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Blood, 1 September 2000, Vol. 96, No. 5, pp. 1670-1673
How I treat older patients with AML
Elihu H. Estey
From the Department of Leukemia, The University of
Texas M. D. Anderson Cancer Center, Houston, TX.
 |
Article |
When managing an older patient with untreated acute
myeloid leukemia (AML), my primary goal is to determine whether
standard treatment, investigational treatment, or palliative care is
most appropriate. "Standard therapy" includes remission induction
regimens, commonly referred to as "3 + 7," containing 3 days of
anthracycline and 7 days of cytarabine (ara-C). Two to six
cycles of the same drugs at equivalent or reduced doses are given
should complete remission (CR) ensue. Although the regimens vary, for
example, in choice of anthracycline or dose of ara-C, I believe the
similarities outweigh the differences. In particular, with all these
regimens, the outcome in adults worsens continuously as age
increases.1-3 Although any age criterion for "elderly
AML" is thus arbitrary, patients are, for practical purposes,
generally considered "older" if above age 55,4-5 or
606; I will adhere to the 55-year-old criterion here. In
such patients, the median time from treatment with 3 + 7 regimens to
death is 5 to 10 months.6-7 While CR rates are about 50%,
the remissions are usually transient (rarely more than 12 months). The
probability of remaining in remission 3 years after beginning
treatment, beyond which time patients may operationally be considered
"potentially cured,"8 is less than 10%. To a
significant extent, these results reflect the association between older
age and factors ("covariates") discussed below that themselves are
associated with resistant AML or with early death following initiation
of treatment. Nonetheless, multivariate analyses generally demonstrate
that older age is prognostically adverse, even after accounting for
these covariates.7,9 Although the above data often make me hesitant about recommending
standard therapy for an older patient, numerous studies have
demonstrated that the results in some older patients may depart
significantly from the average results just
depicted.4,7,10,11 Thus, I believe it crucial to ascertain
whether a particular patient, despite being elderly, may have a
reasonable prospect of benefit from standard therapy in light of
coexisting covariates that might mitigate the age effect. Chief among
these are relatively young age (eg, 55-65), good performance status,
normal organ function, de novo presentation, "intermediate" or
"favorable"cytogenetics and, most recently, lack of multidrug
resistance gene (MDR) expression.4 Data from Leith
et al show the effect of these covariates in refining prognoses.4 Whereas the CR rate following treatment with a typical 3 + 7 regimen was 45% in all of Leith's 146 patients over age 55, it was 81% in the 27 of these 146 with de novo disease, intermediate or favorable cytogenetics, and "no" MDR expression. Similarly, the CR rate of 72% in the 64 of 886 M. D. Anderson patients over the past 20 years who were age 55 to 65, had a
performance status below Zubrod 3, normal serum bilirubin and
creatinine levels, de novo AML, and a normal karyotypeor, very
rarely, an inv(16) or t(8;21)contrasts with the CR rate of 48% in
the remaining 822 patients over age 55. The better group had a median
survival time of 1 1/2 years, and approximately 15% were alive in
first CR at 3 years and, thus, "potentially cured."8
While these outcomes were not materially superior in the 1990s over the
1980s, they were statistically superior (P < .01) to
those seen in the remaining patients. Obviously, then, older patients
with relatively favorable prognoses can be identified. For purposes of
patient management, however, I inquire whether the "relatively
favorable" prognoses described immediately above are sufficiently
favorable to justify use of standard treatment rather than the
alternative of investigational treatment. Leaving until later the
important issue of what investigational therapy might entail, I have
observed that some prognostically favorable older patients, when
informed of the expected outcome with standard therapy, the uncertain
results with investigational therapy (which might be worse than
standard therapy), and the fact that most previous investigational
approaches have been unsuccessful, prefer to receive standard therapy.
Other prognostically favorable older patients, when similarly informed, are simply unprepared to accept a 50% chance of death within 1 1/2 years and opt for investigational therapy. Thus, I believe that both the standard and investigational options are defensible in
the ambulatory patient age 55 to 65 with de novo AML, normal organ
function, a normal karyotype and, when the test is available, no MDR
expression.4 In contrast, I would not recommend the "palliative care" option in this setting. I find persuasive a European Organization for Research and Treatment of Cancer (EORTC) randomized trial indictating that patients over age 65 with good performance status and relatively preserved organ function not only
lived longer if given standard treatment rather than supportive care
but, perhaps more importantly, given the relatively modest 2-month
median difference in survival, also required fewer
hospitalizations.12 Although the trial may be criticized
because patients in the 2 arms might not have had similarly favorable
baseline prognoses, I believe it unlikely that such potential
confounding is the sole explanation for the superior results observed
with standard therapy. I give more attention to the investigational treatment or palliative
care options as the number of adverse prognostic features increases.
Support for this approach comes from Leith et al.4 Considering secondary disease, unfavorable cytogenetics, and MDR expression as adverse features, the CR rate was 4 in 9 (44%) in patients with 1 such feature, 9 in 37 (24%) in patients with 2 features, and 2 in 17 (12%) if all 3 adverse features were present. Of
note, the 54 patients with 2 or 3 adverse prognostic factors represented double the number with no adverse factors, in whom the CR
rate, as noted above, was 81%. Similarly, the 64 previously noted
M. D. Anderson patients with de novo disease and favorable values
for age (55-65), performance status, organ function, and cytogenetics
constituted only 7% of our older patients. A total of 194 patients had
unfavorable values for one of these covariates. Their median survival
was 10 months, with 9% alive in CR at 3 years. While results in the
various groups (eg, only cytogenetics unfavorable, only secondary AML)
differed, in no group was median survival over 1 year. The 76 patients
who were both over age 64 and had unfavorable cytogeneticsany but
normal, inv(16), t(8:21), or insufficient yieldbut were ambulatory
with normal organ function and de novo disease had a median survival of
6 months. Although the CR rate was 51%, only 7% of the 76 patients
remain alive in CR at 3 years. While different physicians and different
patients will disagree as to when the results of standard therapy are
sufficiently poor to justify the alternatives of investigational or
palliative treatment, examples such as those provided above lead me to
recommend the former if any of the following are present in an older
patient: age above 64, performance status above Zubrod 2, abnormal
organ function, secondary AML, or unfavorable cytogenetics as defined above. This recommendation is in fundamental accord with that made by
the AML "expert panel" of the National Comprehensive Cancer Network
(NCCN), a consortium of prominent U.S. cancer centers.13 Importantly, and as discussed below, the type of investigational treatment I recommend depends on how many and which adverse prognostic features are present. If financial or logistical constraints prevent access to
investigational treatment, I would recommend palliative care without specific antileukemic treatment if the patient were age 65 or older and
primarily bedridden (Zubrod performance status 3-4) or age 80 or older
regardless of performance status.14 These covariates are
the principal predictors of early death, as opposed to resistant
disease, following initiation of chemotherapy; in contrast, abnormal
cytogenetics, secondary AML, and MDR expression are prognostically
unfavorable because of their association with resistant
AML.4,15 Among the 90 patients in our database who were
age 65 or older with performance status 3 to 4, the median survival
after the start of chemotherapy was 5 weeks, with 4 patients living
beyond 1 year, and with no difference in outcome in the 1990s versus
the 1980s. Findings are similar in patients over age 80 regardless of
performance status.14 It is difficult to ascertain whether
these results are better or worse than those with palliative care. The
previously mentioned EORTC study12 was limited to patients
with good performance status, while 2 nonrandomized studies report
median survivals of 3 weeks and 9 months, respectively, in 11 and 24 patients receiving palliative care7,16; all but 2 of these
were above age 55. The difference in survival times between the 2 studies probably reflects varying inclusion criteria, although in both
studies a few patients (2 of 11 and 2 of 24) lived more than 1 year;
these patients had low white blood cell counts. Regardless of the comparative merits of standard chemotherapy and
palliative care in the primarily bedridden patient who is age 65 or
older or in the patient who is older than 80, I believe the 5-week
median survivals associated with use of standard therapy in these
patients do not warrant use of such therapy in this setting but,
rather, justify the use of palliative care, including administration of
hydroxyurea if the white blood cell count is more than
25 × 109/L. While the decision to choose
palliative care over standard therapy is obviously best made by
individual physicians and patients, I believe development of a formal
prognostication system incorporating the previously discussed
covariates would be invaluable in informing these decisions. Such a
system would be particularly relevant when presented with the options
of palliative and standard treatment in patients who are younger than
65 or who are age 65 to 80 with good performance status but have
abnormal cytogenetics, secondary AML, or MDR expression. There is also
a need to examine the effects of specific treatment versus palliative
care on "quality of life." When the option of investigational
therapy is available, I recommend this option rather than palliative
care for older patients with relatively unfavorable prognoses. This
recommendation extends to patients at high risk of early death, based
on my assumption that investigational therapies, such those described
below, might successfully address this problem. While duly noting the
difficulties inherent in investigational therapy, as discussed above, I
stress that at least on occasion new therapies are, even unexpectedly, successful (2 CdA in hairy cell leukemia, interferon in chronic myelocytic leukemia), thus providing a modicum of hope for
patients entered in trials of investigational therapies. Finally, I
note that such trials remain the principal mechanism to advance the therapy of AML. Figure 1 summarizes my approach to
therapy of older patients with AML. Clearly, I favor investigational
therapy for most such patients. Before going into detail, I will
dismiss recently investigated therapies whose routine use is, in my
opinion, not supported by evidence from the investigations. Separate
randomized trials conducted by the Southwest Oncology
Group,17 Cancer and Leukemia Group B,18 and
Eastern Cooperative Oncology Group19 have found that high-dose ara-C (HDAC) (2-3 g/m2) given in
remission, or for induction and/or in remission, failed to improve
survival or CR rate in patients over age 55 to 60 and often
produced toxicity, particularly neurotoxicity. HDAC might, however, be used in good-performance status patients age 55 to 65 with
a normal karyotype or with the rare inv(16) or t(8;21). The former may
benefit from 4 cycles of ara-C, 400 mg/m2 daily × 5
continuous infusion given once in CR, and the latter from 4 cycles at 3 g/m2 every 12 hours on days 1, 3, and
5.20 Attempts to reduce the dose of ara-C ("low-dose
ara-C") or anthracycline have generally found that any reduction in
mortality is counterbalanced by an increase in resistant disease with
no material benefit in survival.21-23 Although randomized
trials have not been done, I do not believe that M. D. Anderson
data support the use of fludarabine plus ara-C24 or
topotecan plus ara-C regimens.25-26 Granulocyte-macrophage colony-stimulating factor (GM-CSF) or G-CSF given concomitantly with
and/or after chemotherapy may reduce days spent in the hospital or
febrile episodes but not end points such as survival, CR rate, or
duration.6,27,28 Possibly confounding factors in the one study that found a survival advantage5 are discussed by
Estey et al.29 While some might argue that the reduction
in morbidity justifies routine use of these products, given economic
constraints I administer GM-CSF or G-CSF only in the event of fever or
infection, while granting a lack of empirical evidence bearing on this
practice. I routinely discharge patients from the hospital after
chemotherapy is completed, readmitting them if complications such as
fever develop. I believe this practice not only may reduce the
frequency of nosocomial infections but also maintains patients'
feelings of independence. In patients at high risk of early death (age above 80, or age 65 or older with Zubrod performance status 3-4), I
administer intravenous itraconazole or liposomal amphotericin prophylactically and, if not given prophylactically, begin
amphotericin, and attempt to arrange granulocyte transfusions from
normal donors pretreated with G-CSF should pneumonia ensue or should a
fever of unknown origin fail to respond to 3 days of antibacterial
antibiotics (Figure 1). The goal is to reduce the incidence or severity
of aspergillus infections, a major cause of death in our
patients.30 While recognizing a lack of data supporting
these practices, we are engaged in trials to assess their utility.
Whether such investigational therapies should be employed outside the
context of a clinical trial is a highly complex issue that is beyond
the scope of this paper.
Because the principal cause of treatment failure in older patients is
resistant AML (manifested by short CRs or failure to enter CR), our
investigational strategies should focus primarily on this problem,
particularly in patients with an abnormal karyotype, secondary AML, or
MDR expression. The degree to which an investigational regimen departs
from standard therapy should depend on how poor prognosis is with the
latter. For example, in patients with secondary AML, a particularly
unfavorable karyotype ( 5/ 7 or more than 3 clones), and MDR
expression, it would not necessarily be unreasonable to omit ara-C
(Figure 1). In this setting, for example, we have studied liposomal
daunorubicin (LD) plus topotecan, as well as LD plus ara-C, each with
or without the presumed angiogenesis inhibitor thalidomide, and we are
planning to investigate mylotarg (formerly CMA-676), an anti-CD33
monoclonal antibody conjugated to the anthracycline
calicheamycin,31 and to conduct a phase I/II trial
of the hypomethylating agent decitabine at doses that presumably result
in maximum hypomethylation of inappropriately methylated
genes32 but do not produce myelosuppression, thus permitting investigation of prolonged infusions. Both mylotarg and
low-dose decitabine may also reduce early mortality rates and thus
could be administered to patients at high risk of early death (Figure
1). In contrast, in patients with fewer unfavorable characteristics,
eg, only secondary AML or an abnormal karyotype, ara-C with or without
an anthracycline should be included. Regimens we are investigating or
have proposed to investigate in this setting include cyclophosphamide
plus ara-C plus topotecan with or without liposomal
all-trans retinoic acid, bcl-2 antisense plus ara-C plus
idarubicin, and the checkpoint modulator UCN-01 plus ara-C. Obviously,
the extent to which a new regimen can vary from the standard in a given
prognostic setting is debatable. Furthermore, numerous other regimens
may be at least as useful as those described. These include
continuous-infusion daunorubicin plus ara-C plus cyclosporine,33 allogeneic transplants using intravenous
busulfan,34 or nonmyeloablative regimens that allow
engraftment and a subsequent graft-versus-leukemia
effect.35 Both transplant regimens seem well tolerated in
patients up to age 70. They could conceivably be used not only in
elderly patients in remission but also for remission induction in
clinically stable patients whose white blood cell count is sufficiently
low to permit transplant arrangements to be completed. Use of
transplantation for remission induction is an important consideration
given the low CR rate in elderly patients. I believe it is impossible
to determine which, if any, of the above regimens will be significantly
better than standard therapy in the absence of data from a clinical
trial; after all, neither 2 CdA nor interferon was predicted to be
effective in hairy cell leukemia and CML, respectively, prior to
empirical trial results. Given this consideration and the large number
of treatments to investigate relative to the number of patients
available for clinical trials, I believe that clinical trial design in
older patients should focus as much on small studies of a relatively large number of new therapies as on the conventional large phase III
study of 1 or 2 new therapies. Although the smaller studies may have
relatively high false-negative rates, I believe that the worst false
negative, in the setting described, results when a potentially
important therapy is not investigated at all.36
| |
Footnotes |
Submitted March 1, 2000; accepted April 19, 2000.
The publication costs of this
article were defrayed in part by
page charge payment. Therefore,
and solely to indicate this fact,
this article is hereby marked
"advertisement"
in accordance with 18 U.S.C.
section 1734.
Reprints: Elihu H. Estey, Department of Leukemia, Box 61, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030; e-mail: eestey{at}mdanderson.org.
| |
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J. Menzin, K. Lang, C. C. Earle, D. Kerney, and R. Mallick
The Outcomes and Costs of Acute Myeloid Leukemia Among the Elderly
Arch Intern Med,
July 22, 2002;
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E. H. Estey, P. F. Thall, F. J. Giles, X.-M. Wang, J. E. Cortes, M. Beran, S. A. Pierce, D. A. Thomas, and H. M. Kantarjian
Gemtuzumab ozogamicin with or without interleukin 11 in patients 65 years of age or older with untreated acute myeloid leukemia and high-risk myelodysplastic syndrome: comparison with idarubicin plus continuous-infusion, high-dose cytosine arabinoside
Blood,
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[Abstract]
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