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CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
From the Department of Haematology, University College
London Hospitals and Medical School, London; the Department of
Haematology, University of Wales College of Medicine, Cardiff;
the Division of Medical and Molecular Genetics, Guy's, King's and St
Thomas' School of Medicine, London; the Clinical Trial Service Unit,
Radcliffe Infirmary, Oxford; the Cytogenetics Laboratory, Royal Free
and University College Medical School, London; and the University of
Birmingham Clinical Trials Unit, United Kingdom.
Acute myeloid leukemia (AML) in older adults carries a poor
prognosis, and the optimum treatment remains to be determined. In
younger patients, treatment stratification is frequently based upon
diagnostic karyotype, which was the most important prognostic factor in
the UK Medical Research Council (MRC) AML10 trial. Considered here is whether karyotype is also predictive in older adults; this is done by studying 1065 cases from MRC AML11 (median age, 66 years). Three prognostic groups were distinguished on the basis of
response to induction therapy and overall survival (OS). Those with
t(15;17), t(8;21), or inv(16) composed the favorable risk group.
Overall, these abnormalities predicted a superior complete remission
(CR) rate (72%), reflecting relatively low levels of resistant disease
(RD) (8%), and lower relapse risk (RR) (56%) associated with superior
OS (34% at 5 years). Normal karyotype (CR, 63%; RD, 17%; RR, 78%;
OS, 15%) and other noncomplex abnormalities (CR, 53%; RD, 32%; RR,
85%; OS, 10%) composed the intermediate group; while complex
karyotype predicted an extremely poor prognosis (CR, 26%; RD, 56%;
RR, 91%; OS, 2%). Combining MRC AML10 and AML11 (n = 2677) revealed
that the most favorable changes were rarer in older patients (younger
than 55 years, 24%; 55 years or older, 7%), while complex
abnormalities were more common (6% vs 13%). This study suggests that
hierarchical cytogenetic classification identifies biologically
distinct subsets of AML that are represented in all age groups.
Furthermore, it highlights the importance of karyotype as a critical
independent determinant of outcome in older patients with AML,
providing a potential framework for stratified treatment approaches.
(Blood. 2001;98:1312-1320) Acute myeloid leukemia (AML) occurring in adults
older than 55 years of age is associated with an extremely poor
prognosis with an overall survival (OS) of less than 20% at 5 years
(reviewed by Hiddemann et al1; see accompanying paper by
Goldstone et al,2 page 1302). A number of factors have
been implicated in the adverse outcome of this group in comparison with
younger individuals. These include poorer tolerance of combination
chemotherapy regimens leading to the use of less intensive treatment
protocols, as well as increased levels of primary drug resistance
associated with overexpression of P-glycoprotein (P-gp), which may in
part reflect a higher incidence of secondary leukemias (reviewed by
Willman3). Furthermore, poor prognosis in this age group
has been ascribed to an increased frequency of adverse cytogenetic
features.4,5 However, the prognostic implications of
diagnostic karyotype remain to be established in large numbers of older
adults subject to an intensive treatment approach.
Despite the generally poor outcome of AML in the elderly, it is of
paramount importance to distinguish subgroups of patients with
potentially curable disease, who are likely to benefit from treatment,
from patients who are essentially incurable with current therapeutic
approaches and whose quality of life can perhaps be improved by
supportive measures, rather than intensive therapy. To begin to address
these issues, it is necessary to identify prognostic factors that could
provide the basis for a more rational treatment strategy for AML
arising in older adults. A number of previous studies have identified
diagnostic cytogenetics as a key determinant of outcome in AML
(reviewed by Mrózek et al6,7) although in many
instances the prognostic significance of specific abnormalities was
difficult to determine owing to relatively small sample sizes and/or
variations in treatment approach. However, in the largest study to
date, which considered 1612 children and younger adults (mostly younger
than 55 years) from the UK Medical Research Council (MRC) AML10 trial,
we defined 3 cytogenetic prognostic groups that predicted response to
induction therapy, relapse risk (RR), and OS.8 Patients
with t(8;21)(q22;q22), t(15;17)(q22;q21), or inv(16)(p13q22) were found
to have a relatively favorable prognosis; in the absence of these
changes, the presence of a complex karyotype, monosomies of chromosome
5 or 7 ( It is essential that proposed cytogenetic classification systems be
subject to validation in fresh data sets, with consideration given to
possible influences of age and treatment approach, as highlighted
recently by Slovak et al.10 In the present study, through
analysis of 1065 cases entered into the MRC AML11 trial, we sought to
determine whether the cytogenetic risk groups previously defined in
children and younger adults entered into MRC AML108 are
also predictive of outcome in older individuals.
Patients
Therapy
Cytogenetics Cytogenetic analyses were performed as described previously.8 Cytogenetic data were available for 1065 of 1300 eligible AML11 patients, representing 82% of cases of AML in the trial. Among patients reported to have a normal karyotype (n = 507), outcome of the 34 cases with fewer than 20 metaphases analyzed (range 10-19; median 14) did not differ from those with at least 20 metaphases studied, and hence they were retained within the normal karyotype group. A diagnostic result was not available in 235 cases either because cytogenetic studies were not performed (n = 16) or failed (n = 98) or for unknown reasons. To determine whether there was any association between age and the frequency of secondary leukemias and specific cytogenetic abnormalities, data derived from the AML11 trial were combined with data derived from the previously reported AML10 trial, which considered cytogenetic findings in 1612 AML patients, mostly younger than 55 years of age.8,12 Analyses were restricted to the more frequently observed abnormalities, ie, those found in 10 or more patients. We also sought to determine among AML11 cases whether the hierarchical cytogenetic risk-group classification that we previously defined in younger patients with AML8 was of predictive value in older patients. According to this classification, cases with t(8;21), t(15;17), or inv(16), irrespective of the presence of additional cytogenetic abnormalities, composed the favorable risk group, while cases lacking these favorable risk aberrations in which complex cytogenetic changes (5 or more unrelated abnormalities), 5, del(5q), 7, or 3q abnormalities were identified
composed the adverse risk group. The remaining group of patients
composed the intermediate risk category, which included cases with
normal karyotype, 11q23 abnormalities, trisomy 8 (+8), or other
chromosomal changes not encompassed by the favorable or adverse risk
groups. In analyses using hierarchical cytogenetic classification,
patients were defined by the primary abnormality and hence were counted only once (Tables 3, 4, 6; Figures 1-3).
Definitions of end points A normocellular bone marrow aspirate containing fewer than 5% blasts and showing evidence of normal maturation of other marrow elements was the criterion for the achievement of CR. Persistence of myelodysplastic features did not exclude the diagnosis of CR. As in previous MRC AML trials, full recovery of normal peripheral blood counts was not required to define CR, although at least 95% of patients considered to be in CR according to the protocol definition also satisfied National Cancer Institute criteria.13 Remission failures were classified by the referring clinician either as due to induction death (ID), ie, related to treatment and/or hypoplasia, or as resistant disease (RD), ie, related to the failure of therapy to eliminate the disease (including partial remissions with 5% to 15% blasts). Where the clinician's evaluation was not available, deaths within 30 days of entry were classified as ID and deaths at more than 30 days as RD. The following definitions are also used: OS is the time from entry to death. For remitters, the RR is the cumulative probability of relapse, ignoring (ie, censoring at) death in CR.Statistical methods The Mantel-Haenszel test for trend, Fisher exact test, and the Wilcoxon 2 sample test were used to test for associations with age, type of AML, and white blood cell count (WBC) at presentation. Remission rates and reasons for failure to achieve CR were compared by means of the Fisher exact test. Kaplan-Meier life tables were constructed for survival data and were compared by means of the log-rank test, with surviving patients being censored on June 1, 2000 (AML11), or May 1, 1999 (AML10), when follow-up was complete for at least 98% of patients (the small number of patients lost to follow-up are censored at the date they were last known to be alive). Median follow-up was 54 months (range, 1-112 months) in AML11 and 80 months (range, 4-131 months) in AML10 patients with cytogenetic data. All P values are 2-tailed; because of the large number of significance tests performed and the associated increased probability of obtaining conventionally significant (P < .05) results by chance, only values of P < .01 are quoted.
Incidence of specific cytogenetic abnormalities in AML in older adults The frequency of the most common cytogenetic abnormalities detected at diagnosis among 1065 cases of AML arising in older adults entered into the MRC AML11 trial and their associated clinical features are presented in Table 1. The most common recurring cytogenetic abnormalities among the de novo AML group were a complex karyotype, +8,7/del(7q), 5/del(5q), and t(15;17). The
spectrum of abnormalities observed in cases of secondary AML was
similar; however, the occurrence of a complex karyotype, +8, 7, and
other structural changes was significantly more frequent. No
significant variation in frequency of particular abnormalities across
the age range of patients entered into the trial was noted, with the exception of t(15;17) and del(7q), which were more common in
younger patients.
A number of cytogenetic abnormalities were associated with a lower
presenting WBC, including cases with del(5q)/ Frequency of additional cytogenetic abnormalities in AML arising in older adults: analysis of cases derived from MRC AML11 To further characterize the cytogenetic features of AML arising in older adults, the frequency of additional changes occurring in conjunction with primary chromosomal aberrations among cases derived from the MRC AML11 trial was determined (Table 2). For this analysis, cases were classified according to the original hierarchical system devised for children and younger adults entered into MRC AML10.8 Favorable risk abnormalities, ie, t(15;17), t(8;21), or inv(16), were detected in 78 of 1065 (7%) AML11 cases and were accompanied by additional changes in 47%, 74%, and 42% of cases, respectively. In the majority, the additional changes were from the intermediate risk group of abnormalities: t(15;17) was most commonly associated with +8 (12%) and miscellaneous other structural changes (26%); t(8;21) with del(9q) (9%) and with other numerical abnormalities (57%), particularly loss of a sex chromosome (52%); and inv(16) was accompanied by del(7q) (17%) or other structural (17%) or other numerical (25%) changes. The majority of cases classified within the intermediate hierarchical risk group had a normal karyotype (507 of 776 cases, 65%); multiple intermediate abnormalities were detected in 83 of 776 cases (11%); while in the remaining 186 intermediate risk group cases a single aberration was detected: most commonly, +8 (22%), del(9q) (5%), del(7q) (3%), +21 (3%), and 11q23 (2%) rearrangements (Table 2); the rest were composed of miscellaneous structural or numerical changes with an individual frequency of fewer than 10 cases. Overall, 211 of 1065 cases were assigned to the adverse cytogenetic risk category; in 145 of 211 cases (69%), this was based on the presence of a complex karyotype, of which 65 (45%) possessed one adverse cytogenetic abnormality (eg,5) and 47 (32%) possessed 2 or
more. Hence, adverse cytogenetic aberrations frequently occurred in
conjunction with one another as part of a complex karyotype.
Furthermore, complex karyotypes inevitably included cytogenetic
abnormalities, which in their own right would have been considered
intermediate risk; it is of note that 63% of cases of del(7q), 50% of
cases of +21, and 30% of cases of +8 occurred as part of a complex
karyotype (Table 2). The remaining patients in the adverse cytogenetic risk group were classified on the basis of the presence of adverse cytogenetic features occurring in the context of a less complex karyotype (44 of 211 patients, 21%) or, uncommonly, as the sole aberration (22 of 211 patients, 10%).
Prognostic significance of hierarchical cytogenetic classification in older adults with AML We then sought to determine the prognostic significance of individual abnormalities within the parameters of the original AML10 hierarchical classification (Table 3). Among the favorable risk abnormalities, superior CR rates were observed for cases with t(8;21) where 87% achieved remission. The CR rate among APL cases with the t(15;17) was lower, owing to a high incidence of ID, which was nonsignificantly more common among patients randomized to the inferior short arm of the MRC ATRA trial, whereby patients received ATRA for 5 days prior to induction chemotherapy; 67% of patients receiving extended ATRA therapy simultaneously with induction chemotherapy, but only 42% of patients receiving short-term ATRA therapy, achieved CR. RR for cases with the t(15;17) was 26% at 5 years, which was significantly lower than for all other cytogenetic abnormalities, and was comparable to that observed in younger adults treated with ATRA and chemotherapy.11 This led to a superior OS of 38% at 5 years, which was comparable to cases with t(8;21) (Table 3). A high CR rate was also observed in cases with inv(16); OS was lower than for the other 2 favorable risk abnormalities, although reliability was limited by small sample size.
In comparison with the favorable cytogenetic group, cases classified within the intermediate cytogenetic risk category had a poorer outcome: overall CR rates were lower (60%) owing to a higher incidence of RD (21%), and RR was higher (81% at 5 years), leading to an inferior OS of 13% at 5 years. Overall, cases classified within the adverse cytogenetic risk group were found to have an even poorer prognosis, with only 32% achieving CR owing to high rates of RD (51%); furthermore, the small proportion of patients achieving CR almost invariably relapsed (RR, 86%), leading to an OS of only 4% at 5 years. Further analysis revealed that the subgroup with complex karyotype had the poorest outcome, while the prognosis of cases with noncomplex adverse abnormalities was more comparable to the group with cytogenetic changes classed as intermediate risk (Table 3, Figure 1). The CR rate of 45% for cases with noncomplex adverse abnormalities was significantly better than the CR rate of 26% in cases with complex karyotype (P = .006), but not significantly different from the 54% CR rate observed in the other intermediate cytogenetic risk group (P = .2). Therefore, the hierarchical cytogenetic classification that was devised
for children and younger adults entered into the MRC AML10 trial, which
predicted CR rate, RR, and OS, was also found to be highly predictive
of outcome in older adults entered into the MRC AML11 trial. However,
in contrast to younger patients in whom outcomes of cases with complex
karyotype and noncomplex adverse abnormalities were found to be
comparable,8 the outcome of older adults with noncomplex
karyotypes, including chromosomal abnormalities of 3q, 5, or 7, was
comparable to that of patients with abnormalities associated with
intermediate risk and normal karyotype (Figure 1). This observation led
to development of a revised hierarchical cytogenetic classification
that was more predictive in this age group (Table
4, Figure
2). Differences in outcome between
particular cytogenetic abnormalities remained significant when adjusted
for age, type of leukemia (de novo or secondary), and presenting WBC.
In accordance with the analysis of cases entered into
AML10,8 the presence of additional cytogenetic abnormalities had no significant influence on prognosis in AML11 (favorable alone: CR, 68%; RR and OS at 5 years, 51% and 31%, respectively; favorable plus other aberrations: CR, 76%; RR, 57%; OS,
37%). Among patients in the intermediate cytogenetic risk category,
the relatively small subgroup remaining in first CR at 5 years could
not be distinguished from those who relapsed or died in remission
before 5 years on the basis of pretreatment characteristics (age, sex,
cytogenetic abnormality, type of leukemia, presenting WBC, and platelet
count) or subsequent treatment randomizations. In the subgroup of
intermediate risk patients with a cytogenetic abnormality, increasing
complexity of karyotype was associated with a decrease in OS owing to
poorer CR rates, which reflected increasing rates of RD (for 1, 2, 3, and 4 unrelated abnormalities: CR, 58%, 54%, 24%, 44%,
P = .005; RD, 28%, 29%, 58%, 40%, P = .004; and
OS, 9%, 13%, 6%, 8%, P = .01, respectively). Within cytogenetic risk groups, patients with residual normal metaphases tended to have a better prognosis than those in whom solely abnormal metaphases were detected; however, this effect was not strong enough to
merit any further modification of the cytogenetic classification system.
Influence of age on epidemiology and prognostic implications of cytogenetic aberrations in AML To examine potential reasons for the poorer prognosis of AML in older adults, we considered the frequency of particular cytogenetic abnormalities according to age of patients entered into the MRC AML10 and AML11 trials, representing 2677 cases (Table 5). Favorable risk abnormalities were detected less frequently in older adults than in younger patients; the presence of a complex karyotype,5, and del(5q) were significantly
more common in the older age group. A number of other cytogenetic
aberrations demonstrated significant variation in frequency according
to age. These included changes involving 11q23, t(6;9)(p23;q34), +8,
and +21 and nonrecurring structural abnormalities that were more common
in younger individuals; normal karyotype was more common in older
adults. A significantly greater proportion of cases of secondary AML
was found to have a complex karyotype; 7, del(5q),5, or 3q
abnormalities; or +8 and other numerical and structural abnormalities.
Secondary leukemias were confirmed to be more common in older patients
(P < .001), while t(15;17) was more common in
de novo AML. Table 5 also highlights the rarity of some primary
recurring cytogenetic abnormalities associated with AML such as
t(9;22)(q34;q11) and t(6;9); all remaining recurrent abnormalities that
were not listed were extremely uncommon, with an individual frequency
of fewer than 10, eg, t(8;16)(p11;p13) (n = 6).
The poorer OS of older patients with favorable cytogenetic abnormalities in comparison with younger individuals entered into the AML10 trial could not be accounted for by the frequency, nature, or number of secondary aberrations (Table 2,8 and data not shown). We also sought to investigate the influence of the relative proportions of hierarchical risk groups on outcome of AML arising in different age cohorts (Figure 3). There was a significant increase in the relative proportion of normal and complex karyotypes with advancing age, while favorable karyotypes were infrequent in older patients, being most commonly observed in cases of AML presenting in children and younger adults. The deleterious effect of advancing age at the time of diagnosis on subsequent outcome is highlighted by data presented in Figure 3; indeed, age remained a highly significant prognostic factor (P < .001) even when hierarchical cytogenetic risk group was taken into account. Hierarchical cytogenetic risk group also retained its prognostic value (P < .001) when age was taken into account. This shows that differences in the distribution of cytogenetic risk groups, shown in Figure 3, influence but do not explain the deterioration in outcome with increasing age. The DAT 3 + 10 and ADE 10 + 3 + 5 regimens employed as the first
induction course in the AML11 trial2 were common to the AML10 protocol for younger patients.12 We then considered
the influence of karyotype on response to the initial course of
chemotherapy among cohorts of patients younger than 55 or 55 years of
age or older derived from the MRC trials randomized to DAT or ADE
(Table 6). In both age groups, cases with
favorable karyotype were characterized by higher CR rates associated
with lower levels of RD. In contrast, cases with complex karyotype were
typified by low CR rates owing to high levels of RD (Table 6), while
intermediate CR and RD rates were observed in the group with other
intermediate changes and normal karyotype. This confirmed that the
hierarchical cytogenetic risk groupings are highly predictive of
outcome for AML in all age groups (Table 6).
For many years, it has been appreciated that age is a key prognostic factor in AML, with a steady deterioration in outcome with increasing years (reviewed by Harousseau14). However, in order to improve the therapeutic approach for older patients with this disease it is essential to establish the basis of this phenomenon. This is likely to be a consequence of 3 key variables: the characteristics of the patient population, the intensity of the chemotherapy protocol employed, and the nature of the leukemia itself. However, the extent to which each of these factors contributes to the unfavorable prognosis of AML in older patients has been somewhat unclear. This information is critical to predict whether innovations in treatment are likely to be of any clinical benefit. A potential advantage of studies such as the MRC trials is that they provide some insights into these issues. To some extent, an inferior outcome in older adults is to be expected, owing to the increased likelihood of coexistent end-organ damage leading to a poorer tolerance of combination chemotherapy regimens, associated with higher rates of ID. While it is accepted that older individuals entered into leukemia trials represent a highly selected group and that the number of cases considered was relatively small, AML11 is consistent with the concept that the biological behavior of cases of AML with particular cytogenetic abnormalities in older patients is comparable to that of cases with the same aberrations arising in younger individuals. MRC AML11 also shows that intensive induction therapy is feasible in
some older individuals.2 Concern about toxicity has in
some instances prompted the use of less intensive protocols, including
curtailed or indeed no consolidation therapy. This is likely to be a
key reason why the majority of older patients with AML who successfully
achieve CR nevertheless ultimately die from leukemic relapse. This is
supported from analyses of patients with t(8;21) and inv(16) derived
from AML11. While the CR rate for this group was not significantly
different from that of younger patients with these abnormalities using
identical or comparable combination chemotherapy,8 RR was
significantly higher in patients treated in AML11 (83% in AML11 vs
33% in AML10 at 5 years, P < .0001); however, age could
also be a contributory factor to this phenomenon. Intensive induction
therapy may therefore be beneficial in these cytogenetically defined
subgroups of AML, and it is possible that further improvements may be
feasible with enhanced consolidation therapy. However, the options
available to this age group are relatively limited, owing to the risks
of excessive toxicity. In selected patients, more intensive
chemotherapy, autologous bone marrow transplantation (BMT)/peripheral
blood stem cell transplantation,15 or
nonmyeloablative allogeneic BMT16 could be investigated. However, such strategies are likely to prove impractical for the vast
majority of patients in this age group and confer no overall benefit in
terms of OS or quality of life. Therefore, there is considerable
interest in alternative approaches that are more specific to the
underlying cytogenetically/molecularly defined abnormality and may
provide an inherently less toxic form of consolidation therapy. APL
associated with the t(15;17), leading to formation of the PML-RAR While increased susceptibility to treatment toxicity undoubtedly contributes to adverse outcome in older adults (Table 6), failure to achieve CR in this age group is more commonly the result of intrinsic resistance of leukemic blasts to chemotherapy (Table 3). This observation has led to considerable interest as to whether AML arising in older adults represents a distinct disease entity from that developing in younger individuals, which could be the key reason underlying the adverse prognosis. In this regard, secondary leukemias are more common in older adults (Table 1 and Grimwade et al8), arising following an antecedent hematologic disorder, particularly myelodysplasia, and have been associated with a poor prognosis.22 AML arising in older adults is also associated with higher rates of P-gp expression, correlated with a poor response to induction chemotherapy.5,23 Furthermore, a number of studies have highlighted the detection of adverse karyotypic features, notably abnormalities of chromosomes 5 and 7, in elderly AML, changes that had previously been associated with secondary AML.4,5,24,25 This has led to the suggestion that the disease arising in the elderly is more akin to secondary AML and that in patients lacking a documented history of antecedent hematologic disorder or previous chemotherapy/radiotherapy, it could reflect an increased genetic susceptibility to environmental mutagens (reviewed by Willman3). This is supported by a recent study that has identified cases of AML arising in elderly patients with a mutator phenotype, associated with lack of expression of MSH2 and mutations of p53,26 reminiscent of therapy-related AML in which a high incidence of p53 mutations and microsatellite instability have been reported previously.27 However, it is clear from the present study that the spectrum of cytogenetic abnormalities detected among older patients with AML is identical to that detected in younger patients, although the relative frequency of particular aberrations varies considerably with age (Table 5). Overall, favorable risk abnormalities were relatively uncommon in the elderly, whereas normal and complex karyotypes were more common (Figure 3). However, above 55 years of age no further increase in the proportion of cases with adverse cytogenetic features was observed (Table 1), suggesting that the presumed poorer prognosis of very elderly patients who are rarely entered into clinical trials will not be accounted for by the karyotypic profile of this group. The variation in the relative size of the hierarchical risk groups with age is clearly a major influence, but does not account for the adverse outcome of older adults with AML. This study also shows that high CR rates are attainable in older patients with favorable risk cytogenetic abnormalities, associated with low rates of induction failure due to RD. This would suggest that expression of proteins conferring a drug resistance phenotype is unlikely to be prevalent in this group. This is supported by a number of studies undertaken in younger adults with AML with favorable cytogenetics, though these studies have largely focused on AML with the t(15;17).23,28,29 In the present study, the CR rate for older patients with t(15;17) was inferior to that of younger individuals (63% AML11, 87% AML10, P < .001), owing partly to a higher ID rate among patients randomized to receive only 5 days of ATRA prior to induction chemotherapy; overall, the RR for older APL patients was only 26% at 5 years in AML11, which is comparable to younger patients with this disease (37% in AML10). The European APL93 study has recently reported excellent results in older patients with low presenting WBC induced with extended ATRA and combination chemotherapy (CR, 90%; RR, 7%; and OS, 69% at 2 years).18 It appears highly plausible that AML associated with favorable karyotypes arising in older patients is biologically similar to leukemias with the same abnormalities occurring in younger individuals and demands specific treatment approaches. Furthermore, poor CR rates, which reflected comparably high levels of RD, were observed among older and younger patients with adverse cytogenetic features. Previous work undertaken in elderly AML suggests that this is likely to reflect the high rates of P-gp expression in this group.5 In a more recent study involving a younger cohort of patients with newly diagnosed AML, Leith et al23 also observed a trend toward a higher incidence of P-gp expression in cases with adverse cytogenetics in comparison with those with more favorable karyotypes. Furthermore, Legrand et al30 have reported that combined activity of multidrug-resistance proteins P-gp and MRP1 is more predictive of adverse outcome than the activity of either protein alone, and that coexpression was most closely correlated with the presence of adverse karyotypic features. This is important, since chemoresistance mediated by both of these mechanisms is potentially amenable to modulation, which could lead to significant improvements in clinical outcome. Further evidence supporting the notion that karyotype analysis identifies subgroups of AML that are biologically similar irrespective of the age of the patient has been provided by recent studies reporting a close correlation between cytogenetic subgroup and bax/bcl2 ratio,31 immunophenotypic profile,32 and the behavior of primary leukemic blasts, both in vitro, in terms of proliferative activity, semisolid colony growth, and response to granulocyte-macrophage colony-stimulating factor,33,34 and in vivo, influencing engraftment characteristics in nonobese diabetic/severe combined immunodeficient mice.35 To date, cytogenetic classification systems used to predict outcome in AML have been somewhat inconsistent. This is likely to reflect influences of sample size and interstudy and intrastudy variation in treatment approach, as well as differences in the age of the study population. Recent studies have highlighted the importance of validation of proposed cytogenetic classification systems in independent data sets.10,36 The original MRC AML10 hierarchical cytogenetic classification has subsequently been prospectively validated in children and younger adults entered into the MRC AML12 trial,36 and in the present study, it was also found to be of prognostic value in an older cohort of patients that was the subject of the MRC AML11 trial. However, in the latter group, a minor modification entailing assignment of noncomplex adverse abnormalities to the intermediate risk category was found to provide a more predictive and clinically relevant system. The classification system clearly identified the group with favorable cytogenetics, who appeared most likely to benefit from intensive treatment in terms of CR and OS rates, with a third of patients alive at 5 years. Furthermore, the modified system distinguished those with complex karyotype who had an extremely poor prognosis; in accordance with a recent report from the German AML Cooperative Study Group,37 these patients are only very rarely cured with intensive therapy and might therefore be best treated according to a more palliative approach. While cytogenetic analysis provides a framework that can clearly distinguish groups of patients with differing responses to treatment and likelihoods of relapse, it lacks the ability to distinguish cohorts of patients with differing prognoses within cytogenetic risk groups. This may be enhanced in the future with discovery of novel rearrangements associated with AML, such as Flt3 mutations,38-40 and analysis of larger cohorts of patients, permitting more confident assignment of prognostic significance to rare recurrent cytogenetic abnormalities. Previous work has suggested that determination of P-gp status could be helpful in distinguishing subgroups of patients with differing prognoses within cytogenetic risk groups, which could prove of value to the design of future stratified treatment approaches.5 Studies considering the impact of a multidrug-resistant phenotype on prognosis, in conjunction with the present study considering the outcome of older and younger patients with identical cytogenetic abnormalities treated with comparable induction therapy, afford the opportunity to take a more reasoned approach to treatment of AML in older adults.
We thank all the clinicians participating in the MRC trials, as detailed in the accompanying paper,2 and the cytogeneticists involved in performing the karyotype analyses.
Submitted July 26, 2000; accepted June 6, 2001.
Supported by the Leukaemia Research Fund of Great Britain (D.G.); the MRC trials database is supported by the Kay Kendall Leukaemia Fund.
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: A. H. Goldstone, North London Cancer Network, 6th Floor, Rosenheim Wing, University College Hospital, 25 Grafton Way, London WC1E 6DB, United Kingdom; e-mail: anthony.goldstone{at}uclh.org.
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Abstract
Introduction
), or 3q abnormalities predicted an adverse
prognosis. The remaining patients, including those with normal
karyotype or structural or numerical changes not encompassed by the
favorable or adverse risk groups, had an intermediate prognosis. This
cytogenetic classification system and response to the first course of
chemotherapy were found to provide the 2 most important prognostic
factors in the MRC AML10 trial.
maintenance for 12 months versus no
interferon-
indicates favorable; 
, normal; 
, other intermediate;
, noncomplex adverse; 
, complex.