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CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
Hypodiploidy With Less Than 45 Chromosomes Confers Adverse
Risk in Childhood Acute Lymphoblastic Leukemia:
A Report From the Children’s Cancer Group
By Nyla A. Heerema, James B. Nachman, Harland N. Sather, Martha G. Sensel, Mei K. Lee,
Raymond Hutchinson, Beverly J. Lange, Peter G. Steinherz, Bruce Bostrom, Paul S. Gaynon, and Fatih Uckun
We have determined the prognostic significance of hypodiploidy (F46 chromosomes) in a large cohort of children with
acute lymphoblastic leukemia (ALL) treated by the Children’s
Cancer Group. Among 1,880 patients, 110 (5.8%) had hypodiploid karyotypes: 87 had 45 chromosomes, 15 had 33 to 44
chromosomes, none had 29 to 32 chromosomes, and 8 had
24 to 28 chromosomes (near-haploidy). Six-year event-free
survival (EFS) estimates for patients with 45 chromosomes,
33 to 44 chromosomes, or 24 to 28 chromosomes were 65%
(standard deviation [SD], 8%), 40% (SD, 18%), and 25% (SD,
22%), respectively (log rank, P 5 .002; test for trend, P 5
.0009). The combined hypodiploid group had worse outcome
than nonhypodiploid patients, with 6-year EFS of 58% (SD,
7%) and 76% (SD, 2%), respectively (P F .0001). EFS for the
subgroup with 45 chromosomes was similar to that of
patients with pseudodiploidy (P 5 .43) or 47 to 50 chromosomes (P 5 .76). None of the patients with 24 to 28
chromosomes had a t(4;11), a t(9;22), or a t(1;19), and most
received highly intensive therapy. The adverse risk associated with 33 to 44 and 24 to 28 chromosomes remained
significant in multivariate analyses adjusted for important
risk factors including age, white blood cell count, and
Philadelphia chromosome status. Thus, hypodiploidy with
less than 45 chromosomes, particularly 24 to 28 chromosomes, is a significant adverse risk factor despite treatment
with contemporary intensive therapies.
r 1999 by The American Society of Hematology.
C
primarily by age and white blood cell (WBC) count,6 but early
response to therapy, as measured by the bone marrow or
peripheral blood leukemic blast content, has emerged as an
important prognostic variable.7-10 Genetic and biological characteristics, such as the presence of specific chromosomal translocations or fusion transcripts, may provide the tools required for
more accurately predicting risk of treatment failure. In addition,
further refinement of currently known risk factors may allow
better allocation of less or more intensive and potentially toxic
therapy to patients with lower or higher risk of failure.
Leukemic cell ploidy is a known risk factor for treatment
outcome in pediatric ALL: high hyperdiploidy (.50 chromosomes or DNA index .1.16) is associated with improved
outcome, whereas a hypodiploid (,46 chromosomes) karyotype is thought to be an adverse risk factor.11-17 Pui et al18
reported particularly poor outcome for patients with nearhaploidy, and similarly, Chessels et al19 reported that hypodiploidy with 24 to 29 chromosomes was a significant independent
risk factor for children with ALL. These findings suggested,
albeit with small numbers of patients, that subsets of hypodiploid patients may have different treatment outcomes. Therefore,
we have examined the prognostic significance of leukemic cell
hypodiploidy, including the effect of chromosome number less
than 45, in a very large cohort (N 5 1,880) of children with ALL
treated on contemporary intensive protocols of the CCG. In
both univariate and multivariate analyses, our data indicate that
hypodiploid ALL patients with 45 chromosomes have an
outcome similar to that of ALL patients with pseudodiploid or
low hyperdiploid (47 to 50 chromosomes) ALL, whereas
patients with less than 45 chromosomes, particularly those with
24 to 28 chromosomes, achieve poor outcomes despite intensive risk-adjusted therapy. Thus, hypodiploid ALL is heterogeneous with respect to treatment outcome, and novel therapies
should be explored for those with 24 to 28 chromosomes.
URRENT CHILDREN’S cancer group (CCG) risk groupadjusted intensive therapies for childhood acute lymphoblastic leukemia (ALL) are expected to result in 6-year eventfree survival (EFS) and survival of greater than 75% and 84%,
respectively (Harland Sather, CCG unpublished data). These
intensive therapies have overcome many of the clinical features,
including organomegaly and leukemic cell lineage, that previously were associated with poor outcome.1-5 Thus, the present
challenge is to improve our ability to identify and treat
appropriately those patients who will fail these current intensive
therapies. Higher and lower risk patients are now identified
From the Department of Genetics, Hughes Institute, St Paul, MN; the
Department of Pediatric Hematology-Oncology, University of Chicago,
Chicago, IL; the Department of Preventive Medicine, University of
Southern California, Los Angeles, CA; the Group Operations Center,
Children’s Cancer Group, Arcadia, CA; the Department of Pediatric
Hematology-Oncology, University of Michigan, Ann Arbor, MI; the
Division of Oncology, Children’s Hospital of Philadelphia, PA; the
Department of Pediatrics, Memorial Sloan-Kettering Cancer Center,
New York, NY; the Department of Hematology-Oncology, Children’s
Hospitals and Clinics, Minneapolis, MN; the Department of Pediatric
Hematology-Oncology, Children’s Hospital, Los Angeles, CA; and the
Children’s Cancer Group ALL Biology Reference Laboratory, Hughes
Institute, St Paul, MN. Contributing CCG cytogeneticists are given in
the Acknowledgment.
Submitted March 17, 1999; accepted August 13, 1999.
Supported in part by research grants including CCG Chairman’s
Grant No. CA-13539 and CA-60437 from the National Cancer Institute,
National Institutes of Health.
Address reprint requests to Nyla A. Heerema, PhD, c/o The Children’s Cancer Group, Attention Ms. Lucia Noll, PO Box 60012,
Arcadia, CA 91066-6012.
The publication costs of this article were defrayed in part by page
charge payment. This article must therefore be hereby marked ‘‘advertisement’’ in accordance with 18 U.S.C. section 1734 solely to indicate
this fact.
r 1999 by The American Society of Hematology.
0006-4971/99/9412-0033$3.00/0
4036
MATERIALS AND METHODS
Patients. Diagnosis of ALL required determination of lymphoblast
morphology by Wright-Giemsa staining of bone marrow smears,
Blood, Vol 94, No 12 (December 15), 1999: pp 4036-4046
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HETEROGENEITY OF HYPODIPLOID ALL IN CHILDREN
4037
negative lymphoblast staining for myeloperoxidase, and cell surface
expression of 2 or more lymphoid differentiation antigens.20 Immunophenotyping was performed centrally in the CCG ALL Biology
Reference Laboratory by indirect immunofluorescence and flow cytometry, as previously described.2,20 Patients were classified as B-lineage if
$30% of the leukemic cells were positive for CD19 and/or CD24 and
less than 30% were positive for 1 or more of the T-cell–associated
antigens CD2, CD3, CD5, or CD7. Likewise, patients were classified as
T-lineage if $30% of the isolated blasts were positive for 1 or more of
the T-cell–associated antigens CD2, CD3, CD5, or CD7 and less than
30% were positive for CD19 and/or CD24.
The current study involved children with newly diagnosed ALL
enrolled on CCG risk-adjusted protocols between 1988 and 1995.
Children 2 to 9 years of age with WBC counts less than 10,000/µL
(low-risk ALL) were enrolled on CCG-1881; children 2 to 9 years of
age with WBC counts of 10,000 to 49,999/µL or 12 to 23 months of age
with WBC counts less than 50,000/µL (intermediate-risk ALL) were
enrolled on CCG-1891. After completion of these studies, patients with
low- or intermediate-risk ALL were enrolled on a single protocol,
CCG-1922, for standard-risk ALL (1 to 9 years of age and WBC counts
,50,000/µL) based on National Cancer Institute (NCI) criteria.6
Children 1 to 9 years of age with WBC counts $50,000/µL or $10
years of age (NCI poor-risk group)6 were assigned to CCG-1882. In
addition, children with multiple unfavorable features were enrolled on
the CCG-1901 protocol for lymphomatous syndrome ALL.21 Infants
less than 12 months of age were excluded from this analysis. All
protocols were approved by the NCI and the Institutional Review
Boards of the participating CCG-affiliated institutions. Informed consent was obtained from parents, patients, or both, according to the
guidelines of the Department of Health and Human Services. EFS and
overall survival estimates at 8 years from study entry for the combined
group of patients included in this analysis were 74% (standard deviation
[SD], 2%) and 82% (SD, 2%), respectively.
Cytogenetic analysis. Diagnostic karyotyping of leukemic cells
was performed by institutional laboratories before the initiation of
therapy. Banded chromosomes were prepared from unstimulated peripheral blood or direct and 24-hour–cultured preparations of fresh bone
marrow, as described previously.22 Aberrations were designated according to the ISCN (1995).23 Designation as an abnormal clone required the
identification of 2 or more metaphase cells with identical structural
abnormalities or extra chromosomes or 3 or more metaphase cells with
identical missing chromosomes. Designation as normal required complete analysis of a minimum of 20 banded metaphases from bone
marrow only. A minimum of 2 original karyotypes of each abnormal
clone or of normal cells were reviewed by at least 2 members of the
CCG Cytogenetics Committee.
Between 1988 and 1995, a total of 4,986 children were entered on the
CCG studies included in this analysis. Among these, 1,880 cases had
centrally reviewed and accepted cytogenetic data: 110 cases (6%) were
classified as hypodiploid and 1,770 cases (94%) were classified as
nonhypodiploid. Classification into ploidy groups was based on the
karyotype of the simplest clone.
The current cohort of patients with accepted cytogenetic data was
similar to concurrently enrolled patients who did not have accepted
cytogenetic data with respect to many presenting features, although
patients with accepted data were more likely to be white and to have
high WBC counts, high platelet and hemoglobin levels, a large
mediastinal mass, lymphadenopathy, a T-lineage immunophenotype,
Table 1. Recurrent Chromosome Abnormalities Among Hypodiploid Patients
Karyotypic Group
Abnormality
Chromosome loss
27
213
214
220
2X
2Y
Dicentric chromosome
dic(9;12)
dic(9;20)
dic(7;9)
dic(9;V)
Other dicentric
Other abnormality
del(6q)
Abnormal 9p
Abnormal 12p
Philadelphia chromosome
Monosomy 7
Disomy 7
One aberration
Two aberrations
$Three aberrations
Doubling of abnormal clone
Numerical abnormality only
24-28
Chromosomes
(N 5 8)
33-44
Chromosomes No
Dicentric (N 5 13)
33-44
Chromosomes With
Dicentric (N 5 2)
45
Chromosomes No
Dicentric (N 5 59)
45
Chromosomes With
Dicentric (N 5 28)
8 (100)
7 (88)
6 (75)
8 (100)
3 (38)
1 (13)
6 (46)
6 (46)
4 (38)
5 (31)
3 (23)
5 (38)
1 (50)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
10 (17)
11 (19)
8 (14)
8 (14)
10 (17)
3 (5)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
1 (50)
0 (0)
0 (0)
1 (50)
0 (0)
NA
NA
NA
NA
NA
10 (36)
9 (32)
4 (14)
2 (7)
3 (11)
8* (100)
8* (100)
8* (100)
2 (15)
11 (85)
6 (46)
0 (0)
2 (100)
2 (100)
7 (12)
18 (31)
13 (22)
1 (4)
25 (89)
11 (39)
0 (0)
0 (0)
NA†
NA†
8 (100)
2 (25)
5 (63)
1 (8)
0 (0)
NA†
0 (0)
13 (100)
2 (15)
2 (15)
0 (0)
0 (0)
NA†
1 (50)
1 (50)
0 (0)
0 (0)
3 (5)
2 (3)
6 (10)
16 (27)
37 (63)
0 (0)
6 (10)
0 (0)
1 (4)
13 (46)
7 (25)
8 (29)
0 (0)
0 (0)
Values are the number of patients with percentages in parentheses.
Abbreviation: NA, not applicable.
*All monosomies.
†By definition, patients with 30 to 44 chromosomes had at least 2 aberrations and patients with 24 to 28 chromosomes had at least 3 aberrations.
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4038
HEEREMA ET AL
and a non-L1 French-American-British (FAB) morphology. However,
the actual percentages of patients with or without accepted cytogenetic
data in these categories did not appear to differ; thus, the statistical
differences may be due to the large sample size. Importantly, various
measures of outcome were similar for concurrently enrolled patients
with or without accepted cytogenetic data. For example, similar
percentages of patients in the 2 groups had M1 (,5% blasts), M2 (5% to
25% blasts), or M3 (.25% blasts) at day 7 of induction therapy (P 5
.50). Greater than 97% of each group achieved remission by the end of
induction therapy (P 5 .10), and 6-year EFS estimates were 75% (SD,
2%) and 76% (SD, 1%) for patients with or without accepted data,
respectively (P 5 .36).
Statistical methods. Analyses were based on patient follow-up
through June 20, 1998. Clinical, demographic, and laboratory features
of hypodiploid and nonhypodiploid patients were compared using x2
tests for homogeneity of proportions. Outcome was analyzed using life
table methods and associated statistics. The primary endpoint examined
was EFS from study entry; events included induction failure (nonresponse to therapy or death during induction), leukemic relapse at any
site, death during remission, or second malignant neoplasm, whichever
occurred first. Patients not experiencing an event at the time of EFS
analysis were censored at the time of their last contact. The KaplanMeier24 life table estimate of EFS and its SD25 are provided for selected
time points. An approximate 95% confidence interval (CI) can be
obtained from the life table estimate 61.96 SDs. Life table comparisons
of EFS outcome pattern for patient groups used the log rank statistic.25,26 P values are based on the pattern of outcome across the entire
period of patient follow-up; values #.05 are referred to as statistically
significant and values between .06 and .10 are considered to have
borderline statistical significance.
Within the hypodiploid group, we also compared presenting features
and outcome for patients with 24 to 28 chromosomes (near-haploidy),
33 to 44 chromosomes, and 45 chromosomes (no patients had 29 to 32
chromosomes). These numerical cutoffs were based on the distinct
cytogenetic features found in patients with near-haploidy, as well as on
previous reports that such patients have a very poor outcome.18,19
Multivariate analysis of the prognostic effect of hypodiploid status was
performed using the Cox regression model.27 Significance levels were
based on the likelihood ratio test. The relative risks associated with
hypodiploid status were estimated using the exponentiated maximum
likelihood coefficient from the multivariate regression analysis.
RESULTS
Karyotypes of children with hypodiploid ALL. Of the 110
hypodiploid patients, the majority (N 5 87) had 45 chromosomes in the simplest clone. Of the patients with less than 45
chromosomes, 8 were near-haploid with 24 to 28 chromosomes
(1 with 24; 1 with 25; 2 with 26; 3 with 27; and 1 with 28); none
Table 2. Clinical and Biological Presenting Features for Patients With Hypodiploid ALL
Hypodiploid
Variable
Age (yrs)
WBC (3109/L)
FAB morphology
Immunophenotype
NCI Risk Group‡
Philadelphia chromosome
Liver
Mediastinal mass
Lymph nodes
Nonhypodiploid*
Category
45
Chromosomes
(N 5 87)
33-44
Chromosomes
(N 5 15)
24-28
Chromosomes
(N 5 8)
.45
Chromosomes
(N 5 1,770)
1-9
$10
,20
20-49
$50
L1
L1/L2
L2/L1
L2
B-lineage
T-lineage
CD101
CD102
Standard
Poor
Positive
Negative
Normal
Moderately enlarged
Markedly enlarged
Absent
Moderately enlarged
Markedly enlarged
Normal
Moderately enlarged
Markedly enlarged
60 (69)
27 (31)
45 (52)
17 (20)
25 (29)
61 (70)
4 (5)
13 (15)
9 (10)
52 (93)
4 (7)
63 (9)
6 (91)
42 (48)
45 (52)
6 (7)
81 (93)
42 (48)
44 (51)
1 (1)
85 (98)
0 (0)
2 (2)
41 (47)
42 (48)
4 (5)
9 (60)
6 (40)
8 (53)
4 (27)
3 (20)
10 (67)
2 (13)
1 (7)
2 (13)
8 (80)
2 (20)
7 (64)
4 (36)
6 (40)
9 (60)
1 (7)
14 (93)
6 (40)
7 (47)
2 (13)
14 (93)
0 (0)
1 (7)
11 (73)
3 (20)
1 (7)
5 (63)
3 (38)
4 (50)
1 (13)
3 (38)
4 (50)
1 (13)
1 (13)
2 (25)
6 (100)
0 (0)
6 (100)
0 (0)
4 (50)
4 (50)
0 (0)
8 (100)
7 (87)
1 (13)
0 (0)
7 (87)
1 (13)
0 (0)
1 (13)
5 (63)
2 (25)
1,386 (78)
384 (22)
1,113 (63)
261 (15)
396 (22)
1,368 (78)
152 (9)
103 (6)
123 (7)
1,024 (84)
198 (16)
1,122 (19)
266 (81)
1,101 (62)
669 (38)
37 (2)
1,733 (98)
874 (50)
825 (47)
64 (3)
1,603 (91)
85 (5)
2 (5)
898 (51)
753 (43)
119 (7)
P Value†
.007; .76
.07; .88
.002; .61
.08; .55
.08; .02
.002; .83
.004; .75
.89; .02
.10; .007
.84; .02
Values are the number of patients with percentages in parentheses.
*Nonhypodiploid included 578 normal diploid patients, 496 pseudodiploid patients, 204 low hyperdiploid (47 to 50 chromosomes) patients, and
492 high hyperdiploid (.50 chromosomes) patients.
†Global x2 test for homogeneity; the first P value refers to comparison between combined hypodiploid group and nonhypodiploid group and the
second P value refers to comparison among hypodiploid subgroups.
‡NCl standard risk 5 1 to 9 years of age with WBC count less than 50,000/µL; NCl poor risk 5 $10 years of age or WBC count $50,000/µL.11
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HETEROGENEITY OF HYPODIPLOID ALL IN CHILDREN
had between 29 and 32 chromosomes; and 15 had 33 to 44
chromosomes (1 with 33; 2 with 34; 1 with 36; 1 with 40; 1 with
42; 1 with 43; and 8 with 44). Six patients with a modal
chromosome number of 46 were classified as hypodiploid: 4
cases had Down syndrome with loss of another chromosome; 2
additional cases each had 45 chromosomes in the simplest
clone.
Recurrent karyotypic aberrations of the hypodiploid patients
are summarized in Table 1. A doubling of the hypodiploid clone
was seen in 2 patients with 24 to 28 chromosomes and in 2
patients with 33 to 44 chromosomes. The majority (5/8) of
patients with 24 to 28 chromosomes had numerical aberrations
only, whereas only 2 of 15 patients with 33 to 44 chromosomes
(1 with 33 and 1 with 34 chromosomes) lacked structural
aberrations. All patients with 24 to 28 chromosomes had disomy
of chromosome 21, 4 had disomy 18, and 2 each had disomy 8,
10, or 14. Four of these patients had 2 sex chromosomes (3 were
XY and 1 was XX). Among patients with 33 to 44 chromosomes, 7 had monosomy 7, 6 had monosomy 13, 5 had
monosomy 20, 4 had monosomy 14, and 8 had monosomy X (3
females and 5 males).
Among patients in the subgroups with 33 to 44 and 45
chromosomes, the frequency of specific recurring aberrations
differed among subsets with and without a dicentric chromosome. Among those with 45 chromosomes, dic(9;12), dic(9;20),
dic (7;9), and dic(9;V) were particularly common. Six patients
with 45 chromosomes had numerical abnormalities only (1 had
Fig 1. EFS for hypodiploid and
nonhypodiploid ALL subgroups.
Probabilities for patients with
normal diploidy (N 5 578); pseudodiploidy (N 5 496); low hyperdiploidy (47 to 50 chromosomes,
N 5 204); high hyperdiploidy
(G50 chromosomes, N 5 492);
45 chromosomes (N 5 87); 33 to
44 chromosomes (N 5 12); or
I28 chromosomes (N 5 11).
4039
a constitutional structural abnormality): 2X, 1 patient; 218, 1
patient; 27, 1 patient; 222, 1 patient; and 220, 2 patients. In
contrast, only 2 patients in the group with 33 to 44 chromosomes had dicentric chromosomes. Thirteen patients with 33 to
44 chromosomes had structural aberrations, and 8 patients were
missing a sex chromosome (2X, 3 patients; and 2Y, 5
patients).
Among the combined group of patients with 33 to 45
chromosomes, monosomies, particularly of chromosomes 7
(N 5 17) and 13 (N 5 17), were frequent in patients lacking a
dicentric chromosome. Four of the 7 patients with a Philadelphia chromosome (Ph) also had monosomy 7. In addition to the
17 patients with monosomy 13, 6 patients had partial deletions
of 13q (data not shown). Monosomy of chromosome 14, which
has not been reported previously, and monosomy of chromosome 20 also were relatively frequent, occurring in 12 and 13
patients, respectively.
Other abnormalities that occurred frequently among all
hypodiploid patients included an abnormal chromosome arm
9p, an abnormal chromosome arm 12p, a deletion of chromosome arm 6q, and a Ph. Many patients in the 33 to 44 or 45
chromosome group had 2 or more abnormalities. Constitutional
structural abnormalities were observed in 7 patients, including
the 4 cases with Down syndrome as well as 3 patients with a
modal chromosome number of 45: 1 had inv(1)(q23q32), 1 had
t(3;17)(q25;q23), and 1 had t(10;13)(q26;q21).
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4040
Clinical and biological features of children with hypodiploid
ALL. Distinguishing characteristics of hypodiploid patients at
presentation are shown in Table 2. Hypodiploid patients were
more likely than nonhypodiploid patients to be $10 years of
age (P 5 .007), to be classified as poor risk by NCI criteria (P 5
.002), to have L2/L1 or L2 FAB morphology (P 5 .002), or to
have a Ph (P 5 .004). Comparison of the frequencies of WBC
count and T-lineage and CD101 immunophenotypes reached
borderline significance. No statistically significant differences
were observed for other laboratory or clinical parameters,
including sex, race, organomegaly, platelet or hemoglobin
levels, or presence of central nervous system (CNS) disease,
HEEREMA ET AL
t(4;11), t(1;19), or Down syndrome (data not shown). Within the
hypodiploid group, patients in each of the subgroups were
generally similar with respect to their presenting features,
except that those with 24 to 28 chromosomes were less likely to
have hepatomegaly (P 5 .02) and more likely to have enlarged
lymph nodes (P 5 .02) and be CD101 (P 5 .02); those with 45
chromosomes were less likely to have a mediastinal mass (P 5
.007).
Treatment outcome. Early treatment response was similar
for the 101 hypodiploid and 1,408 nonhypodiploid patients with
a marrow evaluation on day 7 of induction chemotherapy: 75%
of each group achieved a rapid response (M1 or M2 marrow
Fig 2. EFS for patients with less than 45 chromosomes and H45 chromosomes according to NCI risk
classification.11 (A) NCI standard risk (1 to 9 years of
age with WBC counts F50,000/mL). (B) NCI poor risk
(H10 years of age or WBC counts H50,000/mL).
(Inset) Number of patients remaining in follow-up.
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HETEROGENEITY OF HYPODIPLOID ALL IN CHILDREN
status) and 25% were slow responders (M3 marrow status).
Within the hypodiploid subgroups, 80 patients with 45 chromosomes, 15 patients with 33 to 44 chromosomes, and 6 patients with 24 to 28 chromosomes underwent a day-7 marrow
evaluation. A rapid early response was achieved by 75% of
those with 45 chromosomes, 80% of those with 33 to 44
chromosomes, and 67% of those with 24 to 28 chromosomes, although the comparison did not reach statistical significance (P 5 .81). Nearly all hypodiploid and nonhypodiploid patients ($97% in each group) achieved remission
by the end (day 28) of induction chemotherapy (P 5 .68).
Within the hypodiploid subgroups, 97% of patients with 45
chromosomes and 100% of those with either 33 to 44 chromosomes or 24 to 28 chromosomes achieved remission by day 28
(P 5 .95).
EFS was significantly different between hypodiploid patients
and nonhypodiploid patients, with 6-year estimates of 58% (SD,
7%) and 76% (SD, 2%), respectively (log rank, P , .0001).
Overall survival for hypodiploid and nonhypodiploid patients
also was significantly different, with 6-year estimates of 67%
(SD, 7%) and 84% (SD, 1%), respectively (log rank, P ,
.0001). Within the hypodiploid group, we observed a significant
trend for progressively worse outcome with decreasing chromosome number, with 6-year EFS of 65% (SD, 8%), 40% (SD,
18%), and 25% (SD, 22%) for the 3 groups, respectively (Fig 1;
log rank, P 5 .002; test for trend, P 5 .0009). By comparison,
patients with normal diploidy, pseudodiploidy, low hyperdiploidy (47 to 50 chromosomes), and high hyperdiploidy (.50
chromosomes) had 6-year EFS of 81% (SD, 2%), 70% (SD,
3%), 66% (SD, 6%), and 80% (SD, 3%), respectively (Fig 1).
Notably, the subgroup of hypodiploid patients with 45 chromosomes had an EFS outcome similar to that of patients with either
pseudodiploidy (P 5 .43) or low hyperdiploidy (P 5 .76).
Overall survival also was significantly different for the 3
hypodiploid subgroups, with 6-year estimates of 72% (SD, 7%),
47% (SD, 15%), and 50% (SD, 35%), respectively (log rank,
P 5 .02; test for trend, P 5 .01).
Among patients classified as NCI standard risk (1 to 9 years
of age with WBC counts ,50,000/µL), those with less than 45
chromosomes had significantly worse EFS outcome than those
with $45 chromosomes, with estimates of 30% (SD, 15%) and
79% (SD, 2%), respectively (P , .0001; Fig 2A). Similarly,
among patients classified as NCI poor risk (age $10 years or
WBC $50,000/µL), those with less than 45 chromosomes had
significantly worse EFS outcome than those with $45 chromosomes, with estimates of 39% (SD, 21%) and 69% (SD, 3%),
respectively (P 5 .002; Fig 2B). Furthermore, among patients
with less than 45 chromosomes, the outcome of high-risk
patients, all of whom received highly intensive chemotherapy,
was not significantly different from that of standard-risk patients (P 5 .79). Ten hypodiploid patients with 45 chromosomes
had a dic(9;12), and there was a trend for improved outcome
(relative risk 5 .55) among this group, with all events occurring
within 2.5 years of diagnosis. However, log rank analysis
showed similar outcome for these patients and other patients
with 45 chromosomes, with 6-year EFS of 78% (SD, 18%) and
63% (SD, 9%), respectively (P 5 .40). Overall survival also
4041
was similar for the 2 subsets (P 5 .70). Nine hypodiploid
patients with 45 chromosomes had a dic(9;20). Outcome for
these patients was similar to that of other patients with 45
chromosomes, with 6-year EFS of 63% (SD, 22%) and 65%
(SD, 9%), respectively (P 5 .93). Overall survival also was
similar for these 2 groups (P 5 .83).
There were a total of 405 events in the nonhypodiploid
group, 28 events in the group with 45 chromosomes, and
15 events in the group with less than 45 chromosomes
(Table 3). The most common event in all 3 groups was a relapse
involving the marrow, either isolated or combined with relapse
at another site. Relapses involving the marrow were significantly more frequent among the hypodiploid subgroup with less
than 45 chromosomes than in patients with 45 chromosomes
(P 5 .001). Other types of events, including extramedullary relapses, occurred with similar frequency in these 2
groups.
The poorer outcome of the 23 patients with less than 45
chromosomes prompted us to examine their clinical and biological characteristics and treatment in more detail. The majority of
these patients had B-lineage, CD101 ALL, and none of the
patients in the 24 to 28 modal number subgroup had a Ph, a
t(4;11), a t(1;19), CNS disease at diagnosis, or Down syndrome.
Only 1 patient in the 33 to 44 modal number group was Ph1.
Most patients with 24 to 28 chromosomes lacked marked
organomegaly, and only 1 patient had a mediastinal mass.
Karyotypes, race, NCI risk group, and outcome for the 23
patients with less than 45 chromosomes are shown in Table 4.
Nearly all of these patients were white; 10 of the 23 patients (4
with modal number 24 to 28 and 6 with modal number 33 to 44)
were classified as NCI standard risk and 13 patients (4 with
Table 3. Frequency and Type of First Events for Hypodiploid and
Nonhypodiploid Patients
Event Type
Marrow relapse
Isolated
Combined
Total*
Other event†
CNS relapse, isolated
Testicular relapse,
isolated
Other relapse
Second malignancy
Induction failure or
death in induction
Death in remission
Total
Total events
NonHypodiploid Hypodiploid Hypodiploid
hypodiploid
24-28
33-44
45
(N 5 1,770)
(N 5 8)
(N 5 15)
(N 5 87)
11 (13)
3 (3)
14 (16)
8 (53)
0 (0)
8 (53)
3 (38)
1 (13)
4 (50)
206 (12)
23 (1)
229 (13)
5 (6)
0 (0)
1 (13)
69 (4)
2 (2)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
17 (1)
11 (1)
7 (0)
3 (3)
4 (5)
14 (16)
0 (0)
1 (7)
1 (7)
0 (0)
1 (13)
2 (18)
30 (2)
42 (2)
176 (10)
28
9
6
405
Values are the number of patients. The percentage of all patients for
given group is in parentheses.
*Any relapse involving the marrow, alone or in combination with
relapse at another site.
†All events other than a relapse involving the marrow.
From www.bloodjournal.org by guest on September 12, 2016. For personal use only.
4042
HEEREMA ET AL
Table 4. Clinical Characteristics, Karyotypes, and Outcome for Patients With Less Than 45 Chromosomes
Patient
No.
Modal
Chromosome
Number
1
2
3
4
5
6
24
25
26
26
27
27
White
White
White
White
White
Black
Standard
Standard
Poor
Poor
Standard
Poor
7
8
9
27
28
33
Other*
White
White
Poor
Standard
Poor
10
34
Hispanic
Poor
11
34
White
Poor
12
36
White
Poor
13†
40
White
Poor
14‡
42
White
Standard
15
43
White
Poor
16
44
White
Standard
17
18
19
44
44
44
White
White
Hispanic
Standard
Poor
Standard
20
44
White
Poor
21
44
White
Poor
22
44
Black
Standard
23
44
White
Standard
NCI Risk
Group
Race
Karyotype
Outcome
24,X,121/48,idem,x2/46,XX
25,X,2Y,114,121/46,XY
26,X,1Y,114,121/46,XY
26,XY,1del(5)(q13q33),121/52,idem,x2
27,X,1X,118,121,1mar/46,XX
27,X,1Y,1del(13)(q1?4q2?2),118,121/
27,idem,2del(13)(q1?4q2?2),
1dup(13)(q1?3q1?4)/46,XY
27,X,18,110,118,121/46,XX
28,X,18,19,110,118,121/46,XX
3371n8,X,11,12,13,16,17,18,110,111,112,115,
116,222/46,XY
3471n8,X,1Y,11,15,16,18,110,111,118,119,121,
122/46,XY
3471n8,X,11,15,16,inv(7)(p1?5q11.2),18,110,111,
113,114,119,121,122/6973n8,XX,2X,11,22,
23,24,15,16, inv(7)(p1?5q11.2),29,111,212,
113,114,215, 216,217,218,119,120,121,
122/46, XX
36,XX,23,24,25,27,29,213,215,216,217,217,
220,1mar/72,idemx2/46, XX
40,X,2Y,23,der(4)t(3;4)(p21;p16),27,29,215,216,
217,218,12mar/46, XY
42,XY,23,25,der(6)t(6;7)(p25;
q11.2),27,add(8)(p21),der(9)t(9;12) (p22;p13)
t(9;22)(q34;q11),der(12)t(9;12)(p22;p13),213,
der(15;17) (q10;q10),add(22)(p11),1mar/46,XY
43,X,2X,add(1)(p3?4),t(2;12)(p21;p13),27,t(7;
9)(p13;p22),add(12)(p11), 215/46,XX
44,XX,der(2)t(2;7)(q31;p15),27,psudic(9;16)(p2?2;
p1?1.2),der(12)t(7;12)(q1?1.2;p11.2)/45,
idem,1mar/46,XX
44,X,2Y,add(12)(p11),213/46,XY
44,X,2X,26,der(9)t(6;9)(p11.1;p13)/46,XX
44,XY,add(1)(q4?),del(2)(p1?),add(6)(p21),add(11)
(p11.1),?i(12)(p10)x2, 214,220,221,1mar/46,XY
44,X,2Y,der(6)del(6)(p22)del(6)(q12),i(9)(q10),
der(12)t(12;14)(p1?3;q11.2 ),214,add(14)(q32),
add(16)(p13)/46,XY
44,XX,der(4)t(4;18)(p1?5;
q11,21),add(9)(p13),218,220/46,XX
44,X,2Y,add(9)(p22),del(11)(q2?1q2?3),213,add(17)
(p1?3),der(19)t(1;19) (q23;p13)/46,XY
44,XY,dic(9;12)(p11;p12),215
Alive postrelapse
Died postrelapse
Died in first remission
Died after a postrelapse BMT
Alive, event-free
Alive, event-free after a BMT
in first remission
Alive postrelapse
Died postrelapse
Alive, event-free
Died postrelapse
Died after a postrelapse BMT
Alive, event-free
Alive, event-free
Died post-2nd relapse, after
a first remission BMT
Died, postrelapse
Alive, postrelapse
Alive, event-free
Alive, event-free
Alive, event-free
Died in first remission
Died postrelapse
Died postrelapse
Died postrelapse
*Race other than white, black, or hispanic.
†Bone marrow transplant in remission.
‡Ph1 patient.
modal number 24 to 28 and 9 with modal number 33 to 44) were
classified as NCI poor risk. Specific karyotypic features for
these 23 patients were summarized above (Table 1) and are
shown in Table 4 for comparison with outcome and other
features.
Of the 8 patients with 24 to 28 chromosomes, half are
survivors. Two of the 4 patients are alive after a relapse, and 2
are alive event-free for 5 and 9 years; 1 of the event-free
survivors underwent bone marrow transplantation in first remission. Of the 4 patients who died, 1 died after a postrelapse bone
marrow transplant, 1 died in remission, and 2 died after a
relapse. Because of the small number of patients in the group
with modal number of 24 to 28 chromosomes, we were unable
to identify differences in treatment that could account for their
poor outcome. Half of the 8 patients with modal number of 24 to
28 chromosomes were treated on protocols for higher risk ALL,
indicating that, regardless of specific regimen, they would have
received relatively intensive therapy. No obvious associations
were noted between karyotype and outcome for these patients
with modal number 24 to 28.
From www.bloodjournal.org by guest on September 12, 2016. For personal use only.
HETEROGENEITY OF HYPODIPLOID ALL IN CHILDREN
Among the 15 patients with 33 to 44 chromosomes, 7 are
survivors. Six of these 7 patients remain event-free for 3 to 6
years after study entry; 1 of these event-free survivors underwent bone marrow transplantation in first remission. One
patient is alive 2 years after a relapse. Of the 8 patients who
died, 1 died in first remission and the other 7 died after a relapse.
Five of the 7 were in postrelapse remission at the time of death.
One of the 7 patients had Ph1 ALL, underwent bone marrow
transplant in first remission, and died after a second marrow
relapse. Another patient died after a postrelapse bone marrow
transplant. No obvious associations were noted between karyotype and outcome for these patients with modal number 33
to 44.
In addition to the 5 hypodiploid patients with less than 45
chromosomes who underwent bone marrow transplantation, 5
hypodiploid patients with 45 chromosomes also had a transplant. Two patients who had a transplant after a relapse remain
alive 2.5 and 3 years posttransplant (6.7 and 8.5 years after
study entry); the other 3 (1 had a transplant in remission and 2
had transplants after a relapse) died.
Multivariate analysis. The independent significance of hypodiploidy with less than 45 chromosomes relative to hypodiploidy with 45 chromosomes or nonhypodiploidy was determined using a multivariate analysis. Significant factors identified
by stepwise regression for inclusion in the multivariate analysis
model included age, WBC count, spleen size, race, and Ph
status. Using this model, hypodiploidy for all patients with less
than 45 chromosomes remained a significant adverse risk factor
for EFS: relative to the nonhypodiploid group, estimated
relative risks and their 95% CI were 1.53 (1.04, 2.25), 3.34
(1.65, 6.74), and 5.72 (2.53, 12.95) for patients with 45
chromosomes, 33 to 44 chromosomes, or 24 to 28 chromosomes, respectively (P , .0001).
DISCUSSION
We have assessed the prognostic significance of hypodiploidy in a very large cohort of children with ALL. As has been
observed previously,16 the majority (79%) of hypodiploid
patients had 45 chromosomes, whereas the remainder had less
than 45 chromosomes. Most patients had multiple cytogenetic
abnormalities, particularly dicentrics, monosomies, and abnormalities of 6q, 9p, and 12p. In contrast to their counterparts with
33 or more chromosomes, hypodiploid patients with 24 to 28
chromosomes generally had numerical, rather than structural
abnormalities (see below). Although hypodiploid patients were
more likely than their nonhypodiploid counterparts to have
some unfavorable characteristics, presenting features were
generally similar within the hypodiploid subgroups; approximately half of all hypodiploid patients were classified as poor
risk by NCI criteria.
Similar to previous reports,16,18 our results indicate that
patients whose leukemic cells have a hypodiploid karyotype
have a poorer EFS and survival compared with nonhypodiploid
patients. Notably, however, our data demonstrate that hypodiploid patients with 45 chromosomes have EFS and survival
4043
outcomes similar to those of patients with pseudodiploidy or
low hyperdiploidy (47 to 50 chromosomes), whereas patients
with less than 45 chromosomes have significantly worse
outcome. Moreover, there was a significant trend for progressively worse outcome with decreasing chromosome number:
patients with 45 chromosomes had the best outcome, patients
with 33 to 44 chromosomes had intermediate outcome, and
patients with 24 to 28 chromosomes had the worst outcome.
Interestingly, the poor outcome of hypodiploid patients with
less than 45 chromosomes was due to an excess of marrow
relapses rather than to high rates of CNS or other extramedullary relapses. The poorer outcome for patients with less than 45
chromosomes also was observed for patients regardless of NCI
risk classification. In addition, the prognostic effects of hypodiploidy with 33 to 44 or 24 to 28 chromosomes were maintained in
a multivariate analysis adjusted for important risk factors,
including age, WBC count, and Ph status. These findings
indicate that leukemic cell hypodiploidy comprises a heterogeneous group of patients with respect to clinical features at
diagnosis and treatment outcome.
The 8 patients with 24 to 28 chromosomes (near-haploidy) represent a unique subgroup of ALL patients who
lack certain adverse risk factors: the majority are white with
B-lineage, CD101 ALL, and lack CNS disease, t(9;22), t(1;19),
or t(4;11), but have a poor outcome due to high rates of marrow relapse. Two of these patients had a second abnormal cell
line with twice the number of chromosomes seen in the
near-haploid clone; 5 had numerical abnormalities only. Disomies of the sex chromosomes as well as autosomes 21, 18, 14,
10, and 8 were frequent. Previous studies also noted a high
frequency of numerical abnormalities and, in cases with nearhaploidy, the presence of a second abnormal cell line with
twice the number of chromosomes found in the near-haploid
clone.11
In one of the larger series previously studied, Pui et al16
reported that 31 patients with 45 or fewer chromosomes had
worse outcome than patients in other ploidy groups, although
the significance of this difference was not maintained in a
multivariate analysis. In a later study, Pui et al18 reported that
hypodiploid patients with fewer than 45 chromosomes, including those with near-haploidy, had significantly worse
outcome than patients in all other ploidy groups, suggesting that
the precise number of chromosomes may be an important
determinant of risk. More recently, Chessells et al19 reported
that hypodiploidy with 24 to 29 chromosomes was a significant and independent risk factor for children treated on the
Medical Research Council (MRC) United Kingdom ALL group
(UKALL) protocol X. Our data confirm and extend these
previous reports by demonstrating that hypodiploidy in ALL
comprises a heterogeneous group with respect to treatment
outcome, with progressively worse outcome for those with 45,
33 to 44, and 24 to 28 chromosomes. Patients in the subgroup
with 24 to 28 chromosomes represent a subset of ALL patients
with a particularly poor outcome. These findings suggest that
novel treatment programs are warranted for children with ALL
and a hypodiploid leukemic cell karyotype with 24 to 28
chromosomes.
From www.bloodjournal.org by guest on September 12, 2016. For personal use only.
4044
HEEREMA ET AL
ACKNOWLEDGMENT
Contributing Cytogeneticists
Investigator
A.A. Al Saadi
D.C. Arthur
H. Aviv
B.L. Barnoski
P. Benn
R. Best
D.S. Borgaonkar
C. Bradley
A. Brothman
M.G. Butler
Z. Chen
H. Chen
P.D. Cotter
A.J. Dawson
G. Dewald
Y.-S. Fan
P.A. Farber
A.B. Glassman
T.W. Glover
W. Golden
S. M. Golin
D. Harris
N.A. Heerema
R. Higgins
J.V. Higgins
B. Hirsch
D.K. Kalousek
M.M. LeBeau
C. Lee
K. Leppig
S. Lewis
W.D. Loughman
C.B. Lozzio
R.E. Magenis
L. McGavran
L.E. McMorrow
A. Milatovitch
T.K. Mohandas
B. Mouron
A. Murch
P. Nowell
K. Opheim
L. Pasztor
S. Patil
C. Pehl
M.A. Perle
A. Pettigrew
C. Phillips
K. Rao
K.E. Richkind
K.N. Rosenbaum
D. Roulston
C. Sandlin
W.G. Sanger
K.L. Satya-Prakash
S. Schwartz
G.S. Sekhon
S. Sheldon
S. Soukup
R. Sparkes
R. Stallard
W.S. Stanley
J. Stone
P. Storto
K.S. Theil
B. Torchia
D. Van Dyke
N.V. Vigfusson
D. Warburton
J.R. Waterson
S.L. Wenger
G. Williams
K.-L. Yin
C.W. Yu
T. Zadeh
M.C. Zapata
S. Zneimer
Institution
William Beaumont Hospital, Royal Oak, MI
University of Minnesota, Minneapolis, MN
University of Medicine and Dentistry, Newark, NJ
University Medical Center, Camden, NJ
University of Connecticut Health Center, Farmingham, CT
Richland Memorial Hospital, Columbia, SC
Medical Center of Delaware, Wilmington, DE
Children’s Hospital and Medical Center, Seattle, WA
University of Utah, Salt Lake City, UT
Vanderbilt University, Nashville, TN
Genzyme Genetics, Scottsdale, AZ
Louisiana State University Medical Center, Shreveport, LA
Children’s Hospital, Oakland, CA
Cytogenetics/HSC, Winnepeg, MB, Canada
Mayo Clinic, Rochester, MN
London Health Science Centre, London, ON, Canada
Geisinger Medical Center, Danville, PA
M.D. Anderson Cancer Center, Houston, TX
University of Michigan, Ann Arbor, MI
Rainbow Babies & Children’s Hospital, Cleveland, OH
University of Pittsburgh, Pittsburgh, PA
Children’s Mercy Hospital, Kansas City, MO
Indiana University, Indianapolis, IN
Children’s Mercy Hospital, Kansas City, MO
Butterworth Hospital, Grand Rapids, MI
University of Minnesota, Minneapolis, MN
British Columbia Children’s Hospital, Vancouver, BC, Canada
University of Chicago, IL
Izaak Walton Killam Children’s Hospital, Halifax, NS, Canada
University of Washington, Seattle, WA
Scottish Rite Children’s Hospital, Atlanta, GA
Children’s Hospital, Oakland, CA
University of Tennessee Medical Center, Knoxville, TN
Oregon Health Sciences Center, Portland, OR
Children’s Hospital of Denver, CO
University of Medicine & Dentistry, Newark, NJ
Children’s Hospital and Medical Center, Cincinnati, OH
Harbor/University of California Los Angeles Medical Center, Torrance, CA
Children’s Mercy Hospital, Kansas City, MO
King Edward Memorial Hospital, Perth, Australia
Children’s Hospital of Philadelphia, PA
Children’s Hospital and Medical Center, Seattle, WA
Children’s Mercy Hospital, Kansas City, MO
University of Iowa, Iowa City, IA
Loma Linda University, Redlands, CA
New York University Medical Center, New York, NY
University of Kentucky, Lexington, KY
Emory University Hospital, Atlanta, GA
University of North Carolina, Chapel Hill, NC
Genzyme Genetics, Santa Fe, NM
Children’s Hospital National Medical Center, Washington, DC
University of Chicago, IL
Memorial Genetics Center, Long Beach, CA
University of Nebraska, Omaha, NB
Medical College of Georgia, Augusta, GA
Rainbow Babies & Children’s Hospital, Cleveland, OH
University of Wisconsin, Madison, WI
University of Michigan, Ann Arbor, MI
Children’s Hospital and Medical Center, Cincinnati, OH
University of California, Los Angeles, CA
Rainbow Babies & Children’s Hospital, Cleveland, OH
Genetics and IVF Institute, Fairfax, VA and Children’s Hospital National Medical Center, Washington, DC
Genetrix, Inc, Scottsdale, AZ
Michigan State University, Lansing, MI
Children’s Hospital of Columbus, OH
Western Reserve Healthcare, Youngstown, OH
Henry Ford Health System, Detroit, MI
Sacred Heart Medical Center, Spokane, WA
Columbia Presbyterian College of Physicians & Surgeons, New York, NY
Children’s Hospital Medical Center, Akron, OH
University of Pittsburgh, PA
Manitoba Cancer Foundation, Winnepeg, MB, Canada
Children’s Hospital of Los Angeles, CA
Valley Children’s Hospital, Fresno, CA
Genetics Center, Orange, CA
Children’s Medical Center, Dayton, OH
Kaiser-Permanente, San Jose, CA
From www.bloodjournal.org by guest on September 12, 2016. For personal use only.
HETEROGENEITY OF HYPODIPLOID ALL IN CHILDREN
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From www.bloodjournal.org by guest on September 12, 2016. For personal use only.
1999 94: 4036-4045
Hypodiploidy With Less Than 45 Chromosomes Confers Adverse Risk in
Childhood Acute Lymphoblastic Leukemia: A Report From the Children's
Cancer Group
Nyla A. Heerema, James B. Nachman, Harland N. Sather, Martha G. Sensel, Mei K. Lee, Raymond
Hutchinson, Beverly J. Lange, Peter G. Steinherz, Bruce Bostrom, Paul S. Gaynon and Fatih Uckun
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