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CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
From the Department of Haematology, University College
Hospital, London; Department of Haematology, University of Wales
College of Medicine, Cardiff; Birmingham Clinical Trials Unit,
University of Birmingham; Department of Haematology, Southampton
University NHS Trust; Department of Haematology, Leicester Royal
Infirmary; Department of Haematology, Royal Liverpool Hospital; all of
the United Kingdom.
In an attempt to improve induction chemotherapy for older patients
with acute myeloid leukemia (AML),1314 patients were randomized to 1 of
3 induction treatments for 2 courses of DAT (daunorubicin, cytarabine,
and thioguanine) 3 + 10, ADE (daunorubicin, cytarabine, and
etoposide) 10 + 3 + 5, or MAC (mitoxantrone-cytarabine). The remission rate in the DAT arm was significantly better than ADE (62%
vs 50%; P = .002) or MAC (62% vs 55%;
P = .04). This benefit was seen in patients younger and
older than 70 years. There were no differences between the induction
schedules with respect to overall survival at 5 years (12% vs 8% vs
10%). A total of 226 patients were randomized to receive granulocyte
colony-stimulating factor (G-CSF) or placebo as supportive care from
day 8 after the end of treatment course 1. The remission rate or
survival were not improved by G-CSF, although the median number of days to recover neutrophils to 1.0 × 109/L was reduced by 5 days. Patients who entered remission (n = 371) were randomized to
stop after a third course (DAT 2 + 7) or after 6 courses, ie, a
subsequent COAP (cyclophosphamide, vincristine, cytarabine, and
prednisolone), DAT 2 + 5, and COAP. The relapse risk (81% vs 73%),
disease-free survival (16% vs 23%), and overall survival at 5 years
(23% vs 22%) did not differ between the 3-course or 6-course arms. In
addition to a treatment duration randomization, 362 patients were
randomized to receive 12-month maintenance treatment with low-dose
interferon, but no benefit was seen with respect to relapse risk,
disease-free survival, or overall survival.
(Blood. 2001;98:1302-1311) The treatment of acute myeloid leukemia (AML) in
older patients has not improved significantly in recent years compared
with the considerable progress made in younger
patients.1-7 This difference is probably multifactorial
and relates to differences in the biology of the disease in older
patients as exemplified by a higher proportion of patients with an
adverse karyotype, a more frequent expression of a chemoresistant
phenotype, and an increased frequency of disease evolution from a
pre-existing and perhaps unrecognized myelodysplasia. The presence of
comorbidity means that older patients, ie, patients older than 60 years, are less able to withstand intensive chemotherapy, with the
consequence that the patients recruited to trials of intensive therapy
are a selected minority of patients with the disease in this age group.
In the United Kingdom Medical Research Council (MRC) AML trials
database, in patients entered into trials between 1970 and 1990 there
was a modest improvement in remission rate, probably attributable to
improved supportive care, but the long-term survival improvement has
been modest and much less than in younger patients and remains poor.
Several aspects of treatment require improvement. Many studies in older
patients have demonstrated that initial complete remission rates are
around 45% to 55%, and the relapse risk of remitters is around 80%
to 85%.1-6 We have previously demonstrated in older
patients considered fit for chemotherapy that more intensive treatment
in remission induction with a 3 + 10 schedule of daunorubicin,
cytarabine, and thioguanine (DAT), while not improving the
proportion of patients who enter remission, improves long-term survival
with, in total, a reduced requirement in the amount of supportive care
as measured by hospital days, red cell and platelet support, and days
on antibiotics when compared with a more gentle DAT 1 + 5
schedule.8 Similar observations have been confirmed in
other studies.4 Arguably, more effective induction therapy
should not only reduce the proportion of patients with resistant
disease In this trial we report a comparison between 3 induction schedules
aimed at improving initial response: our traditional DAT 3 + 10
schedule versus the same schedule but with etoposide substituted for
thioguanine (ADE), versus a mitoxantrone-cytarabine combination (MAC). During this trial we conducted a placebo-controlled trial of
granulocyte colony-stimulating factor (G-CSF), used as supportive care
after the first course of induction treatment, in an effort to reduce
treatment-related mortality and thereby increase the rate of remission.
Postinduction treatment in younger patients has become intensive,
and it appears that a total of 4 or 5 courses may be optimum. However,
consolidation is less well tolerated in older patients, so the
appropriate treatment has yet to be developed. In our previous MRC AML8
trial, which recruited patients from 1978 to 1983, 6 versus 2 consolidation courses of DAT were compared and failed to show a
survival difference.1 In that trial, patients who remained
in remission for 12 months were randomized to receive a further 3 months of monthly maintenance or 4 courses of late intensification with
COAP (cyclophosphamide, vincristine, cytarabine, and prednisolone). The
COAP schedule was well tolerated and reduced the number of deaths and,
for this reason, was compared with the more intensive MAZE
(M-amsacarine, 5-azacytidine, and etoposide) as consolidation
in the MRC AML9 trial, which recruited patients between 1984 and
1990.16 Although MAZE reduced the relapse risk overall, it
was associated with an excess of deaths in remission and was poorly
tolerated in patients older than 55 years. The addition of maintenance
in that trial provided no benefit.
Here we attempt to define the number of consolidation courses that are
necessary in the older patient by comparing a total of 3 courses with a
total of 6 courses incorporating 2 courses of COAP and 1 of DAT.
At the initiation of this study, interferon- Given the lack of progress in treatment of the older patient, there is
an issue of whether there are subgroups of patients who benefit more
than others and who should continue to be offered intensive
chemotherapy and, by implication, there are groups of patients in whom
the current approach is more likely to shorten life and who should be
offered alternative treatment approaches. We have achieved this in
younger patients based on a limited number of prognostic factors,
including cytogenetics, which have been prospectively validated and are
now used to make treatment decisions.17,18 In addition to
patients considered fit for chemotherapy and who therefore may enter
trials, estimated to be around 10% of older patients in our
experience, substantial numbers of patients are not offered an
intensive approach. Little is known about the outcome for such patients
or whether their quality of life can be improved by developing
improved nonintensive treatments.
In summary, the aims of this study were first to improve
remission induction by comparing 3 induction regimens and to evaluate the benefit of using G-CSF in supportive care. Secondly, we aimed to
define the required number of total treatment courses by comparing a
short (3 courses) versus long (6 courses) approach and sought to
investigate the role of a 12-month maintenance schedule of low-dose
IFN- Patients
The trial was initially designed for patients aged 56 years and older
with the then concurrent MRC AML10 trial recruiting patients up to 55 years. At the end of 1994, the AML10 trial was succeeded by MRC AML12
and the age threshold for AML11 was raised to 60 years and older.
Patients younger than 60 years were, however, permitted to enter this
study if they were not considered suitable for the more intensive
therapy employed in either the AML10 or AML12 trials.
Patients with any form of de novo or secondary AML were eligible.
Secondary AML was defined as AML either following prior cytotoxic
chemotherapy or radiotherapy for other cancers or subsequent to a
preceding hematologic disorder. Patients with blast crisis of
previously documented Philadelphia chromosome-positive chronic myeloid
leukemia were not eligible. The trial required approval of each
institutional ethics review committee and required patients to give
informed consent.
Treatment
Between November 1994 and January 1997, 226 patients participated in a
randomized placebo-controlled trial of G-CSF (Lenograstim) given at a
daily dose of 293 µg by subcutaneous injection starting on day +8
after the end of course 1 chemotherapy and continuing until neutrophil
recovery to 0.5 × 109/L or for a maximum of 10 days if
the neutrophil count had not recovered by this time. There was an equal
distribution of entrants between the induction arms.
Definitions of end points
The following definitions are also used: Overall survival (OS) is the time from entry to death; for remitters, disease-free survival (DFS) is the time from CR to first event (either relapse or death in CR); for remitters, the relapse risk (RR) is the cumulative probability of relapse ignoring (ie, censoring at) death in first CR; and death in first CR is the cumulative probability of dying in first CR ignoring relapse. Statistical methods Randomizations were balanced by minimization. The protocol specified that the primary comparison for the induction randomization would be of the mitozantrone-containing regimen (MAC) versus the daunorubicin-containing regimens (DAT and ADE), with a subsidiary comparison of DAT versus ADE. However, because there is evidence (see "Results") that the outcomes with DAT and ADE are different, it would be inappropriate to combine them for comparison with MAC; therefore, 3 primary comparisons are presented: DAT versus ADE, DAT versus MAC, and ADE versus MAC. Remission rates and reasons for failure were compared using standard 2 tests. Kaplan-Meier life
tables were constructed for survival data and were compared by means of
the log-rank test, with surviving patients being censored at June 1, 2000, when follow-up was complete for all but 15 patients (1%) (the
small number of patients lost to follow-up are censored at the date
they were last known to be alive). All percentage values quoted in the
text for survival, DFS, and RR are at 5 years. Hematologic recovery and
hospital stay were compared by means of the log-rank test. Toxicity and supportive care requirements were compared by means of the Wilcoxon test. All P values are 2-tailed. All analyses are
"intention-to-treat," ie, all randomized patients were included
irrespective of protocol compliance.
Induction randomization Patient characteristics.
The presenting features of the patient population are shown in
Table 1. Both the mean and median ages
were 66 years. Of the 20 patients younger than age 56 years, 12 were
aged 55 years, 7 were aged 52 to 54 years, and 1 was aged 44 years. Of
the 7 patients aged 80 years or older, 4 were aged 80 years, with one each aged 82, 85, and 91 years. Central nervous system involvement was
only reported in 5 patients. Performance status was defined by the
World Health Organization scale. Secondary leukemia was defined on the
basis of a history of previous chemotherapy or radiotherapy (n = 44)
or of a previously documented antecedent hematologic diagnosis
(myelodysplasia, n = 181; myeloproliferative condition, n = 21;
other disorders, n = 31; or unspecified, n = 22). Cytogenetic
information was available in 1065 (79%) patients and is reported in
detail elsewhere (see accompanying article by Grimwade et
al,20 page 1312). Favorable karyotype was defined as
t(8;21), t(15;17), or inv(16) irrespective of the presence of
additional changes. Patients with complex changes (at least 5 unrelated
abnormalities) were defined as adverse risk, while the remainder,
including patients with normal karyotype, were regarded as
intermediate risk.
Compliance with treatment allocation. Information on compliance with allocated induction therapy is available for 95% of patients (94% DAT, 95% ADE, 95% MAC). Compliance was excellent for course 1, with 96% of patients (96% DAT, 95% ADE, 97% MAC) starting their allocated treatment. Twenty-six patients (6 DAT, 9 ADE, 11 MAC) did not commence chemotherapy, while 22 patients (7 DAT, 7 ADE, 8 MAC) received other therapy. Noncompliant patients are included in the analysis. Remission rate.
The overall CR rate was 55%, with failure rates of 19% due to ID and
26% due to RD. The CR rate of patients allocated to DAT (62%) was
significantly better than that of patients allocated to ADE (50%,
P = .002) or MAC (55%, P = .04) (Table
2). As in our other studies, the protocol
did not specify peripheral blood recovery to 1.5 × 109/L
of neutrophils or 100 × 109/L of platelets as in the
National Cancer Institute critera.21 However, at least
95% and 92% of patients who met the protocol definition of CR also
met these criteria at some point during therapy, with 87% and 85%
meeting them after course 1. The reasons for the inferior CR rates with
ADE and MAC were different (Table 2): With ADE there was an excess of
IDs, with MAC there was more RD. No interactions of treatment effect
with age were observed (Table 2).
Toxicity and supportive care.
Courses 1 and 2 were evaluated for toxicity supportive care and
hemopoietic recovery. There were no important differences in
nonhematologic toxicity or for the number of days taken to recover
neutrophil and platelet counts between the treatments after course 1 or
2, although neutrophil recovery was slower in the MAC arm. The
supportive care requirements are detailed in Table
3.
Outcome after complete remission.
For all patients who entered CR, the DFS was 15%, the RR was 82%, and
the actuarial risk of death in remission was 15%. Of the 57 patients
who died in first CR, 35 died within 200 days of remission, usually
from treatment-related causes (mainly infection). The 22 deaths beyond
that point were due to various causes: infection (3), hemorrhage (3),
cardiac failure (6), other cancers (3), other causes (4), and unknown
causes (3). There were no significant differences between DAT, ADE,
or MAC with respect to deaths in first remission, RR, or DFS
(Table 4).
Overall survival.
There were no substantial differences in long-term survival between the
3 induction arms (Figure 2), although
survival was significantly worse with ADE than with DAT
(P = .02), but differences between DAT and MAC
(P = .1) and between ADE and MAC (P = .2) were not significant.
Consolidation and maintenance randomizations Patient characteristics.
The features at diagnosis of the patients who were randomized between
short versus long consolidation and between IFN-
Compliance with treatment allocation. Of the 186 patients randomized to long consolidation, this was started in 156 patients. Of these, 114 received all 3 courses, 22 received 2 courses, and 20 received 1 course. Seventeen patients did not start consolidation, while information on consolidation received is not available for the remaining 13 patients allocated to long consolidation. Among patients allocated to short consolidation, 4 received further unscheduled chemotherapy in first CR. Of the 182 patients allocated to IFN- , 41 are known not to have
started the treatment. This was largely seen in patients allocated to
long chemotherapy, where 55% started IFN- compared with 94% in the
short chemotherapy arm. Of the 131 patients starting IFN-, 42 completed the designated 12 months, 33 completed no more than 2 months,
26 completed 3 to 5 months, 18 completed 6 to 8 months, and 7 completed
9 to 11 months (5 not known). No patients on the control arm are
known to have received IFN-.
Outcome.
There were no significant differences in either randomization with
respect to deaths in first CR, RR, DFS (Table
6, Figure 3A,B), or OS (Figure
4).
Factors that predict outcome Parameters that were found to be highly significantly associated with the achievement of remission in multivariate analysis were cytogenetic group, presenting white blood count (WBC), age, secondary leukemia, performance status, and French-American-British (FAB) type M3 (Table 7). OS was influenced by cytogenetics, presenting WBC, age, secondary leukemia, and performance status. Details of the cytogenetics of this trial are reported elsewhere.20 Only 6% of cases were in the favorable cytogenetic group, but the OS was 34% whereas the 11% known to have adverse cytogenetics had a survival of 2%. WBC became influential at 100 × 109/L, below which survival was 15% and above which it was 7%. Patients younger than 70 years had a 16% OS compared with 11% for patients aged at least 70 years. Secondary leukemia had a similar remission rate to de novo disease (53% vs 57%) but was significantly worse if it developed from preceding myelodysplasia (42%). Patient sex or disease FAB group, apart from FAB M3, were not influential on outcome.
A total of 70% of patients with AML are older than 60 years, and the 1- to 2-year survival reported in various clinical trials ranged between 10% and 15%. There is little evidence that treatment has improved survival rates in the last 25 years although remission rates have gradually increased, most probably reflecting improved supportive care. This contrasts sharply with the situation in younger patients, in whom both remission rates and survival has improved substantially as a consequence of developing more intensive schedules.7,22-24 The overall results reported in this trial are unexceptional and do not provide any evidence to suggest that treatment can be improved overall by the strategies tested. In older patients it is difficult to compare one trial with another or, indeed, to extrapolate the results of a trial to an individual patient in the clinic because of the selected nature of patients who enter trials. Most trial protocols offer an intensive approach to treatment for which patients may not be considered medically fit or into which patients are willing to be recruited. Most (71%) entrants into this trial were younger than 70 years and only 7% older than 75 years, which is clearly unrepresentative of the AML population as a whole. Age 60 years is often, although arbitrarily, used as a cutoff to define "older" patients with AML. Because chronological age is not necessarily a good indicator of biological age and fitness for therapy, AML11 did not specify fixed age limits. If analysis is restricted to patients aged 60 years or older, the results and their interpretation do not alter in any important fashion. Similarly, because patients with acute promyelocytic leukemia still need chemotherapy in addition to ATRA, it is appropriate to include them in studies comparing different regimens even though they are usually considered separately from other forms of AML. Their exclusion from AML11 would not alter the results. There are therefore several issues to be addressed. First, chemotherapy needs to be improved both in induction and postinduction phases. Second, we need to establish in which subsets of patients this is likely to be achievable. Third, we need to determine in which patients an intensive approach is unsuitable and in whom treatment is shortening life. In this respect, end points other than those used to measure disease response should be given equal importance. Fourth, even if progress is made in these areas, there will still be a substantial group of older patients in whom improved nonintensive approaches need to be developed. In this trial we attempted to improve outcome for patients considered
fit for intensive treatment by testing newer induction schedules (ADE
and MAC) against our traditional DAT 3 + 10 protocol, which had been
established in our previous AML9 trial to be superior to a more gentle
DAT 1 + 5 schedule in older patients. It was hoped that the
replacement of thioguanine with etoposide would be more effective, but
this proved not to be the case. Similarly randomized comparisons have
previously suggested that mitoxantrone was more efficacious than
daunorubicin with the possible additional advantage of being less
cardiotoxic, which could be a useful feature in patients in this age
group.25 In this trial the DAT schedule was significantly
better overall and in all patient age subgroups. This does not
necessarily mean that the third drug is of value One difference between the initial response in older and younger
patients is the higher ID rate in older patients. A contributing factor
may be poorer tolerance to neutropenia as opposed to the duration of
neutropenia Despite a superiority in remission rate with DAT, we found no
subsequent difference in RR, DFS, or OS between the 3 induction schedules. In the previous AML8 and AML9 trials, the COAP combination had proved partially effective and tolerable as consolidation compared
with a more intensive MAZE combination which, although able to reduce
RR, was poorly tolerated in older patients. For this reason, COAP was
taken forward as the standard approach to postinduction therapy and we
were able to demonstrate that a total of 3 courses was as effective as
6. Because DAT 2 + 5 and COAP as used here are not intensive
treatments by current standards, it is conceivable that there are
subgroups of patients who were undertreated. For example, patients with
a favorable karyotype when treated with the same induction schedule as
younger patients of the same karyotype had a remission rate of 70%,
which was not significantly inferior to that of younger patients
(90%) In this trial design we chose not to pursue the evaluation of
maintenance chemotherapy because our previous trials had shown no
benefit.1,8 Given the preliminary results available at the
time this trial was planned of IFN- It is clear that, just as is apparent in younger patients, AML is heterogeneous disease in the older patient. Prognostic factors, particularly cytogenetics, have become of central importance in treatment decisions in younger patients.26,28,29 However, these factors only became evident as treatment improved. Treatment options are more limited because of comorbidity in older patients. Young patients seldom elect a palliative approach but some older patients, even though they might be fit for intensive treatment, opt for a palliative approach. Many older patients do not enter current clinical trials, because the trials tend to offer only an intensive approach to treatment.30 Even in patients considered fit for treatment, the lack of therapeutic progress over the last 20 years raises the important issue of determining who benefits from current treatment approaches and who are the patients whose life may be shortened by an intensive treatment. In the former group, improved treatment with curative intent might be possible, whereas in the latter group and for most older patients more useful palliative approaches are needed until novel treatments emerge. In an attempt to define patients who may benefit from intensive chemotherapy, we identified a number of parameters that influenced treatment outcome. Cytogenetic information was obtained in 1065 (79%) patients in this study and are reported in detail elsewhere. It has long been known that one of the explanations of the inferior response in older patients was the different proportions of the favorable and unfavorable cytogenetic groups. Older patients with a favorable karyotype have a similar CR rate but higher RR, possibly because of inferior postinduction treatment in addition to the features of age. Patients with adverse cytogenetics composed 11% in this study and had a low remission rate (26%) and extremely poor survival (2%). There is certainly doubt about the justification of offering such patients currently available intensive treatment approaches. Even if remission is achieved, it is only temporary. This would sustain an argument to identify these patients at diagnosis and avoid the toxicity and indignity of intensive treatment. Many centers cannot obtain cytogenetic data promptly, but there may be a case for the use of rapid assessment techniques to identify these patients. Only one study involving 60 patients prospectively evaluated a strategy of immediate conventional chemotherapy versus a wait-and-see approach using mild therapy with hydroxyurea or cytarabine.4 The survival in the conventionally treated cases was twice as long as with the palliative approach. This has been taken to mean that conventional chemotherapy should be offered to older patients. That trial posed an extremely important question that remains relevant nearly 20 years later, where such a study is still justified in patients known to have a particularly adverse prognostic profile. Based on a prognostic factor analysis of patients in this trial, the features available at diagnosis that predict a lower chance of achieving a CR are WBC more than 100 × 109/L, age over 70 years, secondary leukemia, and poor performance score. Patients with these features will not benefit from the induction approach used in this study. Cytogenetic definition of adverse prognosis will not usually be available to assist in this decision but became very useful in predicting response to postinduction treatment if the patient achieved CR. Such risk profiling could be useful to target subgroups of patients, but no patients in this age category can be considered to have a satisfactory prognosis. The options to improve conventional chemotherapy are limited. Substitution of daunorubicin with a newer drug such as idarubicin has not been shown to be beneficial in older patients.31 The frequency of P glycoprotein expression in older patients and its correlation to treatment response offer a potential target to improve the effectiveness of daunorubicin.32 Several drugs are capable of doing this. The proof of principle is provided in Southwest Oncology Group study in relapsed disease where the addition of cyclosporin A significantly improved DFS and OS.33 The cyclosporine analog PSC-833 is less nephrotoxic and myelosuppressive and is active in vitro at concentrations achievable in vivo. Initial studies in older patients have been associated with increased toxicity, but further studies are needed to evaluate this agent.34,35 There may be benefit in evaluating cytarabine or anthracycline dose levels in the older patients considered suitable for the intensive approach. Older patients will not tolerate high-dose cytarabine, but the dose response seen in younger patients may be available at intermediate doses. This question is now being investigated in our current AML14 trial together with PSC-833 modulation of daunorubicin. Few studies have formally attempted to evaluate a low-dose approach to treatment. In one study of an oral schedule versus a conventional approach, survival was superior with the oral schedule but, as is often the case, this could partly be explained by a poorer than expected result in the conventional arm.36 A novel approach is possible by targeting treatment using immunoconjugates, which have been shown to be effective as single agents in relapsed disease, with a relatively favorable toxicity profile,37 but require prospective evaluation as firstline treatment.
We thank the clinicians who entered their patients into MRC AML11 for their support; Rachel Clack, Jill Crowther, Sarah Cullip, Cathy Hope, Sue Knight, and Angela Radley for data management; and Siân Edwards for preparing the manuscript.
A complete list of the participants in the trial and their institutions is given in an Appendix at the end of this article. Submitted November 21, 2000; accepted April 4, 2001. Reprints: A. K. Burnett, Dept of Haematology, University of Wales College of Medicine, Heath Park, Cardiff, CF14 4XN, United Kingdom; e-mail: burnettak{at}cardiff.ac.uk.
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Abstract
Introduction
about 25% of older patients in our experience
