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Prognostic
Importance
Children
With
By Dorothy
L. Williams,
of Chromosome
Number
in 136
Acute
Lymphoblastic
Leukemia
Anastasios
W. Paul Bowman,
Leukemia
1 36
cell
of
1 59
leukemia
karyotypes
consecutive
(ALL)
patients
who
(67%)
categories
determined
with
were
had
were
were
patients
followed
abnormal
modal
numbers:
hyperdiploid
>50
47-50
(n
pseudodiploid
(n
and
hypodiploid
for
the
(n
in
first
relapse,
category
had
only
2 failures.
the
poorest
had
prognostic
terms
the
the
of
best
to
those
in the
0.001
).
intermediate
46),
with
category
and
influence
had
x
or the
presence
of these
number
on
to
failure
favorable
outcome
(p
significant
was
The
influence
also
prognostic
). The
count
should
at low
or high
more
clearly
within
had
the
common
that
chro-
predictor
variable
of
that
leukocyte
of chromosome
risk
chromosome
single
to
sheep
by the
indicated
only
information
combination
of
that
strongest
the
with
same
group
was
count
mass,
indicated
the
analysis
the
) and
0.001
rosettes
risk,
was
of a multivariate
number
2 clinical
mediastinal
formed
prognostic
the
by a leukocyte
standard
features.
time
mosome
ALL
that
37#{176}C,
and
absence
within
signified
leukemia,
of blasts
<
L. Melvin,
evident
risk,
meningeal
at
Results
Susan
was
high
109/liter,
erythrocytes
kocyte
a third
of chromosome
to failure
groups:
>100
Look,
and Gary V. DahI
on time
0.001
chromosome
formed
A. Thomas
Rivera,
number
ALL.
(induction
3
Gaston
historically
hyperdiploid
treatment.
remaining
same
=
assessed
failure
to
responses
This
was
pseudodiploid
The
of
(n
in the
responses
<
chromosome
normal
Children
Ninety
41 ), hyperdiploid
=
28),
time
mo.
M. Brodeur,
prognostic
distribution
response
or death).
group.
(n
=
Treatment
and
(p
categories
3).
=
categories
failure,
>50
18),
=
Five
on
for
lymphoblastic
up to 35
karyotypes.
based
Garrett
K. Kalwinsky,
at diagnosis
acute
for
designated.
Tsiatis,
David
Untreated
added
count
number
distinguish
(p
and
<
leu-
patients
with
of relapse.
T
some
associated
136 children
and adolescents
with ALL admitted
to St.
Jude Children’s
Research
Hospital
and followed
for up
to 35 mo. The results
clearly
demonstrated
that chromosome
number
is a stronger
predictor
of treatment
HE RELATIONSHIP
of chromosome
abnormalities to prognosis
in acute lymphoblastic
leukemia
(ALL)
has been debated
for a number
of years.
Among
selected
patients,
a poor prognosis
has been
with
cells:
ALL),
the
the
numbers
specific
large
the
ALL).”2
groups
clinical
or
techniques,
chromosome
nized.5’6
Swansbury
More
recently,
et al.8 have
mosome
number
nonrandom
patterns
early
is an
et
the relationship
were
malignant
lished,
the
Divisions
St.
of
Jude
Pathology.
Hematology-Oncology.
Children’s
Research
Hospital.
protocols
vincristine,
and
agent,
with
patients
and
received
sheep
Tenn.
Supported
20180,
National
Submitted
Address
Pathology.
Lauderdale,
© I 982
in part
Clinical
by
Cancer
Cancer
Institute.
January
reprint
St.
14.
Program
Grant
and
by AISAC.
1982;
accepted
requests
Jude
Memphis.
by Grune
to Dr.
Dorothy
Children’s
Research
Tenn.
38101.
& Stratton.
Inc.
0006-4971/82/6005-O010$01.00/0
864
Leukemia
Education
Project
CA-2l
765,
Grant
CA-
from
the
20,
central
L. Williams,
Hospital,
Division
332
North
of
third
for all
all
system
159
included
(E)
was
and
phase
a leukocyte
or blasts
at 37#{176}C.
Patients
the podophyllum
compound
by prednisone,
consisted
VM-26
+
groups
after
ara-C.
of
vincristine,
weekly
MTX
or
three
with
(it.
MTX).
and
high
count
>100
that
formed
remission
asparaginase.
prophylaxis,
One
group
with
courses
induction
with
received
6-MP
x
109/liter,
risk
Blood,
MIX
treated
with
MIX
ara-C,
Continuation
6-MP
prednisone,
with
of relapse
MTX
+
were randomized
high-dose
and
of
of
groups.
rosettes
in combination
patients
daily
risk
treatment
and asparaginase.
alternating
Standard-risk
All
prophylaxis
at standard
VM-26
of
asparaginase.
standard
the
predni-
an intensified
(CNS)
at
among
leukemia,
with
asparaginase
methotrexate
patients
Patients
evenly
CNS
therapy
(ara-C)
and intrathecal
for
distributed
therapy
CNS
on
characteristics.’0
received
received
nervous
(6-MP).
mass,
induction
One-third
arabinoside
radiation
erythrocytes
followed
1982.
with
based
were those without high-risk features.
In study X, patients at high risk of relapse were initially
with
May
received
and another
features
mediastinal
staining
was
cells was attempted
daunomycin.
therapy
High-risk
diagnosis
on request).
IX
cytosine
rad cranial
were
Their
and special
available
in study
Continuation
Memphis.
in
METHODS
center.
of leukemia
patients
relapse
From
evaluated
successful
studies obtained
for 1 36; 53 were entered
in
Study
IX and 83 in Total-Therapy
Study
X (unpub-
6-mercaptopurine
Biostatistics,
factor
for
31, 1980 a total of 159 patients
to this
analysis
treatment
2400
AND
cell cytomorphology
as a fourth
chromo-
prognostic
1, 1978 to July
patients,
with
Total-Therapy
sone,
Workchroaberra-
other
outcome
Treatment
admitted
Cytogenetic
All
indicators.
of the karyotype
and
From July
ALL
indicathat
any
MATERIALS
Patients
al.7 and
that chro-
the Third
International
in Leukemia9
found
also specific
karyotypic
than
to treatment
study.
to
and
recog-
prognostic
prognostic
this
karyousing
abnormalities
began
to be
independent
outcome
at diagnosis
stud-
failed
abnormali-
Secker-Walker
presented
evidence
tor in ALL.
Likewise,
shop on Chromosomes
mosome
number
and
We report
However,
the correlation
between
outcome.4
In later
studies
banding
marker
significant
leukemia
(Ph’-positive
and low modal
of unselected
patients
significance
of specific
ties and patterns,3
type and treatment
were
in
chromosome
(B-cell
ALL),
(near-haploid
ies of
disclose
tions
abnormalities
Philadelphia
14q+
marker
number
vincristine,
and
it.
for continuation
Vol. 60, No. 4 (October).
and
into two
and
MTX
for
therapy;
1982
From www.bloodjournal.org by guest on June 15, 2017. For personal use only.
NUMBER
CHROMOSOME
the other received
by
sequential
PROGNOSIS
1800 rad cranial
courses
adriamycin,
and
continued
AND
of
VM-26
radiation
6MP
ara-C.
+
plus i.t. MTX,
MTX,
+
865
IN ALL
followed
cyclophosphamide
Unless
disease
recurred,
+
therapy
ploid
blasts,
used
for
one
that
the
line
(hyperdiploid
By definition,
contains
abnormalities,
for 2.5 yr for all patients.
predominant
classification.
46
chromosomes
the gain-loss
in all
three)
a pseudodiploid
with
of whole
one
was
karyotype
or
more
chromosomes,
is
structural
or both
types
of
abnormalities.
Chromosome
For
Analysis
chromosome
technique
that
standard
included
we
several
procedures.”2
media
Determination
preparations,
These
used
modifications
for colchicine
include:
of cells
flaming
to the
treatment;
method
technique
(2)
only
a 24-hr
from
lines
and
graphic
modal
prints
karyotype.
to confirm
allowed
study,
a case
clone,
regardless
firmed
this
the DNA
In three
number,
samples
stem
used
may
designated
of the
to
assumption
content
unusual
photo-
cases
groups,
as abnormal
been
if it had
of normal
in most
evident
by the Internaused.
an abnormal
metaphases.
leukemic
microscopically.
flow
cytometric
cells,
based
against
I,
marrows,
We
cALL,
Statistical
Significant
and
factors
age
Fisher’s
exact
then
and
test’7
response
Kaplan-Meier
the
influence
measured
death).
therapy,
The
time
to the chromosome
life-table
con-
subgrouped
according
Because
of the
and
high
to
34
32
30
28
‘26
E
z
the
for
of
race.
number
(failure
on treatbeing
a lack
complete
first
patients
significant
of
for
grouped
by means
differences
with
relapse
time
and
of
were
to failure
in
patients
markers.
of chromosome
number
with
known prognostic factors, the influence of these factors on treatment
outcome was determined by Cox regression analysis.#{176}
Log leukocyte
36
a)
as sex and
was estimated
categories
correlation
chromosome
generalization
during
failure
risks
38
-
to failure
and
42
40
.
the
a relapse
to cell surface
possible
by
such
categories
curves,’
to
of variance’6
of chromosome
as the time
to induction
or
variables
46
44
Fig.
1.
Distribution
of
chromosome
modal
numbers
for 136 children
with ALL. The
distribution.
with a major
peak
at 46
chromosomes
and
a
smaller peak at 55. suggests
a
bimodal
curve with a division
at
60 chromosomes.
The shading
designates
all cases with chromosome
abnormalities;
for
those
with
Down’s
syndrome
(D).
the
shading
designates
abnormalities
in addition
to tnsomy 21 . ND. normal
diploid;
Ps. pseudodiploid.
formation,
heteroantisera
features
and
50
(._)
rabbit
analysis
count,
for discrete
assessed
responses,
prognostic
48
(I,
0)
ALL
or undifferentiated
of E-rosette
with
by one-way
leukocyte
at standard
and hyperdi-
or absence
stains
and spccific/
as common
(B),
reactivity
of
determined
in patients
of
classified
staining
special
Ia antigens.’#{176}
even
analysis
The
peroxidase,
bone-marrow-derived
associations
were
of
were
cytomorpho-
Analysis
number
ment
black,
Lymphoblasts
and
for
special
features.
Sudan
on the presence
immunoglobulin,
assessed
classification),’5
determined
by the chi-square
test.’9
We also compared
the chromosome
Normal
cells.
that had both pseudodiploid
Features
marker
Schiff,
(T),
surface
according
In our
acid
thymus
FAB
surface
esterases.
(cALL),
We
we
any marker
was
Cell
simultaneously
(including
periodic
remission,
in Leukemia’4
by simultaneous
in marrow
44 cases,
were
and
nonspecific
or all chromo-
category.
proportion
have
of most
For the remaining
stem line proposed
to be present
not
from
features
characteristics,
(U)
that
leukemia
was also
prepared
the Denver
on Chromosomes
was
were
identification
the karyotype
assumed
they
Karyotypes
of an abnormal
Workshop
though
26 marrow
of lymphoblasts
of the 1 36 cases.
and
The definition
were
of
the analysis.
the modal
chromosomes,
cells
total
of time
logical
samples
included
use of an edging-
cells and an identified
successful
in 92 (68%)
determined
tional
For
culture
as the
control
(5)
vehicle
the bone marrow.
For each case, 10-30 (mean 20)
were studied by direct microscopy to determine the stem
Banding
somes
of mitotic
the use of
0. 1 ml of packed
25 mm
Marrow
of
and (6) use of a G-banded
Seabright.’3
unstimulated
supplement
metaphases
solution;
of slide preparations;
modified
had a low percentage
line,
hypotonic
(1)
of Other
marrow
as both the carrying
cells or less processed per centrifuge
tube; (3)
time
for exposure to colchicine;
(4) careful
exposure
bone
(unpublished)
modifications
1640 plus 30% fetal calf serum
and the vehicle
a direct
24
22
8
6
4
2
0
8
Karyotype Modal Number
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WILLIAMS
866
Table
1 . Distribution
of Various
Prognostic
Features
Hyperdiploid
Feature
treatment
47-50
Pseudodiploid
Normal
Hypodiploid
(n-41)
(n-18)
(n-28)
(n-46)
3
2
13
12
1
38
16
15
34
2
High
Riskof
Categories
Hyperdiploid
>50
varis
in Chromosome
ET AL.
Standard
(n-3)
failure
Mediastinal
Yes
mass
No
E-rosette
0
6
7
0
40
18
22
39
3
0
2
4
4
1
41
16
24
42
2
1
Positive
status
Negative
Nonwhite
Race
1
White
Sext
Surface
markers
40
CNSleukemia
19
7
18
32
1
11
10
14
2
CommALL
2
33
12
16
31
T-celI
3
3
7
9
Undifferentiated
1
3
3
Leukocyte
2
0
17
33
1
7
5
9
13
2
L-3
0
0
2
0
0
Yes
2
1
2
1
0
39
17
26
3.50
6.90
5.65
8.23
8.59
7.21
5.70
6.45
4.80
4.82
Median
5.60
18.90
22.40
10.65
34.00
66.88
57.97
23.33
22.52
0.01
(generalization
of Fishers
exact
test for discrete
tp
0.05
(generalization
of Fisher’s
exact
test).
the
it improved
the predictive
of the most
important
model’s
predictive
capacity,
assessed
increased
significantly
(p
whether
prognostic
value,
or not chromosome
independent
or one-way
of the
continued
by the
log likelihood
0.05).
This
>
number
of known
variables
ability
variables
no longer
determined
(as categories)
analysis
had
The
20.59
analysis
of variance
28),
single
normal
(n
Chromosome
145.08
for continuous
mode
for
46),
and
=
Categories
Comparison
of
features
of patients
and
classification
the
abnormal
cases-(n
hypodiploid
and
the
54.18
variables).
(n
=
Prognostic
initial
=
3).
Features
clinical
and
laboratory
in the five chromosome
categories
(Table
1) indicated
a significant
relationship
between
chromosome
number
and seven features:
age, sex, race,
mediastinal
mass,
E-rosette
status,
leukocyte
count,
Categories
distribution
122.96
frequent
predictors.
RESULTS
Chromosome
13.40
5.36
15.17
ratio,
14.90
4.04
21.29
inclusion
3
6.45
Mean
Mean
Stepwise
45
SD
#{149}p
until
0
13
SD
was used because
0
0
(X 109/Iiter)
model.
0
34
count’
count
1
3
L-2
Median
(yr)
1
2
22
No
Age’
4
42
Male
B-cell
FAB classification
3
25
Female
L-1
Morphology,
5
13
of chromosome
modal
numbers
for
risk
(p
0.05).
<
The
>50
group
had
all I 36 patients
with
successful
studies
suggested
a
bimodal
curve with a major
peak at 46, a small peak at
55, and a hiatus
at 50 (Fig.
1). The hyperdiploid
group
the most
count
and
favorable
features
fewer patients
with
leukemia,
or
(n
50
pseudodiploid
group had the least favorable.
However,
with the exception
ofthe
two B-cell (L-3) cases,
which
were pseudodiploid,
none of the features
were specific
=
59) was divided
accordingly:
chromosomes
(n = 41)
and
those with more than
those
with
47-50
chromosomes
(n = 18). (In this study,
the term hyperdiploid indicates
any case having
more than 46 chromosomes.
No attempt
was made
to distinguish
near
triploid
and
near
tetraploid
numbers.)
group contained
4 patients
with Down’s
the 4 had chromosome
abnormalities
trisomy
21.
chromosomes
case,
the
In the
most
number
hyperdiploid
often formed
of whole
The
47-50
syndrome;
2 of
in addition
to
>50 cases,
the added
trisomies,
and in each
chromosomes
gained
for any
many
patients
were
Chromosome
When
(n
=
studied,
46)
blasts),
category.
whereas
Although
the
hyperdiploidy
the group
at standard
risk of relapse,
15
were
pseudodiploid.
Similarly,
although
ploid, some
(or
lost) exceeded
the number
of structural
abnormalities.
The other
three groups
were pseudodiploid-the
most
E-rosette-positive
chromosome
characterized
karyotypes
(lower
mean
leukocyte
mediastinal
mass,
CNS
at high risk
hyperdiploid.
Categories
the
times
versus
there
and
to failure
abnormal
was
of relapse
Time
for
(n
no significant
=
were
pseudodi-
to Failure
patients
90)
with
normal
karyotypes
difference
(p
were
=
0.74,
From www.bloodjournal.org by guest on June 15, 2017. For personal use only.
NUMBER
CHROMOSOME
AND
PROGNOSIS
867
IN ALL
1.0
0.90.8
.E
0
U-
:
0.6
.
0.4
I
Abnormal
Normal
No of Pis
Karyotype
_________
Failed
Abnormal
o_
Fig. 2.
Estimated
time-tofailure curves for patients
with
normal
and
abnormal
karyotypes.
The curves of these two
groups
were
not significantly
different.
About
one-third
of
the
patients
in each
group
failed.
Fig.
2).
However,
teristics
on
compared,
Fig.
they
group
patients
The
have
47-50
.0
and
6
I
I
2
8
the
the
normal
‘Ill
I
after
I
I
24
(p
difference
0.001,
<
ploid
group
response:
only
the pseudodi-
response:
had
1111 Il II
1
30
36
Ill
in the
rates
No curve
it contained
the other
intermediate
range.
with Down’s
syndrome
they
could
not account
2 remain
between
the
Since
failed
for
two
in
the
hyperdi-
is shown
for the hypodiploid
only 3 patients;
I failed at 6
in first
complete
remission
at 32 and 33 mo. When
the 47-50,
the normal,
and the
hypodiploid
groups
were combined
into one, the resulting time-to-failure
curve (not shown)
and the >50 and
similar
II
in failure
categories.
because
mo and
19 of 28
group
curves
none of the patients
the 47-50
group,
chromosome
curves
were
an excellent
Conversely,
poor
time-to-failure
charac-
clarified
different
an extremely
failed.
group
was
strikingly
-‘
I
III
II
I
III
I
Hyperdiploid
0.9
C
had
Q
of karyotype
cases
into
time-to-failure
3). The >50 group had
patients
have failed.
ploid
P0.725
Months After Diagnosis
response
were
46
-
0
influence
treatment
division
of the
When
these
further
categories.
2 of4l
the
0j
90
5
X2:0.123
No
of Pts
27
Normal
02
0
Total
>50
.,-
0.8
L.ILL.
_..J.LLIIILL
L
0
U)
0.7
.
0.6-
I
C
Hyperdiploid
a)
C
s
LJ
Fig. 3.
Estimated
time-tofailure
curves
for four
major
chromosome
categories.
The
> 50
group
and the
pseudodiploid
group
had the lowest
and highest
failure
rates.
respectively.
The pseudodiploid
curve
begins
with a lower
proportion
of patients.
indicating
more
induction
failures.
The
intermediate
curves
of the 4750 and normal
groups
were not
significantly
different
and could
be combined
to form an intermediate
prognostic
group (see
47-50
LL_U
0.5
Normal
0.4-
II
II
diploid
II
C
0
f
a
0.3
No of Pts
Failed
_______________
Ploidy Group
Total No
of Pts
0
o_
0. I-
Hyperdiploid
>50
Hyperdiploid
47-50
2
41
5
lB
Pseudodiploid
9
28
Normal
5
46
Diploid
Pseudodiploid
X2:34.445
1
P<0.OOl
0
0
6
2
Months
24
8
After
Diaanosis
30
36
text).
The
three
cases
were
also
hypodiploid
added
to the
combined
group.
even though
this group’s
eventual
classification is uncertain.
From www.bloodjournal.org by guest on June 15, 2017. For personal use only.
868
WILLIAMS
pseudodiploid
curves
(p < 0.001).
Even
differences
among
apparent,
failures.
occurred
as shown
by the
Fifty-three
percent
in the pseudodiploid
proportions
of
of the induction
group.
Analysis
of individual
patient
response
that the two failures
in the >50 group
were
3 patients
with
multiple
abnormal
third
ently
lines
An extremely
important
failures
Equally
induction
important,
failures,
small
and
pseudodiploid
finding
deaths
group.
L.t
J
0.4#{149}
Ploidy Group
L
‘S
Hyperdiploid
Psiudodiploid
Othirs
0.2
C
absence
of
large number
of
occurred
in the
main
that the therapeutic
responses
ently normal
karyotypes
were
of patients
not as good
expect;
a third of the induction
and deaths were in this group.
failures,
38
3
52
5
Psiudodiploid
P<0.00l
A
Hypirdiploid
8-
L
>50
No of Pts
Total No
Foiled
of Pie
Ploidy Group
L.I
o
t
0.5
0
fyperdiploid
>50
Pseudodiploid
Others
X2’6.l58
L_,
0.6
0
3
0
8
P.0.046
I3
5
.L__L_____J
:.
0.4
Others
:
0.3
was
:
with apparas one might
first
of Pts
2
9
0.9
group.
finding
Foiled
0C
C
to the
deaths
Another
>50
Totol No
0
0
the
‘.1
No of Pts
>50
X2’l9.305
‘O
208
the
L.L___i_LJILL
0.5
0
lines had appar56-chromosome
was
:
.
lines.
which
The
>50
\_
0.7
among
in addition
half of the
Hypirdiploid
0.8
disclosed
among
the
line containing
92 chromosomes,
doubling
ofa pseudodiploid
stemline.
induction
,
-‘----
0.6
chromosome
patient
with multiple
abnormal
unrelated
pseudodiploid
and
and has not failed.
--
Q9.
induction
failures
One of the two patients
who failed
had a 53-chromosome line and a small pseudodiploid
line that appeared
to be independent
clones. The other who failed had a
predominant
was an exact
1.0’
were again
significantly
different
at the outset
of treatment,
the
the chromosome
categories
are
ET AL.
j
Pseudodiploid
0.2
I
0.I
relapses,
B
1\
#{212}
_0
I
24
I
30
36
Months After Diagnosis
Chromosome
Time
influence
responses
The
peutic
and
Categories,
Prognostic
Subgroups,
and
to Failure
high
In both
of chromosome
was assessed
risks of relapse
clinical
groups
number
for
on
patients
thera-
at standard
(see Materials
and Methods).
(Fig.
4, A and B), the time-
to-failure
curves
for the chromosome
categories
were
very similar
to those shown in Fig. 3. Studies
were also
done
for
94 patients
with
cALL-antigen-positive
blasts-a
subgroup
with a good prognosis.2’
Again,
the
time-to-failure
curves
corresponded
with those in Fig.
3: only
whereas
I of 33 patients
failed
in the
I 2 of I 6 failed in the pseudodiploid
9 of45
failed in thecombined
23 patients
had T-cell
ALL
ALL,
perhaps
difference
were only
and both
accounting
for the
lack
between
their time-to-failure
two B-cell
cases;
both were
patients
Translocations
Survival
group
(p
and only
died
0.001).
10 had
Only
U-cell
of a significant
curves.
There
pseudodiploid
of disease.
in Pseudodiploid
Cases
and
Duration
translocations,
cations
failed
mo), compared
survival,
we compared
poor prognosis.9
karyotypes
had
the
outcomes
of pseudodiploid
patients
with and without
translocations. Over a 44-mo
period,
80% of those with translo-
(median
survival,
14 mo;
to 6 1% without
translocations
27.5
cation
mo;
categories
range,
1-42
were
not
mo).
range,
line,
the t(8;14)
and
(induction
failure)
patients
with
the
abnormality
and
Philadelphia
failed; three
fourth
is still living at
Philadelphia
chromosome
lines survived
for 1 mo
cation
to chromosome
stem
line
case
with
in only
t(4;1
Five
other
different
and
category.
33+,
cases
did
Survival
23+,
and
and
diagnosis.
chromosome
time-totoo small;
a 46 stem
died
at 3
All
and
four
a 46
died at 7, 10, and 25 mo, and the
40 mo. Another
patient
with the
and 47 and 49 chromosome
(induction
failure).
The translo9 or another
chromosome
could
3 of the
1) was
translo-
in our
failed
5 mo after
1-40
(median
Different
included
failure
analysis
because
the numbers
were
however,
two patients
with B-cell leukemia,
be established
Certain
translocations
carry
a very
Since
10 (36%)
ofthe
28 pseudodiploid
identifiable
<
>50
group,
group
and
Fig. 4.
Estimated
time-to-failure
curves
for standard
and
high-risk
groups,
subdivided
according
to chromosome
categories.
The response
patterns
for the standard
(A) and high-risk
(B)
groups
corresponded
to those
in Fig. 3: good responses
for each
>50
group.
poor
responses
for each pseudodiploid
group,
and
intermediate
responses
for each
combined
group.
The combined
group
labeled
“others”
includes
the 47-50,
the normal,
and the
hypodiploid
groups.
found
5 cases
in this
had
translocations
not match
any
with
22q
-
.
No
study.
that
previously
times
were
7, 1 8 (induction
24+
mo.
All
were
were
recognized
failure),
pseudodiploid
all
From www.bloodjournal.org by guest on June 15, 2017. For personal use only.
CHROMOSOME
NUMBER
AND
PROGNOSIS
Table
2.
IN ALL
Cox Regre
salon
869
Analysis
of Tim s-to-Failure
as a Function
2 x Log Likehood
Prognostic
Variable
Single
Log leukocyte
count
Chromosome
number,
of Prognostic
Variables
Ratio for the Prognostic
Variable
Added to Log
Leukocyte
Count
p Value
p Value
22.64
<0.001
33.81
<0.001
45.29
<0.001
33.62
<0.001
44.76
<0.00
12.97
<0.001
23.29
0.417
7.46
0.006
23.15
0.475
8.04
0.018
27.68
0.080
5.38
0.020
25.44
0.095
5.45
0.020
25.72
0.079
7.68
0.053
25.06
0.489
1.43
0.232
22.89
0.6 17
E-rosettestatus(+/-)
0.95
0.330
22.64
0.975
CNS leukemia
0.08
0.780
22.80
0.689
5 categories
Chromosome
(standard/high)
mass
Age
(<2/2-51>5
Sex
(M/F)
yr)
(white/nonwhite)
Cell markers
(cALL/T/B/U)
FAB morphology
For
single
Variables
that
1
risk
Mediastinal
Race
variable)
number,
3 categories
Relapse
(used as the first
variables,
(L-1/L-2)
2 x log likelihood
significantly
added
ratio
had to exceed
to the prognostic
3.84-9.49
information
(depending
of leukocyte
count
on the number
of categories)
had to add 3.84-9.49
to be significant
to the log likelihood
ratio
at the 0.05
of 22.64
level.
(leukocyte
count alone).
>50.
tHyperdiploid
pseudodiploid,
hyperdiploid
47-50,
normal.
and hypodiploid;
the
last three
groups
were
combined
into
one in the
second
analysis.
High
risk
designated
blasts.
E-rosette-positive
except
somes.
the
last
Multivariate
the
Cox
2, both
p
FAB
treatment
When
there
were
were
analyzed
model,
0.001).
response.
status
Each
low
The
and
lack
influence
these
count
was
may
factors,
the
effects
for
been
due
have
x
1 0#{176}/liter,mediastinal
or an insufficient
features
and
who
were
first
variable
in the
only other
information.
van-
sample
studies,
was
the
were
gories
treatment
groups
into
number
group
justifiable
one
on
to assess
treatment
entered
that
fully
of
because
an
This
some
work
amount
leukemia,
or
of metaphases.
failure
for these
The
23
from those of the
studied.
Thus,
the
inadvertently
biased
by difficul-
patterns
of response
to those
by chromosome
presented
cate-
here.
study
number
provides
definitive
is directly
ALL.
Our
of Secker-Walker
related
that
to treatment
findings
et al.7
agree
Our
evidence
confirm
for
chromooutcome
the
a smaller
earlier
group
with a preliminary
results
also agree
of
report
of
with
the
portions
of data presented
by the Third
International
Workshop
on Chromosomes
in Leukemia,
which
relate
to prognosis
and modal
number
in children
with ALL.
were
to
the
out-
in this study,
23 had
could
not be successinadequate
number
to
significantly
successfully
not
similar
in childhood
come.
Of the 1 59 patients
chromosome
preparations
CNS
DISCUSSION
positive.
subjects
of successive
treatchemotherapy
regimens.
of failures
within
our study
by treatment
Thus,
it was
time
not differ
who were
patients
and closely
Swansbury
et al.8
separated
different.
mass,
in obtaining
the marrow
aspirates.
All studies
presented
in terms of time to failure
were
also analyzed
in terms
of length
of first
complete
remission
and length
of survival.
In these
additional
status,
and CNS
lesser
influence
on
of significant
patients
of chromosome
assessed
> 1 00
ties
number
remaining
leukemia
of
study
factors
Analyses
population
when
not significantly
count
marrow
clinical
and log leukocyte
of outcome
(Table
of the
CNS
numbers
log leukocyte
leukocyte
features.
47 chromo-
chromosome
morphology,
E-rosette
had a significant
but
Our 1 36 patients
were
ment
studies
of different
However,
the proportions
combine
features:
of these
as single
model,
chromosome
number
was the
able that added
significant
prognostic
Other
of these
the absence
patients
did
1 36 patients
regression
<
leukemia,
E-rosette
in which
as 5 or 3 categories)
the strongest
indicators
except
the
case,
all variables
(considered
count
were
to
of one or more
designates
risk
Analysis
When
with
the presence
Standard
of
We offer new information
mosome
number
relative
nostic
and
variables
high
risk
and
on the importance
to currently
recognized
to clinical
subgroups
of chroprog-
at standard
of relapse.
Our decision
to separate
the hyperdiploid
group
at
the 50-chromosome
mark
was somewhat
arbitrary.
However,
a natural
division
at that
point
may exist
because
there appeared
to be a bimodal
distribution
of
From www.bloodjournal.org by guest on June 15, 2017. For personal use only.
870
WILLIAMS
chromosome
responses
Since the
overall,
numbers
and
because
the
treatment
of the >50 and 47-50
groups
were different.
>50 group
had the best therapeutic
response
one
would
expect
concentrated
in
associated
with a good
the
of relapse
and
sented
in Table
that
these
clinical
those
ploid
groups
malities,
the
is unknown.
when
total
cases.
karyotype,
The
guishing
complement
whereas
cells
as compared
with
with
numerical
and
adversely
considered.
more
than
complement
structural
ALL
frequency
(lower
part
of
lack
of a
pseudodiploid
These
counts
Table
of acute
once
however,
prognosis
a large
series
transthese
transloca-
in our
banding,
in 100%
also
is studied
some
ALL
series
Con-
characterize
by
Thus,
a
and
leukemia.
may
techniques.
had
studies
when
of the
nonlymphocytic
findings
to be normal
synchronized
of those
may
cases
have
had
small
morphological
abnormalities
or gene
undetectable
by standard
techniques.
That
group
had an intermediate
prognosis
sug-
that
these
structural
be functionally
different
may
and
Our
pattern
prognosis;
abnormal
high-resolution
gests
abnormalities,
from those
if present,
in our pseu-
dodiploid
group,
which
had the poorest
prognosis.
Leukocyte
count
is generally
regarded
as the best
predictor
of treatment
outcome
in ALL.24 The array
of
differ-
and
cases.9
separated,
the
may be worse.
extremely
mutations
our normal
normal
cells,
prognosis
pseudodiploid
a poor
cases
judged
added
the
a poor
in many
et al.,23
using
high
resolution
identified
chromosome
abnormalities
of their
ALL
of
affect
hyperdiploid
A second
distin-
white
features,
are
sistently
relative
lack of aggres>50 ALL versus
pseu-
initial
of high-risk
in
chroabnor-
both
have
Yunis
recently
pseudodiploid
abnormalities.
contribute
to the
shown
by hyperdiploid
dodiploid
factors
50 chromosomes
may
in addition
to various
could
siveness
pre-
that
amounts
is the uniform
chromosomes
in
a normal
ences
be pertinent
a less prominent
be
locations
with
karyotype
that
risk
cases, a structural
abnormality,
and
Likewise,
the t(4;1 1) abnormality
associated
tion group
most abnormal
morphological
large
been
pseudodiploid
indicate
results
formed
that
material
should
feature
of
contain
It may
possibility
chromosomal
cell function
historically
different
treatment
>50 and pseudodi-
>50 group,
additions;
present,
be
at standard
those
with cALL.2’
The
1 support
this expectation.
within
the
were intact
has
would
subgroups
prognosis:
The
reason
for the markedly
responses
between
the hyperdiploid
each case
mosomes
cases
karyotype
in many
a poor prognosis.22
ET AL.
lower
1). A survival
phenotypes
has helped
that distinguish
to increase
our
malignant
lymphoid
ened
prognostic
lymphoid
knowledge
but has
differentiation,
capability
cell subgroups
of normal
versus
to the degree
not sharp-
that
one would
advantage
of pseudodiploid
cells
over
hyperdiploid
>50 cells,
in the face of equivalent
chemotherapy,
is
suggested
by the outcome
of one of our cases in which
the child had blasts of both types at diagnosis
(predominantly
hyperdiploid),
but only pseudodiploid
blasts
at
relapse.
Thus,
in cases
with multiple
abnormal
chro-
like. Any measure
that could more accurately
indicate
the outcome
of the disease
would
be important,
particularly
in modifying
treatment
for patients
most likely
mosome
high risk of relapse.
concert
may permit
lines,
the
chemotherapy,
may not carry
lines
may
respond
independently
and the predominant
the most prognostic
line
weight.
to
at diagnosis
a poor prognosis
in ALL.
chromosome,
been
pseudodiploid
leukemia
has
Many
a poor
at
been
cases
with
prognostic
diagnosis.’
the
with
The use of these
a sharper
delineation
and therefore
clinical
trials.
future
Phila-
feature,
be of value
two factors
of prognostic
in
in the development
of
ACKNOWLEDGMENT
have
Similarly,
associated
We present
evidence
that,
as a prognostic
factor,
chromosome
number
is as good or better
than
leukocyte
count,
even within
the clinical
subgroup
at
groups
The Third
International
Workshop
on Chromosomes
in Leukemia9
has associated
translocations
with
delphia
to relapse.
We
B-cell
are
indebted
Williams
a pseudodiploid
John
for
to Ann
expert
Gilbert
Harris,
technical
for reviewing
Wanda
assistance,
Lemonds,
and
and
to M.J.
Kenna
Seifert
and
the manuscript.
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of the clinical
in
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N Engl
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From www.bloodjournal.org by guest on June 15, 2017. For personal use only.
1982 60: 864-871
Prognostic importance of chromosome number in 136 untreated children
with acute lymphoblastic leukemia
DL Williams, A Tsiatis, GM Brodeur, AT Look, SL Melvin, WP Bowman, DK Kalwinsky, G Rivera and GV
Dahl
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