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Azacytidine A New Active Agent for the Treatment of Acute Leukemia

Azacytidine A New Active Agent for the Treatment of Acute Leukemia

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1973 42: 359-365

5-Azacytidine: A New Active Agent for the Treatment of Acute Leukemia
Myron Karon, Lance Sieger, Suzanne Leimbrock, Jerry Z. Finklestein, Mark E. Nesbit and Jerry J. Swaney

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Blood (print ISSN 0006-4971, online ISSN 1528-0020), is published weekly by the American Society of Hematology, 2021 L St, NW, Suite 900, Washington DC 20036. Copyright 2011 by The American Society of Hematology; all rights reserved.

From bloodjournal.hematologylibrary.org by guest on September 15, 2011. For personal use only.

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

of childhood action is not DNA and to interfere activity dependency

in Czechoslovakia.’ The known, but the activity RNA with polynucleotidesin DNA, RNA,

presumably related place ofcytidine.2 protein the cell This synthesis.3’4 cycle in vitro study was every to have against

incorporation compound shows shown to

into is known preferential schedule course against

The drug and has

during the in animal of 5-aza-C

S phase of systems.5’6 on a daily

undertaken

establish

a tolerated of this acute

dose

x 5 schedule was found some activity

2 wk. During the impressive activity acute lymphocytic

phase I investigation 5-aza-C myelogenous leukemia, and

leukemia.

From and School atrics, These authors’ the

the USC

Division School

of

Hematology. Calif.; Minn.; and Chicago. revised under

Department Department the Childrens Ill. March the 12, Department

of

Pediatrics. Harbor of Pediatrics.

Childrens General

Hospital Hospital, of the 1973. Study

of

Los and the

A ngeles. UCLA School of Pedi-

ofMedicine; Torrance, University. 22, 1973;

ofPediatrics. Memorial 1973; of CA -0743/ for Division

of Medicine, Northwestern January studies institutions. by Grant DHEW. Karon, Angeles, Fellow. of M.D.: Los Grants were

University and 22, Cancer the National and

Minnesota

of Medicine, Submitted

Minneapolis,

Hospital March

Department

accepted Childrens from Child of

performed CA -02649, from

auspices and

Group Cancer

A Institute

in

the and

Supported Training NIH, Myron of Los Hematology 90027. Hospital sor Minn. of Nesbit, partment © 1973

CA -07306 the of National Pediatrics, Scholar,

HD-00048

Institute Head, Leukemia Childrens Pharmacist. 90027. Jerry Harbor of Pediatrics. Chicago,

Health Hematology, of of

Human Childrens Sieger, Los

Development. Hospital M.D.: Angeles. Childrens ProfesCalif

M.D.: Professor Los Angeles, Division Los Pediatric of of

Calif.;

Society Hospital Division

America. Lance Los of Angeles.

Hematology,

Suzanne
Pediatrics,

Leimbrock,
Angeles. Head. Professor

Pharm.
Angeles,

D.: linical C
Calif University in University. Hematology.

Hematology, Torrance, of Medicine, Hospital

Z.

Fink lestein,
General Hospital. School Memorial

M.D.: Assistant

Mark Calif and

E. the De-

Pediatrics,

Minnesota Childrens Ill.

Minneapolis.

Jerry

J. Swaney,

M.D.: Associate

of Pediatrics, Northwestern by Grune & Stratton, Inc.

Blood,

Vol. 42. No. 3 (September).

1973

359

From bloodjournal.hematologylibrary.org by guest on September 15, 2011. For personal use only.

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

the This known

use

of request

5-aza-C was

activity

Thirty-seven chemotherapeutic institutions.

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

repeated drug was beginning examination, therapy, performed Study

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

forestall blood BUN, a bone in use

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

Dose in Fig. I. Dosage increments were

of dose

illustrated

logarithmic below 100 mg/sq lack of response and toxicity modified Fibonachi numerical

m. The rate at the lower progression

of initial escalation doses. The broken recently proposed

was based on the curve represents a by Dr. Oleg Sel-

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

2

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.

From bloodjournal.hematologylibrary.org by guest on September 15, 2011. For personal use only.

5AC’(flDINE

361

awry quite sponse The patients increased, then such

for similar

predicting to that

dose which

increments.7 was obtained

The by

shape increasing

of

this the

theoretical dose until

curve either

is reof was and of

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

Therapeutic The tients Five 6 mo, within fore, who then

treatment leukemia obtained

are a

tabulated achieved complete

in an

Table Six
.

out 1 which an rate

of marrow

I 5 pastatus. lasted 8 mo, died theremarrow AML,

myelogenous

bone

remission patient with remission

3 mo, 2 mo, 3 wk in partial is 6/ 15 (40%). received only the the

mo, and remission.

2 mo. One The over-all

M1 for

If one one-fiftieth

excludes one patient of the maximum

with acute myelocytic tolerated dose early

leukemia in the study,

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

p <0.008 of the is given 50,000

(Fishers clinical in cells/cu 100,000 dose of of 150

exact test). data on the 2. at Of the mm

eight these time mm. each patients of

patients patients, diagnosis With week, and the the

who six had and

achieved white two had

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

cells/cu 5-aza-C 5 days in five

exception of best response four nadir courses in 5 the day.

1 patient ocin the two white

drug

after

to 200 between

mg/sq m per day x the 10th and the 14th to maintenance Patient CB, days who each

There was who achieved mo, received

approach remission. m on

therapy stayed week.

for those in remission Patient DC

patients for (3 mo)

8

2 consecutive

Table

1.

Treatment

Results
Marrow Over.all M-3 CR PR StatusX NR

Diagnosis’

Patients

Adequate

Treatmentt

M-1

M.2

AML ALL Total AML acute

15 22 37 myelogenous treatment treated

14 22 36 leukemia

6 1 7 as a generic undifferentiated course than 10 mg/sq remission,

0 1 1

9 20 29

5 1 6

1 1 2 ALL The

9 20 29 acute one

name all subcategories for leukemia, 60 m daily AUL mg/sq x 5. m or

of non-ALL; greater daily 5. x

lymphocytic tAdequate inadequately

leukemia,

including acute is at least one had PR, less patient

at a dose of

CR. complete

remission.

partial

NR, no response

or progressive

disease.

From bloodjournal.hematologylibrary.org by guest on September 15, 2011. For personal use only.

362

KARON

ET

AL

.:

0

0

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From bloodjournal.hematologylibrary.org by guest on September 15, 2011. For personal use only.

5-AZACYTIDINE

363

received receiving mg/sq

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

because JB’s 4 wk following mg/sq Toxicity m q.d.

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

of and the some

diarinas

stances by chlorpromazine 24-48 rash

mm intravenous when given

such at least not 14

hr prior occurred

the course of 5-aza-C. patients, but was usually Although recovery

pruritic, transient occurs

follicular and did by day

skin re-

quire drug The drug

dosage modification. is myelosuppressive.

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).

may be Myelosuppression is every instance

more pronot necesexcept one

(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

acute lymphocytic prednisone.l fact that the activity

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 child’s 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

for dose escalation, volves a rapid initial which are predetermined

approach escalation and aimed

was abandoned. followed by at reducing

The Fibonachi decreasing dosage the chance of

search inincrements grossly over-

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

Fibonachi’s

escalation

program

would

From bloodjournal.hematologylibrary.org by guest on September 15, 2011. For personal use only.

364

KARON

ET

AL

‘4 ‘3 2 Fig. 2. Frequency distribu-

tion
particular course.
U)

of

patients

receiving

a

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

k

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

escalation that a series there theraper of pa-

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

indicating there is either mathematical the number

peutic se has The

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

have a posiin more paThis proved The main cumulative

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

REFERENCES
I. hood 2. Sorm
its

Hrodek leukemia. Juvovcik F:

0,

Vesely M, Raska

J: 5-azacytidine 18:493, 1971 K Jr. of and 1965 NH, acid.

in childSovmova a novel CoIl Reineke evidence for F, 4.

LM: azacytidine 30:2760, Raska

Cytotoxicity on KJ and Chem LI2IO 1970 Jr, Juvovcik F: Commun

and leukemia. M, Metabolic

mode

of Cancer

action Res Tykva of 5-

of

5-

Neoplasm

Anabolic
into

transformation 5-azacytidine
ribonucleic

Fucik

V.

antimetabolite,
incorporation

R, Sovmova Z, Sorm
azacytidine CoIl Czech

effects 1966

5aza,2l,deoxycytidine 1:2803, 3

in mice.

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

365 against mam- previously Cancer Res 30:- cer2l:346, R:
and faba 1970 C, IA, in Perrin remission Hartmann E: induction

Phase malian
2770, induction structural

specificity of 5-azacytidine cells in tissue culture.
1970 V. of Michaelis A, segment in vicia

untreated 1968 OS: of

childhood

leukemia.

Can-

6. Fucik

Reigev

On

the

8. clinical sium

Selawry trial on Statistical

Considerations Aspects of

for agents. Protocol

initial SympoDesign,

extension

chromatid

anti-neoplastic

changes

chromosomes

after
7. Murphy

treatment
Leikin ML, SL,

with
Mutat

5-azacytidine
Res :599, 9

and

5-azade-

December
9.

9-10,

1970
KB, Bodey MP, leukemia GP, with Burgess EJ: 5-azacytidine. MA, The

oxycytidine.

McCredie V, of acute
40:975,

Brubaker Wolff

JR,Rodriguez Varying treatment of Blood

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1972

Freireich

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