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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 94 No. 12 (December 15), 1999:
pp. 4036-4045
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
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.
 |
ABSTRACT |
We have determined the prognostic significance of hypodiploidy
(<46 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 = .002;
test for trend, P = .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 < .0001). EFS
for the subgroup with 45 chromosomes was similar to that of patients
with pseudodiploidy (P = .43) or 47 to 50 chromosomes
(P = .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.
© 1999 by The American Society of Hematology.
| |
INTRODUCTION |
CURRENT CHILDREN'S cancer group (CCG)
risk group-adjusted intensive therapies for childhood acute
lymphoblastic leukemia (ALL) are expected to result in 6-year
event-free 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 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 near-haploidy, 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 = 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.
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MATERIALS AND METHODS |
Patients.
Diagnosis of ALL required determination of lymphoblast morphology by
Wright-Giemsa staining of bone marrow smears, 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, 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 = .50). Greater than 97% of each group achieved remission by the end of induction therapy (P = .10), and 6-year EFS
estimates were 75% (SD, 2%) and 76% (SD, 1%) for patients with or
without accepted data, respectively (P = .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  2 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
Kaplan-Meier24 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 ±1.96 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 = 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 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 a constitutional structural abnormality):  X, 1 patient;
18, 1 patient; 7, 1 patient; 22, 1 patient; and
20, 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 (X, 3 patients; and Y, 5 patients).
Among the combined group of patients with 33 to 45 chromosomes,
monosomies, particularly of chromosomes 7 (N = 17) and 13 (N = 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).
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 = .007), to be classified as poor risk by NCI criteria
(P = .002), to have L2/L1 or L2 FAB morphology (P = .002), or to have a Ph (P = .004). Comparison of the
frequencies of WBC count and T-lineage and CD10+
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, 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 = .02) and
more likely to have enlarged lymph nodes (P = .02) and be
CD10+ (P = .02); those with 45 chromosomes were
less likely to have a mediastinal mass (P = .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 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 pa- tients 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 chromo- somes,
although the comparison did not reach statistical significance
(P = .81). Nearly all hypodiploid and
nonhypo- diploid patients (97% in each group) achieved
remission by the end (day 28) of induction chemotherapy (P = .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 = .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 = .002; test for trend, P = .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 = .43) or low hyperdiploidy (P = .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 = .02; test for trend,
P = .01).
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| Fig 1.
EFS for hypodiploid and nonhypodiploid ALL subgroups.
Probabilities for patients with normal diploidy (N = 578);
pseudodiploidy (N = 496); low hyperdiploidy (47 to 50 chromosomes, N
= 204); high hyperdiploidy (>50 chromosomes, N = 492); 45 chromosomes (N = 87); 33 to 44 chromosomes (N = 12); or 28
chromosomes (N = 11).
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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 = .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 = .79). Ten hypodiploid patients with
45 chromosomes had a dic(9;12), and there was a trend for improved
outcome (relative risk = .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 = .40). Overall survival also was similar for
the 2 subsets (P = .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 = .93). Overall
survival also was similar for these 2 groups (P = .83).
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| Fig 2.
EFS for patients with less than 45 chromosomes and 45
chromosomes according to NCI risk classification.11 (A) NCI
standard risk (1 to 9 years of age with WBC counts <50,000/µL). (B)
NCI poor risk (10 years of age or WBC counts 50,000/µL).
(Inset) Number of patients remaining in follow-up.
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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 = .001). Other types of events,
including extra- medullary 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, CD10+ 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 Ph+. 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 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.
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
Ph+ 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 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-hap- loidy) represent
a unique subgroup of ALL patients who lack certain adverse risk factors: the majority are white with B-lineage, CD10+
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 mar- row 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
near-haploidy, 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 signifi- cant 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.
| |
ACKNOWLEDGMENT |
Contributing
Cytogeneticists
| |
FOOTNOTES |
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.
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.
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.
| |
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