Vol 73. No 5 (April),1989: pp 1 1 16-i 122. Acute. Promyelocytic. Leukemia: Treatment. Results. During a Decade at Memorial. Hospital. By. Isabel. Cunningham,.
From www.bloodjournal.org by guest on July 19, 2016. For personal use only.
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
From www.bloodjournal.org by guest on July 19, 2016. For personal use only.
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.
REFERENCES
1. Risak 2.
Hillestad
E: Die Fibrinopenie. LK:
Acute
Scand 159:189, 1957 3. Didisheirn P, Trombold
Z KIm Med promyelocytic
iS, Vandervoort
128:605, leukemia.
RLE,
1935 Acta
Mibashan
Med
RS:
Acute promyelocytic leukemia with fibrinogen and factor V deficiencies. Blood 23:717, 1964 4. Rosenthal RL: Acute promyelocytic leukemia associated with hypofibrinogenemia. Blood 21:495, 1963
From www.bloodjournal.org by guest on July 19, 2016. For personal use only.
CUNNINGHAM
1122
5.
Baker
WG,
Bang
NU,
Nachman
Hypofibrinogenernic
hemorrhage
treated
Ann
with
heparin.
RL,
Raaft
in acute
Intern
Med
61:116,
7.
Rand
JJ,
Moloney
8.
Gralnick
HR.
hemorrhagic 52:167,
WC,
leukemia. Bagley
diathesis
Sise
Arch
HS:
Intern
J, Vandenbroucke J: components as a cause 1965
Coagulation
Med
J, Abrell
of acute
HI:
leukemia
1964
6. Verstraete M, Vermylen C, Vermylen Excessive consumption of blood coagulation of hemorrhagic diathesis. Am J Med 38:899, promyclocytic
F, Horowitz
myelogenous
defects
123:39,
E: Heparin
in acute
treatment
promyelocytic
leukemia.
for Am
the
J Med
1972
9. Bernard J, Weil M, Boiron M, Jacquillat C, Flandrin G, Gemon M-F: Acute promyelocytic leukemia: Results of treatment by daunorubicin. Blood 41:489, 1973 10. Marty M, Ganem G, Fischer J, Flandrin G, Berger R, Schaison
G, Degos
L, Boiron
M:
Leucemie
Etude retrospective de I I 9 malades Rev Fr Hematol 26:371, 1984 11.
Clarkson
chenal I975
JH:
12.
BD,
Drapkin
Kempin
5,
RL,
Gee
TS,
JM,
Gee
TS,
leukemia Dowling
MD,
Cancer
Catovsky
Nouv
Cunningham
in adults.
B: Prophylactic
leukemia.
Bennett
promyelocytaire:
trait#{233}s par daunorubicine.
MD,
of acute
Clarkson
promyelocytic 13.
Dowling
Treatment
aigue
Arlin
heparin
41:2484,
1978
D, Daniel
M-T,
lB.
Cancer
Bur-
36:775,
Z, McKenzie
therapy
5,
in acute
(AMSA)
thioguanine.
in combination
Cancer
Clin
16. Hines JD, Mazza Bennett JM, O’Connell cytosine
ously Oncol
arabinoside
and
Trials
with
G,
Galton
Cordonnier
amsacrine
C, Vernant
arabinoside
and
4:31 7, 1981
Adelstein survival
induction
untreated de novo acute 14:47, 1987 (suppl 1)
17.
cytosine
JJ, Oken MM, MJ: Prolonged
Brun
DJ, after
in patients
nonlymphocytic JP,
Cassileth
Keller A, high-dose with
leukemia.
B, Heilmann
MG,
previ-
Semin Kuentz
M, Bierling P, Farcet JR. Rodet M, Duedari N, Imbert M, Dreyfus B, Rochant H: Acute promyelocytic leukemia in 58 previously untreated patients. Cancer 55:18, 1985 18. Daly PA, Schiffer CA, Wiernik PH: Acute promyelocytic leukemia-Clinical management of I 5 patients. Am J Hematol 8:347, 1980
PA,
Begg
CB,
Bennett
JM,
Bozdech
M,
Kahn
SB,
Weiler C, Glick JH: A randomized study of the efficacy of consolidation therapy in adult acute nonlymphocytic leukemia. Blood 63:843, 1984 25. DiMarco P, Cajozzo A: Acute prornyelocytic leukemia: Management of DIC during remission induction. Third International Symposium on Therapy of Acute Leukemia. Rome, December 1982, p 141 (abstract) 26.
Kantarjian
HM,
Keating
Mi,
MeCredie
K,
Walters
RS,
Estey EH, Smith TL, Dalton WT, Trujillo JM, Freireich EJ: Acute promyelocytic leukemia: The M.D. Anderson Hospital Experience. Am J Med 80:789, 1986 27. Petti MD, Amadori 5, Avvisati G, Baccarani M, Cafolla A, Ruggero D, Tura 5, Mandelli F: Acute promyelocytic leukemia. A collaborative study of 62 patients. Third International Symposium on Therapy of Acute Leukemia. Rome, December 1982, p 20 (abstr) 28.
Flandrin
DAG, Gralnick HR. Sultan C: Proposals for the classification of the acute leukemias. Br J Haematol 33:451, 1976 14. Golomb HM, Rowley JD, Vardiman JW, Testa JR, Butler A: “Microgranular” acute promyelocytic leukemia: A distinct clinical, ultrastructural, and cytogenetic entity. Blood 55:253, 1980 15. Arlin Z, Flomenberg N, Gee TS, Kempin 5, Dellaquila C, Mertelsmann R, Straus DJ, Young CW, Clarkson BD: Treatment of acute leukemia in relapse with 4’(9-acridinylamino) methanesulfonanisidide
promyelocytic leukemia: Results in therapy and prognostic factors. Fourth International Symposium on Therapy of Acute Leukernias, Rome, 1987 (abstr 477) 23. Hurd DD, Vukelich M, Arthur DC, Lindquist LL, McKenna RW, Peterson BA, Bboornfield CD: 15;l7 Translocation in acute promyelocytic leukemia. Cancer Genet Cytogenet 6:331, 1982 24.
1969
ET AL
Larson
RA,
Kondo
K,
Vardiman
JW,
Butler
AE,
Golomb
HM, Rowley JD: Evidence for a 15;17 translocation in every patient with acute promyelocytic leukemia. Am J Med 76:827, 1984 29.
Ruggero
Ricci
D, Baccarani
P. Zaccaria
MA, Tura analysis
A, Lauria
5: Acute
30.
Bevan
Acta
D, Powles
in acute
A, Gugliotta I, Fiacchini
promyelocytic
of 1 3 cases.
induction
M, Guarini F, Tomasini
leukemia:
Haematol
58:108,
RL, Clink
HM,
nonlymphocytic
Results
L, Gobbi
M,
M, Santucci
of therapy
and
1977
Leigh
M: Rapid
leukemia.
Third
remission
International
Symposium on Therapy of Acute Leukemia, Rome, December 1982, p 28 (abstr) 31. Rai KR, Holland iF, Glidewell OJ, Weinberg V. Brunner K, Obrecht JP, Preisler HD, Nawabi 1W, Prager D, Carey RW, Cooper MR, Haurani F, Hutchison JL, Silver RT, Falkson G, Wiernik P, Hoagland HC, Bboomfield CD, James GW, Gottlieb A, Ramanan SV, Blom J, Nissen NI, Bank A, Ellison RR, Kung F, Henry P, McIntyre OR, Kaan 5K: Treatment of acute myelocytic leukemia: A study by cancer and leukemia group B. Blood 58:1203, I981
32. Weinstein Hi, Mayer Ri, Rosenthal DS, Coral FS, Camitta BM, Gelber RD: Chemotherapy for acute myelogenous leukemia in children and adults: VAPA update. Blood 62:3 15, 1983 33. Goldberg MA, Ginsburg D, Mayer Ri, Stone RM, Maguire M, Rosenthal DS, Antin JH: Is heparin administration necessary
19. Collins J, Bboomfield CD, Peterson BS, McKenna RW, Edson JF Jr: Acute promyelocytic leukemia. Management of the coagulopathy during daunorubin-prednisone remission induction. Arch Intern Med 138:1677, 1978 20. Bennett JM, Gebb CB: Eastern Cooperative Oncology Group study of the cytochemistry of adult acute myeloid leukemia by
during
correlation
Espie M, Boiron M: Bisantrene: An anthracycline derivative active in ANLL: Phase II study. Fourth International Symposium on Therapy of Acute Leukemias, Rome, 1987 (abstr 598) 36. McKenna RW, Parkin J, Bboomfield CD, Sundberg RD. Brunning RD: Acute promyelocytic leukaemia: A study of 39 cases with identification of a hyperbasophilic microgranular variant. Br J Haematol 50:201, 1982
41:4833,
of
subtypes
with
response
and
survival.
Cancer
Res
1981
21. Mirto 5, Mandelli F, Petti MC, Avvisati G, Vegna ML, Cantore N, Caronia F, Deriu L, Gabbas A, Neri A, Leone G, Liso V. Martelli M, Musso M, Peta A: Acute promyelocytic leukemia: A prospective Gimema study of 84 previously untreated adults. Fourth International Symposium on Therapy of Acute Leukemias. Rome, l987(abstr 115)
22. Sanz J, Rafecas
M, Jarque J, Pastor
I, Martin-Aragones E, Sayas Mi,
G, Lorenzo I, Martinez Sanz G, Gomis F: Acute
cytic
induction
chemotherapy
leukemia?
Blood
69:187,
for
patients
with
acute
promyelo-
1987
34. Kantarjian HM, Keating MJ, Walters RS, Smith MeCredie KB, Freireich EJ: Role of maintenance chemotherapy acute promyelocytic leukemia. Cancer 59:1258, 1987 35.
37.
Marty
Berger
M,
R,
Isnard
Bernheim
t(l5:I7) Translocation cytological “M3-variant.”
F, Gourmel
A, Daniel
G, Lefebvre
MT.
P. Gisselbrecht
Valensi
in acute promyelocytic Nouv Rev Fr Hematol
F, Flandrin
leukemia (M3) 23:27, 1981
TL, in C,
G:
and
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1989 73: 1116-1122
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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