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Diaziquone
Given
as a Continuous
Infusion
Acute
By Edward
J. Lee,
given
Diaziquone
patients
in
David
with
vitro
as
a
relapsed
data
induced
suggesting
cytotoxicity
increased
duration
terminal
plasma
given
diaziquone
days.
The
maximum
seven
days.
bone
marrow
minimal.
relapsed
ANLL,
28
of
49
to 1 01
days).
six
OMBINATION
seven
28 mg/m2/d
the
to
days
for
duration
>500
only
in
toxic-
in patients
treated
at
responses
of
PMNs
Nonhematologic
were
complete
acute
leukemia
for
(CR)
(AN LL).
Complete
and median
survival
Nonetheless,
the
Relapsed
Adult
Philip
responses
never
Shulman,
(PR)
achieved
in
and
Charles
(8%).
although
platelet
counts
these
patients
A. Schiffer
five
of
eight
>100,000/sL.
was
felt
to
be
a
1986
remission
for
by Grune
& Stratton.
patients
with
ANLL.
Inc.
and
with
an anthraarabinoside
has resulted
in a
in the treatment
of adult
acute
nonlymphocytic
leukemia
(CR)
rates of 609 to 80%
months
have been reported.’
for
manifestation
of diaziquone
effect.
not persistence
of leukemia.
The median
duration
of CR was 1 95 days (range.
88
to 860+
). One patient
had active
CNS leukemia
at the start
of treatment
and has had a durable
(28 + month)
CR in both
sites of disease.
Diaziquone
produced
prolonged
aplasia
in
patients
with
secondary
ANLL
and CML-B
(five of ten
patients
died aplastic).
whereas
patients
with ALL all had
regrowth
of leukemia
and two
failed
to become
aplastic.
The
lack
of significant
nonhematologic
toxicity
and the
activity
in patients
with relapsed
ANLL render
diaziquone
of interest
as second-line
therapy
or consolidation
therapy
S
CHEMOTHERAPY
and
cytosine
improvement
partial
in first
with
effective
(23%)
Nayar,
Thrombocytopenia
chronic
five
with
was
responders
patients
infusion
was
two
relatively
six
Balchandran
in
cells
49
[CML-B],
occurred
26
the
2’ ANLL)
(median,
whom
were
cycline
substantial
crisis
toxicity
Responses
There
and
Agent
Leukemia
of
diaziquone-
leukemia
[ANLL].
dose
dose-limiting
Because
diaziquone.
four
tolerated
range.
ity was
blast
M.S.
effective
of
exposure
of
[ALL],
aplasia
responders;
been
murine
leukemia
in
J. Egorin,
leukemia.
as a continuous
were
C
of drug
leukemia
The
Merrill
not
and
half-life
leukemia
lymphocytic
doses.
human
nonlymphocytic
myelogenous
has
Nonlymphocytic
enhancement
for
short
acute
bolus
Echo,
or refractory
with
(34
A. Van
Is an Active
response
of 18 to 30
majority
of
studies
against
from
L1210
our
center
demonstrated
and
HL6O
leukemia
enhanced
by increasing
the duration
to diaziquone.’4
On the basis of this
ule-dependent
infusion
trial
enhancement
in patients
with
cell
that
cytotoxicity
lines
could
of exposure
demonstration
of cytotoxicity,
solid tumors
was
the University
change
in the
other
diaziquone
using both bolus and continuous
infusion
schedules was myelosuppression,
a continuous
infusion
phase
I/I!
study of diaziquone
was designed
for patients
with relapsed
agents
tion
that
may
combinations
regimens.
Diaziquone
sized
be non-cross-resistant
for use
(AZQ,
either
NSC182986)
aziridinylbenzoquinone
bility
and
low
nervous
system.7
murine
leukemia
human
leukemia
activity
planted
against
tumors
produced
was
From
the
Shore
cleared
Divisions
part
awarded
No.
rapidly
systems,
imof an
minimal
non-
were
observed
in
studies
showed
from
the
plasma
Malignancies
with
a
In vitro
and
Division
by
by
ofOncology,
Public
Develop-
the
NOJ-CM-27541
Manhasset,
Health
National
awarded
Service
Cancer
by the
National
NY.
grant
Institute
No.
and
Institutes
of Health.
Submitted
Address
Maryland
((
1 986
March
reprint
Cancer
by Grune
1 1, 1985;
requests
Center,
accepted
to
22 S Greene
& Stratton,
0006-4971/86/6701--0028$03.00/0
182
Dr
Inc.
July
Edward
18, 1985.
J.
Lee,
St. Baltimore,
no
of
leukemia.
MATERIALS
a bolus schedule
that diaziquone
with
adult
showed
toxicity
University
MD 21201.
AND
METHODS
Eligible
patients
included
the following
adults
(age
>15 years): (a) patients
with de novo ANLL,
either relapsed
(those
who had had a CR to other therapy)
or refractory
(those who had
never achieved
a CR); (b) patients
with ANLL
developing
after a
previous hematologic
disorder or treatment
of another
malignancy
who had already received combination
chemotherapy
with anthracycline/cytosine
arabinoside
(2#{176}
ANLL);
(c) patients
with relapsed
acute lymphocytic
leukemia
(ALL);
(d) patients
with chronic
myelogenous
leukemia
in blast crisis (CML-B).
All patients
had their diagnoses
confirmed
by bone marrow
aspirate
or biopsy, or both when possible. Other eligibility
criteria
included recovery from previous chemotherapy
or radiation
therapy,
a minimum
life expectancy
of six weeks, and adequate
hepatic
(bilirubin
<1.5 mg/dL)
and renal (creatinine
<1.5 mg/dL)
function. All patients
had either a normocellular
bone marrow
with at
least 30% leukemic
cells or evidence
of progressive
leukemia.
This
was defined as increasing
numbers of leukemic cells in the peripheral
blood accompanied
by signs of bone marrow failure, such as anemia,
granulocytopenia,
or thrombocytopenia.
Written
informed
consent
was obtained
from each patient before entry onto study.
During the seven-day
treatment
period, all patients
were exammed at least daily. Complete
blood counts and platelet counts were
obtained
daily; laboratory
profiles,
including
hepatic
and renal
function,
were obtained
twice.
After the chemotherapy
period,
patients had bone marrow aspirates
and biopsies at weekly intervals.
Hematologic,
hepatic,
and renal parameters
were monitored
on at
least a weekly basis and more often as clinically
indicated.
Patients.
in vivo
30 minutes.9”3
of Hematologic
Hospital.
in
1P50CA32107
or refractory
and
only
solu-
University
of Maryland
Cancer
Center,
UniSchool
of Medicine,
Baltimore,
and the North
University
Supported
contract
toxicity
of approximately
Therapeutics,
of Maryland
lipid
intraperitoneally
is given by way
I studies
using
patients
showed
hematologic
half-life
synthe-
good
In murine
and
diaziquone
side effects.9
No responses
leukemia.’#{176}’2 Pharmacokinetic
diaziquone
menial
versitv
HL-60.
intracranially
is seen when
primarily
terminal
line
with
allowing
access
to the central
has activity
in vitro against
the
L1210
and P388 and against
the
route.8 Phase
and leukemia
hematologic
patients
with
that
ionization
Diaziquone
cell lines
the stan-
or consolida-
is a rationally
compound
cell
intrapenitoneal
in solid tumor
with
in induction
Center
As the
a continuous
carried
out at
patients
who achieve
remission,
relapse,
and as many as 20%
fail to achieve
an initial
remission.
Thus,
a need exists
for
dard
of Maryland
Cancer
known
toxicities.’5
be
of the cells
of sched-
of
Blood,
Vol 67. No
1 (January),
1986:
pp
182-187
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DIAZIQUONE
IN
LEUKEMIA
183
The bone marrow response determined
whether a second course of
diaziquone
was given. If the marrow revealed
increasing
cellularity
with persistence
of leukemia
after day 15, then a second course of
diaziquone
was given. No further chemotherapy
was given if nemission was achieved.
Patients
who failed to achieve a response
to a
second course were taken off study.
Responses
were judged according
to the following criteria:
a CR
was defined as an M- 1 bone marrow (a normocellulan
marrow with
<5% leukemic
cells, normal
maturation
of the granulocyte
and
erythnoid
cell lines, and the presence
of megakanyocytes)
and no
evidence of extramedullany
disease. All patients considered
to be in
CR were required
to have normal
peripheral
granulocyte
counts
(> 1,500/zL)
and to have no need for red cell or platelet
transfusions. A “normal”
platelet
count was not required
because
diaziquone has been documented
to cause prolonged
thnombocytopenia.’6
Thus patients
who were felt to have thrombocytopenia
due to the
drug with marnows that were otherwise
M- I were designated
to be in
CR. A partial response
(PR) was defined as a normocellular
bone
marrow with fewer than 5% blasts and fewer than 30% blasts plus
progranulocytes
according
to the criteria of the Cancer and Acute
Leukemia
Group
B (CALGB).
Nonhematologic
toxicity
was
assessed according
to the criteria of CALGB
on a scale from 0 to 4.
Supportive
care for all patients
consists
of oral prophylactic
antibiotics’7;
empiric
or specific
panentenal
antibiotics
for documented or suspected
infections;
prophylactic
platelet transfusions’8;
granulocyte
transfusions
for documented
infections
not controlled
by
appropriate
antibiotics.’9
Drug schedule
and drug administration.
Diaziquone
was supplied in 10-mg vials by the Investigational
Drug Branch
of the
National
Cancer Institute
(NCI) and was reconstituted
with sterile
N,N-dimethyl-acelanide
and phosphate
buffer for injection
according to NCI recommendations.
The total daily dose of diaziquone
was
diluted in 1,000 mL of normal saline and was prepared
within six
hours of use. Bottles were changed
every 24 hours, since diaziquone
in normal saline at the concentrations
used undergoes
I 0% decomposition at 44 hours. The drug was administered
as a continuous
infusion for seven days (with two exceptions
noted later) by infusion
pump.
Cohorts
of two to three patients
were treated
at doses ranging
from 16 mg/m2/d
to 32 mg/m2/d.
The initial dosage was twice the
maximum
tolerated
dose (MTD)
defined in our phase I continuous
infusion trial of diaziquone
in solid tumor patients,’5
but 2/3 of the
MTD in the phase I bolus leukemia
study performed
in our center.’#{176}
Dose escalations
were 4 mg/m2/d
and patients who failed to respond
to their initial therapy were eligible to receive a second course at the
next higher dose.
Table
1 . Patient
Pharmacokinetic
studies.
Blood samples were collected in hepaninized tubes, before institution
of diaziquone
infusion, at 5, 15, 30,
45, 60, and 120 minutes and 24, 48, 72, 96, 120, 144, and 168 hours
into the infusion and at 2, 5, 10, 15, 30, 45, and 60 minutes
after
termination
of the infusion. Samples
were centrifuged
at I ,000 g for
ten minutes,
and the resulting
plasma was removed
and frozen at
20 #{176}C
until assay.
Diaziquone
concentrations
in plasma
were
determined
with the high-performance
liquid chromatography
analysis of Kelley and Siu Chong.#{176}Phanmacokinetic
modeling
was
accomplished
with the MLAB Program.2’
RESULTS
Forty-nine
kemia
were
ALL
had
and
received
patients
with relapsed
entered
onto this study
all received
(de novo)
(n - 34)
induction
after
other
below.
All patients
daunorubicin
with
and
2
#{176}
ANLL
cytosine
were
initially
treated
treatment
in
is described
initially
doses.
induction
regimen
used in each of
with de novo ANLL,
1 1 patients
or more
prior
CRs.
to the tenth
induction
Diaziquone
regimen
represented
given to these
patients
patients
these,
relapse.
(median,
three
prior
regimens).
There
were
I8
with ANLL
who had had a single
prior
CR. Of
I I received
diaziquone
as their
initial
treatment
for
Seven
patients
had
undergone
reinduction
with
either
conventional-dose
(three
patients)
patients)
and
anthracycline/cytosine
or
high-dose
received
arabinoside
cytosine
diaziquone
after
arabinoside
(four
these
were
efforts
unsuccessful.
The
number
of patients
treated
at each
dosage
and
Six patients
24 mg/m2/d
blast crisis
with CML-B
were treated.
One was treated
at
for seven days. This individual
had a lymphoid
treated
with vincristine
and prednisone
with an
excellent
response,
transplantation.
followed
Bone
calcemia,
lytic
bone
by
marrow
lesions
allogeneic
relapse
and
bone
with
pain
bone
marrow
associated
hyper-
developed
a few
Characteristics
ANLL
(n
(n
49)
(2’)
CML-B
4)
In -
-
ALL
61
In
-
5)
47
39
30
(range)
(16-72)
(40-69)
(23-48)
(19-60)
Sex
M
21
1
5
4
F
13
3
1
1
(CALGB)
19
1
3
2
1-2
10
1
2
2
3-4
5
2
1
1
11
0
1
2
1
18
2
0
3
0
5
2
0
0
0
0
5
0
PriorCR2
No prior
treatment
the
treatment
outcome
is presented
in Table
2. No patients
with
ALL responded.
Although
all patients
became
hypocellular,
two were never aplastic
and all had regrowth
of leukemia.
44
status
with
in conventional
Age-median
Performance
0
leuwith
treatments
the initial
the other
arabinoside
Diaziquone
was the second
these patients.
In patients
had had two
from the third
regimens
second-line
were unsuccessful.
Diaziquone
was
five of six individuals
with CML-B;
Diagnosis
ANLL
standard
diaziquone
or refractory
adult
(Table
1). Patients
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184
LEE
Table
2.
Response
to Diaziquone
by Disease
ET
AL
and Dosage
No. of
Disease
ANLL
Dosage
R
PR
1 6 mg/m2
7
3
0
0
1
1
20
7
2
1
0
0
0
24
7
1
0
0
0
0
28
5
1
0
1
0
0
28
7
5
1
3
2
32
7
0
0
1
0
6
2
5
3
0
2
0
(de novo)
Days
Patients
26
1
TOTAL
34
Died Aplastic
Never
Aplastic
ANLL(2#{176})
28
7
4f
0
CML-B
24
7
1
0
0
0
0
28
5
1
0
0
0
0
28
7
4
0
0
3
0
28
7
4
0
0
0
2
32
7
1
0
0
1
0
ALL
Both
tOne
trials
complicated
patient
by bone
inevaluable
for
marrow
response
necrosis.
because
of anaphylaxis.
months
later.
Diaziquone
was administered
and the symptoms
abated
only transiently.
Four patients
with CML-B
received
28 mg/m2/d
for seven
days.
Three
died aplastic
ual had rapid regeneration
but did not return
to the
when relapse
was apparent.
(days
34, 43, and 65) and one had disease
progression
after
prolonged
aplasia
(day 5 1 ). Because
of the prolonged
aplasia, the sixth patient
was treated
for five days at 28 mg/m2/d
28 showed
an M-2 bone marrow
cell lines. No further
specimens
patient
returned
with
obvious
and failed to achieve
ANLL
were treated
days.
No responses
other
PR occurred
in an elderly
patient
with a regenerating
bone
marrow
with
<5%
blasts
and
normal
granulocyte
counts,
who died of infectious
complications
on day 48. All
aplastic.
Of these,
developed
aplasia.
Three
patients
with secondary
at a dosage
of 28 mg/m2/d
for seven
were seen.
All three
patients
became
two died
progressive
aplastic
leukemia.
(days
29 and
A fourth
such
40) and
patient
one
responders
was to
note
had
in these
slow
of normal
hospital
A bone
bone
responders
blood counts
by day 28
until
two months
later,
marrow
aspirate
on day
with maturation
in all three
could be obtained
until the
progressive
leukemia.
The
marrow
is that
recovery
five
of the
(Table
eight
3).
never
Of
had
have received
28 mg/m2/d
for seven days but is inevaluable
for response
due to an anaphylactic
reaction
within
minutes
of starting
diaziquone.
The infusion
was stopped
and not
platelet
counts
over 100,000/zL,
although
all but one were
greater
than 75,000/L
and none were transfusion
dependent. This will be discussed
in detail
later. Thus,
the overall
restarted.
Thirty-four
patients
with relapsed
(29) or refractory
(five)
de novo ANLL
were treated
at varying
doses of diaziquone.
Six CRs and two PRs were seen in the relapsed
ANLL
group.
Five patients
in this group
died
aplastic
without
CR rates
in patients
with de novo ANLL
treated
at what
may represent
effective
doses (20
mg/m2)
is 6/3 1 , or I 9%
(95% confidence
limits 5% to 32%). The CR rates were 6/26,
or 23% (95% confidence
limits
7% to 39%),
if patients
with
primary
refractory
ANLL
are excluded
(Table
4).
evidence
(days
aplasia
and
of leukemia
1 5, 28,
(one
38,
44).
at 16 mg/m2/d
I 4 became
marrow.
in the
38,
aplastic
Responses
but
occurred
marrow
at
the
time
of death
Two
patients
failed
and
the other
at 28 mg/m2/d),
had
regrowth
of a leukemic
at dosages
between
mg/m2/d
for seven days except
for one patient
only a five-day
infusion
(due to patient
refusal
treatment
although
no toxicity
was apparent).
Patient/Response
.
#{149}
Measured
that
20 and
28
who received
to continue
This individ-
patients
exceeded
(eight
bone
Table
Dosage
Img/m2/d
x
No. of Days)
Three
to achieve
months
two
prior
for
a single
had
the
remission
length
compared
regimens;
prior
with
CR;
16+
prior
CR
28 + months
months
for a single
prior
more detailed
description.
at age 53 and was treated
3.
durations
of their
from
diaziquone
remission
durations
of six months
compared
months
to each
with
compared
with
Days
Response
of
(dl
To
Platelet
Transfusion
Last
>500
PMN
JS/CR
20
x 7
88
48
52
AW/CR
28
x 7
108
49
47
TP/CR
28
x 7
860+
101
91
EA/CR
28
x 7
250
46
38
MP/CR
28
x 7
140
54
28
RK/CR
28
x 7
485+
49
40
BB/PR
28x7
8
40
47
KM/PR
28
x 5
71
27
27
from first
day of treatment
with
diaziquone.
eight
CR).
The second
patient
merits
a
She developed
ANLL
(FAB
M-4)
with conventional-dose
daunorubi-
Responders
Duration
of
I 7 months
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DIAZIQUONE
IN
Table
4.
LEUKEMIA
De Novo
ANL L at Eff ective
No.
of
diac,
PR
2
14
4
had
0
0
5
0
institution
arabinoside
with
Disease
with
a CR
that,
intensification
relapse,
she
On
developed
She received
methotrexate
but
with
cytosine
arabinoside
CNS
leukemia
cranial
irradiation
still
had
in
during
and
leukemic
the
in
and
findings
prolonged
of
aplasia
CNS
(101
leukemia
days
her
cleared,
to >500
PMN,
and
91 days
to last platelet
transfusion),
she achieved
a complete
sion and continues
in unmaintained
CR 32 months
remisafter
initiation
of diaziquone.
No responses
were seen in the group
of five patients
who
had no prior CR. Four became
aplastic
before
developing
progressive
leukemia;
one did not become
aplastic.
Five patients
were
escalated
mg/m2/d,
mg/m2/d
The
and
fourth
received
32
the
retreated
treated
but
course
at
improvement
None
was
was
uneventful
mg/m2/d);
at
mg/m2/d.
in his bone
a second
of these
at 28
course,
a CR
after
mg/m2/d.
he
at the
same
received
responded
dose
at
20
relapse.
After
The fifth patient
had
marrow
after an initial
course
patients
had
28 mg/m2/d
initially
unsuccessful
third
(28
to the second
an
a second
a transient
course
and
was
noted.
Hepatic
and was grade
Several
patients
function
late
multiorgan
in their
system
courses
failure,
Of the 1 1 patients
consequences
and
occurred
associated
usually
Table
5.
in 21%
on
Nonhe
with
ten died
patient
day 15.
the central
matologic
of all
2 (one
in liver
infection
as a preterminal
who died aplastic,
one alloimmunized
intracranial
hemorrhage
related
toxicities
involving
Dosage
toxicity
Patient
Courses
2
0
0
20
3
1
0
0
24
3
1
0
0
2
0
0
16(2)
39
32
0
One
initiation
grade
patient
2 or less
not
chloromas),
marrow
aspirates
necrotic
material
of diaziquone
those
here
therapy.
in parentheses
developed
(grade
anaphylaxis
and
and
with
outset,
infection.
After
his bone
resolved
biopsies
the
initiation
multiple
his course.
sites
No
showed
regeneration
of
also
bone
but
developed
marrow
necrosis
and
ALL
thereafter
devel-
leukemia
after 30 days. A third patient
had
but unsuccessful
course
at 32 mg/m2/d
after an initial
Hematologic
course
of diaziquone
at 28 mg/m2/d.
toxicity
was profound.
All patients
red
and
blood
of
pain resolved
within
24
within
a week.
Bone
from
throughout
a performance
a markedly
hypercelludisease
(large
subcuta-
cells
occurred
individual
with
cell
platelet
transfusions.
The
required
dose-limiting
toxicity
of diaziquone
was the duration
of aplasia
(median,
49 days to >500
PMN
for responders;
range,
27 to 101). In
view of this and the occurrence
of bone marrow
necrosis
in
two of three patients
courses
at dosages
at 32 mg/rn2
for seven
above
28 mg/rn2/d
for
days,
seven
no further
days were
Steady-state
studies.
plasma
concen-
trations
of diaziquone
in I I patients
treated
with 28 mg/
m2/d for seven days were 101 ± 10 ng/rnL
(mean
± SEM;
range,
54 to I 50 ng/mL)
and were achieved
45 minutes
after
initiating
treatment.
At the cessation
concentrations
of diaziquone
declined
decay
with a mean
variability
was seen
Previous
demonstrated
of the infusion,
plasma
by monoexponential
half-life
of 47.7 ± I I .4 minutes.
Little
in steady-state
concentrations
in individ-
of
method,
responses,
PR (8%)
5).
This
strongly
was
responsible
mitoxantrone.24
level
of activity
ANLL
who had
26 patients
were
and
six achieved
for an overall
response
rates
compare
other new agents,
such
and
exposure
to diaziquone
trial has been conducted.
a significant
with de novo
In this group,
produced
(Table
3 or 4).
minutes
studies
of diaziquone
given as a bolus have not
activity
either
in ANLL
or in ALL.’#{176}’2 Fifty-
by this
achieved
0
within
at the
elements
or leukemic
after 38 days. A second
that
10
1
with-
normal
marrow
death occurred
scheduling
except
included
had,
treatment
with diaziquone,
hours
and
his chloromas
in patients
remission.
53
All
individual
with increased
duration
of
center,
a continuous
infusion
1
8(1)
before
(broncho-
hypotension)
was successfully
treated
She received
no further
diaziquone.
This
neous
given
3
28x7d
weeks
reaction
seven patients
(36 with ANLL)
have been treated
in these
studies
with no CR or PR reported.
On the basis of observations of enhanced
cytotoxicity
against
leukemia
cell lines
Hepatic
16
28x5d
K two
Her
DISCUSSION
There
were no drugnervous,
renal,
car-
Mucositis
to vitamin
therapy.
event.
of infectious
died
of an
Toxicity
Vomiting
an anaphylactic
ual patients.
and
No. of
Img/m2/d)
reaction
diaziquone
Pharmacokinetic
course.
1 (ten
patients)
or grade
had marked
abnormalities
had
of starting
the initial
drug allergies
and had
given.
Nonhematologic
toxicity
was mild (Table
5).
Grade
3 gastrointestinal
toxicity
occurred
in three
patients
(vomiting,
two patients;
mucositis,
one patient),
and no grade
courses
patient).
occurred.
mg/m2/d).
Toxicity.
4 toxicity
of
oped progressive
an uncomplicated
received
a second
course
of diaziquone.
Two
from
the first two dose
levels
( I 6 to 20
20 to 24
patient
status
of 3, significant
bone pain
lar bone
marrow,
extramedullary
cerebrospinal
fluid and focal symptoms
when she was treated
with diaziquone.
Without
further
specific
CNS
therapy,
the
symptoms
One
Three
courses
of therapy
were given at 32 mg/m2/d
for
seven days. In one patient
with ANLL,
bone marrow
necrosis
bone
intra-
cells
an anaphylactic
spasm,
flushing,
out complications.
every
1 0 weeks,
was unsuccessfully
daunorubicin/cytosine
same
doses
amd
marrow
recovery.
Aplastic
systems.
to diaziquone
within
minutes
She had a history
of multiple
6
cytosine
despite
or pulmonary
reaction
infusion.
Died
CR
arabinoside/6-thioguanine
lasted
for 1 7 months.
thecal
mg/m2/d)
Resistant
5
retreated
(20-32
26
Refractory
and
D oses
Patients
Relapsed
cm
185
response
suggests
for these
favorably
as m-AMSA,22
that
achieved
treated
was
seen
a prior
at doses
CR
(23%)
rate
of 3 1% (8/26)
the
improved
with
at our
When
change
and
two
in drug
results.
response
rates
homoharningtonine,23
These
for
From www.bloodjournal.org by guest on July 12, 2017. For personal use only.
LEE
186
Five
of the
in excess
rows
responders
failed
of l00,000/L.
in each
of these
patients
myeloid
and erythroid
of megakaryocytes.
proven
chronic
active
hepatitis
and
not evidence
patient
had
the
the lack
Prolonged
bone
with CML-B
and
responses
occurred.
days,
five
depleted
died
dosage
cell
aplasia
m2/d
impact
(28+
platelet
1 6 months
with pro-
leukemia.
In the
months),
In these
pools,
two
it may
a year
we feel that
groups
with
with
with
ALL,
the
the
of patients
were seen.
are
reported
Nonhematolgic
toxicity
was
seen in one patient.
Although
to
at
the
to
32 mg/
not have
much
an insufficient
exclude
activity,
minimal.
Anaphylaxis
this complication
has
no
was
been
reported,25
it has, in the past,
only been
associated
with
individuals
who had prior exposure
to the drug. This patient
had no such prior exposure,
although
a recent
reaction
to a
drug with similar
structure
and a history
of multiple
drug
allergies
was present.
Diaziquone
should
be administered
with
caution
to patients
with
similar
managed
of granulocytopenia
resents
the dose-limiting
histories.
The
achieved
steady-state
plasma
in this study agreed
Steady-state
concentration
the
rate
of infusion
will
/4
mild
ited to the mouth.
Of note
toxicity.
In previous
reports
terns of hepatic
abnormalities
of a transient
bin.
late
minimal
not be possible
pattern
is likely
to
be
whereas
related
to diaziquone
Both patterns
were
and
observed
worsening
of hepatic
als died aplastic
(day
bone
marrow
recovery
responders.
.
clearance
and
the
total
body
ziquone
expected.
concentrations
Not only are
actually
measured
but they
(IC50
are
100
growth
of 49 to
the calculated
in our
patients
also in the range
ng/mL)
shown
of human
and
92 ng/mL
would
be
values
similar
to those
(range
murine
leukemia
cells.’4
the favorable
response
seen in the only
ningeal
leukemia
is compatible
with
administration
produces
drug
of diaziquone
concentrations
in the plasma.29
The plasma
patients
treated
terminal
in this
54 to 150 ng/mL),
of diaziquone
concentrations
by us to inhibit
the in vitro
by continuous
in the CNS
half-lives
study
are
In addition,
patient
with leptomethe observation
that
infusion
equivalent
to dogs
to those
of diaziquone
measured
somewhat
longer
than
in
the
3 1- and 33-minute
half-lives
observed
after intravenous
bolus
administration
of diaziquone.9”3
It is possible
that
the
slightly
longer
half-lives
and somewhat
higher
steady-state
diaziquone
concentrations
observed
in our patients
reflect
subclinical
hepatic
clearance
effect,
associated
such
with
as reduced
prolonged
On the
metabolism
infusion
other
hand,
of
high
it may
such alterations,
since
the pharmacokinetic
not
there is
values
measured
previously
schedules.
is the lack of significant
involving
diaziquone,
were described.
One
hepatic
two patconsisted
The lack of extramedullary
or liver toxicity
make
diaziquone
an interesting
drug to combine
with another
agent
of
established
activity
in the treatment
of ANLL.
Indeed,
both
or biliru-
the duration
occurring
The first
in a patient
who
had
failed
reinduction
with daunorubicin
of transaminases
but
second
pattern
of
little
is
not
clinical
der
clearly
therapy
is generally
a preterminal
event.
in the patients
in this study,
yet
two patients
with
biopsy-proven
received
full-dose
diaziquone
(28
without
of infusion
body
with
drug-related
the
diaziquone
from the
full-dose
were lim-
The other consisted
of marked
abnormalities
in the course
associated
with systemic
infection.
consequence,
rep-
of the patients
given
mucositis.
Symptoms
elevation
in patients
of
predicted
of 28 mg/m2/d
to implicate
any
agreement
between
escalations
cytosine
arabiThe prolonged
clearance
values of 5 1 7 ± I 59 mL/min
defined
in the studies
of intravenous
bolus diaziquone,9”3
plasma
steady-state
dia-
be necessary
reasonable
Approximately
developed
course.
consequences
Total
cause this complication,
such
prolonged
duration
of aplasia
the
that
of their
=
of diaziquone.
dose
infectious
concentration
with those
concentrations
ANLL.
diaziquone
much
is unique
to diaziquone
and
studied
in relapsed
leukemia,
and
or
further
for
had
complications
relationship:
some
infection,26
suggests
alike,
AL
toxicity.
Bone marrow
necrosis
occurred
in two of three
patients
given
32 mg/m2/d.
Although
other
causes
exist that may
as leukemia
and
at 28 mg/m2/d
nonresponders
or no infectious
as outpatients
period
From
failure
toxicity
and
minimal
Rate
possibly
to reduce
responders
with
such as anthracycline
analogues,24
high-dose
noside,27
homoharringtonine,23
or etoposide.28
these
bone marrows,
requirement
be necessary
In patients
in conjunction
were
normal
(> I 50,000);
300,000/giL.
Thus,
count,
patients,
courses
This lack of early complications
unlike any other phase II agent
solid tumors,
it is
platelet
count
is
make
it likely
that
diaziquone
will
on the treatment
of ALL.
Although
number
responses
and
marrow
aplasia
was seen in all patients
2 #{176}
ANLL
treated
for seven days, but no
Of the eight
patients
treated
for seven
of diaziquone.
achieve
benign
diaziquone,
normal-appearing
and no transfusion
aplastic.
stem
antedated
response
of a normal
Several
mar-
5% blasts,
of 88,000/jL
is associated
count became
250,000
and
individuals
with otherwise
diminished
megakaryocytes,
should
be considered
CRs.
than
of persisting
best
passed
before
the platelet
currently,
it is between
despite
that
in patients
with
to regain
a normal
drug-related
who
fewer
counts
bone
maturation,
and diminished
One
responder
had biopsy-
and a platelet
count
Because
diaziquone
longed
thrombocytopenia
our feeling
that failure
platelet
of several
revealed
normal
numbers
splenomegaly,
after
treatment.
to regenerate
Examination
ET
chronic
mg/m2/d
function.
One
active
hepatitis
for seven days)
of those
individu-
42). The other
achieved
a CR with
after
six weeks
similar
to other
and
defined
in studies
of response
diaziquone
of interest
or as consolidation
the potential
in
lack
this
using
study
and
strikingly
and
the occurrence
after
initial
of cross-resistance.
described
doses
and
of a durable
to achieve
and cytosine
as either
those
different
CR
remission
arabinoside
second-line
remission
However,
after
ren-
reinduction
because
in view
of
of the
prolonged
duration
of bone marrow
aplasia,
it will be necessary to reduce
either the dosage
or the duration
of infusion
of
diaziquone
for use in combination.
A trial of diaziquone
and
amsacnine
in combination
is in progress
The demonstrated
activity
and mild
ity also raise
tive regimens
at our center.
nonhematologic
the possibility
of using diaziquone
for bone marrow
transplantation
toxic-
in preparafor patients
From www.bloodjournal.org by guest on July 12, 2017. For personal use only.
DIAZIQUONE
with
IN
ANLL.
LEUKEMIA
Resistant
187
leukemia
patients
transplanted
in relapse
who have at least a 1 5% chance
transplantation.6
the
dose
As
of diaziquone
bone
was
remains
a major
problem
in
or first or second
remission
of developing
leukemia
after
marrow
increased,
necrosis
it may
occurred
when
not be possible
to treat
study.
nations
patients
at higher
Nonetheless,
for bone
dosages
than
it should
be noted that
marrow
necrosis
existed.
the role ofdiaziquone
in this
setting
would
that
defined
alternative
Studies
in this
explato define
be of considerable
interest.
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From www.bloodjournal.org by guest on July 12, 2017. For personal use only.
1986 67: 182-187
Diaziquone given as a continuous infusion is an active agent for relapsed
adult acute nonlymphocytic leukemia
EJ Lee, DA Van Echo, MJ Egorin, MS Nayar, P Shulman and CA Schiffer
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