erik Forestier,5 Christine J. Harrison,6
Nicole Dastugue,7 Martin Schrappe,8 Ching-Hon Pui,9 Giuseppe Basso,10 Lewis B. Silverman,11 and Gritta E. Janka-Schaub12
1The University of Chicago Comer Children’s Hospital, IL; 2Columbus Children’s Hospital and The Ohio State University, Columbus, OH; 3Children’s Oncology
Group–Operations Center, Arcadia, CA; 4Midwest Children’s Cancer Center, Department of Pediatrics of the Medical College of Wisconsin, Children’s Hospital
of Wisconsin, Milwaukee; 5Department of Clinical Sciences and Paediatrics, University of Umeå, Umeå, Sweden; 6Leukaemia Research Cytogenetics Group,
Cancer Sciences Divison, University of Southampton, Southampton, United Kingdom; 7Génétique des Hémopathies, Laboratoire d’Hématologie, Hôpital
Purpan, Toulouse, France; 8University Hospital Schwanenweg, Department of Pediatrics, Kiel, Germany; 9St Jude Children’s Research Hospital and the
University of Tennessee Health Science Center, Memphis; 10Pediatrics Department, University of Padova, Padova, Italy; 11Department of Pediatric Oncology,
Dana-Farber Cancer Institute and Division of Hematology Oncology, Children’s Hospital, Boston, MA; 12Children’s University Hospital, Department of Pediatric
Hematology and Oncology, University of Hamburg, Hamburg, Germany
One-hundred thirty-nine patients with
acute lymphoblastic leukemia (ALL) and
hypodiploidy (fewer than 45 chromosomes) were collected from 10 different
national ALL study groups and single
institutions. Patients were stratified by
modal chromosome number into 4 groups:
24 to 29 (N ⴝ 46); 33 to 39 (N ⴝ 26); 40 to 43
(N ⴝ 13); and 44 (N ⴝ 54) chromosomes.
Nine patients were Philadelphia chromosome (Ph) positive (4 cases: 44 chromosomes; 5 cases: 40-43 chromosomes) and
were not considered further. Event-free sur-
vival (EFS) and overall survival (OS) of the
remaining 130 patients were 38.5% ⴞ 4.4%
and 49.8% ⴞ 4.2% at 8 years, respectively.
There were no significant differences in outcome between patients with 24 to 29, 33 to
39, or 40 to 43 chromosomes. Compared
with patients with fewer than 44 chromosomes, patients with 44 chromosomes had
a significantly better EFS (P ⴝ .01; 8-year
estimate, 52.2% vs 30.1%) and OS (P ⴝ .017;
69% vs 37.5%). For patients with 44 chromosomes, monosomy 7, the presence of a
dicentric chromosome, or both predicted a
worse EFS but similar OS. Doubling of the
hypodiploid clone occurred in 32 patients
(24-29 chromosomes [n ⴝ 25] and 33-39
chromosomes [n ⴝ 7]) and had no prognostic implication. Children and adolescents
with ALL and hypodiploidy with fewer than
44 chromosomes have a poor outcome despite contemporary therapy. (Blood. 2007;
110:1112-1115)
© 2007 by The American Society of Hematology
Introduction
Ploidy is a highly significant prognostic factor in childhood acute
lymphoblastic leukemia (ALL).1 A hyperdiploid karyotype with
more than 50 chromosomes (particularly those with trisomies for 4, 10,
17, 18) identifies patients with a favorable outcome.2,3 By contrast,
hypodiploidy (modal chromosome number fewer than 46) is associated
with a poor outcome.4-9 The majority of hypodiploid patients show
45 chromosomes in their leukemic cells and have a significantly better
outcome than patients with fewer than 45 chromosomes.5 It is not
uncommon for leukemic cells with 23 to 29 and 33 to 39 chromosomes
to undergo doubling of the hypodiploid clone such that the modal
chromosome number may fall in the hyperdiploid or triploid range,10
respectively. Analysis of the specific pattern of chromosomal gains and
losses or flow cytometric determination of DNA content can
identify such doubled populations.
Hypodiploidy with fewer than 45 chromosomes is very uncommon. In a large MRC study, excluding patients with an established
chromosomal structural abnormality, 5% of patients had hypodiploidy of which only 1% had fewer than 45 chromosomes in their
leukemic clone.5
To better understand the epidemiology, prognostic factors, and
treatment outcome for children and adolescents with ALL and
fewer than 45 chromosomes, 139 cases were collected from
10 participating cooperative groups and large single institutions in
the United States and Europe for investigation.
This article represents a record review from studies that were
previously approved by each institution’s local IRB. Informed
consent was obtained in accordance with the Declaration of
Helsinki.
Patients, materials, and methods
Patients
Study groups or institutions reviewed their own records and identified ALL
patients with fewer than 45 chromosomes who were registered on ALL
clinical trials between 1986 and 1996. A predefined data set was collected
for each patient and the data were sent to a central coordinating center for
review. Of the 173 patients for whom data were submitted, 2 were ineligible
because their date of diagnosis did not meet study entrance criteria, and 32
had karyotypes that were not evaluable. Thus, 139 cases were eligible.
Cases were accrued from the following groups: AIEOP-3; BFM-5; CCG33; COALL-3; DANA FARBER-4; POG-44; SJCRH-6; UK-20; NOPHO-6; and EORTC-15. Most of the patients received treatment on
higher-risk regimens. Nine patients underwent bone marrow transplantation
in first remission.
Statistical methods
Analyses were based on patient follow-up through December 2003.
Clinical, demographic, and laboratory features of the various hypodiploid
Submitted July 28, 2006; accepted March 12, 2007. Prepublished online as
Blood First Edition paper, May 1, 2007; DOI 10.1182/blood-2006-07-038299.
payment. Therefore, and solely to indicate this fact, this article is hereby
marked ‘‘advertisement’’ in accordance with 18 USC section 1734.
The publication costs of this article were defrayed in part by page charge
© 2007 by The American Society of Hematology
1112
BLOOD, 15 AUGUST 2007 䡠 VOLUME 110, NUMBER 4
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BLOOD, 15 AUGUST 2007 䡠 VOLUME 110, NUMBER 4
CHILDHOOD HYPODIPLOID ACUTE LYMPHOBLASTIC LEUKEMIA
Table 1. Modal chromosome number for non-Phⴙ ALL patients with
fewer than 45 chromosomes
Table 2. Demographic features by modal chromosome number
Modal chromosome no.
46
33 to 39 chromosomes
26
40 to 43 chromosomes
8
44 chromosomes
Modal chromosome no.
No. of cases
24 to 29 chromosomes
50
1113
Fewer than 30
33 to 39
40 to 43
44
Total
Younger than 1
—
—
1
2
3
1 to 9
32
5
6
39
82
Older than 10
14
21
1
9
45
Less than 20
18
19
4
21
62
20 to less than 50
19
5
2
16
42
9
2
2
13
26
Male
23
18
6
25
72
Female
23
8
2
25
58
Age, y
WBC, ⴛ 109/L
subgroups were compared using ␹2 tests for homogeneity of proportions.
Outcome was analyzed using life table methods and associated statistics.
The primary end points examined were event-free survival (EFS) and
overall survival (OS) from study entry; events included induction failure
due to refractory leukemia, induction death, leukemic relapse at any site,
death during remission, or second malignant neoplasm, whichever occurred
first. Patients not experiencing an event were censored at the time of their
last contact. The Kaplan-Meier life table estimate of EFS and its standard
deviation (SD) are provided for selected time points. Life table comparisons
of EFS outcome patterns for hypodiploid subgroups used the log-rank
statistic. P values were based on the pattern of outcome across the entire
period of patient follow-up. Values of .05 or less are referred to as
significantly different. Numeric cutoff levels for the hypodiploid subgroups
24 to 29, 33 to 39, 40 to 43, and 44 were based on previous analyses of
hypodiploid patients. In contrast to prior studies, we found that patients
with 44 chromosomes constituted the largest subgroup of hypodiploid
patients so they were included as a separate group.
50 or more
Sex
— indicates not applicable.
30, 31, 32, or 42. The most common modal chromosome numbers
for patients with 44 or fewer chromosomes were 44 (n ⫽ 50),
26 (n ⫽ 19), and 27 (n ⫽ 13).
Cytogenetic features of hypodiploid subgroups
Nine of the 139 patients with hypodiploidy were Philadelphia
chromosome (Ph) positive; 5 had 40 to 43 chromosomes and 4 had
44 chromosomes. These patients were not considered further,
leaving 130 eligible patients who were divided into 4 groups based
on modal chromosome number: 24 to 29, 33 to 39, 40 to 43, and
44 chromosomes (Table 1). For one patient in the 40 to 43
chromosome group and another in the 33 to 39 group, a modal
chromosome range was provided but the actual chromosome
number could not be accurately assessed. Thus, Figure 1 and the
following analysis of cytogenetic features are based on 128 patients.
Patients with 24 to 29 chromosomes and those with 44 chromosomes accounted for 72.3% of patients. The distribution of modal
chromosome number for patients with 44 or fewer chromosomes is
shown in Figure 1. No patient had a modal chromosome number of
Forty-four chromosomes (n ⴝ 50). Forty-nine of 50 patients had
structural as well as numeric chromosome abnormalities. The most
frequent monosomic chromosomes were 7, 9, 13, and X/Y. Ten
patients had a dicentric chromosome. The most common structural
abnormalities included loss of the short arm of chromosome 9 (9p)
and an abnormal 12p. No doubling of the hypodiploid clone was
seen in this group.
Forty to 43 chromosomes (n ⴝ 7). All patients had disomies
for chromosomes 2, 6, 10, 11, 20, and 22. Structural abnormalities
occurred in 6 patients. No doubling of the hypodiploid clone
was seen.
Thirty-three to 39 chromosomes (n ⴝ 25). Nine patients had
structural abnormalities; in 8 of these, the modal chromosome
number was fewer than 36. Disomies for chromosomes 3, 7, 16,
and 17 were rare. In 7 patients, doubling of the hypodiploid clone
was present.
Twenty-four to 29 chromosomes (n ⴝ 46). Thirty-three patients had only numeric abnormalities. All patients were disomic
for chromosome 21. Disomies for chromosome X/Y (n ⫽ 30) and
14 and 18 (n ⫽ 24 each) were also common. Twenty-five patients
had doubling of the near-haploid clone.
Figure 1. Distribution of modal chromosome numbers in hypodiploid cases
with fewer than 44 chromosomes. There are no patients with 30, 31, 32, or 42
chromosomes. For 2 patients, modal chromosome number could not be accurately
determined.
Figure 2. EFS and OS for non-Phⴙ hypodiploid patients.
Results
Karyotypes of hypodiploid patients
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BLOOD, 15 AUGUST 2007 䡠 VOLUME 110, NUMBER 4
NACHMAN et al
Event - free Survival
1114
Figure 3. Comparison of EFS for non-Phⴙ hypodiploid patients with 44
chromosomes or fewer than 44 chromosomes.
Clinical and biologic characteristics of patients with 44
or fewer chromosomes
Approximately 90% of patients showed a B-precursor immunophenotype; almost all were CD10⫹ and 8 had CNS involvement at
diagnosis. Of the 8 T-cell patients, 7 had 44 chromosomes. Table 2
shows the age, white count, and sex distribution for the 130 patients.
Patients with 33 to 39 chromosomes were a unique group; 21 of
26 patients in this subgroup compared with 24 of 104 patients in the
other groups were older than 10 years at diagnosis (P ⱕ .001).
Only 2 of 26 patients with 33 to 39 chromosomes compared
with 23 of 104 patients in the other hypodiploid subgroups had a
white blood cell (WBC) count greater than 50 ⫻ 109/L (P ⫽ NS).
There was also a male predominance in the patients with 33 to
39 chromosomes and in the small subgroup of patients with 40 to
43 chromosomes; patients in the fewer than 30 and 44 chromosome
groups had a male to female ratio of one.
Treatment outcome and prognostic features
All 130 patients achieved a complete remission but 78 patients had
a postremission event, including marrow relapse in 56 patients
(51 isolated; 5 combined), CNS relapse in 10 patients, testicular
relapse in 2 patients, death in initial remission in 6 patients, and
second malignant neoplasm in 1 patient. The type of adverse event
was unknown in 3 patients.
The 8-year EFS and OS for the whole group of 130 patients
were 38.5% ⫾ 5.7% and 49.8% ⫾ 6.0%, respectively (Figure 2).
Nine patients underwent bone marrow transplantation in first
Figure 4. Comparison of survival for non-Phⴙ hypodiploid patients with 44
chromosomes or fewer than 44 chromosomes.
Figure 5. EFS for 130 evaluable, non-Phⴙ patients by modal chromosome
number: 44 chromosomes, 40 to 43 chromosomes, 30 to 39 chromosomes, and
24 to 29 chromosomes.
remission at a median of 3 months (range, 2 to 8 months) from
diagnosis, and 5 of them had an adverse event after transplantation.
With this relatively small number of patients, EFS and OS did not
differ significantly between patients who did or did not undergo
transplantation.
Patients with 44 chromosomes fared significantly better than
those with fewer than 44 chromosomes in terms of EFS (P ⫽ .01)
and OS (P ⫽ .002). The 8-year EFS was 52.2% versus 30.1%, and
8-year OS was 69% versus 37.5%, respectively (Figures 3,4).
There were no significant differences in outcome between patients
with fewer than 30 chromosomes, 33 to 39 chromosomes, or 40 to
43 chromosomes (Figure 5 [EFS] and Figure 6 [OS]; Table 3).
For the 50 patients with 44 chromosomes, 16 had either
monosomy 7, a dicentric chromosome, or both. The 8-year EFS for
patients with either or both of these abnormalities was
31.2% ⫾ 11.6% versus 68.5% ⫾ 8.3% for those with neither
abnormality (P ⫽ .025). However, the survival was 68% for both
groups. There was no difference in outcome for patients with
doubling of their hypodiploid clone versus those in whom a
doubled clone was not observed (data not shown).
Discussion
In previous studies of ALL, outcome for patients with fewer than
46 chromosomes in their leukemic clone has been poor, ranging
Figure 6. OS for 130 evaluable, non-Phⴙ patients by modal chromosome
number: 44 chromosomes, 40 to 43 chromosomes, 30 to 39 chromosomes, and
24 to 29 chromosomes.
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BLOOD, 15 AUGUST 2007 䡠 VOLUME 110, NUMBER 4
CHILDHOOD HYPODIPLOID ACUTE LYMPHOBLASTIC LEUKEMIA
Table 3. Outcome by modal chromosome number
among these cases, recognition of this finding is important to
distinguish these patients from hyperdiploid cases who have a
superior outcome and require less intensive therapy.1-8
Clearly, new treatment approaches need to be developed for the
small subgroup of ALL patients with fewer than 44 chromosomes.
There were no induction failures in these patients, in contrast to a
high induction failure rate in other high risk subgroups such as
Ph-positive patients. Whether hypodiploid cases have a high level
of minimal residual disease after remission induction therapy
requires further investigation. Patients with hypodiploid ALL tend
to fail early in treatment (within 2 years). The efficacy of
transplantation in these patients cannot be adequately addressed in
this study because only 9 patients underwent this procedure. In the
current Children’s Oncology Group protocols, patients with hypodiploid ALL are switched to a very high-risk protocol at the end of
induction featuring blocks of intensive myelosuppressive therapy
(cytoxan, high-dose cytosine arabinoside, VP-16, high-dose methotrexate). Patients with a matched sibling donor are eligible to
receive a bone marrow transplantation in first remission.
Modal chromosome no.
Fewer than 30
33 to 39
40 to 43
44
No. of patients
46
26
8
50
Events
33
16
6
23
18.7 ⫾ 15.8
52.2 ⫾ 7.4
50 ⫾ 17.7
69 ⫾ 6.7
8-year EFS, %
28.3 ⫾ 6.6
8-year survival, %
33.9 ⫾ 7.6
36.9 ⫾ 9.8
40 ⫾ 10.1
from 25% to 40%.4-9 In an MRC study, the 3-year EFS for the
20 children with 25 to 39 chromosomes was 29% compared with
66% for the 121 patients with 42 to 45 chromosomes.5 Only 7
children in that series had 42 to 44 chromosomes. Of these, 3 with
T-cell ALL relapsed and died while 3 of the 4 patients with
B-lineage ALL remained alive in continuous remission. The
Children’s Cancer Group reported on 23 patients with fewer than
45 chromosomes.8 The EFS for patients with 24 to 28 chromosomes and 33 to 44 chromosomes was 25% and 40%, respectively.
In this study, we collected data on patients with fewer than
45 chromosomes. This is a retrospective study with potential
selection bias, and the findings reported herein need to be
confirmed in prospective trials. In contrast to the MRC data,
patients with 44 chromosomes (N ⫽ 50) represented the largest
subgroup in our series. There were only 8 patients in the 40 to 43
chromosome group, and no patients had 30 to 32 chromosomes. We
confirmed the poor outcome for patients with hypodiploidy of
fewer than 45 chromosomes. The 8-year EFS and OS for the whole
group of 130 hypodiploid non-Ph⫹ patients were only 38.5% and
49.8%, respectively (Figure 2). For patients with 24 to 43
chromosomes, 8-year EFS and OS were 30.1% and 37.5%,
respectively. In contrast to previous studies suggesting that nearhaploid cases with 24 to 29 chromosomes have particularly poor
outcome, we found no difference in outcome between patients with
24 to 29, 33 to 39, or 40 to 43 chromosomes. A relatively favorable
prognosis was observed for patients with 44 chromosomes who had
an 8-year EFS of 52.2% and an 8-year OS of 69%, a finding that
was not previously recognized. Moreover, within the 44 chromosome group, patients with neither a monosomy 7 nor a dicentric
chromosome had significantly better EFS; albeit, there was no
difference in survival compared with those with either or both
abnormalities.
Doubling of a hypodiploid clone occurs frequently in patients
with 24 to 29 chromosomes and less frequently in patients with
33 to 39 chromosomes. The original hypodiploid clone could be
identified in all cases in which doubling occurred. Patients with
doubling of a hypodiploid clone had a similar outcome to those
without evidence of the doubled population, although this has not
been the case in all studies (MRC and French series). Even though
doubling of a hypodiploid clone has no prognostic significance
1115
Acknowledgments
This work was supported in part by Cancer Center Support
Grant CA21765, the American Lebanese Syrian Associated
Charities, the American Cancer Society–FM Kirby Clinical
Research Professorship, the Regional Grant AIRC, the Foundation Città della Speranza, PRIN, National Institutes of Health
(NIH) PO1 grant CA68484, the MACC Fund, the Ponte di
Legno collaboration, representing the Nordic Society of Pediatric Hematology and Oncology (NOPHO), the Swedish Children’s Cancer Foundation, Leukaemia Research, United Kingdom, and NIH U10 CA 98543. A complete listing of grant
support for research conducted by the Children’s Cancer Group
and the Pediatric Oncology Group before initiation of the
Children’s Oncology Group grant in 2003 is available online at
http://www.childrensoncologygroup.org/admin/grantinfo.htm.
Authorship
Contribution: All authors contributed to all aspects of preparing
this paper.
Conflict-of-interest disclosure: The authors declare no competing financial interests.
Correspondence: James Nachman, The University of Chicago
Comer Children’s Hospital, 5841 S Maryland Ave C-429, Chicago,
IL 60637; e-mail: [email protected].
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From www.bloodjournal.org by guest on April 18, 2017. For personal use only.
2007 110: 1112-1115
doi:10.1182/blood-2006-07-038299 originally published
online May 1, 2007
Outcome of treatment in children with hypodiploid acute lymphoblastic
leukemia
James B. Nachman, Nyla A. Heerema, Harland Sather, Bruce Camitta, Erik Forestier, Christine J.
Harrison, Nicole Dastugue, Martin Schrappe, Ching-Hon Pui, Giuseppe Basso, Lewis B. Silverman
and Gritta E. Janka-Schaub
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