Acute Promyelocytic Leukemia: Treatment Results ...

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Acute

Promyelocytic

Leukemia:

Treatment

at Memorial By

Isabel

Cunningham,

Fifty-seven

adult

patients

mia

were

treated

(APL)

daunorubicin

(DNR)

m-anisidide sine

in

6-thioguanine

early

fatal

(CR),

hemorrhage or

serum

lactate

was

hemorrhage described

published

Didisheim

lower

and

at

57 cases

found

that

only

and

achieved

who

leukemia

of

of earlier and were

early

the

disseminated

typical of successful.58 used

simultaneously

In 1967, caused

with

Bernard

the complete

I 3% to 43%, those

remission

and

in other

induction

At

that

the

of

heparin

use

induced

cell

daunorubicin

not be

(DNR)

to increase lasted

However,

who and

remission

longer

(and

adequate were

was

period

concurrent

more

of

therapy lengthy;

that

payment.

“advertisement” indicate (.)

I 989

costs ofthis This

article

in accordance

must with

this fact. by Grune

& Stratton,

0006-497l/89/7305-0002$3.00/0

1116

article

Inc.

in acute were

every

1 2 hours

as

nonlymphoblastic

included

attained beyond

with

Ara-C

and

reported

in the report

remissions

the

TG.

median

The

previously

MATERIALS

Patient mally

release),

that

lasted

of 9 months

of the

results

by Drapkin

remismedian

AND

Fifty-seven

APL

were

seen

1974 and June 1984 (Table whose ages ranged from 1 5 patients were aged over 50 morphology according to the

“typical”

prevent or interrupt did a patient with

population.

pretreated

system

granular” Karyotype

system’3 were

(cases

classified

M-3

for

first

15

et al.’2

with

untreated

Hospital

or mini-

between

May

1). There were 27 men and 30 women, to 7 1 years (median 35 years). Twelve years old. The diagnosis was based on French-American-British (FAB) clas-

occurring and

marrow

the

adults

at Memorial

prior

publication

considered

of

patients to have

this had

“micro-

known as the “M-3 variant.” on direct or 24-hour culture

of 1 9 patients

characteristic

to

Forty-four

I 3 were

which is also was performed

of the showed

METHODS

retrospectively).

marrows,

ApL,’4 analysis

preparations of these

after

I5q:17q

December

1980;

translocation;

and

13 the

other 6 showed only normal karyotypes. All patients were evaluable for study. Most patients presented with leukopenia and thrombocy-

2 years.9

10021.

The publication

to

arabinosyl-

without APL. because of the reported success in treating APL and heparin, it was decided to use these agents in

were

sification

From the Hematology Service, Department of Medicine. Memorial Sloan-Kettering Cancer Center. New York. Submitted August 24. 1987; accepted November 14. 1988. Supported by Grant No. CA-O582#{243}from the National Institutes ofllealth, Bethesda. MD. Addres.s reprint request.s to Isabel Cunningham, MD, Memorial Sloan-Kettering Cancer Center. 1 275 York Ave. New York, NY

charge

patients all well

of

chemotherapy-

fail to achieve by 1973, the

Three

the patients In 1974, with DNR patients

to

suggested

procoagulant could Rarely

than

(TG)

study

period with

than

decreased

This

hemorrhage.

combination

from

the incidence

deaths

60%.0

uncontrollable, coagulopathy.

received remissions length

hemorrhagic

the

same

treated

6-thioguanine Six patients

16 to 75 months,

(DIC),

begun, were that heparin

(ANLL).”

this

were

leukemia

in APL

surpassed during

kill

before DIC was the consumption APL sion,

rate

APL

protocol

(1970

Inc.

of the protocol, and four more were identified among the other patients in that series on subsequent review. None received heparin. Of these ten patients, seven died early of

and

CR

and

L-6

60

fron,

coagulation

status,

(Ara-C)

v 9

5%).

v

during

with

(24 than

longer

more

from central nervous system (CNS) days of starting induction therapy, Beginning in I 972, heparin was added to therapy for all patients, regardless of

as the

Hospital,

patients

of the

(35%

median

survived

early death, mainly hemorrhage within remained near 50%. the same induction

l0,000/jzL.

The

but

fibrinogen

our laboratory minimum of I 50 mg/dL “normal” values ( 150 to 280 mg/dL), was 1,160 mg/dL. The median fibrinodegradation products were elevated in

The

prothrombin

time

was

prolonged

by

more than two seconds in 23 patients; two-thirds of patients with normal prothrombin time had low fibrinogen. When first examined, all patients with platelets 20,000/jzL; fresh-frozen plasma was not administered routinely. Heparin was discontinued early if there were signs of significant hemorrhage or headache,

(/jLL)

100.000

4 (mg/dL)

0-135

37

150-280

17

1,160

1

Notdone

2

Prothrombin

time

(see)

12-14

34

>14

was

begun

simultaneously

with

mucosa

PROTOCOLS

51

GI or GU

Gross

(mg/M2)

10

Occult

11

Vaginal

Treatment. three induction

During the 10-year protocols for APL

with

Ara-C

and

TG

courses,

half

in combination

of which

I

Ara-C

period of this study, there were (Fig I ). All involved remission with

DNR

(DAT)

required

hospitalization.

TG

There-

was

days,

preceded

with

the

by a bolus

TG

dose

unchanged.

of 25 mg/rn2

The

Group

intravenously

(IV)

by a multiple-drug

maintenance

regimen

for 2 years.

200

1977-1980

16

pts.

TG

ttt 1-

x 5

100 ql2h

tftjj

____

____

heparin

/ \

to

Group

Ill

60/50

‘ft 225/190

Ara-C

1980-1984 25

DNR

or AMSA

ptS.

25 x 1-

200/160 TG

From

1979 on, a patient aged I0,000/jtL:

mg/dL ( I 3 months Microgranular

was The

and

WBC

from

There study.

at ages

median

count

6 weeks.

of

induction and four of them died. There was of remission rate with WBC level, but the

with

was

aged

of remission. >10,000/jiL

a WBC

disease. in this

duration

remission

in Table 4. The WBC count in predicting both life-threatening

directly

relapse

platelet

morphology; and

remission

at 81/2+

that correlated the incidence

of the patients who did not achieve remission died within 2 months; the remaining patient lived for 7 months. When patients relapsed after their first remission, median survival CNS leukemia

and

(LDH);

attained

Diagnosed

continue

The duration

one

dehydrogenase

women

patients:

women

are shown important

remission with VP-l 6 and one consolidation course

for the total

three

and died. In original regiwho

168

Although the incidence of remission is lower in patients >60 years, the remissions are as durable as those of

younger

trials and

the

died. aged

63 months

lactate

decade from age I 5 to 59 years was at 75% to 84%. Of the seven patients

years,

was

only

serum

each equal

secondary

remission

patient,

hemoglobin,

coagulation parameters; and the amount protocol therapy. Patient age did not predict response. The

transplant with the

One

WBC,

in

of six 1 1+

initial

at

relapsed

Four

age;

patients

The

who

analyzed:

in remission relapsed

of

protocols.

were

at 65 months. DAT-induced

two

144

CR

counts;

He then responded to AAT and for 17 months; his second remis-

underwent bone patients, reinduction

produced

and

in a man

with DAT. on AMSA

patient other

patients

FROM

120

at

34

leukemia 1 5 after

Reinduction

occurred

continues

these

primary

after induction was maintained produced

of

of

96

changed

in remission

continued

72

Remission duration for 36 patients (excluding seven given bone marrow transplantation). Kaplan-Meier product-limit estimate of remission duration for patients who attained remission on any protocol. Tick marks represent patients who continue in remission.

underwent bone of the 36 other

Twelve

a second relapses:

a variety

remission

2).

for 5 years

and one developed have been 20

was

48

Fig 2. who were

Died

therapy

I I continuing

(Fig

at risk

Subsequently,

months There

after

24

MONTHS

Survived

Retroperitoneum

Excluding transplantation,

remissions 42+

Lungs

0

statistically

dif-

hemorrhage. amount

of DNR

per

course

from

90


CUNNINGHAM

1 120

Table

Prognostic

AL

Variables

Life-Threatening Hemorrhage

Pts

WBC (/jiL) 2

treatment

were

reported

in addition

to our

induction,

usually

after

Ara-C

Median remission months to 4 years.

years)

studies”2’9’2226

without

complete

and

5 years

of

in four own.

in these median

used

level

intensive

on reexposure

to

in the consolidation H#{244}pital Saint-Louis of DNR and meth-

(methyl-GAG) followed this

to a total DNR with maintenance

They

observed

dose to

for lethal Kantarjian

APL such

with with

Ara-C.

The

percentage

maintenance or other agents of long

survivors

also decreased from I 1 to 49 (22%) to one of 34 (3%) with the change in consolidation and maintenance.’0 A review of the

M.D.

Anderson

also showed which

that

POMP

the number received less appeared received was

Hospital remission

experience duration

maintenance

by Kantarjian

decreased

was

to decrease. no maintenance

The incidence the lowest

Seven of relapsed.

of hemorrhagic in any published

cantly lower than induction regimen

in protocols

eliminated.34

of long-term survivors intensive consolidation

In our

nine death series

total

dation

(14%) signifi-

patients of 53%

heparin,’#{176}”7#{176}2224’26 whereas

treated to 73%

studies

same time interval on 69 patients showed CR rates of 1 2% to 56%.29.32 heparin

and

conclusively eight other

between 1972 using protocols

conducted

during

did

not,

CR

rate

care

the course

reflect

study,

of this

improvements

have

patients study

correlated

to bleed.

and the in groups

our The

Ten

in

than the Therefore, inclusion in which

of fatal

may initial

WBC

patients

had

an

highest value in the groups may

the not

of heparin may patients are at higher

hemorrhage,

and AMSA in combination TG, are effective regimens

by the study of associated with for

remission

has

with Ara-C, and those using

duration

observation that zL) is associated intensive

relapsed as a useful and

in

from and APL.

higher with

regimens

of

been

Evidence consolidation

may

with

a randomized study of cannot be done. Both with or AMSA

by limited data in this study. are too small to demonstrate a

a phase-Il study role of methyl-GAG

protocols

have risk

particularly

difference. Another promising which produced remission in

be reevaluated. suggests that

have

of Kantarjian

high

of our

remains to be elucidated, and an uncommon disease probably

in The

and

this and maintenance

Many

studies

agent 1 1 of and part

of

particular

refractory of consoli-

should

other

perhaps

studies’#{176}34 may prolong

agree

initial WBC count (>10 shorter remission26’36’37 be

may be 14 (78%)

with

our

to 15,000 and more

value

in

these

patients.

and with ACKNOWLEDGMENT

the

treated without heparin In studies in which some

other

study

in incidence

significant Bisantrene,

who

because

supportive

during

would

for hemorrhage.

may be superior, as suggested However, the patient groups

patients cases.35

in five patients

considered at high risk for hemorrhage.26 ideal induction regimen for treatment of patients

DNR without

who also

that of our historic control group, whose did not include DNR or heparin. The role

groups, studying -280 1986 reported CR rates

received

patients

in this study on APL, and

in

study,

among patients or maintenance

of heparin in decreasing mortality cannot be proven without a randomized study. However,

patients

et al,

with

decreased

hemorrhage. This idea is supported et al, in which use of heparin was

a decrease

a marked

6-mercaptopurine, were replaced in combination

present

and

availability, nor do the studies of cover the same years.26’34 In compari-

tendency

be comparable particular value

patients The

(POMP) of DNR

the

with

2) that

initial WBC count greater Goldberg study (41,000fitL).

decrease in median remission length (48 to 1 5 months) when these reinduction courses followed by prednisone, vincristine, and methotrexate rotating courses

(Table

at greater

et al and

single-institution

Each

relying

treatment.

TG.’#{176}”733

durations The longest

an anthracycline or AMSA repeatedly period. The group of investigators at originally administered repeated courses yl-bis-guanylhydrazone of 25 to 30 mg/kg

and

and

of induction therapy. any significant improve-

results

blood product et al which

or

and

of

1974

investigators

bleeding

treatment

care or Kartarjian

with

heparin,

have

study using

review

These

deaths

Remission rates >65% have been achieved with total DNR doses varying from I 20 to 400 mg/m2,’#{176}”823 and as low as 90

study,

without

severe

hemorrhagic

period

of our

The only of groups between

platelets.

10-year

those

hospitals

protocols

induction

heparin Our study

ment

Boston

and

CR

that

it.2025’26 to those

et al,33 a retrospective

at two

plasma

of improved

effec-

similar

of Goldberg

25 patients

fresh-frozen

maintenance.

approximately

superior published

reported

determine

or the

anthracyclines

AAT remis-

et al.’6 to

consolidation

include

with

of seven).

by Hines

of remission of

in APL,

2 years after similar lengthy

impossible

for induction

or

APL

in AML

study,

dosage length

with

observed

this

remission

(92%), in patients who do four), and in patients who

was

We thank the physicians and technologists care of these patients, and Anna Campbell, Miller,

and

Dr

Phyllis

Hyde

for help

who participated Judy Nicolosi,

in manuscript

in the Wendy

preparation.

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Acute promyelocytic leukemia: treatment results during a decade at Memorial Hospital I Cunningham, TS Gee, LM Reich, SJ Kempin, AN Naval and BD Clarkson

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