Chronic Granulocytic Leukemia: Cytogenetic

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Chronic
Cytogenetic
M arrow
With
Granulocytic
Conversion
Cycle-specific
By R. V. Smalley,
J. Vogel,
C. M. Hug uley,
Sixteen patients
with
Ph1-positive
chronic
granulocytic
leukemia
(CGL) were entered
on a pulsing
chemotherapy
program
consisting
of cytosine
arabinoside
100 mgI
sq m/day
x 5 and
thioguanine
100
mg/sq
m/day
x 5 every
21 days in an
attempt
to convert
the Pht-positive
marrow to a Pht-negative
state and thereby
achieve
a complete
remission.
Twelve
patients had an adequate
trial of drug treatment,
and ten of these
had
adequate
chromosome
examinations.
There
were
two
“conversions,”
one of which
was
C
HRONIC
which,
mosome
GRANULOCYTIC
in most
patients,
(the
Ph’-positive
Jr.,
maintained
D1 Miller
and
for
mo,
5+
while
the
other
was transient.
The program
was
unacceptable,
however,
to most patients du. to
intolerable
nausea
and vomiting.
Thus a
prospective
chemotherapeutic
attempt
to
convert
a Ph’-positive
marrow
without
splenectomy
has induced
a conversion
in
two of ten patients.
Other regimens
which
might
induce
less nausea
and vomiting
and a higher
rate of conversions
should
be sought
in future
attempts
to alter the
invariably
fatal outcome
of CGL.
LEUKEMIA
of abnormal
a clone
clone)
Leukemia:
of the Bone
Chemotherapy
populates
(CGL)
is a disorder
in
cells with
a marker
chro-
the
marrow
and
which,
in
time,
evolves
into an acute
leukemia,
the so-called
blast
crisis.
The
I chromosome
remains
demonstrable
in all marrow
cells during
the course
of the disease
and,
in the majority
of patients,
additional
chromosome
abnormalities
are present
during
position
the
blast crisis.
and likewise
Conventional
chemotherapy
has not successfully
induced
blast crisis.
Both
Chervenick
growth
of colonies
Colonies
were
From
the
et
the
Duke
in vitro
of
University,
Supported
by the following
institutions:
CA 15584
CAO3J
the
Emory
School
Research
cine.
©
Blood,
Western
Medical
for
of
with
Health
A ilanta.
March
Ga.
,
demonstrated
Ph’-positive
or
CGL.
Ph ‘-negative),
Sciences
Center,
and
Department
the
mdi-
Philadelphia,
of
Pa.,
Medicine,
Reserve
of
of
San Juan,
Tenn.;
the
of
from
School
Ga.;
Pa.;
CA 12640
University
Augusta,
National
School
Durham.
Temple
Georgia,
the
Alabama
University
Medicine,
Atlanta.
Philadelphia.
to
8. 1977.
Grants
University
Medicine.
College
Knoxville,
the
School
CA07961
of Medicine,
St. Louis,
Address
Si..
Case
University
Center,
Center,
have
Ph ‘-positive
University
Research
to
Medical
to the
accepted
USPHS
School
Ill.;
Nankin2
of patients
(either
University.
CA03013
the
Duke
Chicago,
CA06807
23. 1 976;
University
Pennsylvania
Center,
Rico
to
77 to the
marrow
Temple
Emory
and
this predispatients
in
N. C.
September
Ala.;
from
of Medicine.
Durham,
Shadduck
pure
Medicine,
Submitted
following
and
cytogenetically
Department
Department
al.’
has not altered
remissions
for
Cancer
of
of
Medicine,
N.
C.;
CA 12639
to
Ga.;
Puerto
Rico;
CA 13237
and
CA03376
to
the
CA 12223
to the
University
Ohio;
to
University
University
of
Medical
Philadelphia,
of Tennessee
University
the
CA 1 1263
Luke’s
Medicine,
Washington
and
Presbyterian-
of
to ihe
to
Birmingham,
Cleveland,
CA03227
to Rush-Presbyterian-Si.
School
Institute
Medicine,
Pa.;
of
Puerto
Memorial
School
of
Medi-
3401
N.
Broad
Mo.
reprint
requests:
Philadelphia,
Pa. 19140.
1977 by Grune & Stratton,
Vol. 50, No.
1 (iuly),
1977
Dr.
Inc.
R.
V. Smalley,
Temple
University
Hospital,
ISSN0006-4971.
107
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1 08
SMALLEY
cating
some
the existence
patients
with
of a normal
CGL.
If such
the marrow
following
ablation
mission
would
be obtainable
Dowling
et al.3 were
treated
radiation,
21
the
patients
followed
stem cell
a normal
ofthe
in these
first
were
Ph’-positive
patients.
to attempt
intensively
early
by splenectomy
cycle-active
agents
inase,
and vincristine.
marrow
to a normal
population
cell line
in the marrow
of at least
capable
of repopulating
line,
this
then
a true
therapeutically
in their
clinical
and
aggressive
cytosine
arabinoside
Of the 21 adults
chromosome
state
ET AL.
complete
re-
in patients.
course
with
chemotherapy
They
splenic
with
(ara-C),
thioguanine
(TG),
treated,
5 had
“conversion”
(predominantly
Ph’-negative
irthe
asparagof their
cells);
of
these 5, 2 have been maintained
on hydroxyurea
with a 98%-l00%
Ph’-negative
marrow
for 8+ and 44+
mo, while
2 conversions
were transient
and
1 fluctuated.
These
therapeutic
observations
in vivo
confirmed
the
observations
in vitro,
indicating
the existence
of a normal
stem
cell line in some
CGL
patients
and demonstrated
its ability
to repopulate
the marrow.
If one could
consistently
obtain
and maintain
this cytogenetic
and hematologic
complete
remission, it might
be possible
to prevent
the occurrence
of the invariably
fatal blast
crisis and beneficially
The Southeastern
affect
Cancer
the survival
curve
ofpatients
Study
Group
has performed
with CGL.
a study
designed
to
determine
if intermittent
courses
(pulses)
of the cycle-active
agents
ara-C
TG, without
the aid of splenectomy
or splenic
irradiation,
would
eliminate
suppress,
at least temporarily,
the Ph’-positive
clone
of patients
with CGL
and
or
who
are in hematologic
herein.
remission
induced
by
MATERIALS
Patients
were
positive
eligible
metaphases
in
by a hemoglobin
platelet
in
margin).
In
induction
of
each
gave
institution
Eligible
and
both
patients
to
and
on
the
(but
without
were
same
used for
technique
adequate
sidered
and
direct
the
trial
evaluable
75,000/cu
they
and
for
Tjio
mitotic
specimens
throughout
had
at
m
21
mm
to
by
evening
until
reported
of
least
80#{176})Ph’-
10,000/cu
as
mm
(myelocytes
(defined
by
at
remission
immature
as
busulfan,
Patients
palpable
less,
a
younger)
at
the
the
with
defined
or
or
although
pretreated
treatment
costal
time
from
splenic
irradi-
were
days,
if
were
of
Whang4
or
and
least
these
study.
three
was
approved
six
of
to
in
at
courses
the
with
of
culture
a shorter
analysis.
For
study
(Table
chromosome
levels
had
A
therapy.
method
culture
The
1000/cu
dose
least
dose
mm
conhypoanalysis
following
Slight
“mar-
modifications
Moorhead
time
performed
of
and/or
remained
chromosome
once
of
5 days
“marrow
each
individual
1). Patients
who
evaluations
for
constituted
courses.
have
therapy.
therapy
morning
treatment
less than
Subsequent
trial”
for chromosome
the course
of the
of this
5-day
for
considered
six
study
every
Each
possible,
cycle-active
stimulants
bolus
5 days.
achieved.
levels
to
the
granulocytopenia
completion
and
and
committee.
intravenous
for
an “adequate
prior
the
of
of
purposes
count
investigations
every
received
after
technique
addition
no
induced
prior
course
these
aspirates
also
obtaining
was used
every
achieved
marrow
cell
varied.
human
100 mg/sq
for each
than
study
with
hematologic
splenomegaly
was
consent
local
repeated
20
by definition
the
m orally
who
blood
mm,
no
are
eligible.
ara-C
were
less
hypoplasia”
of either
informed
patients
performed
row
not
escalated
Those
plasia.”
as
were
their
courses
as
and
results
CGL
complete
a white
remission
into
Ph -positive
in
400,000/cu
blood,
entry
received
thrombocytopenia
stant.
and
The
METHODS
had
were
greater,
hematologic
100 mg/sq
and
drugs
or
they
and
by the appropriate
thioguanine
a course
g/dl
AND
if
marrow
peripheral
cases,
remission
patients
study
130,000
or splenectomy
All
an
12.0
the
all
the
their
between
granulocytes
ation
of
count
for
busulfan.
of
et al.5
24-28
hr)
patient
the
had received
were
con-
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CYTOGENETIC
Table
CONVERSION
1 . Institutions
OF
and
MARROW
Individuals
109
Performing
Chromosome
Institution
a.
Emory
University,
Temple
b.
Atlanta,
University,
Emory
College
Analysis
J. Vogel,
Ga.
Philadelphia,
University,
Medical
Atlanta,
Pa.
J. Vogel,
Augusta,
MT.,
University,
Reading
Hospital,
d.
Washington
University,
St. Louis, Mo.
S. Sebhon,
e.
Birth
Evaluation
Center
C. B. Lozzio,
Reading,
of Tennessee
Research
and Hospital,
Center
Hospital,
University
1. E. Schultz,
Techniques
24-48’hr
culture
R. Smalley,
M.D.,
24-48-hr
culture
M.D.
M.D.
Direct
M.D.
Direct
24’hr
M.D.
culture
Memorial
Knoxville,
Philadelphia,
of Pennsylvania,
by
Used
Pa.
Pa.
of the University
Presbyterian
Techniques
M.D.
and G. Faguet,
Temple
f.
Philadelphia,
Ga.
and
and
R. Smalley,
Go.
of Georgia,
Performed
MT.,
c.
Defects
Analyses,
Tenn.
Pa.
Philadelphia,
P. Nowell,
M.D.
Direct
Pa.
RESULTS
The
following
results
Entered:
were
obtained:
16
Adequate
Evaluable:
trial:
12
10
Conversion:
2
Sixteen
patients
were entered
therapy
and 12 had an adequate
The nadir
granulocyte
and
it, and the course
by which
on study.
Of these,
15 received
trial;
3 did not achieve
“marrow
platelet
counts
achieved,
the nadir
was achieved
the
are
let nadirs
occurred
between
days 1 1 and 16 following
locyte
nadirs
occurred
between
days 21 and 27 and
administering
mal-only
one
Table
dose
listed
Absolute
Granulocyte
Drug
and
Platelet
Count
Dose in 1 2 “Adequately”
Nadir
Nadir
After
Abs.
(x
Age
Sex
1
29
F
2
0.060
No.
10
utilized
to achieve
in Table
2. Plate-
to hypoplasia
Achieved
Abs.
Maximum
(x
Individual
10)
Dose
6
Drug
(mg/sq
51
F
2
0.600
67
100
3
47
F
1
0.600
19
100
4
53
M
2
0.600
76
120
5
56
M
3
1.200
40
140
6
44
F
5
0.130
200
140
7
43
M
1
0.800
49
100
8
38
M
2
1.000
15
100
9
28
F
3
0.800
28
180
10
52
F
2
0.500
35
160
11
45
M
4
1.500
55
120
12
38
F
2
0.400
120
100
Drug
dose
of
both
ara-C
achieved.
and
TG
escalated
20%
with
each
course
m)
100
2
thrombocytopenia
mini-
by Escalating
Platelet
)
was
Patients
Nadir
Granuloyte
Patient
Course
Nadir
Treated
of
each course,
while
granufrequently
caused
delay
in
the subsequent
course.
Morbidity
related
episode
ofclinical
infection
occurred.
2.
six courses
hypoplasia.”
until
granulocytopenia
and/or
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110
SMALLEY
Table
3.
Chromosome
Analysis*
Performed
of 10 “Adequately”
Base line
Patient
Institutiont
%
No.
During
on Bone
Treated
Co urses 1-3
%
Marrow
Specimens
During
No.
Co urses 4-5
%
After
No.
C
6
ourse
%
No.
1
a
100
23
-
-
100
42
100
38
a
100
52
100
50
100
50
100
35
3
a
100
25
100
8
92
25
100
14
4
b
100
50
100
50
93
100
89
65
5
b
100
22
-
-
100
100
6
f
100
25
100
55
100
50
7
c
100
50
98
50
-
8
d
100
100
30
100
15
10
e
80
24
63
12
93
0
50
12
f
100
25
100
50
100
17
*Analyses
were done
at least three
of karyotypes
times as baseline,
Ph1’positive;
tChromosome
analysis was performed
viduals and techniques
listed in Table 1.
Cycle-active
tients
due
therapy,
No.,
on bone
as outlined
to morbidity.
Of
during,
number
and after
here,
was
16, 9 developed
basically
50
-
-
11
28
-
six courses
in the
“intolerable”
100
100
counted
specimens
100
7
100
-
of metaphases
marrow
AL.
Patients
2
%, percentage
El
and
-
of cycle-active
therapy.
analyzed.
institutions
and
unacceptable
by
the
mdi’
to most
nausea
and
pa-
vomiting
throughout
the 5-day
period,
while 4 additional
patients
complained
of minimal
nausea
on treatment.
One patient
refused
further
therapy
after
the first course
because
of gastrointestinal
symptoms,
and the majority
had to be actively
encouraged
to continue
treatment.
Ofthe
12 patients
receiving
an adequate
trial
of drug,
10 had at least
two
adequate
marrow
chromosome
analyses
performed
subsequent
to achieving
hypoplasia;
of these
10, 2 “converted”
(Table
3). Patient
10 had
80%
Ph’positive
metaphases
in the marrow
lowing
the initial
course
of therapy,
hypoplasia
was documented
after
analysis
prior
to cycle-active
peripheral
counts
were
not
the second
course.
A marrow
therapy.
obtained,
aspirate
Folbut
ob-
tamed
3 wk after starting
the first course
of therapy
revealed
88% Ph’-negative
cells. Subsequent
marrows
done
3 mo and 5 mo following
the first course
of
therapy
revealed
l00#{176}
and 89% Ph’-negative
cells,
respectively.
Following
six
courses
and despite
her documented
conversion,
she refused
further
therapy
because
of intolerable
nausea
diagnosis
but has refused
verted”
following
the sixth
ever,
No
2 mo
later,
the
marrow
maintenance
therapy
Ofthe
7 patients
who
pulsing
treatment,
and vomiting.
She
subsequent
marrow
course
ofcycle-active
had
again
reverted
was given following
the
had a negative
leukocyte
6 became
positive
while
remains
alive
examination.
therapy
(140
72 mo
Patient
mg/sq
to a Ph’-positive
sixth course.
alkaline
phosphatase
state
following
5 “conm). How(100%).
prior
to
on treatment.
DISCUSSION
Treatment
ofpatients
with CGL
has not
The median
duration
of survival
following
irradiation
is generally
3-4 yr.6 However,
fluenced,
treatment
is capable
of inducing
therefore
improving
the
quality
of life.
had a significant
impact
on survival.
either
busulfan
therapy
or splenic
although
survival
has not been
ina complete
clinical
remission
and
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CYTOGENETIC
CONVERSION
OF
It has been
determined
The etiologic
significance
may be used as a marker
ment
induces
a clinical
cytogenetic
dard
which
crisis,
remission
MARROW
that
88%
of patients
with
CGL
are Ph’-positive.7
of this chromosome
abnormality
is unknown
but it
for diagnostic
and therapeutic
purposes.
While
treatand
hematologic
remission
in nearly
all patients,
a
has
only
been
therapy.
Eventually,
over
is unresponsive
to cytotoxic
68%
111
demonstrate
obtained
inadvertently
80% of patients
chemotherapy.
additional
and
develop
Of those
aneuploid
features.8
rarely
an acute
developing
The
by stanblast
crisis
the blast
evolutionary
pro-
cess leading
to this acute
blast
crisis
has been
examined
cytogenetically
and
some
order
or pattern
may be discerned.9”0
Most
patients
in the blast
crisis
demonstrate
aneuploidy
with duplication
of the Ph’ chromosome
and/or
a C
group
chromosome
and
deletion
of an E group
chromosome
as common
10
The
etiology
parent
that
or mechanism
the
of this
Ph’-positive
cell
transformation
line
is unknown
is extremely
susceptible
but
to this
it is ap-
karyotypic
evolution.
If therapy
were capable
of eliminating
the Ph’-positive
line, a true
complete
(hematologic,
clinical,
cytogenetic)
remission
could
be obtained
and
treatment
might
then have a significant
impact
on survival.
To date,
this objective has not been achieved
with standard
busulfan
or splenic
irradiation
therapy,
although
in isolated
instances
busulfan
appears
to have
inadvertently
induced
prolonged
conversions.
The
drug
is capable
of inducing
long-term
(6-12
patient,
(<50%
recent
mo)
suppression
of
induced
significant
Ph’-positive
cells),
case report
has noted
<50%
The
Ph’-positive
coexistence
tients
with
mixture
of
CGL
has
and
succeeded
of human
10-14
days
of
from 2 patients
had
20 colonies.
they
provided
with
by
cells.
cells.
samples
cells
from
leukocytes
or by the
chromosome
only
Ph’-positive
only
Ph’-negative
Although
the
important
support
with
a normal
busulfan
effects
these
with
10 patients
10 patients,
et al.’
disease
attempted
Ph’-positive
in relapse
analyzable
to the
theory
clone.
with
cells)
cells
Following
that
and
10
busulfan
demonstrable
were
a normal
small
in
All colonies
analyzed
in
1 from
another)
were
Ph’-negative
recovering
from
the effects
of
(10
and
of busulfan
of a feeder
media.
was performed.
Of the 14 colonies
a
pre-
to dem-
with
was
CGL,
with
9 had
from the effects
plating
on top
of analyzable
cell
and
patients
noted
of conditioned
analysis
cells.
cell remains
in the marrow
of at least some
“total”
ablation
of the Ph’-positive
clone
of the marrow
covering
from
busulfan
therapy.’2
in the marrows
of pa-
7 patients
recovering
by either
addition
cells
numbers
from
5. In 3, the
incubation,
revealed
4 (3 from one and
The fifth patient,
Of
has,
in one
reported
marrow
conversion
survival.
A second
yr) of a patient
with
179
al.7
Chervenick
marrow
1 was pancytopenic
and
growth
was stimulated
2 other
patients,
were
Ph’-positive.
therapy,
(68%-98%)
formation
of
et
Ph’-negative
and
partial
yr)
(8+
short-term
cells
In a study
Whang-Peng
and
Ph’-positive
colony
following
Ph’-negative
documented.
Ph’-positive,
Ph’-positive
1, in blast crisis;
therapy.
Colony
layer
been
were
dominantly
onstrate
cells in his marrow
of Ph’-positive
and
CGL
158 of whom
bone
marrow
function
hypoplasia,
probable
and
a prolonged
(10+
the prolonged
survival
in this
from
study,
Ph’-negative
stem
patients
with CGL,
indicating
that
might
be followed
by repopulation
Their
patient
only
Ph’-negative
with
pancytopenia
cells as well
as
rethe
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1 12
case
SMALLEY
report
cited
above”
provided
clinical
evidence
that
such
El
an approach
AL.
was
feasible.
Dowling
et al.,3 in a prospective
fashion,
demonstrated
version
was possible
in at least 25% of patients.
Following
that
a marrow
the induction
conof a
clinical
remission
their
patients
underwent
splenic
irradiation,
then
splenectomy,
and then aggressive
cycle-active
chemotherapy
(ara-C
120 mg/sq
m i.v.
and TG 100 mg/sq
m p.o. every
12 hr: L-asparaginase
8000
U/sq
m iv. for
14 days with vincristine
1 .5 mg/sq
m iv. on days 7 and 14). The present
study
has confirmed
their
findings
and indicated
the ability
of aggressive
cycle-active
chemotherapy
nectomy
and
cedures
Most
to convert
a Ph’-positive
splenic
irradiation.
Whether
may increase
the conversion
of the chromosome
data
marrow
without
the addition
the addition
of these
latter
rate is undetermined.
obtained
from
CGL
marrows
the “direct”
technique,7
0.13.14
which
does
not
mitotic
stimulation.
However,
use of a 24-48
mitotic
stimulators
(i.e.,
phytohemagglutinin-PHA)
has
use either
hr culture
of spletwo probeen
ob-
tamed
period
without
by
or
a culture
technique
has
demon-
strated
of both
leukemic
equivalent
abnormalities.
Sandberg
et al.’5 demonstrated
the capability
leukemic
Ph ‘-positive
and Ph ‘-negative
cells as well as presumably
nonPh’-negative
granulocytic
cell precursors
from patients
with
CGL
to
divide
in vitro
in the absence
of PHA.
Speed
and
Lawler’3
have
discussed
the
comparability
of the two techniques
and stated
that during
the chronic
phase
of
CGL
the Ph’ chromosomal
content
of the marrow
cells was the same
by either
direct
examination
or a 22-30-hr
culture.
A direct
comparison
6 of the
two techniques
in patients
with
Ph’-positive
CGL
analyzing
marrow
cells
using
the
direct
technique
demonstrated
parable
when
and peripheral
their comparability.
evaluating
the
blood
cells using a short-term
culture
Additionally,
the two techniques
presence
of the Ph’ chromosome
in
(46-51
hr)
were compatients
in
early relapse
in the study
of Fitzgerald
et al.’7 Both
techniques
were used in the
current
study,
and although
both “converters”
were studied
by the culture
technique,
the comparability
demonstrated
in previous
studies,
the fact that
the
same
technique
was used throughout
each
individual
patients’
study,
and the
short
period
of culture
time
sured
reliability.
It is impossible
to conclude
irradiation
and/or
splenectomy
sion with cycle-active
therapy.
sented
that such a conversion
used
without
from
any
increases
an
of
the
exogenous
the
data
likelihood
Neither
is it apparent
is of therapeutic
benefit
mitotic
available
stimulator
whether
of achieving
ensplenic
a conver-
from
any data
yet preto the patient.
The transi-
ent conversion
(2 mo) obtained
in patient
5 would
probably
not influence
his
survival.
It is possible,
however,
that an extended
conversion
such
as that
obtamed
in the patient
of Finney
et al”
and of Golde
et al)2 plus the two prolonged
conversions
achieved
by Dowling
et al.3 has prolonged
survival.
Patient
10 in our study
has refused
subsequent
marrow
chromosomal
analyses
but remains
alive 6 yr after diagnosis.
Cycle-active
chemotherapy,
as employed
in this study,
was unacceptable
to
patients
because
of gastrointestinal
toxicity.
Additional
regimens
should
be
sought
which
will be capable
of inducing
more
conversions
of longer
duration
while producing
less morbidity
for the patient.
From www.bloodjournal.org by guest on December 22, 2014. For personal use only.
CYTOGENETIC
CONVERSION
113
OF MARROW
ACKNOWLEDGMENT
The
following
members
of
the
Southeastern
John R. Durant,
M.D.,
University
Kellermeyer,
M.D.,
Case
Western
Harold
Silberman,
M.D.,
and
Sharon
Fisher,
of Georgia,
sity
M.D.,
Charles
of
M.
Augusta,
Ga.:
Hospital,
Reading,
Ill.:
Enrique
Pa.;
Rico:
Stephen
Krauss,
Center,
cine,
St. Louis.
I.
Chervenick
M.D.,
Philadelphia,
H. Knospe,
University
M.D.,
and
Temple
of
Takuo
Tenn.:
Loeb,
Jr.,
of
Rico
M.D.,
of
Washington
Center,
Philadelphia,
Medicine,
University
M.D.,
niverReading
Medical
Center,
of
Ga.:
College
M.D.,
Luke’s
School
Keller,
Medical
Lusch,
Medical
W.
Presbyterian-U
I.
Rush-Presbyterian-St.
University
study:
Atlanta,
M.D.,
M.D.,
Charles
this
James
Medicine,
Faquet,
Gardner,
Pa.;
Puerto
Sonoda,
Virgil
Guy
Frank
in
Ala.;
Robert
W.
Cleveland,
Ohio;
NC.;
School
Pa.:
and
M.D.,
M.D.,
M.D.,
Knoxville,
Philadelphia,
participated
Birmingham,
of Medicine,
Durham,
University
Center,
Smalley,
Group
Center,
Emory
Murphy,
William
V.
Velez-Garcia,
search
Scott
Study
of Medicine,
School
Medical
M.D.,
Hospital,
Medical
Richard
School
University
University
Jr.,
Episcopal
Pennsylvania
Chicago,
Duke
Huguley,
M.D.,
Cancer
ofAlabama
Reserve
San
Pa.:
Juan,
Tennessee
Puerto
Memorial
University
School
Re-
of
Medi-
Mo.
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From www.bloodjournal.org by guest on December 22, 2014. For personal use only.
1977 50: 107-113
Chronic granulocytic leukemia: cytogenetic conversion of the bone marrow
with cycle-specific chemotherapy
RV Smalley, J Vogel, CM Jr Huguley and D Miller
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