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Blood First Edition Paper, prepublished online May 1, 2007; DOI 10.1182/blood-2006-07-038299
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
From The University of Chicago Comer Children’s Hospital, Chicago, IL (J.B.N.); Columbus
Children’s Hospital and The Ohio State University, Columbus, OH (N.A.H.); Children’s
Oncology Group –Operations Center, Arcadia, CA (H.S.); Midwest Children’s Cancer Center,
Department of Pediatrics of the Medical College of Wisconsin, Children’s Hospital of
Wisconsin, Milwaukee, WI (B.C.); Department of Clinical Sciences and Paediatrics, University
of Umeå, Sweden (E.F.); Leukaemia Research Cytogenetics Group, Cancer Sciences Divison,
University of Southampton, Southampton, United Kingdom (C.J.H.); Génétique des
Hémopathies, Laboratoire d’Hématologie, Hôpital Purpan, Toulouse, France (N.D.); University
Hospital Schwanenweg, Department of Pediatrics, Kiel, Germany (M.S.); St. Jude Children’s
Research Hospital and the University of Tennessee Health Science Center, Memphis, TN (C.H.P); Pediatrics Department, University of Padova, Padova, Italy (G.B.); Department of
Pediatric Oncology, Dana-Farber Cancer Institute and Division of Hematology Oncology,
Children’s Hospital, Boston, MA (L.B.S.); and Children's University Hospital, Department of
Hematology and Oncology, Hamburg, Germany (G.E.J.).
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, UK 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
All authors contributed to all aspects of preparing this manuscript.
Corresponding Author: Dr. James Nachman, The University of Chicago Comer Children’s
Hospital, 5841 S. Maryland Ave C-429, Chicago, IL 60637; e-mail:
[email protected]; phone: 773-702-6808; fax: 773-702-9881.
Copyright © 2007 American Society of Hematology
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Summary
One hundred and thirty-nine patients with acute lymphoblastic leukemia (ALL) and
hypodiploidy (less than 45 chromosomes) were collected from 10 different national ALL study
groups or single institutions. Patients were stratified by modal chromosome number into four
groups: 24-29 (N=46); 33-39 (N=26); 40-43 (N=13) and 44 chromosomes (N=54). Nine patients
were Philadelphia chromosome (Ph) positive (four cases - 44 chromosomes; five cases - 40-43
chromosomes) and were not considered further. Event-free survival (EFS) and overall survival
(OS) of the remaining 130 patients were 38.5% ± 4.4% and 49.8% ± 4.2% at 8 years,
respectively. There were no significant differences in outcome between patients with 24-29, 3339, or 40-43 chromosomes. Compared to patients with <44 chromosomes, patients with 44
chromosomes had a significantly better EFS (P=.01; 8-year estimate, 52.2% vs 30.1%) and OS
(P=.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=25) and 33-39 chromosomes
(n=7)) and had no prognostic implication. Children and adolescents with ALL and hypodiploidy
with less than 44 chromosomes have a poor outcome despite contemporary therapy.
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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 less 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 less than 45 chromosomes.5 It is not uncommon
for leukemic cells with 23-29 and 33-39 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 less 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 less 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 less than 45 chromosomes, 139 cases were collected from 10
participating cooperative groups and large single institutions in the USA and Europe for
investigation.
This article represents a record review from studies that were previously approved by each
institution’s local IRB.
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Patients and methods
Patients
Study groups or institutions reviewed their own records and identified ALL patients with less
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, two 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; CCG-33; COALL-3; DANA FARBER -4; POG-44; SJCRH-6; UK20; 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 subgroups were compared using χ2 tests for
homogeneity of proportions. Outcome was analyzed using life table methods and associated
statistics. The primary endpoints 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
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across the entire period of patient follow-up. Values ≤ 0.05 are referred to as significantly
different. Numerical cutoff levels for the hypodiploid subgroups 24-29; 33-39; 40-43; 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.
Results
Karyotypes of hypodiploid patients
Nine of the 139 patients with hypodiploidy were Philadelphia chromosome (Ph) positive; five
had 40-43 chromosomes and four had 44 chromosomes. These patients were not considered
further, leaving 130 eligible patients, which were divided into four groups based on modal
chromosome number: 24-29, 33-39, 40-43 and 44 chromosomes (Table 1). Patients with 24-29
chromosomes and those with 44 chromosomes accounted for 72.3% of patients. The distribution
of modal chromosome number for patients with ≤ 44 chromosomes is shown in Figure 1. No
patient had a modal chromosome number of 30, 31, 32 or 42. The most common modal
chromosome numbers for patients with ≤ 44 chromosomes were 44 (N = 50), 26 (N = 19) and 27
(N = 13) For one patient in the 40 – 43 chromosome group and another in the 33 – 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 is based on
128 patients.
Cytogenetic features of hypodiploid subgroups
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44 chromosomes (N=50). Forty-nine of 50 patients had structural as well as numerical
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.
40-43 chromosomes (N=7). All patients had disomies for chromosomes 2, 6, 10, 11, 20 and 22.
Structural abnormalities occurred in six patients. No doubling of the hypodiploid clone was seen.
33-39 chromosomes (N=25). Nine patients had structural abnormalities; in eight of these, the
modal chromosome number was less than 36. Disomies for chromosomes 3, 7, 16, and 17 were
rare. In seven patients, doubling of the hypodiploid clone was present.
24-29 chromosomes (N=46). Thirty-three patients had only numerical abnormalities. All
patients were disomic for chromosome 21. Disomies for chromosome X/Y (N=30); 14 and 18
(N=24 each) were also common. Twenty-five patients had doubling of the near-haploid clone.
Clinical and biologic characteristics of patients with ≤ 44 chromosomes
Approximately 90% of patients showed a B-precursor immunophenotype; almost all were
CD10+ and eight had CNS involvement at diagnosis. Of the eight T-cell patients, seven had 44
chromosomes. Table 2 shows the age, white count, and gender distribution for the 130 patients.
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Patients with 33-39 chromosomes were a unique group; 21 of 26 patients in this subgroup as
compared to 24 of 104 patients in the other groups were more than 10 years of age at diagnosis
(P ≤ .001).
Only two of 26 patients with 33-39 chromosomes as compared to 23 of 104 patients in the other
hypodiploid subgroups had a WBC greater than 50x109/L (P= NS). There was also a male
predominance in the patients with 33-39 chromosomes and in the small subgroup of patients with
40-43 chromosomes; patients in the less 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 post-remission event,
including marrow relapse in 56 patients (51 isolated: five combined), CNS relapse in ten
patients, testicular relapse in two patients, death in initial remission in six patients, and second
malignant neoplasm in one patient. The type of adverse event was unknown in three 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
remission at a median of 3 months (range, 2 to 8 months) from diagnosis and five 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 <44 chromosomes in
terms of EFS (P=0.01) and OS (P=0.002). 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
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outcome between patients with less than 30 chromosomes, 33-39 chromosomes, or 40-43
chromosomes (Figure 5 [EFS], 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= 0.025). 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, outcomes for patients with less than 46 chromosomes in their
leukemic clone have been poor, ranging from 25% to 40%.4-9 In an MRC study the 3-year EFS
for the 20 children with 25-39 chromosomes was 29% as compared to 66% for the 121 patients
with 42-45 chromosomes.5 Only seven children in that series had 42-44 chromosomes. Of these,
three with T cell ALL relapsed and died while three of the four patients with B-lineage ALL
remained alive in continuous remission. The Children’s Cancer Group reported on 23 patients
with less than 45 chromosomes.8 The EFS for patients with 24-28 chromosomes and 33-44
chromosomes was 25% and 40%, respectively. In this study, we collected data on patients with
less 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 eight patients in the 40-43 chromosome group, and no patients had 30-32
chromosomes. We confirmed the poor outcome for patients with hypodiploidy less than 45
chromosomes. The 8-year EFS and OS for the whole 130 hypodiploid non Ph+ patients were
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only 38.5% and 49.8%, respectively (Figure 2). For patients with 24-43 chromosomes, 8-year
EFS and OS were 30.1% and 37.5%, respectively. In contrast to previous studies suggesting that
near-haploid cases with 24-29 chromosomes have particularly poor outcome, we found no
difference in outcome between patients with 24-29, 33-39 or 40-43 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 no difference in survival compared to those with either or both
abnormalities.
Doubling of a hypodiploid clone occurs frequently in patients with 24-29 chromosomes and less
frequently in patients with 33-39 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 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 less 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
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requires further investigation. Patients with hypodiploid ALL tend to fail early in treatment
(within two years). The efficacy of transplantation in these patients cannot be adequately
addressed in this study because only nine 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 bone marrow transplant in first remission.
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References
1. Chessels JM, Swansbury GJ, Reeves B, Bailey CC, Richards SM. Cytogenetics and
prognosis in childhood lymphoblastic leukemia: results of MRC UKALL X. Br J Haematol.
1997;99:93-100.
2. Moorman AV, Richards SM, Martineau M, et al. Outcome heterogeneity in childhood highhyperdiploid acute lymphoblastic leukemia. Blood. 2003;102:2756-2762.
3. Heerema NA, Sather HN, Sensel MG, et al. Prognostic impact of trisomies of chromosomes
10, 17, and 5 among children with acute lymphoblastic leukemia and high hyperdiploidy (> 50
Chromosomes). J Clin Oncol. 2000;18:1876-1887.
4. Raimondi SC, Zhou Y, Mathew S, et al. Reassessment of the prognostic significance of
hypodiploidy in pediatric patients with acute lymphoblastic leukemia. Cancer. 2003;98:27152722.
5. Harrison CJ, Moorman AV, Broadfield ZJ, et al. Three distinct subgroups of hypodiploidy in
acute lymphoblastic leukaemia. Br J Haematol. 2004;125:522-559.
6. Pui CH, Carroll AJ, Raimondi SC, et al. Clinical presentation, karyotypic characterization,
and treatment outcome of childhood acute lymphoblastic leukemia with a near-haploid or
hypodiploid < 45 line. Blood. 1990;75:1170-1177.
7. Pui CH, Williams DL, Raimondi SC, et al. Hypodiploidy is associated with a poor prognosis
in childhood acute lymphoblastic leukemia. Blood. 1987;70:247-253.
8. Heerema NA, Nachman JB, Sather HN, et al. Hypodiploidy with less than 45 chromosomes
confers adverse risk in childhood acute lymphoblastic leukemia: A report from the children’s
cancer group. Blood. 1999;94:4036-4046.
From www.bloodjournal.org by guest on June 16, 2017. For personal use only.
9. Gibbons B, MacCallum P, Watts E, et al. Near haploid acute lymphoblastic leukemia: seven
new cases and a review of the literature. Leukemia. 1991;5:738-743.
10. Charrin C, Thomas X, French M, et al. A report fro the LALA-94 and LALA-SA groups of
hypodiploidy with 30 to 39 chromosomes and near-triploidy: 2 possible expressions of a sole
entity conferring poor prognosis in adult acute lymphoblastic leukemia (ALL). Blood.
2004;104:2444-2451.
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Table 1. Modal chromosome number for non Ph+ ALL patients with less than 45
chromosomes
Modal chromosome number
Cases
24-29 chromosomes
46
33-39 chromosomes
26
40-43 chromosomes
8
44 chromosomes
50
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Table 2. Demographic features by modal chromosome number
Modal chromosome number
Fewer than 30
33-39
40-43
44
Total
1
2
3
Age (years)
Less than 1
1-9
32
5
6
39
82
More than 10
14
21
1
9
45
Less than 20
18
19
4
21
62
20-less than 50
19
5
2
16
42
50 or more
9
2
2
13
26
Male
23
18
6
25
72
Female
23
8
2
25
58
WBC (x109/L)
Gender
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Table 3. Outcome by modal chromosome number
Modal chromosome number
Fewer than 30
33-39
40-43
44
Number of patients
46
26
8
50
Events
33
16
6
23
8-year EFS
28.3%±6.6%
36.9%±9.8%
18.7%±15.8%
52.2%±7.4%
8-year survival
33.9%±7.6%
40%±10.1%
50%±17.7%
69%±6.7%
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Figure legends
Figure 1. Distribution of modal chromosome numbers in hypodiploid cases with <44
chromosomes. There are no patients with 30, 31, 32, or 42 chromosomes. For two patients,
modal choromosome number could not be accurately determined
Description: Figure 1 reflects the frequency of modal chromosome numbers in hypodiploid study
group.
Figure 2. Description: EFS & OS for non Ph+ hypodiploid patients.
Figure 3. Description: Comparison of EFS for non Ph+ hypodiploid patients with 44
chromosomes or less than 44 chromosomes.
Figure 4. Comparison of survival for non Ph+ hypodiploid patients with 44 chromosomes or less
than 44 chromosomes.
Figure 5. EFS for 130 evaluable, non Ph+ patients by modal chromosomes number 44
chromosomes, 40-43 chromosomes, 30-39 chromosomes and 24-29 chromosomes
Figure 6. OS for 130 evaluable, non Ph+ patients by modal chromosomes number 44
chromosomes, 40-43 chromosomes, 30-39 chromosomes and 24-29 chromosomes
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Figure 1
50
45 Distribution
of Modal Numbers in
Hypodiploid Cases
40
20
18
35
16
30
14
25
12
10
20
8
156
104
2
50
0
19
13
mn
8
6
5
2
1
24
25
26
27
28
5
5
29
3
3
3
1
33
50 cases with 44 chromosomes
34
35
36
37
38
2
39
1
1
40
41
43
24 25 26 27 28 29 33 34 35 36 37 38 39 40 41 43 44
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Figure 2
1
8-yr Rates:
0.9
0.8
EFS
38.5%(se 5.7%)
OS
49.8%(se 6.0%)
Probability
0.7
0.6
Overall Survival 25-44C
(Non-PH+) (N=130)
0.5
EFS 25-44C (Non-Ph+) (N=130)
0.4
0.3
0.2 At Risk:
0.1 130
74
51
36
26
12
8
1 EFS
130
92
64
44
33
18
12
2 OS
2
4
6
8
10
12
14
0
0
Years Followed
16
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Figure 3
1
0.9
8-yr EFS:
0.8
44C(Non-Ph+)
52.2%(se 9.3%)
Others(Non-Ph+)
30.1%(se 7.0%)
Event Free Survival
0.7
0.6
44C (Non-Ph+) (N=50)
0.5
0.4
0.3
0.2
Others (Non-Ph+) (N=80)
p=.01
At Risk:
0.1 50
35
24
20
14
6
5
0 44C(Non-Ph+)
0 80
0
39
27
16
12
6
3
1 Others(Non-Ph+)
2
4
6
8
10
12
14
Years Followed
16
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Figure 4
8-yr Survival:
1
44C(Non-Ph+)
0.9
69.1%(se 8.6%)
Others(Non-Ph+) 37.5%(se 7.7%)
0.8
44C (Non-Ph+) (N=50)
Overall Survival
0.7
0.6
0.5
0.4
Others (Non-Ph+) (N=80)
p=.001
0.3
0.2
At Risk:
0.1 50
40
30
25
19
10
7
1 44C(Non-Ph+)
80
52
34
19
14
8
5
1 Others(Non-Ph+)
2
4
6
8
10
12
14
0
0
Years Followed
16
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Figure 5
At Risk:
1.00
.90
.80
0
2
4
6
8
10
12
14
(Year)
46
20
12
8
7
4
2
1
<30C
26
14
12
6
4
2
1
8
5
3
2
1
50
35
24
20
14
30-39C
40-43C
6
5
44C
Probability
.70
.60
44C (Non-Ph+) (N=50)
.50
.40
30-39C (Non-Ph+) (N=26)
<30C (Non-Ph+) (N=46)
.30
.20
.10
40-43C (Non-Ph+) (N=8)
Log Rank p=.06
2
4
6
8
Years Followed
10
12
14
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Figure 6
1.00
Log Rank p=.01
.90
.80
44C (Non-Ph+) (N=50)
Probability
.70
.60
40-43C (Non-Ph+) (N=8)
.50
30-39C (Non-Ph+) (N=26)
<30C (Non-Ph+) (N=46)
.40
.30
.20
.10
At Risk:
46
29
17
10
8
5
3
26
17
13
7
5
3
2
8
6
4
2
1
50
40
30
25
19
10
7
1
2
4
6
8
10
12
14
Years Followed
1
<30C
30-39C
40-43C
44C
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Prepublished online May 1, 2007;
doi:10.1182/blood-2006-07-038299
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
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