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Use
of All-Trans
Retinoic
of Acute
By
Huang
Meng-er,
Twenty-four
(API)
Ye Yu-chen,
patients
were
with
treated
mg/m2/day).
Of these.
sponsive
or resistant
1 6 cases
were
complete
eight
hypoplasia.
previously
Bone
morphological
maturation
staining
tion
confirmed
tiated
to
(as
All
cultures
as well
acid-induced
NBT).
CUTE
the
parameters
subclinical
only
stud-
retinoic
acid
Eight
acetate
leukemias
distinct
a
entity
among
Hemorrhagic
(AML).
diathesis
results
in a rapid
fatal
usually
attributed
to thrombocytopenia
intravascular
outcome.
coagulation
of a procoagulant
The
use
improvement
of daunorubicin
in supportive
rate
of
complete
increased
APL
mortality
than
in other
to be refractory
The
(DIC),
from release
granules.
at
conclude
to
(CR)
induction
treatment
in
to result
APL.2’3
and
some
be
However,
is higher
cases
DIC
Retinoic
and
the
in
continue
remains
an
alternative
acid
(RA),
a
an
analogue
of vitamin
A, is one of the many
agents
that can
induce
differentiation
and terminal
cell division of leukemic
cells in vitro.5
At present,
several
cases of APL treated
with
1 3-cis
RA
We report
patients
have been reported
in vitro studies
and
using
all-trans
MATERIALS
with encouraging
therapeutic
trials
results.9
of 24 APL
RA.
AND
METHODS
The diagnosis
of APL was made according
to the
criteria
of the French-American-British
(FAB) cooperative
study
group.’#{176}
Every patient presenting
to our hospitals
since early 1986
with a diagnosis
of APL was included
in this study. The clinical
characteristics
of the 24 patients
with APL are shown in Table 1.
Eleven females and 13 males with a mean age of 35.5 years (range 5
to 69 years)
were studied. The total WBC counts ranged from 0.5 x
109/L to 15.8 x 109/L, including
20 cases (83.3%) with <3 x 109/L,
3cases(12.5%)between3
x l09and
10 x 109/L,and
lcase(4.l%)
with >10 x 109/L. The hemoglobin
concentrations
ranged from 41
to 121 g/L including
8 cases (33.3%) with <60 g/L, 12 cases (50%)
between 60 and 90 g/L, and 4 cases (16.7%) with >90 g/L. Platelet
counts ranged
from 10 x 109/L to 337 x l09/L, including
15 cases
(62.5%)
with <50 x l09/L, 7 cases (29.2%)
between
50 x l09/L
and 100 x I09/L and 2 cases (8.3%)
with >100 x l09/L.
The
percentage
of promyelocytes
in the marrow
ranged from I 5.6% to
94%, with 22 patients
having >30% and the remaining
2 patients
have
for
to
of
that
attaining
an
months
& Stratton,
absence
dryness
are
of
2
to
5
being
acid
remission
any
lips
and
symptoms.
months
in complete
still
retinoic
of
The
of the
digestive
remain
and
all-trans
complete
none
coagulation
coagulation.
after
others
attained
cytosine
of therapy.
in the
and
relapsed
The
11 +
mild
headaches
but
is
of
remis-
followed
an
up.
effective
in API.
Inc.
15.6% and 30%. Of the 24 patients,
16 had never
The other 8 (cases I through
8) had previously
been
treated
with chemotherapy
(HOAP,*
HOP, OH, COH, H). Of the 8
treated
patients,
3 were in relapse after I to 30 months of CR and 5
were resistant
to or could not tolerate
the chemotherapy
(5 to 62
days of treatment).
Twenty-two
of the patients
showed
mild to
moderate
hemorrhagic
manifestations
(purpura,
gingivorrhagia,
gastrointestinal
bleeding),
but no laboratory
evidence
of DIC prior
to treatment
with RA except for a positive plasma protamin
sulfate
paracoagulation
(3P) in three of the cases.
Marrow
preparation
and culture.
A modification
of the method
of Flynn and colleagues6
for short-term
suspension
culture was used.
Marrow
cells were aspirated
from the iliac crest, layered
onto
Ficoll-Hypaque
(sp gr 1.077),
and centrifuged
at 800 g for 15
minutes.
Interface
cells were collected,
washed with McCoy’s
5A
medium,
and resuspended
at a concentration
of 5 x 10 cells/mL
in
McCoy’s
5A medium
containing
15% fetal calf serum
(FCS).
All-trans
RA (Shanghai
No. 6 Pharmaceutical
Factory)
was dissolved in absolute
ethanol
to a concentration
of I mmol/L
and
further diluted with the medium so that the final ethanol concentration in the cultures
was 0.1% and the final RA concentration
was 1
been
promyelocyte
therapy
may
APL.
are
1 +
course
Zhen-yi
low-dose
suggesting
consisted
by Grune
having
disseminated
the
chemotherapy.
of
and
the
Wang
acid
of
intravascular
remission.
We
retinoic
abnormalities
measured.
patients
sion
occurs
any
occasional
differen-
is conmyeloid
During
effects
examina-
induction
therapy
has greatly
raised
during
common
lethal complication.
Induction
of differentiation
approach
from
we
and
addition
disseminated
complete
episodes
is believed
which
in
therapy
to induction
often
bleeding
factor
of AML,3’4
acute
and/or
remission
forms
(APL)
the
with
showed
with
a 1988
Gu Long-jun.
after
(ara-C).
side
inducer
Lin,
treatment
patients
skin.
cells
leukemia
PROMYELOCYTIC
sidered
remission
had
as electronmicroscopic
retinoic
to
complete
patients
a-naphthyl
Zhoa
resistant
marrow
were
to the
and
Lu Jia-Xiang,
arabinoside
other
Treatment
Leukemia
attained
bone
of these
100
nonrethe
patients
Fourteen
in response
to
either
developing
esterase
that
been
(45
granulocytes
with
increased
functional
maturameasured
by nitroblue
tetrazolium
reduction.
The single nonresponder
to retinoic acid in vitro was
tion
A
had
suspension
patients.
Chloroacetate
leukemia
acid
chemotherapy;
untreated.
marrow
24
esterase
cases
without
ied in 1 5 of the
(1 ,tmol/L).
retinoic
to previous
remission
Chai Jin-ren,
promyelocytic
all-trans
in the
Promyelocytic
Chen Shu-rong.
acute
with
Acid
between
treated.
izmol/L.
Controls
were cultured
in medium
alone. (Ethanol
0.1%
had previously
been shown to have no effect on cell growth
or on
differentiation
of HL-60
cells.”)
All cultures
were incubated
at
37#{176}C
in a 5% CO2 atmosphere
for up to 7 days. Cell density
was
determined
by hemacytometer,
and cell viability was determined
by
trypan blue dye exclusion method. Aliquots of cells were removed for
Patients.
Blood,
Vol 72. No 2 (August).
1988:
pp 567-572
Harningtonin
(0.02 to 0.07 mg/kg/day);
0, oncovin (0.02 to 0.03
mg/kg/day);
A, Ara-C; P. prednisone;
C, cyclophosphamide.
From the Shanghai
Institute
of Hematology,
Shanghai
Second
Medical
University;
Shanghai
Zhong-Shan
Hospital;
Shanghai
Children’s
Submitted
Address
Hospital.
July
reprint
14, 1987; accepted
requests
March
to Z. Y. Wang,
31, 1988.
MD.
280
South
Rd. Shanghai
Second Medical
University,
Shanghai,
Republic
of China.
The publication
costs ofthis article were defrayed
in part
charge payment.
This article must therefore
be hereby
“advertisement”
in accordance
with /8 U.S.C. section 1 734
indicate this fact.
© I 988 by Grune
& Stratton.
Inc
Qing
Chong-
People’s
by page
marked
solely to
0006-4971/88/7202-0053$3.OO/O
567
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568
MENG-ER
Table
PB
Previous
Cas
Sex
1
Age
F
5
Therapy/Duration
(x
H/20
of 24 Patients
-
BM
wsc
10’/U
Prom
1.16
78
HOAP/7days
HOP/9
1 . Data
With
API
BM
Present
PR
(day)
Therapy
(%)
(mg/m2/day)
RA8O
ET AL
.
CR
(day)
Prom
(%)
Further
Therapy
31
68
1.5
(1)
Duration
of CR
(mo)
8
days
days
2
M
6
HOP/26days
1.7
73.5
RA100
18
28
2.5
3
F
28
HOA/62days
1.8
89
RA6O
21
34
2.0
(3)
(3)
4
M
HOAP/lOdays
2.2
33
RA8O
18
43
3.6
(2)
5
7.7
15.5
RA45
17
20
4.5
(1)
5
4.0
28.5
RA45
22
22
2.0
(1)
4
2
8
OH/21
-t
4
days
CR/3
mo
Relapse
5
F
38
HOP,HOAP,H
CR/i
mo
Relapse
6
F
54
HOP,HOAP
CR/30
mo
Relapse
7
M
54
H/l0days
1.4
94
RA45
29
38
1.0
(1)
8
F
69
H/5
0.5
48
RA 45
22
44
4.0
(3)
9
M
61
Untreated
1.0
74
RA45-50
29
36
2.5
(2)
10
M
31
Untreated
1.6
76
RA5O
35
35
1.5
(2)
11
12
M
F
37
Untreated
1.4
65
RA45
26
43
3.5
(1)
18
Untreated
0.9
81.5
RA45-50
21
40
2.5
(4)
8
13
F
35
Untreated
2.2
70
RA5O
20
39
2.0
(2)
4
14
M
45
Untreated
2.1
84.5
RA45
36
119
1.0
(4)
5
15
F
57
Untreated
1.9
88.5
RA45
23
51
2.5
(4)
5
16
F
20
Untreated
0.9
85.5
RA5O
22
46
2.0
(1)
8
17
M
32
Untreated
1.1
78
RA45
29
39
3.0
(4)
4
18
M
36
Untreated
1.1
89.7
RA5O
35
52
2.0
(4)
4
19
F
53
Untreated
15.8
75.5
RA45
23
39
0
(3)
51
20
M
30
Untreated
6.5
90
RA45
46
46
2.5
(4)
31
21
F
36
Untreated
1.7
91
RA5O
36
50
1.0
(3)
1
22
M
21
Untreated
1.7
90
RA45
28
56
1.0
(4)
2
23
M
45
Untreated
1.4
78
RA45
25
45
3.0
(4)
1
24
M
34
Untreated
1.1
30
RA45
60
98
1.5
(4)
3
days
+
PB. peripheral
30 mg/m2/day);
with
HOAP,
WBC;
ReIapse
Prom.
(2) RA (20 to 30 mg/m2/day)
maintained
Greater-than,”
tLost
BM, bone marrow;
by 6-mercaptopts’ine,
still under
promyelocyte;
+ ara-C
methotrexate,
PR (day).
( 10 mg every
time
are-C
to partial
1 2 h) or H (0.5
1#{149}
11
5
10
20
remission;
mg/m2/day);
CR (day),
time
to complete
(3) are-C ( 10 mg every
remission;
1 2 hours);
(1) RA (20 to
(4) consolidated
or cyclophosphamide.
follow-up.
to follow-up.
after
CR.
morphological
examination
on the second, fourth, and sixth day of
culture.
Morphological
studies.
Differential
counts
were performed
on
cell smears stained
with Wright’s
solution.
Chloroacctate
esterase
and a-naphthyl
acetate
esterase
stains
were done by standard
techniques.’2
Samples
from four cases
were prepared
for transmission electronmicroscopic
study. The nitroblue
tetrazolium
(NBT)
reduction
assay was done as described
by Francis and co-workers)3
The percentage
of cells containing
intracellular
blue-black
deposits
was determined
in 200 cells on Wright’s-stained
slide preparations.
Colony
formation
assay.
Blast
cell colonies
were grown
as
described
by Minden
and colleagues.’4
Conditioned
medium
was
prepared
from leukocytes
(10’ cells/mL)
incubated
at 37#{176}C
for 7
days in McCoy’s
5A medium
with 10% FCS and 1% (vol/vol)
phytohemagglutinin-P
(PHA-P)
(Difco, Detroit)
and stored at 4#{176}C
until used. The preparation
was termed PHA-LCM.
Bone marrow
cells were plated
at I x 106 cells/mL
using
McCoy’s
5A medium
supplemented
with 0.3% agar, 20% FCS, and 25% (vol/vol)
PHALCM.
GM-CFU
count was determined
according
to the technique
of Pike and Robinson’5
for colony growth in agar. Marrow cells 2 x
i05 were plated in 35-mm tissue culture dishes over a feeder layer of
I x 106 leu1ocytes
from healthy donors. The plates were incubated
at 37#{176}C
in a humidified
5% CO2 atmosphere.
L-CFU colonies (>20
cells) were scored on day 8, and GM-CFU
colonies (>40 cells) were
scored on day 10.
Treatment
of patients.
The 24 patients
in this series received
all-trans
RA (45 to 100 mg/m2/day)
as remission
induction
therapy.
Informed
consent was obtained
from all patients
(or their parents).
Peripheral
blood counts, bone marrow
aspiration,
and coagulation
parameters
(in 2 1 cases)-including
thrombin
time, prothrombin
time, plasma protamin
sulfate paracoagulation
test, euglobulin
lysis
test, and fibrinogen
levels-were
determined
before the start of
therapy
and at regular
intervals
thereafter.
CR is defined as <5%
blasts plus promyelocytes
in a normal cellular marrow with a normal
peripheral
blood count and an absence
of signs and symptoms
of
leukemia
on physical
examination.”
Partial
remission
(PR)
is
defined
as <5% blasts plus promyelocytes
in a normal
cellular
marrow,
but presence
of a clinically
moderate
anemia.
Blood trans-
From www.bloodjournal.org by guest on June 16, 2017. For personal use only.
TREATMENT
OF
APL
WITH
RETINOIC
ALL-TRANS
ACID
569
Fig 1 .
Morphological
maturation of leukemic
cells of case
10 in vitro and in vivo.
(A) Cells
cultured
without
RA. consisting
of promyelocytes
with
characteristic
cytoplasmic
granules
( x 1 ,000).
(B) Cells
cultured
with RA, showing
maturation
to
granulocytes
(xl,000).
(C)
Bone
marrow
before
RA treatment.
The predominance
of
promyelocytes
(76%)
indicates
typical
API.
(D) Bone marrow
after 5
weeks
of RA treatment.
Promyelocyte
level
<2%
and
restoration
of normal
hematopoiesis
without
a phase of aplasia are consistent
with
differentiation
induction.
fusion and
necessary.
antibiotics
were
given
as supportive
treatment
when
RA
cytes
vitro
studies.
Leukemic
I 5 patients
culture,
with
and
bone
incubated
or without
all-trans
for
RA
Table
Blasts
Case No.
Control
marrow
7 days
(1
2.
(%)
cells
Response
Promyelocytes
RA-treated
Control
leukocytes,
1 5.4%,
respectively.
cells was
of the control
sent
data
age
±
from
To examine
cells
time
various
(%)
The
42.0%
group
when
morin with
of promyelogroup
was
respectively.
The percent+ bands
+ polymor-
was
rate
4.7%
of NBT
±
(4.2%
±
3.5%).
studied
and
the
of cellular
patients
with
and
4.5%
53.9%
reduction
significantly
7.5%,
±
and
showed
cultured
percentage
RA-treated
the patients
progression
from
four
intervals.
to RA in Suspe nsion
Myelocytes
maturation
PMNs)
control
in RA-
higher
(All
than
results
are the mean
repre-
percent-
SD.)
incubated
of Prom yelocytes
RA-treated
phonuclear
of both
>75%.
I 4 patients
and 5.9%
± 5.0%,
cells (metamyelocytes
12.8%
±
that
showed
functional
of mature
treated
derived
.imol/L),
and
83.5%
in suspension
Viability
(Table
2), (Fig lA and B). The
in the control
group
v the
age
±
density.
cells was consistently
promyelocytes
from
phological
RESULTS
in
in cell
RA-treated
Leukemic
Continuation
therapy
following
CR.
Twenty-three
patients
were followed up after they attained
CR. Further
therapy
was as
follows: (a) maintained
by RA, 20 to 30 mg/m2/day
(6 cases); (b)
maintained
by RA, 20 to 30 mg/m2/day
plus low-dose ara-C [10 mg
intramuscularly
(IM) every 12 hours] or low-dose harringtonin
[0.5
mg/m2 intravenously
(IV) daily] in rotation
(4 cases); (c) maintamed
by low-dose
ara-C,
10 mg IM every 12 hours, (5 cases); (d)
consolidated
by chemotherapy
(HOAP)
and maintained
by 6mercaptopurine
(2 mg/kg
daily p.o.) and methotrexate
(10 mg/m2,
IV weekly),
or cyclophosphamide
(200 mg/m2,
IV weekly)
(9
cases).
from
change
little
After
48
differentiation,
I zmol/L
RA
hours,
morphologically
Culture
(%)
I
Control
RA-treated
Control
(%)
NBT (Xl
RA-treated
Control
RA-treated
1
3
2
68
7
15
34
4
48
ND
3
0
0
86
1
6
26
7
73
3.5
4
0
1
47
4
14
48
18
36
ND
9
0
0
95
5
2
25
1
63
3
54
10
0
0
98
2
0
24
2
74
5
38
11
2
3
78
2
5
26
11
64
ND
12
2
1
81
4
9
27
6
62
2
13
0
0
86
9
8
38
6
53
ND
14
0
0
86
3
11
29
3
68
ND
ND
16
0
0
93
12
6
36
1
52
0
35.5
18
1.5
0
77
1
20.5
42.5
1
55
12
19
0
0
92
4
0
53
2
39
ND
20
0
0
90
8
8
38
2
52
ND
21
0
0
91.5
20
3.5
62
2
15
4
0
84
80
2.5
24
Control,
0
RA not
Metamyelocytes
added
to the
+ bands
culture.
+ polymorphonuclear
leukocytes.
4
6.5
7
ND
ND
52
ND
ND
39
ND
43
ND
ND
33
ND
we
for
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recognizable
changes
observed.
The
granules
were
of culture,
the
promyelocytes
became
observed
larger,
in the cytoplasm.
cells
gave
rise
On
be
DIC.
the
fourth
condensed,
visible.
with
test
day
filled
appearing
by day 6 as well as some
granulocytes.
days,
with
When
the
relative
in the
positive,
whereas
granules
were
mulated
portion
a stronger
Transmission
confirmed
been
esterase
that
in the
presence
changed
of RA
granulocytes.
evident,
and
to a bean-shaped
form.
Neutrophilic
scattered
throughout
or even
granules
were
the cytoplasm.
for
one
patient
(patient
marrow
proliferation
of leukemic
promyelocytes.
mg)
was added
IM every
in 98 days (Table
1).
In the
1 2 patients
effect
tiation
(163.3
pressed
±
reached
who
of
129.0
(0.63
no growth
of L-CFU
Pattern
of clinical
tematic
observation
treatment
the
between
with
7 and
was
hemoglobin
most
initiation
14 days.
month
(Fig
accompanied
lips and
(20.8%),
exfoliation
these side
lC
and
D).
tions did not occur when
remission with RA.
patients
The
Among
the
low-dose
ara-C
after
to follow
in
CR
1+
promyelocytes
1 relapsed
1 + to 5 + months.
relapsed
8+
at
months.
relapse
those present
at the
start
all-trans
induction
RA
that
PR
Therapy
by mild toxicity
hypercellularity
could
with
be expected
oral
(10
all-trans
approaches
the
other
3
remaining
have
and
9
regior
been
in CR
of
were
APL
from
resistant
to
in vitro.
in treatment
that
at a concentration
humans.”0
13-cis
in
RA
acteristics
then
fell
Increase
in
One
cytoplasm
ferences
with
neous entities
Bone
In 1983,
existed
was
All
the
died
with
RA
elevated
of treatment.
APL
in relapse
(1 mg/kg)
normal
blood
co-workers8
APL
of myeloid
is pharmacologically
and
all-trans
in
obtainable
RA
were
equally
effec-
differentiation
in vitro.5
Our
studies
leukemic
promyelocytes
could
be
RA
to differentiate
toward
mature
was
that
prominent
to RA
the
cells
from
The morphological
cells
revealed
coarse
may
granulation.
be owing
patient
charscanty
a
The
to the
dif-
heteroge-
of APL.2”22
markedly
weeks
inducer
Flynn
and colleagues6
described
the first case of
treated with
13-cis-RA.
Unfortunately,
this patient
from
disseminated
candidiasis,
although
he had
a
APL
1
less
use of
D3, or
and in
is a potent
exception
in sensitivity
include
as RA, vitamin
both in vitro
promyelocytic
cell line HL-60
as
from patients
with APL,
and
resistant
to RA induction.
of these
RA-resistant
of the
within
of
that, in vitro,
by all-trans
24 were
reach-
that
RA
induction
granulocytes.
of leukemia
agents”
such
Numerous
studies
revealed
have
confirm
induced
rose
SGPT.
when
the
seven
of treatment
both in the
well as in fresh promyelocytes
or
consisted
of dryness of the
skin (100%),
headache
(25%),
nausea
or vomiting
moderate
bone
or joint
pain
(12.5%),
and mild
dosage of oral RA was reduced.
Recent
vivo
that
(8.3%).
Two patients
had elevated
effects
were well tolerated
or alleviated
and
of differentiation
“differentiation-inducing
low-dose
ara-C.’7’9
revealed
RA
and
Of
The
new
population
differed
morphologically
differentiation,
count
slow.
on RA with
in rotation,
DISCUSSION
Sysduring
and
and
to
not
CR
Elevation
reluctant
induced
consolidated
by chemotherapeutic
on 6-mercaptopurine,
methotrexate,
two
to
maintained
harringtonin
up,
patients
who were
mens and maintained
from
patients
low-dose
for
cyclophosphamide,
little
patients
3 weeks.
appeared
were
in 4 months,
lost
tive
count
APL
remained
with
WBC
with
7 to 10 days
complica-
was
was supGM-CFU
of treatment
negative
hemorrhagic
during
previously
of
had
differen-
WBC
been
had
ara-C
of granulocytes.
prominent
marrow
aspirate
revealed
throughout
RA
treatment.
3P(+)
became
DIC or other
had
cells
acid.
counts
total
who
of 4 to 5 months.
Of the 5
ara-C
alone,
I case (case 2)
predominant
colonies)
The
maturation
concentration
and who were
RA. Therefore,
after
patients
parame-
no changes
three
relapsed
within
a period
patients
maintained
on low-dose
achieved
was
untreated
of change.
progressive
platelets
55.1
±
previously
starting
ing a peak
growth
(100.2
patterns
progressively
patient
after CR was achieved.
response
to trans-retinoic
of the peripheral
blood
of the
specific
three
other
in coagulation
showed
four
to the induction
L-CFU
levels
The
normal
therapy
of
were
When
the
responded
RA,
were
RA
of
Of
or
diffusely
granules
colonies)
and GM-CFU
growth
1 .3 colonies)
prior to treatment.
±
normal
some
12 hours,
were
four
a segmented
cells
levels)
either
were treated
with
both PR and CR
whose
1 8 who
beginning
RA in vitro. Subsequent
bone
patient
revealed
a continuing
when
fibrinogen
4 months.
smaller
and
Azurophilic
24),
cultured
with
examination
of this
inducible
and
cells
Condensation
the nucleus
were markedly decreased.
Clinical
studies.
Twenty-four
patients
all-trans
RA as a single
agent.
All achieved
except
the
test,
time,
paracoagulation
cells
RA-treated
examination
to mature
became
lysis
thrombin
sulfate
patients maintained
on RA alone, four were still in remission
for a period of 5 to 10 months.
Two patients
relapsed
in 2 and
positive
control
(including
protamin
Duration
of clinical
remission.
Twenty-three
patients
were followed
after
induction
of CR (Table
1). Of the six
or accu-
Most
activity;
reaction.
electronmicroscopic
been differentiated
the heterochromatin
often
of the cytoplasm.
nonspecific
patients,
before
treated
esterase
scattered
plasma
euglobulin
treatment.
to moderately
intensely
diffusely
and
increased.
mildly
cultures
either
ters
granules
chloroacetate
from
in RA-treated
in some
cultures
that
cells
(3P),
these
fully mature
for 7 to 8
granulocytes
showed
control
secondary
bands
and
were continued
of mature
apparent,
weak
and
cultures
analysis
varied
showed
the
primary
number
Cytochemical
activity
both
nuclei
parameters
time,
AL
measured simultaneously
in 21 patients
at the beginning
RA
therapy
and throughout
the course
of treatment.
containing
or horseshoe-shaped
indented
Coagulation
prothrombin
primary
to myelocytes
cytoplasm
with
fewer
granules.
The nuclear
chromatin
was
and the nucleoli
were either vague or no
An elevated
population
of metamyelocytes
evident,
RA
could
and
or secondary,
more
longer
was
in
nucleus
these
specific,
had
ET
MENG-ER
570
and
and
reported
complicated
peripheral
granulocyte
count
Nilsson7
reported
a 30-year-old
for 10 months.
She was treated
began
bone
to respond
marrow
after
for
a 33-year-old
by fibrinolysis
patient
and
1 month,
I 1 months.
after
2
woman
by 1 3-cis
and
Daenen
with
Aspergillus
had
and
refractory
pneumo-
From www.bloodjournal.org by guest on June 16, 2017. For personal use only.
TREATMENT
OF
He was
niae.
attained
tion
58-year-old
failed
to
resulted
patient’s
in the presence
Sampi
dactinomycin,
man
RA
(l0_6
who
not only
effective
chemotherapy,
the
to i0
but
was
(a
also
ment
who
effective
APL
retinoid)
were
been
in those
cation
vated
“de
had
appearance
ing DIC
aggravation
of coagulation
during
Leukemic
with
nal cell
coagulant
the
cells
RA,
division,
factors
parameter
the course
striking
advantage
ing leukemic
cells
from
of hemorrhagic
of RA
but
to
novo”
improve-
often
None
abnormalities
aggraof our
or
suggest-
This
would
may
not
but instead
granules
into
be destroyed
may
the
during
differentiate,
and
lose the capacity
during
this process.
treatment
undergo
to
That
facof
termi-
release
these
there
was no
of APL,
four
different
it is too early
From
the cytogenetic
clones
by Daenen
regimens
obtained
studies
(unpublished
after
which
both
from
the
patible
with
other
The
toxicity
of all-trans
well
Based
literature.
reports
on
of 1 3-cis
the
toxicity
but in our experience
by the patients,
some
RA
for
on
>
these
10 months
with
are
com-
all-trans
than
effects
have
untoward
we conclude
RA is an effective
agent
for obtaining
CR
of maintaining
and prolonging
the duration
further
lower
the side
of whom
of
inten-
is derived
data
of oral
no severe
observations,
that
RA
Our
is relatively
RA
our clinical
we suggest
RA,25
tolerated
taking
dermatologic
was
is the
the persistence
sive chemotherapy
after CR may be beneficial.
Knowledge
about
the side effects
of oral
mainly
CR
of these
from
showing
data),
is
and
relapsed
in 6 and
the patients
were
to conclude
the data
during
of remission
reported
and co-workers,9
In our series,
and
abnormal
requires
circulation.
with
cellularity
possibility.
in the maintenance
cases
effective.
be a
over aggressive
chemotherapy-destroyand causing
release
of procoagulant
azurophilic
most
survey
RA.25
manifestation
treatment.
and Fontana
respectively.
treated
authors,
the main problem
of APL
is
treatment,3’4’24
especially
because
of
hemorrhage.
DIC
is the most common
complifrequency
are
use of heparin.
colleagues8
1 2 months,
of marrow
this
RA
Two
induced,
refractory
with
role of all-trans
further
was
an increase
supports
undetermined.
and
to
RA
rather
therapy
and
to find predictive
value in the
The single
patient
who was
of APL.
Its severity
and
by chemotherapy,
despite
patients
The
a
sensitive
All-trans
had
1 3-cis
to most
induction
intracerebral
APL
of
to RA induction
failed
to show marrow
when treated
with RA as the sole agent.
According
death
during
tors
relapsed
but
induction
In vitro
reported
form
cells
decrease
differentia-
had
in vitro.
patients
Moreover,
we were able
in vitro differentiation
studies.
showed
and
asso-
with
13 days.
colleagues23
leukemic
APL.
resistant
also
mol/L)
in our
and
treated
blasts
etretinate
although
all-trans
alone
Fontana
after
and
571
ACID
mg/day)
APL
leukemic
to
(80
in CR
of RA.
Japanese
respond
RA
Recently,
of refractory
that
of this
studies
RETINOIC
1 3-cis
7 weeks.
a case
mg/m2)
ALL-TRANS
with
after
reported
(100
WITH
treated
a CR
ciates9
RA
APL
that
were
been
effects.
that
all-trans
in APL.
A method
of CR, however,
study.
ACKNOWLEDGMENT
We are grateful
to Professor
Samuel
Waxman
of Mount Sinai
School
for his kind comments
and suggestions
in editing the manuscript and to other physicians
and hematologists
at Shanghai
Rui-iin
Hospital,
Shanghai
Zhong-Shan
Hospital,
Shanghai
Chang-Zhen
Hospital,
and Shanghai
Institute
of Pediatrics
for providing
samples
and care to our patients.
We are also grateful
to Zhao iin-Chai
for
expert technical
assistance.
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1988 72: 567-572
Use of all-trans retinoic acid in the treatment of acute promyelocytic
leukemia
ME Huang, YC Ye, SR Chen, JR Chai, JX Lu, L Zhoa, LJ Gu and ZY Wang
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