From www.bloodjournal.org by guest on July 12, 2017. For personal use only.
Comparison
Strategies
By Harvey
Preisler,
Roger
B. Davis,
Kopel,
Robert
N. Levy,
Samuel
Patients
with
domized
to
of
seven
acute
nonlymphocytic
receive
days
remission
of
daunorubicin
by
+ 3”)
either
extension
of the
ten
Additionally.
days.
receive
or
not
to
the
increase
in intensity
treated
T
TREATMENT
patients
with
remission
the
standard
phase
designed
to prolong
of cytosine
(DNR)
(“7
Cancer
and
3”)
(CR)
rate.
of moderate
the
designed
of the
during
there
patients
for
described
an
in the
increase
here,
nor
of
of
the
the
intensity
paper
demonstrate
of 7 +
administration
presented
kemic
reinforce
may
occur
3 therapy,
was
as
neither
described
results
hypothesis
of at least
in an
that
two
leu-
patient
to
(FAB)
with
the
acute
in November
1979
and
was
party
infections
Informed
was
were
consent
eligible
eligible
was
leukemia
by
required
the
for
only
Blood,
study.9
upon
prior
study.
(ANLL)
French-AmericanPatients
control
to entry
of such
into
the
the
two
con-
rate
for
of long-
patient
groups.
advantage
all
who
therapy
any
differences
at
renal
8
patients
or
Statistical
a number
above
these
toxicity.
Patients
o1
limits.
included
in the
whether
Any
creatinine
cytotoxic
of 30
levels,
to determine
in response
or whose
levels
were
performed
analysis.
function.
permissible
slightly
these
associated
Under
patient
level was >2.0
with
therapy
a
history
were
of
not eligible
Methods).’#{176}”
Study
induction
induction
levels
being
from
and
(See
Remission
for the
had
mg/dL
excluded
disease
inadequate
for creatinine
ineligible,
was >40
was
had
maximum
I .5 mg/dL
analyses
Treatments
Figure
therapy.
phase
of the study.
1A provides
Patients
were
the schema
initially
random-
ized to induction
therapy with the standard
7 + 3 regimen
(cytosine
arabinoside,
100 mg/m2/d
by continuous
infusion
for seven days,
and DNR, 45 mg/m2 on days I, 2, and 3) or with induction
therapy
the
Roswell
ofPublic
Science
Clinic,
Park
Health
NY;
Long
of
MN;
Island
NY;
Cotton
May
Supported
in part
additional
by
by
the
grant
reprint
T.J.
support
Elm St. Buffalo,
The publication
NY 14263.
costs ofthis
indicate
©
in
Center,
Cancer
Park,
NY;
University
Syracuse,
NY,’
NH.
December
13,
1986.
CA-33601,
Institute,
and
and
CA-
National
Human
Foundation.
to Harvey
Oncology,
“advertisement”
Shore
Mayo
Brooklyn,
Insti-
Services
(See
and
Appendix
by
for
information.)
requests
This
Hyde
CA-02599,
ofHealth
of Hematologic
payment.
NC;
Center,
New
Medical
accepted
Martell
Buffalo,-
North
Hanover,
Grants
Department
the
Center,
Boston;
National
Boston;
Foundation,
Medical
Center,
19, 1986;
Harvard
Institute,
Winston-Salem,
Upstate
Cancer
Submitted
awarded
Medicine,
Hospital,
Manhasset,
Norris
Research
Medical
General
Buffalo;
Cancer
Maimonides
Jewish
Massachusetts
Institute,
Dana-Farber
Technology
School
Rochester,
Memorial
and
and
Bowman-Gray
charge
with
relapse
proportion
of a survival
if they
careful
BUN
Address
established
to
Although
Inc.
specified
entered
tutes ofHealth.
a grant
from
nonlymphocytic
criteria
working
life-threatening
infections.
showed
04326
Eligibility
British
they
and
Design
CALGB
study
7921
was activated
closed to accrual in November
1982.
Any
with
Hospital.
distinct
METHODS
AND
ineligible
technically
study,
Frontier
processes.7’8
according
were
School
maintenance
chemoIn addition,
data
an earlier
as a result
MATERIALS
Study
that
of cotrimoxazole
that
relapse
biologic
were
Although
therphase
or
discontinue
& Stratton.
for randomization
was
in
to
the
the
this
all treatment
of 3 years.
in
therapy.
is a suggestion
by Grune
patients
neoplastic
study
the postinduction
1987
by the
antibacterial
in the complete
of the
To
months.
197412
maintenance
improvement
in the CR rate and that
therapy
beyond
8 months
is unnecessary.
are
randomized
patients
a total
identical
for
whose
mg/dL
used
since
was
issue
chemotherapy
for
increase
there
the
chemotherapy.
to discontinue
discontinued
remitters
addressed
maintenance
a transient
Patients
part
study
therapy
Additionally.
From
in this
Ill, H. Clark Hoagland,
0. Ross McIntyre,
randomized
of
who
Postinduction
Leukemia:
maintenance
Although
the protocol
mg/dL
for BUN and
a postinduc-
regimen
was
term
of this
were
to
of daunorubicin
phase
patients
part
to
necessary.6
Accordingly,
all patients
received
maintenance
chemotherapy
for 8 months,
at which
time half were randomized
to discontinue
all therapy
and the other
half to
continue
monthly
courses
of maintenance
therapy
for a total
of 3 years.
The data
Two
Richards
long-term
maintenance
to determine
standard
seven
of cotrimoxazole
in an increase
end.
a
first
second
of
8 months
phase
The
days
The
utility
leukemia
and
prolonged
Frederick
tinue
an
53%
induction
remission.
second
Dupre,
after
regimen.
B (CALGB)
whether
intensity
antibacterial
+ 3”
induction
The
to determine
the
above
to normal
Group
administration
would
result
remission
designed
remission
Neither
nor
three
Eloise
by
pro-
phase.
nonlymphocytic
and
Leukemia
and/or
the
prophylaxis3’5
apy
arabinoside
+
arabinoside
rate
the study
to be reported
here was
whether
an increase
in the intensity
days
or
randomized
remission
the
of
regimen
antibacterial
“7
of acute
(ANLL)
consists
of
a
designed
to return
hematopoiesis
tion
same
were
cotrimoxazole
the
days
6-thioguanine
induction
Regimens
and
Nonlymphocytic
Group
B Study
ran-
consisting
three
the
of
of chemotherapy
increased
patients
and
receive
remission
Kirshner,
were
of cytosine
all
receive
during
HE
to
addition
administration
phylaxis
prophylaxis
or
the
Jeffrey
therapy
arabinoside
Induction
of Acute
Leukemia
Robert Carey, Phillip Schulman,
Arlan J. Gottlieb,
and the Cancer and Leukemia
Group B
leukemia
induction
cytosine
(7
intensified
of Three
Remission
for the Treatment
A Cancer
and
Roswell
article
accordance
D. Preisler,
Park
article
must
with
MD,
Memorial
were defrayed
therefore
18
U.S.C.
be
Department
Institute,
666
in part by page
hereby
§1734
marked
solely
to
this fact.
1 987 by Grune
& Stratton,
Inc.
0006-4971/87/6905-0027$3.00/0
Vol 69. No
5 (May),
1987:
pp
144 1-1449
1441
From www.bloodjournal.org by guest on July 12, 2017. For personal use only.
1442
PREISLER
LIV
fguIII
R
R
A
A
N
N
0
0
0
0
N
N
LiY
ET
AL
I
DAyS
I
DAYS I-?
1III
z
C
1IIV
1
DAYS 1-10
III
Days
I
DNR 45 MG /M2
I
I
lv
3 4
5
6
7
8
9 10
A- Co-Tr,moxozo$s (80 MG Tr,methoprwni’400
Sulfamethozozole)
P0. B 0
IV hfusion
Conhnuotm
PQql2h,
%V16-TGIO0NG/M2
2
1,2,3
I V. Days
ARA-C 100 MG /M/0
I
MG
B- No Co-Tr,moxozols
Bone Morrow Biopsy and DapErole 7 Days After
...
End of First
Days 1-7
Counie
I
Second Course
S
R
A
K
rJ
Dacontmue
Therapy
AND
OBSERVE
T
CYCLE I
D
CYCLE 2
E
0
S
T
V
II
=
N
=
=
I1
WEEKS
0
MONTHS
I
C
2
4
6
OOMG/M2SC
6-’rG,00MG/N2
I
‘
‘,
whose
was
of the 7
the
therapeutic
were
the addition
26
based
V
‘Each
Each
by extending
the administration
the
initiation
standard
These
reports
two
in the
regimen
modifications
literature
might
administration
administration
of chemotherapy
or until
the patient
that
be improved
to ten days12
or by
of course
2. Half
of the
patients
randomized
to receive cotrimoxazole,
two
(80 mg trimethoprim
and 400 mg sulfametwice a day starting
on the day before
and
was
continuing
removed
from
until
remission
the study
occurred
as a treatment
The study
years
old.
Cycle
Course
was
amended
regimens
This
was
modification
in November
reduced
was
IN2
I
V (MAX
2 MG)
PO(MAX
1980
to 30 mg/m2/d
introduced
100MG)
Fig
1.
Treatment
(A) Remission
induction
(B) Maintenance
phase.
so that
the
for patients
as a consequence
Courses ci Chemotherapy,
Given at 2e Day Intervals
Consisls
is
of
DNR
dose
over
4
CALGB
would
protocol
increase
the CR
in ANLL
rate
and
that
suggested
reduce
that
the death
schema.
phase.
this
rate
change
for older
patients.2
Patients who entered CR or partial
course of induction
therapy advanced
remission
following
to the maintenance
remaining
to be
patients
were
considered
treatment
the second
phase. The
failures
and
were removed from the study.
Dose reductions
of 50% and/or dose interruptions
were permitted
for severe gastrointestinal
toxicity,
hepatic
dysfunction,
or renal
dysfunction.
A lumbar puncture
was performed
on the day prior to
the initiation
ofchemotherapy
and every 6 months for 5 years. If any
leukemic cells were seen on a cytocentrifuge
preparation,
the patient
received 50 mg of cytosine arabinoside
intrathecally
every four days
until
leukemic
cells
were
no longer
detectable
in the
CSF,
and
this
was followed by the same dose of cytosine arabinoside
every 4 weeks
for 8 months.
Maintenance
therapy.
As indicated
in Fig I B, maintenance
therapy consisted of a series of monthly five-day courses of combination
failure.
in all three
VCR 2 MG
previous
of 6-TG.’3”5
to preclude
Relapse
2.
A second
course
of therapy
was administered,
as indicated
in Fig
IA, if the patient’s
leukemia
failed to enter remission.
The only
exceptions
were patients
who achieved
a partial
remission
and in
whom the severity of toxicity during the first course of therapy
was
felt
Cycles
Until
(“
upon
arabinoside
on each program
were
regular-strength
tablets
thoxazole),
by mouth
Treatment
z
28
8
2H.tO)
arabinoside.
of our
cytosine
24
I 0 + 3”) or by the addition
of
at 100 mg/m2 every 12 hours for seven
cytosine
efficacy
by extending
I
22
Continue
PRED4OMG/M/DAV,5
either
TAD)
with
3 regimen
+
20
6
(0
to ten days
(6-TG;
concurrent
=
P0
increased
arabinoside
6-thioguanine
days
me
16
1DNR45MG/N2.
iv DAYS I S 2
FOR DNR DOSING BEYOND CYCLE
(MAXIMUM
500 MG /M2)
intensity
of cytosine
14
4
ARA-C
(R
42
10
V
II
Ii
8
H
V
V
/
N
chemotherapy.
Sequential
60
sine
arabinoside
of the
tine
(courses
Each
courses
cycle
consisted
together
2 and
was
composed
of five days
with
4), or DNR
6-TG
(course
(course
of four
such
courses.
of administration
of cyto-
1 ), prednisone/vincris-
3) administered
on a rotating
From www.bloodjournal.org by guest on July 12, 2017. For personal use only.
1443
OF ANLL
TREATMENT
When
a cumulative
dose
of 500 mg/m2
of DNR was
reached,
the third course of each cycle was modified by replacement
of DNR with 6-TG, 100 mg/m2 orally every 12 hours for ten times.
Following
two cycles of maintenance
therapy
(8 months),
marrow
schedule.
aspiration
and
biopsy
were
performed.
Patients
who
were
still
in CR
at this time were randomized
either to stop maintenance
chemotherapy immediately
or to continue
maintenance
for an additional
seven
cycles
(for
until
the time
a total
duration
of relapse
completed.
Bone marrow
aspiration
for
regardless
all
patients
of maintenance
if that
occurred
therapy
before
was repeated
of their
of 3 years)
the seven
cycles
every 4 months
maintenance
or
were
until relapse
treatment
assign.
ment.
estimator)
using
of Kaplan
the
usually
as a result
prior
sidered
A CR was defined by the criteria previously
reported
by Rai et al.’
In brief, a bone marrow aspirate
had to contain <5% abnormal
cells,
with
a normal
and
cellularity
erythropoiesis.
count within
blood
symptoms
and
normal
granulopoiesis,
attributable
as a return
of leukemic
cells to the marrow
in
Patients
who
completion
Patients
initiation
of protocol
clearly
who
were
ineligible
were
registered
therapy
and
but
patients
excluded
from
withdrawn
with
prior
no
this
and
follow-up
agent
of cotrimoxazole,
were
stratified
and
by the
the
evaluations
induction
of this
regimen
(ie,
after
stratified
two
by the
cycles
of maintenance).
induction
These
chemotherapy
maintenance
randomization
was
All P values reported
are
duration
curves as well as any
were calculated
by using the
Table
1 . Study
regimen
of Patients
in the
were
since
tration
for
of response
for response,”
of marrow
status
study.
in their
of entry
duration
Patients
initial
into
who
remission
that
program
but continued
entered
were
con-
for
calcu-
to be followed
for
treatments
under
CALGB
study
toxicity
was
criteria.2
assessed
Specific
by
using
comparisons
of cotrimoxazole.
TAD
Induction
The Outcome
Therapy
ofRemission
the
percent
4% achieved
7+3
TAD
Therapy
py,
14%
survived
inevaluable
The CR
56.9%,
Fewer
patients
but
.011),
not
enter
Total
the
remission,
time
to
for
three
regimens
weeks;
regimens
was
life-threatening
patients
median
different
7 + 3, 4.4
the
TAD,
4.1
identical,
thera-
and
1% were
or
no antimicrobial
2.
was
of
7%
to
I 1% of
renal,
were
were
during
he-
randomized
randomized
remission
to
to
induc-
56% whether
or not
In addition,
cotrimoxazole
n Induction
Therapy
TAD
211
“10+3”
216
111(53)
remissiont
toxicity
experienc-
and
patients
patients
Outco mes of Remissio
CR
The
not
3, 4.8
+
life-threatening
prophylaxis
tion therapy.
The CR rate
patient
received
cotrimoxazole.
was
(10
all patients
toxicity,
severe
patic, and/or
cardiac
toxicity.
Three
hundred
twenty-three
receive
cotrimoxazole,
and 345
receive
remission
weeks).
with
hematopoietic
experiencing
Partial
749
CR,
during
(
Numberofpatients
10+3
entered
expired
remission
1 5% of complete
responders)
treated
with 7 + 3 (29%)
or TAD
(28%)
but
significantly
ing
did
patients
24%
and 57.3%,
respectively
(Table
2) (P = .6).
treated
with 10 + 3 required
two courses
of
therapy
to enter
than did patients
=
eligible
because
of a lack of definitive
marrow
studies.
rates for 7 + 3, TAD,
and 10 + 3 regimens
were
52.6%,
(P
668
remission,
“7+3”
Cotrimoxazole
10+3
Induction
of the
a partial
Table
entered
241
123(57)
13 (6)
138(57)
6 (3)
10 (4)
Noresponsealivet
38(18)
31(14)
26(11)
Expired
45
55
63
-
106
110
Ineligible
1
119
116
2
111
2
5
135
2
697
5
17
Not evaluable
Cancelled
1
1
3
1
0
1
7
‘Number
No follow-up
2
0
0
1
0
2
5
tPatients
administered.
Casesanalyzed
made
test
of infection rates between the cotrimoxazole-treated
and the control
groups
were used to determine
the efficacy of prophylactic
adminis-
Study
cancer
Patientsrandomized
date
Without
Cotrimoxazole
Prior
the
reported
the three
stratified
in that way.
two sided. Survival
and response
rates computed
from these curves
life table method
(product
limit
Status
7+3
comparisons
assigned
With
Patients
at the
of
previously
weeks;
antimi-
assigned.
For the maintenance
phase of the study, the primary
end points
were time to relapse and survival.
Both end points were measured
from the date of CR and from the time of maintenance
randomization
this
while
of the remission
Fifty-six
evaluable.
assignment
crobial
censored
lation
data
The primary
end points of interest
for the induction
questions
were response
rates and duration
of survival.
Analysis
of these end
points
were stratified
by age (60 and under
v over 60). Comparisons
of the three induction
regimens
were also stratified
by the randomized
were
chi-square
to the
after registration
were also excluded.
Patients with prior cancer were
not eligible for randomization
but were nonrandomly
assigned
to
treatment
with 7 + 3 without
cotrimoxizole
and have been excluded
from this report. Seven hundred
forty-nine
patients were registered
in the study. Their study status is shown in Table 1 . Six hundred
sixty-eight
(95.8%)
of the 697 patients with primary
leukemia
were
eligible
The
documentation
of
programs
Remission
were
analysis.
comparisons
test)7
RESULTS
Methods
Statistical
of inadequate
to
Toxicity
to leukemia.
Relapse was defined
excess of 25%.
rank)
survival.
thrombopoiesis,
Additional
requirements
included
a peripheral
normal
limits and clearing
of all signs and
Survival
(log
posttreatment.
For purposes
of estimating
and comparing
response
rates,
a conservative
approach
was used with respect
to these
patients. They were assumed to have been treatment
failures, ie, they
were included
in the denominators
of the rates, but not in the
numerators.
A number of patients
entered
bone marrow transplantation
protransplantation
of Response
Meier.’6
contingency
tables was used for overall comparisons
rates across strata.’5
A number of patients
were deemed “not evaluable
grams
Evaluation
and
Mantel-Haenszel
102
107
114
109
109
127
(21)
4 (2)
of patients
whose
during
remission
(26)
4 (2)
(%).
leukemia
proved
to be resistant
668
$Death
(26)
1 (0.5)
induction
therapy.
to the
chemotherapy
the
From www.bloodjournal.org by guest on July 12, 2017. For personal use only.
1444
PREISLER
had no effect on patient
survival
with each of the chemotherapy
or on the toxicity
treatment
arms.
Table
associated
4.
Factors
of Prognostic
Factorsfor
Induction
3 lists
for
the
possible
induction
patient
of Remission
Only
related
borderline
Age
important
to treatment
old
factor,
entering
that
to the
4).
with
only
remission
as
evalu-
20 characteristics
and
Age
was
by
41%
of 104
one
far
was
the
patients
compared
of
single
with
a creatinine
compared
was
<1.6
level
with
(P
associated
.006).
=
with
patients
whose
An
a CR
SGOT
at diagnosis
of
of only
as compared
38%
below
this
WBCcount
.041
NS
.013
Infection
.057
NS
.008
of
level
was
(P
.032
NS
NS
Creatinine
.006
NS
.016
SGOT
.018
NS
.0001
.001
.008
was
with a CR rate
54%
for patients
(P
involvement
Forty-three
infection.
These
than
the
documented
57%
rates
with
for patients
presence
good
patients
ofskin
sign,
presented
tended
P
.07).
=
The
diagnosis.
tion during
were
and/or
(60%
presence
afebrile
or febrile,
no
infected
information
on
from
(P
=
or
a
regarding
3.
Patient
the
the
outcome.
whereas
types
of infection
5
I 39
Characteristics
for Potential
Prognostic
at Diagnosis
receive
cotrimoxazole.
cause
of first
causes
of second
in the
(29%).
cotrimoxazole
the Outcome
initiated,
years
provides
by
patients
dosage
the
of age
of
protocol
would
was
receive
died
during
received
the
lower
not significantly
patients
treated
therapy
(3 1%
v
dosage.
different
at the
45%
(39%
lower
respectively,
Table
5.
Types
With
of Induction
Cotrimoxazole
(n
Severe
Infection
First
Infections
Without
323)
-
(n
Life-Threatening
Infectiont
Cotnimoxazole
345)
Life-Threatening
Infection
Severe
Infection
induction
infections
Bacterial
14
20
14
Fungal
6
11
5
Viral
3
0
1
1
Multiple
2
3
1
5
37
FUO
not reported
5
40
9
49
6
54
25
66
13
28
Evaluated
Second
Significance
induction
infection
Age
Infection
Bacterial
3
20
4
Sex
CNS involvement
Fungal
9
14
6
7
Race
Skin
Viral
0
0
1
0
Multiple
0
3
0
3
4
19
0
5
7
23
1
12
gingival
Hepatomegaly
WBC
count
Number
Splenomegaly
of circulating
Hematocrit
cells
Lymphadenopathy
BUN
Hemoglobin
Platelet
Ieukemic
level
count
Bleeding
Temperature
Creatinine
SGOT
Bilirubin
30
.028).
at
infecafebrile
experienced
not
was
>60
the CR rates were
respectively),
fewer
being
assowith a CR
(P = .057).
Table
study
patients
Although
V 43%
Type
Table
after
so that
dosage,
P=
severe
73% to 59% by the adminis.01 3), but as noted earlier,
this
treatment
did
the predominant
were frequent
mg/m2/d
of DNR
rather
than 45 mg/m2/d.
One hundred
eleven
patients
in this age group
received
the higher
DNR
v 52.6%
The incidence
of severe
or life-threatening
induction
therapy
for patients
who were
effect
year
modified
rate
or not infected
analysis.
Miscellaneous
Observations
Regarding
Remission
Induction
Therapy
had
of
or
were
infections
of cotrimoxazole
had no effect
on the
or on the survival
of patients
whether
at diagnosis
was reduced
tration
ofcotrimoxazole
had
CR
received
infections
Fungal
One
fever
a higher
univariate
infections
and were
more
common
group
(50%)
than in the control
group
being
without
to have
infection
was also of prognostic
significance,
ciated
with a CR rate of only 40% as compared
rate of 57% for patients
without
severe
infection
or not they
rate
a count
or gingival
prognostic
of patients
who were
febrile
infection
at the time of diagnosis
The administration
outcome
of treatment
a CR
with
of 68% as compared
with a CR
without
such
extramedullary
=
.032).
percent
of patients
respectively,
was
59% for
A WBC count
using
NS. not significant.
who
Bacterial
infections.
with
mU/mL.
are P values
Abbreviation:
patients
level
mU/mL
associated
58%
The
of 40
NS
Results
of
remission
creatinine
compared
<40
with
.041).
=
level
47%
or gingival
Hemoglobin
65%
entered
whose
SGOT
rate
was an unexpectedly
associated
rate
of
CR
patients
100,0O0fiL
>
value
involvement
for
5urvival
>60
with
of I .6 to 2.0 mg/dL
56%
Duration
<.0001
patients
s60 years old (P < .00001).
The next most important factor
was serum
creatinine
levels. Only 36% of patients
as
Remission
.023
involvement
were
Outcome
<.00001
Skin
of remission
outcome,
(Table
were
outcome
five of these
significance
years
characteristics
relationship
therapy.
significantly
most
Outcome
Therapy
Table
ated
the
Significance
Remission
Induction
Prognostic
ET AL
involvement
FUO
Type
not reported
Abbreviation:
LocaI
or
FUO,
fever
visceral
of undetermined
infection
with
origin.
systemic
signs
and/or
a fever
38#{176}C.
tFulminant
system
failure.
Type
local
of infection
or
visceral
documented
infection
by culture
with
sepsis,
or by biopsy.
shock,
or
other
of
From www.bloodjournal.org by guest on July 12, 2017. For personal use only.
TREATMENT
OF
ANLL
1445
Duration
Remission
Figure
2A
patients
after
provides
who
the
entered
remission
CR.
The
duration
median
curve
was
52.4
for
weeks;
22%
of patients
were projected
to be in remission
at 3 years.
was no statistically
significant
difference
in remission
tion between
patients
treated
on the three
induction
The
overall
courses
remission
necessary
single
course
who
v
entered
partial
weeks,
weeks.
with
One
1 5 1 were
median
zation
courses
no patient
relapsed
remaining
forty-eight
patients
of second
therapy.
randomized,
and
significant
patients
who
status
relapsed
of 20.7
beyond
3 years
remission
continue
or died
before
were
not.
There
were
no
differences
in remission
duration
were or were
not randomized.
The
later
duration
or to stop
100
randomization
to stop or to
Of the remaining
patients,
73
(Fig
2b).
curve
therapy.
This
for
The
figure
patients
randomistill to be
also
diverged
to
relapse
therapy
was
weeks
in patients
effect
and
after
randomization.
randomization
discontinued
who
or to continue
patients
(P
had
maintenance
The
no statistically
for patients
whom
with
.62).
=
median
in
compared
therapy
therapy
persistently
The
45 weeks
continued
to relapse
became
for
was
induction
on the time
Toxicity
to
3 months
Associated
Toxicity
cycle
data
71
type
significant
randomized
to stop
chemotherapy.
With
were
therapy
second
severe
cycle.
Seventy-five
or worse
hematologic
cycle
1 with
threatening
ulocyte
a
levels
count
Maintenance
available
of maintenance
Chemotherapy
for 329
patients
and
220
for
for the
patients
percent
of patients
toxicity
at some
reduction
of
(WBC
count
to
<500/giL,
to <25,O00/,.L)
occurring
percent
of patients
who
the
blood
counts
reduced
to
and/or
<
in 51%
of
received
cycle
Death
in remission
was
clearly
remission
for patients
years
and
old,
occurred
only
related,
with
age
<40
years
14% for patients
to
1 ,000/tL,
platelet
lifegrancount
3%
life-threatendescribed.
cycles
I and
death
rate
old, 9% for patients
>60
the
patients.
Sixty-six
2 of therapy
had
during
a
first
on
experienced
time during
severe
hematologic
toxicity,
with 3 1% having
ing reductions
in blood counts
to the levels just
and
provides
randomized
curves
after
who
duration
of remission
for all patients
after
was 67 weeks, with 38% of patients
projected
in remission
a
of
Patients
at a median
in this
time
converged
those
durations
.02).
=
of
but
75 weeks
of remission
required
than
remission
P
There
duraarms.
number
who
remissions
(median
status
to the
Patients
longer
respectively,
the point
maintenance
statistically
between
had
remission
hundred
reaching
continue
the
two
related
a CR.
therapy
weeks
45.4
was
to induce
of
required
55.9
duration
all
randomization
superimposable
years
old
(P
2
in
41 to 60
=
.03).
AIM
B’#{176}
.9
.8
>-
-J
.7
.6
.5
.4
0
52
104
56
208
0
.3
0.
.2
260
52
)
04
WEEKS
CNSR
106
-RESPONDERS
56
20C
260
WEEKS
RLAPS
266
TOTAL
372
MEDIAN
52.4
CENSORED RELAPSED
-ALLPTS
Dl.0
cl.
57
94
04
156
TOTAL
151
MEDIAN
670
.9
.8
ll-
>-
I-#{149}
_J
.6
.5
.4
, ,,,
l,
.4
0
.3
a.
52
04
56
208
.3
.2
0
260
52
WEEKS
AGE
MAINTENANCE
------
Fig 2.
subsequent
cessation
STOP
CONTINUE
CENSORED
29
28
208
260
WEEKS
RELAPSED
48
46
TOTAL
77
74
MEDIAN
45.4
70.9
-14-40
41-60
----61+
CENSORED
29
47
30
RELAPSED
90
102
74
TOTAL
119
MEDIAN
42.7
149
68.3
04
49.9
Remission
duration.
(A) Remission
duration
curve
for all patients
whose
leukemia
entered
CR. (B) Remission
duration
to randomization
to stop or continue
maintenance
therapy-all
patients-and
(C) relationship
of remission
duration
to the
or continuation
of chemotherapy
beyond 8 months.
(D) Relationship
between
age and remission
duration.
From www.bloodjournal.org by guest on July 12, 2017. For personal use only.
1446
PREISLER
Clinical
Prognostic
Of the various
initial
nostic
Factorsfor
factors
hemoglobin
factors
for
Remission
evaluated,
and
younger
remissions
P
hemoglobin
with
of 49.9
values
hemoglobin
(P=
between
durations
age at diagnosis
and
and
had
significantly
42.7
months
represents
shorter
are
nance
Table
Survival
able
presents
patients.
The
the
median
survival
curve
for
duration
of survival
the
668
were
From
the
of factors
to
the
The
survival
a characteristic
curve
slope.
steepest
slope,
therapy.
The
to
during
and
the
age
represents
relapse
is 41 .2 weeks;
remission
first
death
second
component
during
the
were
of
this
effect.
first
two
were
of
prognostically
provided
important
it can
because
remission
Note
cycles
first
2
induction
therapy.
mainte-
induction
that
as
important
be seen
that
of their
relation-
therapy.
the
Once
the
period
the
Figure
severity
of
tion increases,
the fall in the first part of the survival
becomes
greater,
thus indicating
increasing
mortality
evalu-
has
The
related.
that
data
outcome
3B illustrates
3 years.
AL
and the third component
represents
late
As noted earlier,
the only deaths
seen in
4 lists the factors
majority
ship
3A
at
with
subsequent
occurred
therapy
for survival.
.002).
Figure
alive
each
death
remission
respectively,
had a median
of 5 1 weeks,
and those
of I 2 to 1 8 had a median
of 36 weeks
values
patients
components,
years of remission,
relapses
and death.
a hemoglobin
value of 8 to 1 2 g/dL
duration
of 57.6 weeks;
those with
<8
of
component,
which
has the
during
remission
induction
41 and 60 years of age
(median,
68.3 weeks).
individuals
(medians
.026).
Patients
with
a median
remission
=
had
only
1 8%
three
level were statistically
significantly
progremission
duration
(Table
4). Figure
2C
demonstrates
that patients
had the longest
remission
Older
Duration
ET
infec-
curve
during
of induction
I .0
A
.8
>-
5-..
:
5
4
.4
0
.3
.2
0.
52
104
156
208
260
D
SURVIVAL
WEEKS
-ALL
PTS
ALIVE
II?
MAINTENANCE
DEAD
TOTAL
551
668
MEDIAN
41.2
1.0
.9
B’#{176}
.8
.9
.7
.8
I-
.7
-J
.6
FROM
RANDOMIZATION
6
-J
.5
4
.4
4
a.
0
.3
.2
a0
0
52
104
156
208
52
104
260
WEEKS
SEVERITY
ALIVE
DEAD
TOTAL
MEDIAN
82
348
430
45.4
13
80
93
33.3
18
86
04
36.5
2
33
35
NONE
-
MILD
---MODERATE
-
-
-
-
-
SEVERE
-ALL
E
260
DEAD
75
SURVIVAL
TOTAL
151
MEDIAN
150.7
BY
ASSIGNMENT
Fig
7
:i
.6
Survival.
(A)
Survival
N
.8
5-.
.7
survival:
_J
.6
\
4.
taneous
or upper
respiratory
infection
without
fever;
moderate infection.
evidence
of infection
with
temperature
>38#{176}C;
severe
infection,
local or visceral
infection
with
systemic
signs
and/or
temperature
>38#{176}C.(C)
Relationship
between
age and
survival.
(D) Survival
after
randomization-all
patients-and
(E) survival
after
randomization
by treatment
arm.
.9
>-
3.
curve for all patients
entered
this study.
(B) Relationship
tween
severity
of infection
.8
.5
4
>-
0’
.2
a..
1444.ff.
-
I.
0
“-I4lI1.4H
4
0
52
104
156
208
260
.3
.2
.1
0
‘
0
52
WEEKS
AGE
-40
AND
41-60
---61+
208
I .0
.9
a..
ALIVE
76
PTS
MAINTENANCE
8.6
C’0
I-.
156
WEEKS
ALIVE
UNDER
36
56
25
‘
‘
104
56
I
208
260
WEEKS
DEAD
38
185
228
TOTAL
174
241
253
MEDIAN
52.0
MAINTENANCE
62.5
-STOP
5.7
CONTINUE
ALIVE
DEAD
TOTAL
MEDIAN
44
33
77
UNDEF
32
42
74
95.7
mild
infection.
mild
into
beand
cu-
From www.bloodjournal.org by guest on July 12, 2017. For personal use only.
TREATMENT
death
OF ANLL
is passed,
that
all
infection
to the
the
curves
has
entering
hand,
relationship
curves
thereafter
for patients
tion
treated
regimens
both
duration.
<40
old are
therapy
the
than
three
of
3C
more
likely
older
patients,
remission.
data
When
these
presented
in Fig
are at a disadvantage
higher
death
rate
and
subsequent
have
a higher
is
likely
of age
3D
randomized
32 weeks
is 1 50.7
weeks,
years
those
who
had
to
older
relapse
induction
from
their
also
of
The
the
median
it
relapse
to 60
remission
151
The
examination
demonstrated
same
CR
although
improve
that
rate.
The
all
Evaluation
of the types
that almost
ciated
with
two
death
terized
persistent
by
the induction
regimens
dramatic
increase
in
treatment
the
with
individual
the design
patients
administration
of
of severe
induction
of treatment
was
52.4
at
suggest
therapy
infections3’5
weeks,
failure
with
3 years.
remission
have
7 months.2325
of
to be alive
at
due
a result
of
data
patients
treated
projected
to be in
presented
elsewhere
similar
remission
induction
any therapy
after
having
of remissions
in the
duration
curves
for
to stop or to continue
maintenance
approximately
3 months
after
to an increase
therapy
to converge
therapy
to be
Perhaps
administra-
for the
median
duration
The remission
a significant
whose
appears
that cotrimoxazole
only
to a modest
of patients
contrast,
those patients
randomized
therapy
began
to diverge
in whom
then began
and
of cotrimoxazole
22%
In
of the
patients
infections.21’22
rate.
of remission
that patients
who receive
and who do not receive
entered
range
patients
provides
is
3
I I.
.
earlier
tinued.
in this
the
cotrimoxazole,
infection,
or survival
patients
did not
rates.
patients
might
it is clear that
here
rate.
of regimens
who
survived
might have
less toxic
benefited
induction
in the
relapse
rate
was discontinued.
6 months
after
fall
had
in
been
the
of those
The
relapse
randomization
relapse
rate
discontinued.
of
The
those
curves
in patients
Once
the
at I ‘/2 years after randomization
and
Both relapse
curves
have a point of
in whom maintenance
lower relapse
rate
term
of
therapy
was disconphase
began,
the con-
remission
over
therapy.
months
Patients
appear
receive
3 years
advantage
after
The relatively
chemotherapy
and
above
that
likely
to demonstrate
of 6-TG
a
in
to the needs
of
1 7 months,
approach
to
beyond
of therapy,
perhaps
modest
therapeutic
has resulted
in the
to the
Although
any
“7
+
produced
3”
by 8 months
of
at 8
who
because
of a survival
efficacy
introduction
of maintenance
of intensive
Roswell
intensive
Park Memorial
consolidation
over
administered
The median
30%
A successor
of patients
study,
followed
duration
by 3 years
of
of remission
was
remaining
which
or four courses
of intensive
consolidation
maintenance
therapy,
has produced
similar
theraothers
with
effect
on the rate
of
of patients
in long-
relapse.
were
therapy.
5 years.
chemothe first 2
in whom
therapy
was discontinued
to have survived
longer
than
patients
chemotherapy
maintenance
to produce
selectivity
maintenance
relapse
during
administration
but has no
thereafter
or on the proportion
is likely
Rather,
most
combination.
years
relapse
consolidation
chemotherapy.6
In one
Institute
study,
three
courses
of
tailored
be the
that the administration
of conventional
therapy
for 3 years retards
leukemic
have benefited
from
no single alteration
in
benefit
arabinoside/DNR
for the
the CR
duration
as
produced
peutic
cytosine
accounts
to improve
The median
time
failure’9’2#{176}demonstrates
in
addition
tion
after
therapy
the overall
CR rate.
study
reported
here failed
the
administration
tinued
administration
of chemotherapy
had no effect on the
rate of relapse.
Hence,
the data
reported
here demonstrate
improve
The
from
the
The
cotrimoxazole
granulocytopenic
in fungal
DNR
6-TG.
to
reason
together
with the fact
reduced
bacterial
infections
extent
of
respect
that
to severely
and
addition
the latter
treatment
survival
P value
regimens
may
with
of severe
likely
indicative
of a change
from a high rate of relapse
to
relapse
rate. This change
in relapse
rate occurred
induction
studied
the CR
here
an increase
TAD
to be most
arabinoside
to the
with
therapy
thirds
of the treatment
failures
were assoduring
therapy
and one third were charac-
the latter
therapy,
appear
cytosine
than
observations
differences
these
inflection
a lower
therapy.
Given that the former
patients
from
a less intensive
and
therefore
regimen
and
more intensive
would
Any
between
to stop or to continue
for greater
survival
for
three
leukemia
the
agent
used.
superimposable
so thereafter.
also
the current
reducing
the incidence
either
the remission
in
rather
that
efficacy
regi-
cytosine
became
remained
3D
of remission
from
3” therapy
+
the incidence
patients
curves
DISCUSSION
study
“7
randomization
patients
differ
in therapeutic
TAD
the
the
projected
Figure
old,
40
longer
maintenance
but
DNR
previous
remission
and a
therapy
after
for
associated
here
patients
rate
patients
curve
the
patients
survive
the
of patients
therapy,
60
with
40 to 60 years
for patients
randomized
appears
to be a trend
stopped
that
that
of maintenance.
randomization.
curves
There
together
younger
ability
survival
48%
patients
induction
over
with
used
reported
reduces
and
patients
patients
or to continue
with
after
survival
therapy.
the
respect
that
of a higher
remission
Although
have
gives
confirm
remission
considered
advantage
to stop
induc-
with
whereas
than
greater
might
remission
therapy
rates
schedules
to differences
observations
induction
remission
and
dose/schedules
curve
curves
importance
it is apparent
rate
their
years
the first
2C,
survival
due
high
exist
and
survival
demonstrates
are
to relapse.
that
any
at diag-
very
doses
and
might
regimens
likely to die early in therapy
rate during
the first year of
because
both during
relapse
offsets
durations.
Figure
data
that
antimicrobial
to survive
years of age are not only more
but also have a higher
death
the
arabinoside
survival
of the
The
different
remission
Figure
are
levels
phase
on
of its
the
reported
mens,’3’5
identical.
was of prognostic
outcome
remission
first
not shown).
virtually
age
the
years
with
were
In contrast,
to
(data
case,
hemoglobin
the
have
level,
because
In this
for
indicates
subsequent
hemoglobin
important
different
identical
which
on events
The
duration.
with
virtually
diverge
parallel,
remission.
to remission
are
are
no effect
is prognostically
for patients
nosis
but
the
at diagnosis
patient
other
1447
provided
in remission
for three
therapy
and no
results.23’26
Simi-
lar results
for intensive
consolidation
therapy
reported
by other investigators,
but the follow-up
have
times
been
have
From www.bloodjournal.org by guest on July 12, 2017. For personal use only.
PREISLER
1448
been shorter.2729
At the present
time
prospective
randomized
comparison
sive consolidation
chemotherapy.3#{176}
intensive
consolidation
CALGB
is engaged
in a
of the efficacy
of intenOne problem
with
the
therapies
has
been
that
they
associated
with significant
morbidity,
with mortality
ranging
from 5% to 20%.27.29
Hence,
the net beneficial
of intensive
therapy
in remission
is less than one might
on the
tions
basis
of reduced
regarding
relapse
rates.
the prognostic
characteristics
and
the
potential
cell
cycle
pretherapy
could
be
cells,3’
significance
of
surface
was
the
age
most
being
important
Age >60 or <40
latter
observation
was associated
is curious
patients
with
failed
treated
to demonstrate
An elevated
very
with
with shorter
since
a recent
similar
an effect
serum
creatinine
duration.
slides,
no
The
therapies
level,
duration.8
the presence
of
than 100,000/zL
at the
all associated
with death
Of interest
is the unex-
that a hemoglobin
level between
8 and 12
prognostic
sign with respect
to remission
Since there
comment
relationship
rate.
remissions.
The
review
of 760
maintenance
or SGOT
with
remission
of age on remission
infection,
and a WBC count greater
time of initiation
of treatment
were
during
remission
induction
therapy.
plained
observation
g/dL
was a good
factor,
a low
between
observations
was
can
no provision
be made
FAB
type
reported
regarding
the interpretation
as allogeneic
bone marrow
and
for a central
review of
regarding
the possible
response.
here
also
have
of other studies.
transplantation
long
at least
gain
some
subsequent
of patients
who
relapses
Finally,
remission
were
remission
at 8 months
sity of a control
arm
late
support.
selected
in fact
somewhat
durations
and
by having
(Figs 2B, 3D)
in interpreting
performed
attained,
are
the
sur-
remained
demonstrate
the efficacy
in
the necesof thera-
several
months
to years
be these
interventions
transplantation3537
or “late
intensification”
after
bone
chemo-
perhaps
therapy.
This
risks of intensive
prognostic
associated
unexpectedly
vivals
that
may
AL
biologic33
cells,34
therapy.
advanced
leukemias”
marrow
therapy.38
markers,32
assessments
of these leukemic
cell characteristics
used
to identify
patients
who will have
a long
consolidation
the hypothesis
“new
peutic
interventions
remission
has been
observa-
molecular
leukemic
remission
when
treated
with
maintenance
would
allow
these
patients
to avoid
the
Age
effects
expect
of the cytogenetic
cell
of both
characteristics
rates
recent
significance
of the leukemic
and
Given
are
then
ET
implications
Therapies
such
in remission3537
may also have their primary
effects
on the first part of the
relapse
curve
and may be associated
with a similar
low but
significant
late relapse
rate. Should
this prove to be the case,
APPENDIX
Participating
institutions
of the Cancer
and Leukemic
Group B
Study:
Bowman-Gray
School of Medicine,
Winston-Salem,
NC,
Robert
Cooper
(CA-03927);
Mayo
Clinic,
Rochester,
MN,
Robert
Kyle (CA-04646);
Maimonides
Medical Center, New York, Sameer
Rafla (CA-25l
19); Long Island Jewish Medical Center,
New Hyde
Park, NY, Kanti Rai (CA-11028);
MassachusettsGeneral
Hospital,
Boston, Robert Carey (CA-l2449);
Cornell
Medical
Center,
New
York, Richard
R. Silver (CA-07968);
Upstate
Medical
Center at
Syracuse,
NY, Arlan Gottlieb
(CA-21060);
McGill Cancer Center,
Montreal,
J.L. Hutchinson
(CA-3l809);
Columbia
University,
New
York, Rose Ruth Ellison (CA-120l
I); University
of California
at
San Diego,
Mark
Green
(CA- I 1789); University
of Missouri,
Columbia,
Michael
Perry (CA-I 2046); Finsen Institute,
Copenhagen, Nis I Nissen; Rhode Island Hospital,
Providence,
Louis Leone
(CA-08025);
University
of Maryland
Cancer
Center,
Baltimore,
Joseph Aisner (CA-31983);
West Virginia
University
Medical Center, Morgantown,
Peter Raich (CA-28562);
Wilmington
Medical
Center,
DE, Irving Berkowitz
(CA-37041
); Mount Sinai School of
Medicine,
New York, James F. Holland (CA-04457);
Walter Reed
Army Medical
Center,
Washington,
DC, Raymond
Weiss (CA26806); Dartmouth-Hitchcock
Medical Center, Hanover,
NH, Gibbons Cornwell
(CA-04326);
Ochsner
Clinic, New Orleans,
Carl G.
Kardinal;
Virginia
Mason Medical
Center,
Seattle,
Albert B. Emstein Jr; Roswell
Park Memorial
Institute,
Buffalo;
Edward
S.
Henderson
(CA-02599)
Georgetown
University
Hospital,
Washington, Lucias
Sinks (CA-2l083);
and Thomas
Jefferson
Medical
Center,
Philadelphia,
Farid Haurani
(CA-05462)
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1987 69: 1441-1449
Comparison of three remission induction regimens and two postinduction
strategies for the treatment of acute nonlymphocytic leukemia: a cancer
and leukemia group B study
H Preisler, RB Davis, J Kirshner, E Dupre, F 3d Richards, HC Hoagland, S Kopel, RN Levy, R Carey and
P Schulman
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