From www.bloodjournal.org by guest on July 31, 2017. For personal use only.
Two-Cycle
Timed-Sequential
Adult
Acute
By William
Based
on
leukemia
have
a
series
cell
developed
an
daunorubicin
syl
and
cytosine
cytic
for
leukemia.
remission
(12%)
apy
of
of
kinetics
remain
after
intensive
the
with
and
However,
schedules
talization
infusion
of
of
this
without
complete
course
tolerate
remission
early
clinical
1-f3-D-arabinofuranosyl
leukemia
to give
studies,
cell kill,
and
no chemotherapy
long (four or more
remissions
were
obtained
then,
the
same
of
doses
hospifailed
disease.7
to
high-dose
and
was
numbers
for
addition,
given
disease
optimally
at relapse
in remission
timed
prolonged
or
sequential
survival
but
at
relapse.’5
In
chemotherapy
did not produce
any cures, while significant
numbers
of animals
were
cured
when
the same
therapy
was given
in early
remission.
Blood,
Vol 64,
(21 %)
in
Beginning
adults
early
with
first
remain
was
with
CR
clinical
and
timed-sequential
given at the time
despite
early
first remission
produce
significant
chemotherapy-free
was
Patients
was
nondiagnostic.
and bone
11
of
con-
risk
involved,
chemotherapy
of minimal
residual
been
of human
disease
in
AcDAc
to
in
initiated
During
the same
the
of this
AcDAc
after
US
patients
chemotherapy
early
chemotherapy
regimen,
The Johns
therapy
of
with
iohns
The
CA06973-20
accepted
May
Hopkins
received
a
cycle
of
The
of the same
details
care
filed
Human
a second
occurred.
Center,
No.
clinical
and
patients
cycle
All
of
an assurance
then
supportive
Oncology
have
done.
intervals.
part
of Health
if relapse
a second
coat,
phenotype
chemotherapy
the
period,
remission.
by grant
as
approval
its toxicities,
buffy
study
and
done
antibodies
in accord
only
Hopkins
in part
blood,
these
control
received
was
marker
was the only
at diagnosis
in first
biopsy
was not routinely
Department
historical
therapy
thoroughly
or if the aspirate
monoclonal
this
chemotherapy
treated
Supported
received
by the
marrow
during
Committee,
approved
cycle
as
of ANLL
us and
and surface
regimen9
only
of
be obtained
analysis
of the iohns
diagnosis
of peripheral
done,
patients
have
Investigations
Services.
stains
usually
these
Service
by one
Bone
determined
reported
and
Leukemia
seen
Chromosome
of
investigations
remission.
METHODS
could
chemotherapy
any
first
the presumptive
were
Special
routinely
patients
AND
aspirate
were
available.’6
to
in early
the diagnosis.
marrow
marrow
From
but
follow-up
and
with
intervals
to confirm
if no bone
recently
death.
observations
toxicity
to the Adult
Center
study
only
single
toxic
a median
laboratory
to patients
referred
Oncology
the
with
one
Treatment
patients
Human
25
chemotherapy
might
be sufficiently
effective
numbers
of patients
remaining
CR long enough
to be considered
given
and
The
this
first
the
MATERIALS
given
of
the
Of
of this
however,
cycle
cures.
Consequently,
we began
a clinical
trial
a second
cycle
of timed-sequential
chemo-
therapy
become
remis-
years.
intensive
ANLL
has
cycle
there
us that,
during
in 1 980,
second
remission.
in
vinced
Hopkins
a
a second
remission.
(44%)
in second
the number
of patients
for four years
or more
in remission
consenting
first
evaluated
after only a single cycle of chemotherapy,
but the
majority
of patients
relapsed
within one year. A second
cycle
of the same
timed-sequential
chemotherapy
given at relapse
often produced
a second
remission,
and in a few cases, these second remissions
have been
durable,
but the majority
are shorter than the patient’s
own first CR.
During
that period,
we developed
a model
for
chemotherapy
of ANLL
with ara-C using the Lewis x
Brown
Norway
rat (LBN)
myelocytic
leukemia
(ML).’#{176}This rat leukemia
is similar to human
ANLL
with respect to cytologic
characteristics,
suppression
of
normal
hematopoiesis,
pattern
of growth and dissemination, and sensitivity
to ara-C.’#{176}’3Studies
in this rat
model confirmed
the synergistic
effect of optimally
timed sequential
chemotherapy
for late stage diseas&4
and demonstrated
that the same sequence
timing was
effective
all
These
no chemotherapy
seven
chemotherapy.
three
All
of patients
and
remain
treated
almost
achieved,
in remission.8’9
In these
years) chemotherapy-free
for small
gave
potential
in which
Con-
(ara-C)
if CR
last
patients
daunorubicin
(DRN)
for adult ANLL,
we elected
to
give a single
cycle
of chemotherapy
in a timed
sequence
that was designed
to produce
maximum
initial
to
in early
in
cytosine
expected
their
J. Burke
to
from
ther-
Treatment
without
trials
increased
further
has
in this
at relapse
sion
patients
of
chemotherapy)
prolong
regimen
chemotherapy
(CRs)
of significant
being
achieved
by the
can
and Philip
four
chemotherapy
adults
E. Karp,
therapy.
of follow-up.
for
Leukemia
we
nonlympho-
achieving
cycle
continuing
in our
regimen
acute
patients
a second
(maintenance
sequently,
of
we
with acute
nonlymphocytic
leukewith intensive
initial
chemother-
that
substantially
studies
chemotherapy,
adult
years
with
Judith
1 -$-D-arabinofurano-
remission
of five
majority
of patients
mia (ANLL)
treated
apy.’3
34
REMISSIONS
are currently
duration
to
of
first
in complete
C OMPLETE
P. Vaughan,
timed-sequential
a single
patients
Nonlymphocytic
laboratory
infusion
treatment
a minimum
relapsed
and
responses
high-dose
Of the
(CR)
clinical
and
Chemotherapy
of
the
more
AcDAc
AcDAc
requirements,
Baltimore.
and CA23973
from
the NCJ/NIH/DHHS.
Submitted
Address
Nebraska
Dec 27, 1983;
reprint
Medical
requests
to Dr William
Center,
42nd
and
15, 1984.
P. Vaughan.
Dewey
Ave.
University
Omaha,
of
NE
68105.
© I 984 by Grune
& Stratton,
Inc.
0006-4971/84/6405--0005$03.00/0
No 5 (November),
1984:
pp 975-980
975
From www.bloodjournal.org by guest on July 31, 2017. For personal use only.
VAUGHAN,
976
and
the
response
lished.9
evaluation
Briefly,
days
DRN,
1, 2, and
continuous
3, and
infusion
(AcDAc
between
biopsies
contained
significant
days
leukemia.
who
been
first
evaluated
at
8 or
for response
aspirates
only
and
Any
time
criteria’7
all
if they
1975
diagnosis
apy and
who
and
of AN
gave
LL
informed
of timed-sequential
in remission.
patients
achieved
complete
by day
I 4, attained
relapse.
Between
I 5 patients
of this therapy
met
These
on day
(60%
AcDAc,0
v 56%,
Table
remission.
control
Patients
monthly
bone
marrow
was
leukemia
usually
included
Between
ANLL
ianuary
received
chemotherapy
who,
by day
of infection
four
in
in the historical
patients
with
by
less
but
these
control
during
time
groups
were
was
not
adults
with
cycle
of the
(by day 70) to all patients
discharge),
These
period
were
and other
to meet
treated
patients
to achieve
of
as patients
the
CR
duration
they
rate
for
can
on day
one cycle
for CR
none of the data
more
than
in
chemoafter
investigational
required
of
be achieved
criteria
alternate
of
were
who achieved
of less intensive
minimum
who
addi-
relatively
the marrow
to what
Consequently,
contains
These
because
from
courses
with
CR.
one
chemo-
on duration
of
one course
of
CR.
Duration
of
first
CR
discharge,
or as soon
met,
first
until
evidence
was calculated
first
from
of
CR
the product
limit
All
were
April
1, 1984.
for first
relapse
if
analyzed
on the
plus
CR
and
basis
were
second
were
was
Meier,’8
done
hospital
met
remission
function
was
of
for CR’7
a second
of Kaplan
by treatments
day
of first
probability
method
test.’9
the
criteria
Duration
all criteria
second
of CR
from
as all ALGB
duration
son of duration
data
calculated
of relapse.
the day
evidence
The
was
thereafter
CR
until
was
calculated
and compari-
using
the
of patient
log-rank
status
as of
RESULTS
Given
a Second
Cycle
in Early
Relapse
of Timed-Sequential
stringent
uniformly.
A second
chemotherapy
failing
were
Chemotherapy
the historical
all consenting
recovery.
further
up to three
or no therapy.
Patients
second
residual
of patients
hospital
Patients
manner
on day
without
analysis
of leukemia
controls
leukemia
trial
is comparable
with
of AcDAc
the
are included,
70%)
adults
in
for
clinical
in the same
clearance
patients
(33/47,
criteria
1982
historical
function
after
patients
and
CRs
not managed
CR
marrow
this
until
CR
after
these
marrow
included
to
the
CR
of
had residual
normal
were
1980
complete
from
and
If a second
achieved
in early
during
patients
occurred.
of CR.
different
ALGB
managed
after
age
five patients
and were
have
1982,
not
meet
the
subsequently
using
a
counts,
was given
were
weeks
without
seen
blood
group
of first
followed
in remission,
of remission
iuly
was given
as above,
patients
patients
obtained.
form
were
distribution
were
to
remission
the
AcDAc8
did
for induction
and had complete
followed
The
and
induction
who
the patients
1980
the
patients
poor-risk
of duration
63 (about
periods
chemotherapy,
AcDAc,0
same
time
chemotherapy
This
because
study.
if relapse
periods,
duration.
in the analysis
for this
of
to reduce
to
clearance
the
BURKE
Statistics
was
in duration
16 tumor
and
sufficient
poor-risk
in
infusion
with
day
AcDAc,
additional
therapy
therapy
achieving
AND
addi-
schedule
combined
complete
only
alternate
than
also
chemotherapy
until
an
remission
were
these
16 occasionally
after
periods
then
time
The
chemotherapy
no further
of short
control
during
of AcDAc
day
or
recovered
remission
a single
and
ara-C
better
examinations,
these
doses
was no difference
without
cycle
on
criteria3
CR
physical
During
I 6, but
therapy.
19
chemotherapy
8 in order
therapy.’5
of 34 patients
aspirates
achieved,
relapse.
1). An
cycle
marrow
following
the second
patients
series,9
bone
1978,
without
significantly
these
group
a second
not
and there
achieving
with
CR
),
I
Therefore,
historical
given
of the
was
and
from
criteria
ofday
cycle
regimen
chemotherapy
same
that
instead
toxicity
using
CR
(Table
unselected
a single
reported
December
the
except
with
of
entering
AcDAc
the
chemother-
AcDAc5
previously
response
received
group,
the
also followed
10 (AcDAc,0)
gastrointestinal
rate
same
patients
treated
and
with
no prior
no further
1977
the
patients
of leukemia
received
and were
as the earlier
begun
were
In this
and
all
had received
clearance
CR,
1977,
using
September
tional
drugs
who
consent
no chemotherapy
remission.
August
chemotherapy
cycle
cycle
I 6. When
February
confirmed
percentage
first
CR
not die of toxicity.
Between
the
tional
be residual
at this
B (ALGB)
10
to this
elements.
could
py, the
on
as a 72-hour
leukemia
Group
daily
on day
marrow
time
no residual
Leukemia
given
hernatopoietic
this
pub-
given
again
bone
normal
previously
was
was
16, when
had
by Acute
ara-C
1 and
were
14 and
all
on day
cellularity
Patients
CR
of
no residual
myeloid
achieved
did
Patients
have
of 45 mg/rn2,
2 g/m2
beginning
8 or 10).
therapy
criteria
at a dose
KARP.
were
free
patients
until
were
relapse.
similar
unselected
The median
for the
duration
34 patients
of first chemotherapy-free
who
cycle
of timed-sequential
1975
to 1979
period
patients
(1 2%) remain
achieved
CR
after
chemotherapy
was 31 weeks.
in chemotherapy-free
Four
5, 7, 8, and almost
9 years
of follow-up
quently
have not required
a second
cycle
The 30 patients
who relapsed
had durations
from
four
weeks
to
years
4’/2
(Fig
CR
only
a single
during
the
of these
CR after
and conseof AcDAc.
of first CR
1).
to the
series
of
1.0
respect
tations
(frequency
WBC
or low platelet
and
all other
of FAB
known
phenotype.
Table
1 . Results
to age (median,
of
infection,
count,
preleukemic
presence
or suspected
The
factors,
prodrome,
elevated
Three
disease,
to thera-
for Induction
Time
.8
etc),
distribution
responding
Chemotherapy
1975to1977
manifes-
including
of patients
During
presenting
ofextramedullary
risk
percentage
of AcDAc
Remission
50 years),
of
p
.8
.4
.
__J_U_a
---
.2
Periods
1977to1978
1980to
1982
50
100
150
200
WEEKS
Therapy
AcDAc8
34
Evaluable
Day
l6tumorclearance
Toxic
deaths
Complete
Age range
25(74%)
6 (18%)
remission
1 9 (56%)
AcDAc,0
4 (16%)
1 5 (60%)
47
36 (77%)
8 (17%)
28
(60%)
(median)
ofpatientsinCR
15-62(36)
16-75(40)
300
350
400
450
AcDAc,0
25
19(76%)
250
IN REP4SSS$ON
16-65(39)
Fig 1 .
Probability
of remaining
in first CR for 33 patients
(bold
lines) entering
remission
after AcDAc
during 1 980 to 1 982 (25 of
these
patients
received
a second
cycle of AcDAc
in early
first
remission)
compared
to the probability
of remaining
in first CR
(narrow
lines)
for 34 patients
entering
remission
after
AcDAc
during 1 975 to 1 979 (no chemotherapy
in remission).
P < .025. log
rank.
From www.bloodjournal.org by guest on July 31, 2017. For personal use only.
TWO-CYCLE
Table
2.
CHEMOTHERAPY
Status
IN ACUTE
of 30 Patients
AcDAc
LEUKEMIA
Relapsing
Time-Sequential
After
977
a Single
Cycle
of
Patients
Chemotherapy
Status
Given
a Second
Chemotherapy
Referred
progressive
for bone
disease
2
2 (Failed
with
AcDAc
6 (23%
Complete
Twenty-six
ble
retreated)
5 ( 19% of those
retreated)
1 5 (58%
of these
cycle
of
30 patients
AcDAc
in
for antineoplastic
2). Six
leukemia
residual
of those
of these
the same therapy
ance of leukemia
of those
early
recurrent
leukemia
were
tolerated
(Ta-
until
(23%)
had
26 evaluable
still
a second
median
more
resistant
as defined
by
on day 1 6 of
patients
sensitive
(77%)
enough
duration
of these
patients’
to
second
CRs
Thus,
remain
seven
of the
in first or second
first
CR
their
first (two patients),
since
(four
their
last
34 historical
control
or in second
CR
with a minimum
chemotherapy.
The
20
aver-
first
of this data
occurs
at 21%
at
3’/2
and
died
Eleven
statistically
count
to 200
greater
weeks
a median
than
their median
follow-up
is now
duration
of CR for the entire
received
sion
two
a second
is projected
and three
historical
of
AcDAc
to be
years.
12 1 weeks
Comparing
remaining
as initial
in
therapy
discharge,
in early
longer
than
duration
of
(Fig
2).
first
greater
.:__J__JJL
than
first
CR
that
after
significant
chemotherapy
CR
duration
given
examine
the
influence
CR
with
achieve
of timing
cycles
of
.00 1 , log
<
historical
CR
of
same
to
cycle
of
survival,
we comin first chemothera-
for the
the
control
period
second
Despite
cycle of AcDAc
only
the shorter
follow-up
if they
of the
treated
in early
remission,
CR
cycle
of the
Consequently,
during
first
after
another
two cycles
of AcDAc
probability
of remaining
chemotherapy-free
in first
of the second
of disease-free
of remaining
after
the
proba-
of remaining
with a second
in early relapse.
therapy
on duration
pared the probability
py-free
therapy
may
remis-
the
two
(P
is significantly
the probability
unmaintained
and
and will be between
these
data
to the
be calculated
first
a
141 weeks.
The median
group
of patients
who
of AcDAc
it can
and
However,
transfusion
on day 26.
remain
in CR
hospital
cycle
controls,
from
not
of 36 days
1,000/j.L
hemorrhage
25 patients
from
did
AcDAc
unless
relapse
of AcDAc
was
well-
CR after only a single cycle of this therapy.
As shown above, however,
patients
relapsing
l.a
#{149}‘
not
despite
of an intracerebral
(44%)
of these
88
second
P
otherwise
not had
by day
rank)
are still in
years
patients,
WBC
of the 25 had
from marrow
in second
CR from the beginning
of first CR until second relapse
for these 34 patients
was from four weeks to over nine
years (median,
37 weeks). A “plateau”
on the life table
analysis
first
CR
to 1982
in early
by any clinical
parameter
group
of 34 patients
who
second
cycle
of
The
second
cycle
by most
achieved
of follow-
of four years
total
were
who
in the 1980
cycle of AcDAc
similar
period
of severe
thrombocytopenia.
one patient
became
refractory
to platelet
bility
CR.
patients
CR, and six of these
patients)
was
remissions
aged about
one half the duration
of their
However,
three of these 1 5 patients
remain
CR at 16 months,
six years, and eight years
up.
again
marrow.
Five of
but I 5 (58%)
second
patients
AcDAc
a second
different
control
a
from
had
CR.
individual
receive
occurred.
and
achieve
complete
clearance
from the
these
died of toxicity
of the therapy,
and
a
that had produced
complete
clearfrom the marrow
when used initially.
20 of the
The
with
of the regimen
than at presentation,
in the bone marrow
However,
weeks,
treated
relapse
33
of
25 patients
significantly
the historical
retreated)
were
effect
patients
at relapse
myeloblasts
achieved
of Timed-Sequential
Remission
first remission
(by day 70). Three
complete
clearance
of leukemia
16. These
remission
evaluable
CR)
responding
disease
second
second
26
No response
Died with
to achieve
of the
after
a first cycle
clinical
trial received
marrow
transplantation
Retreated
First
Number
Twenty-five
Died with
Cycle
in Early
these
as initial
in first or
patients
who
treated
received
a
relapsed
(Fig 2).
group
of patients
data
suggest
that,
in addition
to longer
total time in chemotherapy-free
complete
remission
for the patients
as a whole,
substantial
benefit
of giving
the second
cycle
of this
.4
t
80
I
100
180
200
WEEKS
I
I
280
300
I
350
I
400
I
480
IN REMSSION
Fig 2.
Probability
of remaining
in first CR for patients
entering
remission
after one cycle of AcDAc.
receiving
a second
cycle in
early first remission.
and then no further
therapy
(25 patients,
bold
lines). compared
to the probability
of being alive and in CR without
chemotherapy
in remission
after
a single
cycle
of AcDAc
at
presentation
and second
cycle.
if necessary.
at relapse
(34
patients,
narrow
lines), P < .025. log rank.
intensive
realized
chemotherapy
early in first
in larger
numbers
of patients
ease-free
long enough
to be considered
(41% V 21% by life table analysis).
Eight
patients
cycle of therapy
sions were
patients),
because
patient
remission
will be
remaining
dispotential
cures
in this trial did not receive
a second
in early
first remission.
These
excluof persistent
infectious
refusal
(three
patients),
focus (four
and
late
From www.bloodjournal.org by guest on July 31, 2017. For personal use only.
VAUGHAN,
978
marrow
excluded
recovery
because
one of these
this
time,
eight
(one
patient).
No
patient
was
of suspicion
of early
relapse.
Only
patients
(12.5%)
remains
in CR at
eight
and
the
patients
experience
was
was
who received
median
duration
30 weeks.
the
same
of CR
This
as that
only a single
for
remission
duration
patients
cycle
of AcDAc
the duration
of first
prior
to first
with
apy
and
better
tumor
risk patients
who entered
clearance
on day 16 during
periods
in first
(Fig
CR
weeks).
Thus,
1 ). Twelve
for from
CR after complete
the historical
control
that
remission
survival
the significant
increase
in
and
probability
of
achieved
by the group
received
a second
cycle of AcDAc
was not a result of patient
selection.
in early
long
who
goal
studies
of our
series
phase-specific
sequence
should
reduce
the
ness and
intensive
drug,
limit
development
acceptable
therapy
and
laboratory
has
been
to
The
effective-
study design.
for induction
of
infusion
in a cycle of timed-sequential
chemotherapy
is
timed
to coincide
with a predictable
and (in late stage
disease)
demonstrable
increase
in leukemic
cells that
to this
and,
therapy.
tance
In the
or
absence
as a result,
drug.2’
believe
that
such
“recruitment”
potentially
proliferating,
leukemia
second drug in sequence
term remissions
without
have an
It is reasonable
of
noncycling,
cells prior
to
but
to the
should
produce
stable longrequirement
for additional
of absolute
pharmacologic
biochemical
sanctuaries,
some
resis-
cures
of
ANLL
should
result
from this limited
probability
of cure should
be increased
therapy.
The
if this therapy
is repeated
in early remission,
is low22 and before
spontaneous
tumor
volume
has a chance
when the
resistance
to develop.23
The
appear
Thus,
apy
or were
CR
of timed-sequential
“salvaged”
will
chemother-
long
of patients
that
given
approximately
stable
course
resistance
chemotherapy-free
of this therapy
achieve
ty-five percent
their
marrow
given
at
treated
in CR at this time,
20 months
to almost
proportion
into
cycle
it appears
patients
years.
achieved
a second
long-term
chemotherapy-free
CR
of this timed-sequential
chemother-
CR with a second
However,
nine
have
after
chemotherapy
I I of 25 patients
a significant
stable,
cycle
to over
patients
long
twice
as many
chemotherapy-free
of timed-sequential
therapy
conclusions
to chemotherapy
at relapse.
is
regarding
in leukemia.
Twen-
of patients
failed to clear leukemia
from
with the initial
cycle of chemotherapy,
relapse
to those
same
drugs
in the same
dose
and
schedule.
Six of 26 patients
failed
to clear
leukemia
from bone marrow
with the second
course
of AcDAc
of resistance.
into cell cycle
five
a
for
in optimum
timed
marrow
toxicity
and
ara-C,
normal
toxicity
of a second
cycle of the
in early remission
in this study
may
sensitivity
years.
only
and leukemia
recurring
after only a single cycle of this
therapy
for induction
of remission
and no chemotherapy in remission
was most
often
less responsive
at
remission
and as intensive
chemotherapy
in first remission
is supported
by our
in vitro
model,20
animal
models,’4”5
and
clinical
data.8’9
The
second
ara-C
increased
from
course
after
BURKE
chemotherapy
timed-sequential
On the other
hand,
did achieve
with a single
CR
AND
maximal
leukemic
cell
to drug.
The
short
of the cell cycle
5-
be due, in part, to this timed-sequential
The use of timed-sequential
therapy
are “recruited”
of
a second
clinical
chemotherapy
produces
exposure
infusion
achieved
given early in first remission.
These
data also permit
some
of clinical
of timed-sequential
devise
a therapy
that
kill with
the shortest
exposure
to high-dose
in CR
CR if the second
remission
DISCUSSION
The
who
timed-sequential
in early first remission
remain
these have been followed
for
four
(36%)
of these patients
remain
88 to 200 weeks
(median,
1 19
it is clear
duration
of first
chemotherapy-free
CR
of
remain
cycle
relapse.
for all 33
In addition,
cycle
ANLL
patients
who achieved
CR during
this time period
was
significantly
(P < .025) greater
than for the 34 slightly
relapse.
of 34 patients
Another
two, or possibly
three,
stable
long-term
chemotherapy-free
these
of previous
Four
single
KARP,
long-term
results of this series
to confirm
these
theoretical
of clinical
trials
considerations.
given
in early
relapse,
and all but three
patients
who
achieved
second
remission
had
second
remissions
shorter
than their first. This progressive
clinical
resistance
was
most
pronounced
in patients
with
relative
clinical
resistance
de novo. All six patients
who did not
clear leukemia
with the second
course
of AcDAc
given
in early relapse
had prior remissions
of less than four
months
in duration
(median,
14 weeks).
In contrast,
the median
duration
of prior
who remained
drug-sensitive
CR for
at relapse
the 20 patients
was 32 weeks
(P < .05), and the three
patients
with second
remissions longer
than their first all had first remissions
of
greater
than
1 8 months.
These
observations
are very
much
in accord
et al with
and with
with
retreatment
predictions
similar
results
achieved
by Fisher
of relapsed
Hodgkin’s
disease24
made
by Howard
Skipper
based
on statistical
models
from animal
and clinical
data.25
It has been suggested
that the use of different
drugs
for intensive
therapy
in early
remission
might
prove
more effective.23’25
alternate
therapy
However,
regimen,
when used at relapse,
no
including
marrow
lethal-
combination
radiation
and chemotherapy
followed
by
allogeneic
bone marrow
rescue,26’27
produced
significantly
higher
reinduction
rates for adults
than AcDAc.
Using
marrow
transplantation
in
first
remission,
From www.bloodjournal.org by guest on July 31, 2017. For personal use only.
TWO-CYCLE
CHEMOTHERAPY
IN ACUTE
Table
3.
LEUKEMIA
Comparison
979
of Four Diffe rent
Therapies
for A dults
With
ANLI
in Complete
Th&apy#{149} (Divation)
AcDAc(1
of
(Median)
Patients
Reference
course)
25
17-74(35)
28
52
20-30+
VAPA(l4mo)
30
27
HDARAC(1-2courses)
31
16
Cy/TBI/BMT
(1 course)
AcDAC,
see Materials
adriamycin,
prednisolone,
and
Methods;
Cy/TBI/BMT,
ara-C;
HDARAC,
high-dose
tIn CR on no therapy.
Estimates
from published
selected
children
long-term,
life tables,
and
young
disease-free,
comparable
adult
AcDAc.28’29
we have
reported
long-term
and
reported
here
using
ment
program
that
can
and
tion.
are considerably
cated
report,
that
ANLL
good
rates
high-dose
2(7%)
26mo
14-65(34.5)
3(19%)
16+mo
patients
than
be
to
treat-
children
transplantahowever,
in children.
irradiation/bone
ara-C
induce
In a
mdi-
in
adult
remission
intensive
results
infusions
of all of these
chemotherapy
encouraging
of ANLL
(Table
29mo
10(62.5%)
20mo
transplantation;
VAPA,
vincristine,
dissimilar
costs
toxic
It seems
that
result
time
long-term
as
morbidiof
intensive
remission
appears
not at high risk
an increasing
from
further
to
for
cure
efforts
rate
in this
direction.
The
in remis-
to
remission
comparison
in first
adults
likely
will
and
as well
investigation
for ANLL
for consenting
disease
and
of
used
ACKNOWLEDGMENT
approaches
in first
3). However,
continuing
CR,
therapy,
of death
chemotherapy
be justified
death.
of
subsequent
in risk
ty. Certainly,
by dissimilar
distribution
intensity
of the therapy
definition
and
containing
sion.
long-term
remission,
between
authors
Tempero
The
marrow
8(37%)
daunorubicin).
of this
have
achieved
of a regimen
intermittent
to
of
comparable
colleagues32
may
body
also received
therapies
is complicated
risk factors,
such as age,
also
intensive
marrow
approaches,
and
with one to two courses
very
48 mo
18-50(34.5)
cycle
by most
in adults
results
34mo
30%
survival
a 14-month
Wolff
11 (44%)
13 mo
in a relatively
be tolerated
poorer
preliminary
3Omo
colleagues3#{176} have
young
adults
without
bone
The results
of both of these
Follow-up
1 (4%)
(< 30)
achieved
a second
disease-free
those
Number
30%
(some
have
achieved
with
Weinstein
Median
Survival
data not given.
adults
population
Toxic Deaths
cyclophosphamide/total
ara-C
chemotherapy-free
to what
unselected
actual
Median
Disease-Free
Range
Curesf
Potential
.
Age
No.
Remission
are
of these
would
like
to thank
for constructive
Chlan
and
Elaine
housestaff
and
Hospitals
critical
Ryan
for
fellows
expert
of The
for outstanding
to protocol
Drs
care
Curt
review
Civin
and
Margaret
of the manuscript;
secretarial
iohns
Hopkins
of these
patients
Barbara
assistance,
and
and
Baltimore
and careful
the
City
attention
requirements.
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From www.bloodjournal.org by guest on July 31, 2017. For personal use only.
1984 64: 975-980
Two-cycle timed-sequential chemotherapy for adult acute nonlymphocytic
leukemia
WP Vaughan, JE Karp and PJ Burke
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