вход по аккаунту



код для вставкиСкачать
Leukemia Long-Term Survival: Collaborative Task Force
Review and Analysis
Supplement to Cancer
Long-Term Survival in Acute Myeloid Leukemia
The Eastern Cooperative Oncology Group Experience
John M. Bennett, M.D.1
Mary L. Young, Ph.D.2
Janet W. Andersen, Ph.D.2
Peter A. Cassileth, M.D.3
Martin S. Tallman, M.D.4
Elisabeth Paietta, Ph.D.5
Peter H. Wiernik, M.D.5
Jacob M. Rowe, M.D.1
BACKGROUND. The data base of the Eastern Cooperative Oncology Group (ECOG)
provides access to data on a large adult patient population drawn from more than
25 major university institutions and hundreds of participating hospitals. Extensive
medical files are maintained at the ECOG Coordinating Center and are updated
METHODS. Data on 1414 eligible patients with acute myeloid leukemia (AML),
treated on 6 ECOG protocols during the period 1976–1994, were reviewed to deter-
Hematology/Medical Oncology Unit, University
of Rochester Cancer Center, Rochester, New
Dana Farber Cancer Institute, Boston, Massachusetts.
Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida.
Northwestern University Medical School, Chicago, Illinois.
Albert Einstein Cancer Center, Bronx, New
mine the number of long-term survivors (LTS) and to identify factors that predicted
LTS. Disease free survival and factors impacting quality of life were examined as
RESULTS. Of the 1414 patients, 274 survived for ¢3 years and were considered
LTS. A logistic regression analysis revealed that factors predicting LTS included
age õ 55 years, female gender, treatment between 1985 and 1990, white blood
cell count õ 10,000 cells/mm3, and hemoglobin ú10 g/dL. Disease free survival
improved with escalating intensity of therapy. Quality-of-life data showed that
infections were fairly common. Significant graft-versus-host disease occurred in 6
of 40 patients who received allogeneic bone marrow transplantation and contributed to the deaths of 4 individuals. Information on employment, insurance, social
or marital difficulties, and psychosocial issues was more difficult to obtain.
CONCLUSIONS. Prognosis in AML is a complex interaction involving the cellular
origin of the malignant clone, morphology, and evolving therapeutic strategies.
The most recent ECOG studies incorporate these variables and should provide
additional insights into factors affecting LTS in patients with AML. Cancer
1997;80:2205–9. q 1997 American Cancer Society.
KEYWORDS: acute myeloid leukemia, long-term survival.
Presented at Leukemia Long-Term Survival:
Collaborative Task Force Review and Analysis,
Orlando, Florida, December 5, 1996.
This study was conducted by the Eastern Cooperative Oncology Group and supported in part
by the following U.S. Public Health Service
Grants from the National Cancer Institute, National Institutes of Health, Department of Health
and Human Services: 1CA 11083, 2CA 22318,
CA 15488, 4CA 17158, and 5CA 14958.
Address for reprints: John M. Bennett, M.D.,
Hematology/Medical Oncology Unit, University
of Rochester Cancer Center, 601 Elmwood Avenue, Box 704, Rochester, NY 14642.
Received August 13, 1997; accepted September
8, 1997.
he data base of the Eastern Cooperative Oncology Group (ECOG)
provides access to data on a very large adult patient population
drawn from more than 25 major university institutions and hundreds
of participating affiliated hospitals, predominantly in the Eastern half
of the United States. Extensive medical files, on both computer and
paper, are maintained at the ECOG Coordinating Center and are updated on a regular basis via a long-term follow-up form.
We have reviewed data on 1414 eligible and evaluable patients
with a pathologic diagnosis of acute myeloid leukemia (AML), FrenchAmerican-British (FAB) types M1 – M7, who were treated on 6 ECOG
protocols during the period 1976 – 1994. The purpose of this review
was to determine the number of long-term survivors (LTS), identify
factors that predicted for LTS, and identify other factors that might
impact on the quality of life of these individuals. We have included
a brief review of disease free survival (DFS) as well.
q 1997 American Cancer Society
/ 7b92$$1443
11-10-97 03:02:55
W: Cancer
CANCER Supplement December 1, 1997 / Volume 80 / Number 11
Six protocols were active during the 18-year accrual
period (E2476, E1479, E3483, PC486, E1490, and
E2491). Induction1 and postremission2 results from all
6 studies have been extensively reported recently.
All protocols included daunorubicin and cytosine
arabinoside (cytarabine) for induction, except for
E2491, in which half the patients with promyelocytic
leukemia received all-trans retinoic acid (ATRA) in induction. All protocols included consolidation with the
induction regimen and most included some form of
maintenance (usually 6-thioguanine and subcutaneous cytarabine), except for E3483, in which patients
not eligible for allogeneic bone marrow transplantation (BMT) were randomized to observation alone,
consolidation therapy only, or maintenance only. In
the more recent protocols, intensive postremission
therapy with high dose cytarabine or allogeneic/autologous bone marrow transplantation was employed.
The definition of ‘‘cure’’ was developed in a previous publication.3 We argued that an important issue
in analyzing long-term DFS was the question of ‘‘uninformative censoring.’’ Patients who are at risk for failure may be ‘‘lost to follow-up’’ (although they are
known to have died), but without the investigator’s
knowledge of when or whether relapse occurred. Early
in a study, deaths are very likely leukemia-related, but
later deaths are more difficult to define without specific bone marrow data. In a sense, we are performing
an analysis of competing risks. Estimates of cure are
affected by whether cases of ‘‘death without documented relapse’’ are considered to be treatment failures or censored. Additionally, analyses of study specific DFS do not capture the benefit of effective salvage
therapy after relapse. This is especially important for
transplantation as second-line therapy. Also, the impact of lingering or late toxicity is not captured. Survival is the ultimate test of patient benefit. Therefore,
this discussion focuses on LTS, defined as survival of
3 years or more after study entry. Specifically, patients
who continued in complete remission for at least 3
years were considered ‘‘cured’’ because relapse was
extremely rare after that time point.
Fisher’s exact test4 and the Wilcoxon rank sum
test were used in the univariate comparisons of LTS
vs. non-LTS. Overall survival curves were produced
using the Kaplan – Meier method.5 A logistic regression
model was used to predict LTS versus non-LTS.4
Among the 1414 eligible patients, 870 had complete
remissions (62%) and 660 (76%) relapsed or died. The
median overall DFS was 0.75 years and the 5-year DFS
rate was 22% (95% confidence interval: 19%, 25%).
/ 7b92$$1443
11-10-97 03:02:55
FIGURE 1. Overall survival, representing all protocols, is shown.
FIGURE 2. Overall survival from the time of diagnosis is shown by age
(excluding protocol E2491).
Figure 1 illustrates the overall survival for all 1414 patients. As shown in Figure 2, the 5-year survival rate
ranged, by protocol, from 9% to 33% (excluding protocol E2491) for patients age õ 55 years and from 6% to
13% for patients age ¢55 years.
Disease Free Survival Data
Among patients age õ 55 years, the DFS rate for those
who received induction only was 0%, with a 5-year
survival rate of 10%. Low dose maintenance therapy
raised the 5-year DFS rate to 13% and the 5-year survival rate to 19%. Intermediate dose consolidation
therapy further improved the DFS rate to 24% and
the 5-year survival rate to 33%. The results were not
different with high dose cytarabine. The results with
autologous or allogeneic BMT appeared better. The 5year DFS rate rose to 55% with autologous BMT vs.
40% with allogeneic BMT; the 5-year survival rates
were 53% vs. 45%, respectively (Table 1).
W: Cancer
AML Long-Term Survival: ECOG Experience/Bennett et al.
Escalating Intensity of Postremission Therapy: Patients Age õ55
5-yr DFS
Prognostic Factors: Univariate Analysisa
5-yr survival
Postremission therapy
Study no.
(95% CI)
(95% CI)
Maintenance and intermediate
dose consolidation 1 2
Intensive consolidation 1 1
Autologous BMT
Allogeneic BMT
1479, 3483
(0, 0)
(7, 19)
(0, 23)
(12, 26)
(14, 33)
(14, 34)
(40, 70)
(22, 58)
(22, 43)
(18, 39)
(38, 69)
(27, 63)
DFS: disease free survival; CI: confidence interval; BMT: bone marrow transplantation.
For patients age ¢55 years, the impact of intermediate or high dose cytarabine was much worse. For
example, the 5-year DFS rates were only 16% and 22%,
Long-Term Survival Data
Of the 1414 eligible patients, 274 have survived for ¢3
years and are therefore LTS. We have chosen this time
as a reference point because it approximates the previous definition of ‘‘cure.’’
There are several categories of LTS. The largest
group is composed of patients who remained in their
first remission for ¢3 years (n Å 132, or 48%). The
second largest group is composed of those whose remission was õ 3 years in duration and who died after
surviving for ¢3 years (n Å 50, or 18%). The third
largest group includes patients whose remission lasted
õ3 years but who are still alive beyond 3 years because
of a second remission from chemotherapy or BMT, or
who are in relapse but still alive (n Å 33, or 12%). A
small number of patients never achieved a complete
remission but are alive beyond 3 years (n Å 15, or 6%)
or survived for at least 3 years without ever achieving
a remission and then died (n Å 8, or 3%). Finally, there
are patients whose initial complete remission lasted
¢3 years and who died without relapse (n Å 5, or 2%)
and those whose complete remission lasted ¢3 years
and are alive after relapse (n Å 3, or 1%). An additional
55 patients (4%) are alive at õ3 years and could become LTS, but are classified as non-LTS for the purpose of this analysis.
A significantly higher number of males were nonLTS than LTS (54% vs. 46%, respectively; P Å 0.02).
The median age was 40 years for the LTS versus 48
years for the non-LTS. Patients age õ 55 years were
more likely to be LTS (P õ 0.01). This result should be
/ 7b92$$1443
11-10-97 03:02:55
Age (yrs)
Period treatment began
WBC (cells/mm3)
Hemoglobin (g/dL)
LTS (n Å 274)
No. of patients
(n Å 1140)
No. of patients (%)
Fisher’s exact
P value
129 (17%)
145 (22%)
626 (83%)
513 (78%)
200 (22%)
73 (14%)
703 (78%)
435 (86%)
36 (12%)
71 (19%)
135 (26%)
32 (14%)
257 (88%)
309 (81%)
377 (74%)
197 (86%)
137 (22%)
76 (19%)
36 (12%)
476 (78%)
329 (81%)
264 (88%)
168 (18%)
102 (22%)
749 (82%)
360 (78%)
LTS: long-term survivors; WBC: white blood cell count.
Some data are missing for age, gender, WBC, and hemoglobin.
viewed with caution because the recipients of BMT
are younger and other relative factors may be involved.
Treatment regimens changed over the 18 years
covered by this analysis. Patients treated between 1985
and 1990 were more likely to be LTS (P õ 0.001). It is
important to note that even if all 55 living patients
with insufficient follow-up to qualify them as LTS were
eventually to become LTS (52 of 55 were treated between 1990 and 1994), the P value would still be significant (Table 2).
There was a significant difference in white blood
cell counts (WBCs) in LTS vs. non-LTS. Patients with
counts õ 10,000 cells/mm3 were most likely to be LTS.
Patients with counts ¢50,000 cells/mm3 were the least
likely to be LTS (P õ 0.001). Hemoglobin levels did
not differ significantly between LTS and non-LTS (P
Å 0.09). See Table 2 for more details.
We have examined the association of the FAB
morphologic subtypes in the LTS vs. the non-LTS.
There was a higher proportion of FAB M4 (myelomonocytic type) in the LTS and a higher percentage of
M5 in the non-LTS, the Pearson chi-square value being
0.05 (Table 3).
A logistic regression analysis was performed with
the following predictors: age (with a cutoff at 55 years);
gender; FAB type (M3 treated with ATRA vs. M3 treated
only with chemotherapy vs. other FAB types); period
in which treatment began, in 5-year intervals (1975 –
W: Cancer
CANCER Supplement December 1, 1997 / Volume 80 / Number 11
Impact of FAB Subtypes on LTS
No. of patients (%)a
FAB classification
M type
56 (20%)
65 (24%)
51 (19%)
77 (28%)
14 (5%)
6 (2%)
5 (2%)
201 (18%)
269 (24%)
191 (17%)
279 (24%)
124 (11%)
41 (4%)
35 (3%)
257 (18%)
334 (24%)
242 (17%)
356 (25%)
138 (10%)
47 (3%)
40 (3%)
FAB: French-American-British; LTS: long-term survivors.
Pearson chi-square P Å 0.05.
FIGURE 3. Overall survival is shown by protocol.
1980, 1980 – 1985, or 1985 – 1990 vs. 1990 – 1994); WBC
(õ10,000 vs. 10,000 – 50,000 vs. ¢50,000 cells/mm3);
performance status (ECOG 0/1 vs. 2, 3, or 4); and hemoglobin (õ10 vs. ¢10 g/dL). In this model, the significant predictors of LTS were age õ 55 years (P Å
0.002); female gender (P Å 0.03); treatment between
1985 and 1990 (P Å 0.0001); WBC õ 10,000 cells/mm3
(P Å 0.02); and hemoglobin ú 10 g/dL (P Å 0.02).
Quality-of-Life Issues
Quality-of-life issues belonged to 2 major categories:
interference with normal life activity secondary to
medical complications attributable to the disease, or
secondary issues that may impair the quality of life.
From the ECOG follow-up forms, infections were documented in 16% of the LTS. The most frequent were
‘‘hepatitis’’ (elevated liver function tests), herpes zoster, and herpes simplex. None of these were life-threatening. A small number of urinary tract and upper respiratory tract infections were noted.
Significant chronic graft-versus- host disease was
observed in 6 patients and contributed to the deaths
of 4 (among some 40 patients) who received allogeneic
It has been very difficult to document other important quality-of-life factors, such as employment,
insurance, social or marital difficulties, and psychosocial issues. Most cooperative groups, including the
ECOG, have relied on a long-term follow-up form,
which is requested every 3 months for 2 years, then
every 6 months for Years 2 – 5, then yearly. A review
revealed that only 10% of 274 forms contained any
information on employment, 3% had information on
insurance, and none provided any insight into social
or marital problems. A telephone survey was con-
/ 7b92$$1443
11-10-97 03:02:55
ducted with the physicians responsible for the care
of 25 of the LTS (only those in continuous complete
remission). The interview was scheduled ahead of time
to allow chart access or patient contact if desired by
the physician. Each call was 5 minutes in duration.
In contrast to the paucity of data from the followup forms, significantly more information was obtained
from the telephone interviews. For example, employment status was documented in 14 of 25 cases and
insurance coverage in all cases, but very little information was obtained in the other areas.
A small number of second neoplasms were noted.
These included skin, pancreatic, gastrointestinal, and
bladder cancers and one case of atypical chronic myeloid leukemia, for a total of 9. An additional 6 patients
developed a myelodysplastic syndrome prior to a documented relapse of AML.
The ECOG experience in the study of nearly 1500
adults with previous untreated AML confirms and extends our previous observations.3 The percentage of
5-year survivors increased modestly, probably more
as a result of better consolidation or intensification
therapy than because of any change in the complete
remission rate. In the multivariate analysis of factors
contributing to LTS, we continue to demonstrate that
age and the WBC are important and have added a
significant new factor, namely, more recent therapy
(which includes allogeneic BMT, autologous BMT, and
high dose cytarabine). Additional insight into these
factors can be observed in Figure 3, which shows that
survival seems to be longer in the more recent protocols. Although the ‘‘cure model’’ predicts well for LTS,
there continue to be a small number of ‘‘bona fide’’
relapses between Years 10 and 15 (2 of 45 patients).
W: Cancer
AML Long-Term Survival: ECOG Experience/Bennett et al.
The disease was classified as FAB M3 in one of these
patients and as M4 (myelomonocytic leukemia) in the
It is clear that quality-of-life issues are identified
much better when a specific set of questionnaires is
used.6 In the ECOG, the Health Behavior and Practice
Committee has assumed this responsibility.
Prognosis in AML is a complex interaction involving the cellular origin of the malignant clone (as defined by molecular and cytogenetic immunophenotyping), morphology (for example, the presence or absence of dysplasia), and evolving therapeutic strategies
(including BMT). Our most recent studies incorporate
all these variables and should provide further insight
into the factors that lead to LTS.
Rowe JM, Andersen JW, Cassileth PA, Oken MM, Bennett JM,
/ 7b92$$1443
11-10-97 03:02:55
Wiernik PH. Clinical trials in adults with acute myelogenous
leukemia: experience of the Eastern Cooperative Oncology
Group. In: Büchner T, editor. Acute leukemias. 4th edition.
Berlin: Springer-Verlag;1994:541–6.
Rowe JM, Andersen JW, Cassileth PA, Oken MM, Bennett
JM, Wiernik PH. Post-remission therapy in adults with acute
myelogenous leukemia: the Eastern Cooperative Oncology
Group (ECOG) experience. Leukemia 1992;4:75–7.
Bennett JM, Andersen JW, Cassileth PA. Long term survival
in acute myeloid leukemia: the Eastern Cooperative Oncology Group (ECOG) experience. Leukemia Res 1991;15:223–
Cox DR. Analysis of binary data. London: Methuen and Co.,
Kaplan EL, Meier P. Nonparametric estimation form in complete observations. J Am Stat Assoc 1958;53:457–81.
Kornblith AB, Herndon J, Zuckerman E, Cella DF, Cherin E,
Wolchok S, et al. Comparison of long term psychosocial
adaptation of Hodgkin’s disease and acute leukemia survivors (CALGB 8561/8562,8963). Proc Am Soc Clin Oncol
W: Cancer
Без категории
Размер файла
121 Кб
Пожаловаться на содержимое документа