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5-Azacytidine:
Treatment
By Myron Karon, Lance
A New
of
Sieger,
Active
Acute
Suzanne
Agent
Leukemia
Leimbrock. Jerry
for
the
Z. FinkleStein,
Mark
E. Nesbit.
and Jerry
J. Swaney
children with acute leukemia plete remission which lasted 3 mo The were treated with 5-azacytidine in 5-day maximum tolerated dose is between 150 courses given every 14 days. Six out of 14 200 to mg/sq m on a daily x 5 schedule children with acute myelogenous leukemia given every 1 4 days. The impressive acwho were adequately treated achieved an tivity of 5-aza-C in patients with acute M1 marrow. Five of these subsequently myelogenous leukemia resistant to cytodeveloped complete remissions lasting sine arabinoside indicates that this drug 8 mo, 6 mo, 3 mo,2 mo, and 2 mo. Of will become an important addition to the 22 children with acute lymphocytic leuketherapeutic armamentaria against this type mia, one achieved anM1 marrow and one of leukemia. an M2 marrow. The former attained a cornThirty-seven
5
critical
-AZACYTIDINE
the treatment step in the
(5-AZA-C)
of acute mechanism to The
is
an
analog
of
cytidine
first
introduced
for is and
leukemia of drug
in Czechoslovakia. The known, but the activity RNA with polynucleotidesin DNA, RNA,
presumably related place ofcytidine.2 protein the cell This synthesis.34 cycle in vitro study was every to have against
undertaken
establish
dose
leukemia.
the USC
Division School
of
of
Childrens General
of
of Medicine, Northwestern January studies institutions. by Grant DHEW. Karon, Angeles, Fellow. of M.D.: Los Grants were
Minnesota
of Medicine, Submitted
Minneapolis,
Hospital March
Department
auspices and
Group Cancer
A Institute
in
the and
Supported Training NIH, Myron of Los Hematology 90027. Hospital sor Minn. of Nesbit, partment 1973
HD-00048
Institute Head, Leukemia Childrens Pharmacist. 90027. Jerry Harbor of Pediatrics. Chicago,
Health Hematology, of of
Calif.;
Hematology,
Suzanne
Pediatrics,
Leimbrock,
Angeles. Head. Professor
Pharm.
Angeles,
D.: linical C
Calif University in University. Hematology.
Z.
Fink lestein,
General Hospital. School Memorial
M.D.: Assistant
E. the De-
Pediatrics,
Minneapolis.
Jerry
J. Swaney,
M.D.: Associate
Blood,
1973
359
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360
KARON
ET
AL
MATERIALS
Informed child that ment prior all for other their consent to treatment. agents child.
patients agents ranging were in treated age with
AND
was based been 17 yr had
from to 2
METHODS
obtained on used. the from potential There were at least efficacy no one of parents of the 5-aza-C who parents and refused of the each fact treat-
for of
use
of request
5-aza-C was
activity
with acute
at a starting
leukemia
dose2
refractory
mg/sq of m and/or at
to standard
the authors
5-aza-C
The
5 days
drug
and
was
administered
every
as either
14 days,
an intravenous
depending upon
push
response
or a 15-mm
toxicity.
fast (Fig,
drip,
Generally
daily
for
in the
some nausea
absence
instances and
of
the
significant
toxicity,
administered of
the
dosage
in
was
increased
doses physical acid, were Criteria contains
by
either
50
every
increments
8 or 12
I).
In
divided included
hr
to
vomiting. at marrow During Cancer the treatment platelet complete at least Group A.7 every count, blood 28 examination, alkaline at less least of evaluation blasts a complete phosphatase, weekly were or and those other uric counts days. SGOT, repeated for
5#{176}/a
Observations
count,
and marrow by the
abnormal
a bone
urinalysis.
aspiration Childrens
cells.
Ani marrow M
or
5-aza-C
Cancer mm of
was supplied
Institute. The
in 50-mg
drug since was the drug
vials
dissolved
by the
5 in ml to
Clinical
of distilled decompose
Drug
in
Evaluation
water aqueous and solution
Branch
administered within
of
the
within 1 hr.
National
15
reconstitution
begins
RESULTS
Determination The pattern of Maximally escalation Tolerated
is
of dose
illustrated
logarithmic below 100 mg/sq lack of response and toxicity modified Fibonachi numerical
Fig. 1. Dose escalation of 5-azacytidine. Dose escalation was logarithmic until a dose of 100 mg/sq m when there was a decrease in this rate based on the occurrence of response and/or toxicity. Each point represents a dose increment actually used one or more times. The
INCREMENTS
broken curve represents a modified Fibonachi search procedure designed to permit rapid escalation of the dosage initially while diminishing the rate of increase near the maximum tolerated dose in order to avoid excessive toxicity. The modified Fibonachi series is as follows: 2, 0.7. 0.5, 0.3.... These numbers are used as coefficients to predict dose increments. If the starting dose based on 0.1 LD10 in animals was 2 mg/sq m, then dosage increments would be 2, 4, 6.8. 10.2, 13.5 mg/sq . m Blind adherence to such a scheme would unnecessarily prolong a phase I trial if the starting dose was too low.
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5AC(flDINE
361
for similar
predicting to that
dose which
The by
shape increasing
of
this the
curve either
or toxicity occurred. maximum tolerated given a particular the number of abruptly was used Efficacy over-all with of acute these results children 2 of to
dose was obtained by determining the number dose of 5-aza-C per course. As the dose of drug patients at a given dose increased to a maximum between estimate 150 the and lower 200 mg/sq m. The plateau limit of drug toleration. value
declined a curve
are a
in an
Table Six
.
of marrow
myelogenous
bone
M1 for
If one one-fiftieth
remission rate becomes 6/14(42%). 22 patients with acute lymphocytic leukemia (ALL), one patient achieved an Ml marrow and another an M2 marrow. The child with the M1 marrow obtained a complete remission which lasted for 3 mo. The child with the M2 marrow (9% lymphoblasts) died of infection before achieving a complete remission. The difference in remission rates (M1) between AML and ALL
Of
is significant, A summary tive counts blood who curred patients. blood response below
an blood
objeccell a white
Table
cell count above received a lower after two courses At a dose of cell count occurred no uniform complete 90 mg/sq
drug
after
to 200 between
mg/sq m per day x the 10th and the 14th to maintenance Patient CB, days who each
approach remission. m on
2 consecutive
Table
1.
Treatment
Results
Marrow Over.all M-3 CR PR StatusX NR
Diagnosis
Patients
Adequate
Treatmentt
M-1
M.2
14 22 36 leukemia
0 1 1
9 20 29
5 1 6
1 1 2 ALL The
9 20 29 acute one
leukemia,
at a dose of
CR. complete
remission.
partial
NR, no response
or progressive
disease.
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362
KARON
ET
AL
.:
,
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E
C)
C)
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CD C)
E
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c
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CD
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c .!
c
cii.,
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5.
C)
CD
CD
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CD N
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CD
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&
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0)
CD
CD
CD
g
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;
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=
V
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N
C)
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_tc)
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5-AZACYTIDINE
363
150 mg/sq m q.d. for 2 consecutive 230 mg/sq m q.d. 5 x every 3 wk. m q.d. x 5 every 5-6 wk. This more white blood therapy. x 5 once cell Patients per count KK continued and PJ
days every week. Patient NS Patient JB has received 150 prolonged interval was necessary to were decrease maintained for approximately 5-aza-C on 100
is
month.
The
150 rhea former,
most disabling toxicity involves mg/sq m or above, 5-aza-C causes in all patients. The severity of
can be the reduced use of a can be of to in beginning 50% of the by 15 use giving the
the gastrointestinal tract. At doses profound nausea and vomiting these toxic manifestations, especially drug in in divided fast drip. relatively A doses or in Antiemetics large doses
diarinas
hr prior occurred
skin re-
usually
at a dose of 150 mg/ sq m daily 5, x myelosuppression longed, especially at 200 mg/sq m or above. sarily untoward and accompanied response in ble2).
(Ta-
DISCUSSION
These leukemia against kemia against receiving The has data in acute indicate children. myelogenous recently been that The 5-aza-C compound leukemia. demonstrated leukemia of 5-aza-C in newly could is an active has Activity by drug of McCredie diagnosed be demonstrated for 5-aza-C and patients in the treatment impressive against who adult were co-workers8 of acute activity leuand also with particularly
children
advanced refractory leukemia has important implications for the evaluation of other new drugs. Agents of uncertain potency do not need to be tested early in the course of a childs disease to demonstrate activity. Indeed, the activity of vincristine, ara-C, and L-asparaginase, all effective antileukemic agents, was demonstrated under similar circumstances. Since 5-aza-C is not cross-resistant to ara-C, the use of these two agents in combination for the treatment of AML should be Although promising. the original this dose plan was to adhere to a modified Fibonachi search
shooting the maximum tolerated dose. The original plan for on Fig. 1 as an interrupted line, and is based on the series The initial starting dose was 2 mg/M2, the LD10 determined pharmacology. Because this dose proved to be 70-100-fold
to
escalation is shown 2, 0.7, 0.5, 0.3 in preclinical less than the maxi.
mum
tolerated
dose,
strict
adherence
Fibonachis
escalation
program
would
From bloodjournal.hematologylibrary.org by guest on September 15, 2011. For personal use only.
364
KARON
ET
AL
tion
particular course.
U)
of
patients
receiving
dose of 5-aza-C per The plateau of this curve determines the maximum tolerated dose of 5-aza-C since courses which do not produce toxicity or therapeutic effect sive given patients. courses or which toxicity to a produce excesare usually not large number of
40
80 DOSE
(20 PER
60 COURSE
200 (mg/M2)
240
320 280
while tolerated that affect the disease favorably are used in an increasing number of patient. All patients receiving the drug are included as long as they were in the induction phase. A patient can be represented only once for each dose level.
have curve,
is a
been
completely
unworkable.
The
shape
of
the
actual
dose
however, is similar to the Fibonachi modification, need to reduce the rate of dosage increment once effect or some toxic no particular magic. maximum tolerated manifestations, dose was estimated but that by this plotting
tients receiving a given dose per course. Clearly tive slope at doses which were well tolerated tients and a negative slope when the tolerated to be the case danger of a (Fig. more 2) and rapid was a useful way escalation scheme of is
such a curve would and, therefore, used dose was exceeded. predicting drug the development dosage. of
toxicity. This can be obviated by escalating the dosage every second course as the maximum tolerated dose is approached. The achievement of complete remission in two patients whose initial white counts were in excess of 100,000 indicates that such high white blood cell counts may not necessarily predict for a poor prognosis, especially in advanced disease. This may be the result of a selection since patients with acute leukemia who live long enough to receive phase I agents have usually responded to other agents. The practice sion rate in advanced of their initial white some phase II studies designed disease to exclude certain patients blood cell count may not necessarily in to estimate because be justified. of the the remisheight
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antimetabolite,
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R, Sovmova Z, Sorm
azacytidine CoIl Czech
effects 1966
5aza,2l,deoxycytidine 1:2803, 3
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Czech 3. Li
Chem LH,
Commun Olin J,
30:3370,
Boskivk
5. Li LH, Olin
EJ,
Fvosev
Ti,
Bhuyan
BK:
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5-AZACYTIDINE
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childhood
leukemia.
Can-
6. Fucik
Reigev
On
the
8. clinical sium
Considerations Aspects of
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extension
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anti-neoplastic
changes
chromosomes
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7. Murphy
treatment
Leikin ML, SL,
with
Mutat
5-azacytidine
Res :599, 9
and
5-azade-
December
9.
9-10,
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KB, Bodey MP, leukemia GP, with Burgess EJ: 5-azacytidine. MA, The
oxycytidine.
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40:975,
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Sullivan
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dosage