ORIGINAL PAPER

Nagoya 1. Med. Sci. 62. 135 - 144, 1999

ACUTE MYELOID LEUKEMIA IN THE ELDERLY:
- 159 NAGOYA CASE STUDIES -
EIICHI NAGURA,I) SABURO MINAMI,2) KOICHIRO NAGATA,3) YOSHIHISA MORISHITA,4)
HIDEO TAKEYAMA,5) HIROSHI SAO,6) HISAMITSU SUZUKI,7) TOMOKI NAOE,8)
SHOZO YOKOMAKU,9) HARUMITSU MIZUNO, Ill) TAKUHEI MURASE,II)
NORIYUKI HIRABAYASHI,12) TAKAAKI TAKEO,13) MITSUNE TANIMOTO, 14)
KOHEI KAWASHIMA
I4
) and HIDEHIKO SAITO
I4
) comprising the Nagoya Cooperative
Study Group for Elderly Leukemia
IIDepartmem of lJ1lernal Medicine, National Institute for Longevity Sciences, Chubu National Hospital
2
J
DepartmeJ1l of Internal Medicine, Japanese Red Cross Nagoya First Ho.lpital
31Departmem of Internal Medicine, Anjo Kosei Hospital
. 4)DepartmeJ1l of Internal Medicine, Konan Showa Hospital
")Department of Internal Medicine, Nagoya Ekisaikai Hospital
6)Department of Internal Medicine, Meitetsu Hospital
7
1
Department of lJ1lernal Medicine, Okazaki Municipal Hospital
SJDepartmeJ1l of Infectious Diseases, Nagoya University School of Medicine
9)Department of Internal Medicine, Aichi Sannomaru Hospital
JI))De/lartment of Hematology, Social Insurance Chukyo Hospital
1)DepartmeJ1l of Hematology, Toyota Memorial Hospital
J2JDepartment of Hematology, Nagoya Daini Red Cross Hospital
)3)Department of Internal Medicine, Yokkaichi Municipal Hospital
J4)First Departlllent of Internal Medicine, Nagoya University School of Medicine
ABSTRACT
To obtain background information on elderly acute myeloid leukemia (AML), unselected data covering
159 patients aged 60 years or over with AML from 14 hospitals in Nagoya, Japan was analyzed retrospec-
tively. Among these patients, 119 had de novo acute AML, 32 had AML which evolved from
myelodysplastic syndrome (MDS-AML), and 8 had other types of leukemia.
The survey showed that MDS-AML tended to be more prevalent in patients aged 70 years and older
and that MDS-AML showed a significantly more severe degree of leukopenia and anemia than de novo
AML. MDS-AML also showed a significantly lower complete remission (CR) rate than that of de novo
AML [6.9% (2/29) vs 58.3% (67/11), P < 0.01] and significantly shorter survival times than those of de
novo AML [median: 3.6 months vs 9.6 months, P < 0.01 (generalized Wilcoxon test; GW].
In de novo AML, the proportion of patients treated with conventional therapy (CT group) decreased
significantly, and that of those with attenuated therapy (AT group) increased significantly as age elevated
(P < 0.01). The CT group showed a significantly higher CR rate (65.4% vs 41.2%, P < 0.05) and a signifi-
cantly longer survival period than those of the AT group [median: 11.6 months vs 4.8 months, P < 0.05
(GW)]. Overall survival rates of the older age groups became significantly shorter with aging [P < 0.01
(GW)].
Key Words: ELDERLY LEUKEMIA, ELDERLY AML, DE NOVO AML, AML EVOLVED FROM
MDS
Correspondence address: Eiichi Nagura, MD Department of Internal Medicine, National Institute for Longevity
Sciences, Chubu National Hospital, 36-3 Gengo, Morioka-cho, Obu, Aichi 474-8511, Japan
Telephone: +81-562-46-2311; Facsimile: +81-562-44-8518; E-mail: nagura@chubu-nh.go.jp
135
136
Eiichi Nagura et 01.
INTRODUCTION
Acute leukemia is more common in older people than in young and middle-aged adults. 1.2..1)
Age is one of the major adverse prognostic factors in both acute myeloid leukemia (AML) and
acute lymphoblastic leukemia (ALL), and the prognosis is known to be poor in elderly pa-
tients.
I
.
S
) The poor outcome of treatment is due to both host-related and intrinsic biological fac-
tors.
l
) It has also been pointed out that most studies of treatment for elderly acute leukemia
describe highly selected groups of One of the arguments for the selection bias is
that some patients in each trial might be excluded by various causes, such as the eligibility cri-
teria of a protocol or a discrete decision by the physician in charge,6'9) and another important
consideration is that the care for elderly patients with acute leukemia is often in the hands of
local physician/hematologists rather than referral centers.?) Although some elderly patients with
AML have antecedent myelodysplastic syndrome (MDS-AML), it is not clear what proportion
these patients represent the published series on elderly In order to obtain realistic
background information on elderly leukemia regarding distribution of types, clinical features,
actual treatment and outcomes, we conducted a retrospective study of 159 patients 60 years of
age or older with acute leukemia admitted to l4 general hospitals in the Nagoya area between
January 1990 and December 1995.
METHODS
Patients
Between January 1990 and December 1995, 159 acute leukemia patients aged 60 years or
over at 14 institutes in the Nagoya area of Japan were entered in this study. Acute leukemia
was defined and classified according to FAB morphological and cytological criterialo.12l by he-
matologists at each institute. De novo AML was defined if no documented hematologic abnor-
mality was identified more than 2 months before the diagnosis of AML.
13
) The diagnosis of
antecedent myelodysplastic syndrome was based on the FAB
Our analysis included clinical and biological characteristics at diagnosis such as age, sex,
type of leukemia, findings of peripheral blood and bone marrow, cytogenetical analysis, WHO
performance status (PS), complications, hepato-renal biochemical data, induction chemotherapy
administered and its outcome and survival, as well as the attitude of the patients or physician
in charge towards the treatment.
Treatments
Induction treatment was at the discretion of each hematologist in clinical charge of the pa-
tient. Treatment was classified by the physician into conventional chemotherapy (CT group),
including so-called intensive or standard chemotherapy, attenuated chemotherapy (given a re-
duced dosage of more than 30% less than the conventional therapy: AT group) or no induction
chemotherapy.
Among the 119 de novo AML cases, 4 patients, who were judged to have poor toleration of
chemotherapy, were given supportive care only. Fifty-four patients (including 18 in the AT
group) were treated with the induction regimen of behenoyl cytosine arabinoside (N4-behenoyl-
I -j3-D-arabinofuranosylcytosine; BH-AC), daunorubicin (DNR), 6-mercaptopurine (6MP), pred-
nisolone (PSL) (BH-ACDMP)15) or ara-C, DNR with/without PSL. The standard dosage of BH-
ACDMP consisted of a 10- to 14- day treatment of daily BH-AC (170 mg/sqm daily 2-h i.v.),
daily 6MP (70 mg/m
2
daily p.o.), and daily PSL (20 mg/m
2
daily p.o.) together with intermit-
tent DNR (25 mg/sqm daily bolus days I and 2; thereafter, as necessary if a hypoplastic bone
137
ELDERLY ACUTE MYELOID LEUKEMIA IN NAGOYA
marrow finding was not attained).151 Nineteen patients (including one in the AT group) were
treated with a combination of DNR plus cytosine arabinoside (ma-C) with/without PSL, which
was administered ara-C 70-150 mg/sqm 7-day continuous infusion (c.i.) and DNR 25-40 mg/
sqm bolus days I, 2 and 3, with/without PSL (20 mg/sqm p.o. day 1-7). The number of cases
with other drug combinations regimens were as follows: 9 cases in ara-C, DNR plus
mitoxantrone (MIT) (I in AT group); 7 cases in BH-AC, DNR plus VPI6 with/without 6MP
with/without PSL; and 26 cases including 6 cases in the AT group treated with low dose ara-C
(LDAC; ara-C 10-20 mg/sqm s.c. or continuously day 14-28).
Among the 32 MDS-AML patients, BH-ACDMP was given in II cases. LDAC was given
to 9 patients. Other regimens were administered to 9 cases. The remaining 3 patients received
no chemotherapy because of a high risk of toxic death.
All treatment was given with the consent of the patients or their guardians. Complete remis-
sion (CR) was defined by normocellular bone marrow containing normal erythroid and granular
series with less than 5% blasts, accompanied by normal levels of peripheral white blood cells
(WBC) and a platelet count with no circulating blasts. The duration of overall survival time
was measured from either the data of the first day of induction chemotherapy or the date of
diagnosis to the time of death.
Statistical Evaluation
Discrete variables were compared between groups, such as the type of disease, patient age
those between 60-69 y.o. (60s), between 70-79 y.o. (70s) or between 80-89 y.o. (80s), the X
2
test and Fisher's exact test where applicable. Continuous variables were compared between
groups using Student's t-test, or were stratified into groups of comparable size and compared
using the X
2
test or Fisher's exact test. Overall survival curves were drawn by Kaplan-Meier
estimates, and compared using a generalized Wilcoxon test and a log-rank test. The closing
date of this study was March 31, 1996.
RESULTS
(I) Clinical and Biological Characteristics
One hundred fifty-nine cases of patients with AML aged 60 years or more were collected.
Among these, I 19 had de novo AML, 32 had MDS-AML, and 8 had other types; namely two
cases of therapy-related leukemia, two AMLs from myelofibrosis, one AML from essential
thrombocythemia, one adult T cell leukemia, one mixed leukemia, and one undetermined acute
leukemia.
Table I compares the clinical and biological data of 119 de novo AML and 32 MDS-AML
patients. The median ages were 69 y.o. for de novo AML and 72 y.o. for MDS-AML. The ra-
tio of de novo AMLlMDS-AML decreased from 5.3 (64/12) in the 60s group, 2.5 (40/16) in
the 70s group, to 3.8 (15/4) in the 80s group, showing an increased tendency fowards MDS-
AML incidence in patients aged 70 or more with no statistical significance (P = 0.102).
Male over female ratios were 65/54 in de novo AML and 21/11 in MDS-AML, showing
male predominance in MDS-AML, but with no statistical significance.
In the FAB classification of de novo AML, the proportion of M3 decreased significantly
from 17.3% (ll/64) in the 60s group to 3.6% (2/55) in the 70s and 80s groups (P < 0.05).
WBC counts of MDS-AML (median: 3.250/J..II) were significantly lower than those of de
novo AML (median: 7600/J..II, P < 0.0 I). The proportions of patients with WBC counts less
than 4,000/J..II of the total cases for a disease type group were 40.3% in de novo AML and
138
Eiichi Nagura el al.
56.7% in MDS-AML. The percentage of blasts in peripheral WBe was significantly less com-
mon in MDS-AML than in de novo AML (P < 0.0 I). Hb concentration of MDS-AML was
significantly lower than that of de novo AML (P < 0.0 I). As for the cellularity of bone mar-
TABLE 1. Clinical and biological characteristics of elderly acute myeloid leukemia
de /lOVO AML
Number of patients 119
Age (y.o.)
median 69
(range) (60-88)
60-69 64
70-79 40
80-89 15
MalelFemale 65/54
Peripheral blood
WBC ( I ~ I )
median 7,600 7,600
(range / ~ l ) (600-406,500)
% of blast in WBC (%)
median 47
(range %) (14-98)
Hb (gldl)
median 8.3
(range) (3.5-14.4)
Platelet (xl 0'/ Ill)
median 4.9
(range) (0.4-38.2)
AML evolved from MDS
32
72
(60-89)
12
16
4
21/11
3,250
(500-213,900)
6
(0-84)
7.3
(4.7-10.6)
5.1
(0.3-60.8)
P value
NS
NS
P < 0.01
(proportion of WBC < 4,000)
P < 0.01
P < 0.01
NS
Cellularity of bone marrow
hypoplastic
normoplastic
hyperplastic
FAB morphology
MO, MI (L1)
M2 (L2)
M3
M4, M5
M6, M7
undetermined
Cytogenetics
normal
t(8, 21)
t(9,22)
t(l5,17)
abn. of 5 or 7
other abn.
Performance status
0, 1,2 72.0%
3,4 28.0%
Complications necessitating
treatment modification
9.5%
25.3%
65.3%
23
37
13
35
10
I
51.9%
4.7%
o
7.5%
10.4%
25.5%
72.0%
28.0%
13.4%
28.0%
28.0%
44.0%
56.0%
o
o
o
16.0%
28.0%
80.0%
20.0%
18.8%
P < 0.05
NS
NS
Rates of effective answers were 100% in number, age, sex, WBC and complications, 94.1 % in % of blasts in
WBC, 99.2% in Hb and Platelet, 84.9% in Performance Status, and 81.6% in cytogenetics.
139
ELDERLY ACUTE MYELOID LEUKEMIA IN NAGOYA
row, hypoplastic bone man'ow was less and hyperplastic marrow was more common in de novo
AML than in MDS-AML (P < 0.05). However, statistical differences for these hematological
parameters were not detected among the 60s, 70s or 80s subgroups of the elderly patients (data
not shown). The proportion of patients with cytogenetical abnormalities was 48.1 % in de novo
AML and 44.0% in MDS-AML.
At diagnosis, 15.1 % of all 159 patients had severe complications which influenced their
treatment modality, though no statistical differences were observed among each disease type
group. The complicating factors were pneumonia(6), renal failure(5), heart failure(2), sepsis(2),
C-type hepatitis(2), hepatic cirrhosis(2), DIC(2), and others(3). Other items, such as WHO per-
formance status, platelet counts, GOT, GPT, LDH, BUN and creatinine, did not show any sta-
tistically significant differences among disease types or age groups (data not shown).
(2) Induction chemotherapy
Although 115 patients with de novo AML were treated by various regimens, their remission
rate was 58.3% (67/115). The CR rates in each age group were 63.5% (40/63) in the 60s,
53.8% (21/39) in the 70s and 46.2% (6/13) in the 80s, showing a somewhat decreasing ten-
dency with aging with no statistical significance.
In de novo AML, 81 cases (68.1%) were treated with CT, 34 (28.6%) with AT and 4
(3.4%) with supportive care only. The proportions of each type of induction therapy were
87.5%, 10.9% and 1.6% in the 60s group, 52.5%, 45.0% and 2.5% in the 70s group, and
26.7%, 60.0% and 13.3% in the 80s group, thus indicating that the size of the CT group de-
creased significantly (P < 0.01), and conversely, that the size of the AT group increased sig-
nificantly (P < 0.0 I) with aging.
The CR rate of the CT group was 65.4% (53/81), which was significantly higher than the
41.2% (14/34) for the AT group (P < 0.05). Although the CT group showed a significantly
higher percentage of blasts in WBC (median; 62% in CT vs 38% in AT), the proportions of
WBC counts less than 4,000/ml were 34.6% in CT and 50.0% in AT with no statistical signifi-
cance (P = 0.122). Both CT and AT groups did not significantly differ in other hematological
and laboratory findings. However, the proportion of PS 3 and 4 in the AT group was 42.9%,
which was significantly higher than the 22.1 % in the CT group (P < 0.05). In addition, G-CSF
was given, to a significant degree, more frequently in the AT group than the CT group (59.3%
vs 29.7%, P < 0.01). The frequency of complications at diagnosis was 17.6% with AT and
ILl % with CT (P = 0.324).
The attitude of patients towards treatment was evaluated by a physician and placed into one
of 4 categories: positive, passive, no desire for induction chemotherapy, or unknown. The pro-
portions, excluding 4 cases without records in de novo AML, were 59.0%, 21.3%, 0% and
19.7% in the 60s group; 35.9%, 30.8%, 5.1% and 28.2% in the 70s group; and 13.3%,73.3%,
0% and 13.3% in the 80s group. These data indicate that a significantly higher proportion of
patients less than 70 years old showed a positive attitude forwards treatment (P < 0.0 I), and
that a significantly higher proportion of patients aged 80 or more showed a negative attitude
forwards treatment (P < 0.01).
The CR rate of MDS-AML, excluding 3 cases with supportive care only, was 6.9% (2/29),
which was significantly lower than that of de novo AML (P < 0.01).
(3) Survival
The median survival times were 9.6 months for de novo AML (3-year rate: 21.9%) and 3.6
months for MDS-AML C3-year rate: 8.8%).
The patients with de novo AML survived significantly longer than those with MDS-AML [P
140
Eiichi Nagura et al.
< 0.01 (GW), P < 0.01 (LR)].
In Fig. 1, the median survival times in de novo AML were 17.8 months for the 60s group,
7.7 months for the 70s group and 3.1 months for the 80s group. Overall survival progressively
and significantly decreased with aging [P < 0.01 (GW), P < 0.01 (LR)].
Analysis of survival based on whether patients were treated with CT or AT (Fig. 2) zyielded
-- 60 - 69 y.o. (64 pts)
- - - 70 - 79 y.o. (40 pts)
-- 80 89 y.o. (15 pts)
I
L _
I
I
('Yo)
100
90
80
Survival
70
Rate
60
50
40
30
20
10
0
0 2 3 4 5 6 7
Years
Fig 1. Survival time of de novo AML according to age groups.
The survival curves of patients aged between 60-69 y.o. (60s), those between 70-79
y.o.(70s) and those between 80-89 y.o.(80s) in de novo AML significantly shorten with
advancing age. [P < 0.01 (generalized Wilcoxon test), P < 0.01 (log-rank test)]
7 6 5 4
-- conventional (51 pts)
- - - attenuated (34 pts)
3 2
1-
1
_
1
- - _t_,
'L tL,
I
I
I
I
I
,
,
"-,
(%)
100
90
80
Survival
70
Rate
60
50
40
30
20
10
0
0
Years
Fig 2. Survival time of de novo AML according to the intensity of induction chemotherapy.
The survival curve of the patients treated with conventional therapy (CT group) was sig-
nificantly longer than that of the patients with attenuated therapy (AT group) [P < 0.05
(generalized Wilcoxon test), P < 0.05 (log-rank test)]. The median times were 11.6 months
for the CT group and 4.8 months for the AT group.
141
ELDERLY ACUTE MYELOID LEUKEMIA IN NAGOYA
a significantly longer survival curve for the CT group than that of the AT group (P < 0.05
(GW), P < 0.05 (LR)]. The median survival periods were I 1.6 months for the CT group and
4.8 months for the AT group.
Early death rates within 7 days from the time of induction or diagnosis, and the death rates
at 30-days were 4.2% and I 1.8% in de novo AML, and 0% and 9.1 % in MDS-AML, respec-
tively.
DISCUSSION
Although a statistically significant relationship was not detected among the patient population
aged 60 years or more, the incidence of MDS-AML, compared with that of de novo AML,
tended to increase with age. Myelodysplasia is predominantly a disease of the elderly and ap-
proximately 30% of these cases are estimated to evolve into AML.
I
) This leads to a signifi-
cantly higher proportion of MDS-AML in elderly patients than in younger patients.
K1
The real
incidence of preleukemic myelodysplasia is difficult to ascertain in the elderly. In clinical re-
ports the proportion of MDS-AML in elderly AML varied from 12.7% to 37.0%,8.13.17.211) includ-
ing our 21.2% (32/l51) in an unselected group of AML cases. These differences have been
ascribed to the background of the patient population, such as single or multi-institutional data
or multi-institutional protocol studies, and to the number of patients on referrals from primary
physicians. In our study, patients with MDS-AML produced a significantly lower CR rate than
those with de novo AML, and survived for a significantly shorter period of time than those
with de novo AML, which confirms other reports. U.17) According to Gajewski et al. 's report,
both antecedent preleukemic syndrome and advancing age were independent negative prognostic
factors for achieving remission.
13
) Thus, the higher incidence of MDS-AML with a poor prog-
nosis is a fundamental feature of elderly acute leukemiaY)
The proportion of the FAB M3 subtype in de novo AML became significantly lower in pa-
tients aged 70 or over than those less than 70 years of age. It was reported that the FAB M3
subtype was rare, accounting for only 1.3% and 4% of elderly patients compared with 11.7%
and 16% in younger adults in a single hematological department experience
8
) and population-
based study,7) respectively. This report may indicate that elderly leukemia arises from less ma-
ture leukemic clones of elderly leukemia as suggested by leukemia cytology, cytochemistry, and
immunophenotype data. I I
Although the choice of treatment for individual elderly patients was mainly left to the dis-
cretion of the physician in charge, the patient's attitude towards therapy is quite important in
applying the treatment modality. In non-elderly adult AML, it is extremely rare that the patient
would not desire conventional chemotherapy, which clearly has brought about the recent objec-
tive improvement in both the CR rate and the number of long-term survivals. Our data on de
novo AML revealed that the proportion of patients with a "positive" attitude towards therapy
decreased significantly from 59.% in patients less than 70 years old to 13.3% in those 80 y.o.
and more (P < 0.01). The attitude towards chemotherapy may be influenced by such factors as
chronological and physiological age, philosophy of life, socio-economic situation and under-
standing of the disease. The interaction between the physician and the elderly patient is also
important in decision-making.
21
) However, we could not investigate which factors had a more
critical impact on patient preference.
In our study, the selection of a therapy for de novo AML was not carried out in a random-
ized fashion nor based on selection criteria. However, we found a marked trend for longer sur-
vival in elderly patients treated by conventional induction treatment. Although it could not be
142
Eiichi Nagura el 01.
determined whether this result should be attributed to the selected group of patients or to the
effect of the treatment itself, this result confirms the prognostic value of therapeutic choice.
S
)
Many investigators now agree that intensive chemotherapy is the best choice for selected eld-
erly patients with AML.
I
) Yet, the question as to what selection criteria should be applied in
the elderly remains. I) In our comparison of CT and AT group characteristics, the criteria of
age, blast percentage in WBC and PS were significant factors. Since debilitated patients with a
poor PS would be candidates for the AT group, PS, which is one of the fundamental eligibility
criteria in the protocol study,s.22) would be quite an important factor in choosing appropriate
therapy. I) We did not find any laboratory data, such as albumin, RBC or BUN, to be a signifi-
cant factor in selecting treatment modality. One of the interesting reports was a clinical trial for
elderly patients assessed not to be able to tolerate full-scale intensive chemotherapy, which pro-
duced a 60% CR rate with a 9.9 month median survival time using oral etoposide and 6-
thioguanine with idarubicin.
19
) However, the eligibility criteria and the background patient popu-
lation were not clearly described.
One of the main characteristics of treatments for elderly patients with acute leukemia is the
high incidence of early death or therapy-related death.
I
.
S
) The death rates varied between 0-
5.0% within 7 days and between 10.0-15.0% at 30-days in the three types of acute leukemia.
Induction mortality decreased from about 30% in the I980S
23
) to 10-20% in recent clinical tri-
als.IS.2U.24) One of the reasons for the reduction in our data might be because the most prevalent
induction therapy used, BH-ACDMP, was a response-oriented therapy, the drug dosages of
which were adjusted depending on the hematological effects of the anti-leukemic drugs on the
preceding day, signifying a 'tailor-made' regimen.
l
) This suggests that careful assessment and
treatment would decrease the risk of early death in elderly patients with acute leukemia.
Since it is well recognized that the chronological age of an elderly patient may differ greatly
from his or her biological age, it is difficult to define a true 'elderly patient' .1) Our data
showed that patients aged 80 y.o. or more had significantly poorer survival times than those
under 80 y.o. in de novo AML. The proportion of patients treated with conventional therapy
and having a 'positive' outlook towards treatment were significantly low in the 80s group.
Thus, we would propose that patients aged 80 or more should be handled in another category
as true elderly patients.
We think that this retrospective analysis is representative of a realistic clinical spectrum of
elderly acute leukemia, showing the essential background information on distribution of types
and outcomes. Further study is warranted to determine what selection criteria should be applied
to choose the most appropriate form of therapy in elderly patients suffering from acute leuke-
mia.
ACKNOWLEDGMENTS
The authors are grateful to Ms. Miki Morita for her assistance in the statistical analysis of
this study. This research was supported in part by grants from the Aichi Cancer Research
Foundation and the Aichi Hematological Research Foundation.
REFERENCES
I) Johnson, P.R.E., Liu Yin, J.A.: Acute myeloid leukemia in the elderly: Biology and treatment [Clinical an-
notation]. Br. J. Hoell/alai., 83, 1-6 (1993).
2) Whitely, R., Hannah, P. and Holmes, F.: Survival in acute leukemia in elderly patients: No improvement in
the 19805. J. A11/. Gerialr. Soc., 38, 527-530 (1990).
143
ELDERLY ACUTE MYELOID LEUKEMIA IN NAGOYA
3) Sorenson, J.T., Gerald, K., Bodensteiner,D. and Holmes,F.F.: Effect of age on survival in acute leukemia:
1950-1990. Cancer, 72, 1602-1626 (1993).
4) Legrand, 0., Marie, J.P., Marjanovic, Z., Cadiou, M., Blanc, c., Ramond, S., Viguie, F., Purrot, J.Y. and
Zittoun, R.: Prognostic factors in elderly acute lymphoblastic leukemia. Er. 1. Haemalol., 97, 596-602
(1997).
5) Hamblin, T.1.: Disappointments in treating acute leukemia in the elderly [Editorial]. N. Engl. J. Med., 332,
1712-1713 (1995).
6) Copplestone, J.A., Smith, A.G., Oscier, D.G. and Hamblin, T.1.: True outlook in acute myeloblastic leuke-
mia. Lancel, I, 1104 (1986).
7) Taylor, P.R.A., Reid, M.M., Stark, A.N., Bown, N., Hamilton, P.1. and Proctor S.1.: De novo acute myeloid
leukemia in patients over 55-years-old. A population-based study of incidence, treatment and outcome. Leu-
kemia, 9, 23 I-237 (1995).
8) Baudard, M., Marie, J.P., Cadiou, M., Viguie, F. and Zittoun, R.: Acute myelogenous leukemia in the eld-
erly: Retrospective study of 235 consecutive patients. Er. J. Haemalol., 86, 82-91 (1994).
9) The Toronto Leukemia Study Group: Results of chemotherapy for unselected patients with acute myeloblas-
tic leukemia: Effect of exclusions of interpretation of results. Lancel, I, 786-788 (1986).
10) Bennett, J.M., Catovsky, D., Daniel, M.T., Flandrin, G., Galton, D.A.G., Harvey, R., Gralnick, H.R. and Sul-
tan, C.: Proposed revised criteria for the classification of acute myeloid leukemia: A report of the French-
American-British Cooperative Group. Ann. Intern. Med., 103, 626-629 (1985).
II) Bennett, J.M., Catovsky, D., Daniel, M.T., Flandrin, G., Galton, D.A.G., Harvey, R., Gralnick, H.R. and Sul-
tan, c.: Criteria for the diagnosis of acute leukemia of megakaryocyte lineage (M7):A report of the French-
American-British Cooperative Group. Ann. Inlern. Med ., 103, 460-462 (1985).
12) Bennett, J.M., Catovsky, D., Daniel, M.T., Flandrin, G., Galton, D.A.G., Gralnick, H.R. and Sultan, C.: Pro-
posal for the recognition of minimally differentiated acute myeloid leukemia (AML-MO). Er. J. Haemalol.,
78,325-329 (1991).
13) Gajewski, J.L., Ho, W.G., Nimer, S.D., Hirji, K.F., Gekelman, L., Jacobs, A.D. and Champlin, R.E.: Effi-
cacy of intensive chemotherapy for acute myelogenous leukemia associated with a preleukemic syndrome. J.
Clin. Oncol., 7, 1637-1645 (1989).
14) Bennett, 1.M., Catovsky, D., Daniel, M.T., Flandrin, G., Galton, D.A.G., Gralnick, H.R. and Sultan, c.: Pro-
posals for the classification of the myelodysplastic syndromes. Er. J. Haematol., 51, 189-199 (1982).
15) Nagura, E., Kimura, K., Yamada, K., Ohta, K., Maekawa, T., Takaku, F., Uchino, H., Masaoka, T., Amaki,
I., Kawashima, K., Kariyone, S., Toyama, K., Ichimaru, M., Nomura, T., Sakai, Y., Takatsuki, K. and
Hamajima, N.: Nationwide randomized comparative study of daunorubicin and aclarubicin in combination
with behenoyl cytosine arabinoside, 6-mercaptopurine, and prednisolone for previously untreated acute my-
eloid leukemia. Cancer ChemOlher. Pharmacol., 34, 23-29 (1994).
16) Nagura, E., Kimura, K., Yamada, K., Ohta, K., Maekawa, T., Takaku, F., Uchino, H., Masaoka, T., Amaki,
I., Kawashima, K., Ohno, R., Nomura, T., Hattori, J., Kawamura, S., Shibata, A., Shirakawa, S. and
Hamajima, N.: Nationwide randomized comparative study of doxorubicin, vincristine and prednisolone com-
bination therapy with and without L-asparaginase for adult acute lymphoblastic leukemia. Cancer
Chemother. Pharmacol., 33, 359-365 (1994).
17) Liu Yin, J.A., Johnson, P.R.E., Davies, J.M., Flanagan, N.G., Gorst, D.W. and Lewis, M.1.: Mitozantrone
and cytosine arabinoside as first-line therapy in elderly patients with acute myeloid leukemia. Er. J.
Haematol., 79, 415-420 (1991).
18) Feldman, E.1., Seiter, K., Damon, L., Linker, c., Rugo, H., Ries, c., Case, D.C., Beer, M. and Ahmed, T.:
A randomized trial of high- vs standard-dose mitoxantrone with cytarabine in elderly patients with acute
myeloid leukemia. Leukemia, II, 485-489 (1997).
19) Ruutu, T., Almqvist, A., Hallman, H., Honkanen, T., Jarvenpaa, E., Jarventie, G., Koistinen, P., Koivunen,
E., Lahtinen, R., Lehtinen, M., Nousiainen, T., Pelliniemi, T.T., Rajamaki, A., Remes, K., Sarkkinen, R.,
Sinisalo, M., Timonen, T., Volin, L. and Elonen, E.: Oral induction and consolidation of acute myeloid leu-
kemia with etoposide, 6-thioguanine, and idarubicin (ETl) in elderly patients: A randomized comparison
with 5-day TAD. Leukemia, 8, 11-15 (1994).
20) Heyll, A., Aul, C., Gogolin, F., Runde, V., Sohngen, D., Meckenstock, G., Wolf, H.H., Zahner, 1., Burk,
M., Winkelmann, M. and Schneider, W.: Results of conventional-dose cytosine arabinoside and idarubicin in
elderly patients with acute myeloid leukemia. Ann. Hemalol., 68, 279-283 (1994).
21) Ganz, P.A.: Interaction between the physician and the older patient: The oncologist's perspective. Cancer,
80, 1323-1325 (1997).
22) Johnson, P.R.E., Hunt, L.P. and Liu Yin, J.A.: Prognostic factors in elderly patients with acute myeloid leu-
kemia: Development of a model to predict survival. Er. J. Haematol., 85, 300-306 (1993).
144
Eiichi Nagura el 01.
23) Tilly, H., Castaigne, S., Bordessoule, D., Casassus, P., Prise, P.Y., Tertian, G., Desablens, B., Henry-Amar,
M. and Degos, L.: Low-dose cytarabine versus intensive chemotherapy in the treatment of acute
nonlymphocytic leukemia in the elderly. 1. Clin. Oneol., 8, 272-279 (1990).
24) Bow, EJ., Sutherland, l.A., Kilpatrick, M.G., Williams, GJ., Clinch, J.J., Shore, T.B., Rubinger, M. and
Schocter, B.A.: Therapy of untreated acute myeloid leukemia in the elderly: Remission-induction using a
non-cytarabine-containing regimen of mitoxantrone plus etoposide. 1. Clin. Oneol., 14, 1345-1352 (1996).