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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 92 No. 7 (October 1), 1998:
pp. 2322-2333
The Importance of Diagnostic Cytogenetics on Outcome in AML:
Analysis of 1,612 Patients Entered Into the MRC AML 10 Trial
By
David Grimwade,
Helen Walker,
Fiona Oliver,
Keith Wheatley,
Christine Harrison,
Georgina Harrison,
John Rees,
Ian Hann,
Richard Stevens,
Alan Burnett, and
Anthony Goldstone on behalf of the Medical
Research Council Adult and Children's Leukaemia Working Parties
From the Departments of Haematology, University College London; the
Royal Free and Great Ormond St Children's Hospitals, London; Royal
Manchester Children's Hospital, Manchester; University of Cambridge
and University of Wales College of Medicine, Cardiff; the Division of
Medical and Molecular Genetics, United Medical and Dental Schools of
Guy's and St Thomas's Hospitals, London; and the Clinical Trial
Service Unit, Radcliffe Infirmary, Oxford, UK.
 |
ABSTRACT |
Cytogenetics is considered one of the most valuable prognostic
determinants in acute myeloid leukemia (AML). However, many studies on
which this assertion is based were limited by relatively small sample
sizes or varying treatment approach, leading to conflicting data
regarding the prognostic implications of specific cytogenetic abnormalities. The Medical Research Council (MRC) AML 10 trial, which
included children and adults up to 55 years of age, not only affords
the opportunity to determine the independent prognostic significance of
pretreatment cytogenetics in the context of large patient groups
receiving comparable therapy, but also to address their impact on the
outcome of subsequent transplantation procedures performed in first
complete remission (CR). On the basis of response to induction
treatment, relapse risk, and overall survival, three prognostic groups
could be defined by cytogenetic abnormalities detected at presentation
in comparison with the outcome of patients with normal karyotype. AML
associated with t(8;21), t(15;17) or inv(16) predicted a relatively
favorable outcome. Whereas in patients lacking these favorable changes,
the presence of a complex karyotype,  5, del(5q), 7, or
abnormalities of 3q defined a group with relatively poor prognosis. The
remaining group of patients including those with 11q23 abnormalities,
+8, +21, +22, del(9q), del(7q) or other miscellaneous structural
or numerical defects not encompassed by the favorable or adverse risk
groups were found to have an intermediate prognosis. The presence of
additional cytogenetic abnormalities did not modify the outcome of
patients with favorable cytogenetics. Subgroup analysis demonstrated
that the three cytogenetically defined prognostic groups retained their
predictive value in the context of secondary as well as de novo AML,
within the pediatric age group and furthermore were found to be a key
determinant of outcome from autologous or allogeneic bone marrow
transplantation (BMT) in first CR. This study highlights the importance
of diagnostic cytogenetics as an independent prognostic factor in AML,
providing the framework for a stratified treatment approach of this
disease, which has been adopted in the current MRC AML 12 trial.
| |
INTRODUCTION |
PRESENTATION CYTOGENETICS is widely
recognized as one of the most important prognostic determinants in
acute myeloid leukemia (AML). However, many studies on which this
assertion is based were limited by consideration of relatively small
numbers of patients or were confounded by amalgamation of groups
receiving widely differing treatment protocols.1-9 This has
in a number of cases led to conflicting data regarding the prognostic
implications of specific cytogenetic abnormalities. The Medical
Research Council (MRC) AML 10 trial for children and younger adults
with AML, which was designed to evaluate the role of bone marrow
transplantation (BMT) in first complete remission (CR), affords the
opportunity to determine the independent prognostic significance of
cytogenetics at diagnosis in the context of a large group of patients,
who apart from the transplant randomization, received equivalent
induction and consolidation therapy. Furthermore, this study also
enables one to determine the relative impact of pretreatment
cytogenetics on the outcome of subsequent transplant procedures.
Overall 1,938 children and adults with de novo or secondary AML were
recruited to the trial; the present study considers the prognostic
implications of pretreatment cytogenetics in 1,612 patients in whom
karyotype analysis was successful.
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MATERIALS AND METHODS |
Patients.
The MRC AML 10 trial began in May 1988 and closed in April 1995, having
accrued 1,966 patients, including 364 children (<15 years) and 1,602 adults, mostly up to 55 years of age. A total of 1,797 were registered
as having de novo AML (337 children, 1,460 adults), 141 cases of
secondary AML were entered (22 children, 119 adults), while the
remaining 28 trial patients were excluded from further analysis, as
they were subsequently found not to have AML. Cases of AML were
classified as secondary on the basis of a history of previous exposure
to chemotherapy or radiotherapy or of an antecedent hematologic
condition including myelodysplasia and myeloproliferative disorders.
Therapy.
The trial, which sought to determine the relative efficacy of two
different induction protocols and also to establish whether there is a
role for allogeneic or autologous BMT in the treatment of patients in
first CR, has been fully described previously.10 Briefly,
patients were randomized to receive induction therapy with two courses
of DAT (daunorubicin, Ara-C, 6-thioguanine: course 1, DAT 3 + 10;
course 2, DAT 3 + 8) or ADE (Ara-C, daunorubicin, etoposide: course 1, ADE 10 + 3 + 5; course 2, ADE 8 + 3 + 5). From January 1993, those with a clinical diagnosis of acute promyelocytic leukemia (APL)
were eligible for the MRC ATRA trial whereby 75 patients
were randomized to receive either short or extended courses of
all-trans retinoic acid (ATRA), in addition to the AML 10 chemotherapy protocol, as previously described.11 A further
six APL patients also received ATRA, but were not entered into the MRC
ATRA trial. The third and fourth courses of consolidation chemotherapy
of AML 10 comprised MACE (m-amsacrine, Ara-C, etoposide) and MIDAC (mitozantrone, Ara-C), respectively, with bone marrow harvest being
scheduled between the third and fourth courses, provided morphologic CR
at this stage was confirmed. Patients achieving CR were subsequently
scheduled to proceed to allogeneic BMT if a matched sibling donor was
available; patients lacking a suitable donor could be randomized to
receive an autograft or no further therapy. No significant difference
was found in either CR rate, relapse risk, or overall survival between
patients randomized to DAT or ADE induction.10 Overall
1,365 of 1,612 patients (85%) achieved CR, of which 428 (31%)
received BMT in first CR (211 sibling allo BMT, 199 autologous BMT, six
matched unrelated donor, five autologous peripheral blood stem cells
[PBSC], three allogeneic PBSC, two mismatched and two
syngeneic). In the remaining 937 patients (69%), consolidation was
with chemotherapy alone. There were no significant differences in the
treatment received according to the cytogenetic abnormality detected at
diagnosis.
Cytogenetics.
The majority of cytogenetic analyses were performed at 41 local
laboratories, subject to monitoring by a central quality control scheme
(UK NEQAS, National External Quality Assessment Schemes). Where no
local cytogenetics service was available, examinations were undertaken
at the central MRC AML trials cytogenetics laboratory at University
College Hospital, London (n = 180). Bone marrow for cytogenetic
analysis was cultured according to standard methods; 20 or more cells
were fully analyzed to exclude clonal abnormalities, which were defined
in accordance with International System for Human Cytogenetic
Nomenclature (ISCN) guidelines.12 For patients with a detectable clonal abnormality, at least 10 metaphases were examined to exclude secondary changes in accordance with NEQAS guidelines for clinical cytogenetics. Complex karyotype was defined by
the presence of a clone with at least five unrelated cytogenetic abnormalities, as we found that the outcome of these patients was worse
than that of patients with fewer clonal abnormalities. A successful
analysis was available for 1,612 patients, representing 83% of cases
of AML in the trial. A diagnostic result was not available in 326 cases
either because cytogenetic studies were not performed (n = 94) or
failed (n = 136), while the reason was unknown in the remainder.
Failure rates were greater among samples analyzed centrally in
comparison with examinations performed at local laboratories (27%
v 5%), most likely reflecting sample deterioration during
transit. We report here an analysis of the more frequently observed
abnormalities, ie, those found in 20 or more patients. Initially, we
sought to determine the prognostic impact of each specific abnormality
taken in isolation; hence in these analyses, patients may be counted
more than once due to the presence of multiple cytogenetic changes
(Figs 2, 3A and B, and Tables 1 and 2). These analyses led to the
development of a hierarchical classification based on recognized
commonly recurring primary abnormalities (Tables 4-6). In these
analyses, patients are defined by the presence of primary abnormalities
and hence are counted only once.
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| Fig 2.
Overall survival of patients with adverse cytogenetic
abnormalities, irrespective of the presence of additional
abnormalities. The group with normal karyotype is included for
comparison.
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| Fig 3.
Overall survival of patients with intermediate structural
(A) or numerical (B) cytogenetic abnormalities, irrespective of the
presence of additional abnormalities. The group with normal karyotype
is included for comparison.
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| Fig 1.
Overall survival of patients with favorable cytogenetic
abnormalities, irrespective of the presence of additional
abnormalities. The group with normal karyotype is included for
comparison.
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Definitions of endpoints.
A normocellular bone marrow aspirate containing less than 5% blast
cells and showing evidence of normal maturation of other marrow
elements was the criterion for the achievement of CR. The persistence
of myelodysplastic features did not exclude the diagnosis of CR. Full
recovery of normal peripheral blood counts was not required to define
CR, which might contribute to the relatively favorable CR rates
observed in this study. Remission failures were classified by the
referring clinician as due either 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 20% 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: overall survival (OS) is the time
from entry to death: for remitters, the relapse risk (RR) is the
cumulative probability of relapse, ignoring (ie, censoring at) death in
CR.
Statistical methods.
The Mantel-Haenszel test for trend and Wilcoxon two 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 using 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 August 1, 1997, when follow-up was up-to-date for
over 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 61 months (1 to 111 months). All P values are
two-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 P
values < .01 are quoted.
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RESULTS |
Incidence of specific cytogenetic abnormalities in AML and their
prognostic significance.
The frequency of the most common cytogenetic abnormalities detected at
diagnosis among 1,612 patients with AML and their associated clinical
features are presented in Table 1. On the
basis of response to induction therapy, RR, and OS, three prognostic
groups were retrospectively distinguished by the presence of specific
abnormalities, initially irrespective of additional cytogenetic
changes, (Table 2). Patients with t(8;21),
t(15;17), and inv(16) comprised a group with relatively favorable
prognosis, characterized by low rates of primary drug resistance and
superior OS associated with a reduced RR (Table 2,
Fig 1). The outcome of the subgroup of APL
cases with the t(15;17) who were not treated with ATRA (n = 117) was
also found to be significantly better (CR 88%, RR at 5 years 41%;
P < .01, OS at 5 years 61%; P < .001) than
patients with normal cytogenetics, thereby justifying inclusion of
t(15;17) in the favorable cytogenetic risk category. Virtually all
patients with t(8;21) achieved CR (98%); CR rates for those with
t(15;17) and inv(16) did not differ from patients with normal karyotype due to ID, reflecting the associated hemorrhagic diathesis and propensity to high presentation WBC, respectively (Table 1). In
contrast, the presence of complex cytogenetic changes,
5/del(5q), 3q abnormalities, or 7 was found to predict a
significantly poorer outcome than patients with normal cytogenetics.
Patients within this adverse cytogenetics group were significantly less
likely to achieve CR associated with higher rates of primary RD
and/or ID; furthermore they had poorer OS reflecting increased
risk of death on induction and/or relapse (Table 2,
Fig 2). The remaining patients were placed
within the intermediate risk group (Table 2,
Fig 3A and B). For the purposes of this
analysis, cases with del(9q) were included in this group, despite their
relatively favorable outcome due to the frequent association with
t(8;21) (Table 3). Similarly, cases with
del(7q) or other structural and numerical changes were also included in
the intermediate group, although they exhibited a poorer outcome than
patients with normal cytogenetics due to an association with
abnormalities within the adverse risk category (Table 3). However, in
the absence of associated favorable or adverse cytogenetic features,
the outcome of patients with del(9q), del(7q), or those with other
structural or numerical abnormalities did not differ significantly from
patients with normal cytogenetics (Table 3), thereby justifying their
present inclusion in the intermediate risk category. Stratification by age, WBC at presentation, and type of leukemia (de novo/secondary) confirmed diagnostic cytogenetics as an independent prognostic factor
in AML (Table 2). Indeed, subgroup analysis confirmed t(8;21) as a
favorable prognostic factor in pediatric as well as adult AML. Of 41 children with t(8;21), 98% achieved CR associated with an OS of 83%
at 3 years (cf OS of 59% for children with normal cytogenetics, P < .01). Differences in outcome between
cytogenetic risk groups could not be accounted for by significant
variation in deaths in remission (Table 2) or postremission therapy.
Influence of additional cytogenetic abnormalities on outcome in AML.
Additional cytogenetic abnormalities, irrespective of the nature or
complexity, were found not to have a deleterious effect on the outcome
of patients with the t(8;21), t(15;17), or inv(16) (Table 3 and
Fig 4). Coexistence of abnormalities
associated with the favorable and adverse risk categories was
associated with a favorable outcome, whereas the presence of adverse
abnormalities in patients with intermediate risk changes had a
deleterious effect on outcome (Table 3 and Fig 4). Subgroup analysis of
patients with 11q23 abnormalities suggested a poorer outcome among
those with t(10;11)(p12;q23), compared with patients with
t(9;11)(p22;q23), although this needs to be confirmed in a much larger
patient group (Table 3).
Prognostic value of a hierarchical cytogenetic classification in
newly diagnosed AML; importance in predicting outcome following
postremission BMT.
Consideration of the influence of additional cytogenetic abnormalities
on outcome permitted a more refined hierarchical prognostic classification as shown in Table 4. This
revised classification can distinguish groups with highly significant
differences in CR rates, RR, and OS (summarized in
Table 5) and has been adopted to direct
treatment approach in the current MRC AML 12 trial. The hierarchical
classification was subsequently evaluated in a variety of clinical
contexts and was found to retain its predictive value in all age groups
examined, in both de novo and secondary AML, in patients treated with
chemotherapy alone, and among those receiving autologous or allogeneic
BMT (Table 6). Furthermore, stratified log
rank tests showed that cytogenetic risk group (P < .001) was
the most important predictor of relapse risk after BMT; while
cytogenetics (P < .001) and age (P = .004) were the most important predictors of posttransplant survival. While we have
shown that the three cytogenetic risk groups were independent of the
postremission therapy received in the context of the AML 10 protocol,
applying whether or not BMT was performed, it should be noted that the
analysis presented here cannot be interpreted as indicating that BMT is
beneficial. Relapse rates after BMT will be lower in all cytogenetic
risk groups when compared with relapse rates after CR for
nontransplanted patients, as the median times from CR to allogeneic and
autologous BMT were 157 and 171 days, respectively. Thus, patients
receiving BMT will already have an improved prognosis by virtue of
having remained in CR long enough to reach transplant. This selection
factor will apply especially to poor risk patients who have a very high
early relapse rate, so those who reach BMT represent a better risk
subset within this group.
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Table 6.
Evaluation of the Prognostic Value of Hierarchical
Cytogenetic Risk Group Classification in Newly Diagnosed AML and in
BMT in First Remission
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DISCUSSION |
For well over a decade, it has been appreciated that diagnostic
cytogenetics provides one of the most valuable prognostic indicators in
AML.1-9 However, many studies on which such conclusions were drawn were compromised to a variable extent either by relatively small sample size or by inconsistency of treatment approach. These limitations have in a number of instances resulted in contradictory data regarding the prognostic implications of specific cytogenetic abnormalities, undermining employment of karyotype at diagnosis as a
means of directing treatment strategy. Nevertheless, the majority of
studies associate inv(16) with a relatively favorable outcome and
7, 5/del(5q) and complex cytogenetic abnormalities with
an adverse prognosis, suggesting that in many cases, cytogenetic abnormalities reflect basic differences in leukemia biology that transcend the relative sensitivity to a particular treatment approach. However, there has been little consensus as to the prognostic significance of a number of frequently recurring abnormalities: for
example, t(8;21) and t(15;17) have been variably assigned to favorable
and intermediate risk groups, while +8 and 11q23 abnormalities have
fluctuated between intermediate and adverse-risk categories. The MRC
AML 10 trial affords the opportunity to resolve such issues in the
context of large patient groups receiving equivalent therapy.
On the basis of response to induction therapy, RR, and OS, three
prognostic groups could be defined by cytogenetic abnormalities detected at presentation in comparison with cases with normal karyotype
as summarized in Tables 4 and 5. Patients with AML associated with
t(8;21), t(15;17) and inv(16) were found to comprise a group with
relatively favorable outcome (Table 2). Conversely, detection of
complex cytogenetic changes, 5, del(5q), 7, or abnormalities of 3q defined a group with adverse prognosis (Table 2).
Bivariate analysis showed that adverse prognosis previously ascribed to
del(7q) was due to a close association with complex cytogenetic
abnormalities. Indeed, for patients with del(7q) in the absence of
cytogenetic features associated with adverse-risk, outcome did not
differ significantly from the group with normal karyotype, although
this analysis was based on small numbers (Table 3). This latter result
is consistent with the outcome of the Fourth International Workshop on
Chromosomes in Leukemia, which found del(7q) without concurrent
abnormality of chromosome 5 to be associated with a relatively
favorable outcome.7 In addition to normal karyotype and
del(7q), the intermediate prognostic category included patients with
11q23 abnormalities, +21, +8, +22, and del(9q). It is worth noting that
the latter three abnormalities are frequent secondary changes in
t(15;17), inv(16), and t(8;21) associated AML, respectively. However, a
recent study suggests that the relatively good prognosis of +8, +22,
and del(9q) even in the absence of overt t(15;17), inv(16), or t(8;21)
cannot be accounted for by cryptic rearrangements of their respective
fusion genes.13 The intermediate prognostic category also
incorporated a miscellaneous group of other structural and numerical
changes not encompassed by the other two risk groups, which were too
infrequent to be confidently assigned a prognostic significance in
their own right. Similarly, prognostic implications of 11q23
abnormalities detected in individual patients could not be reliably
established, due to considerable molecular heterogeneity within this
cytogenetic category leading to relatively small sample sizes. 11q23
abnormalities typically disrupt the MLL gene,14
which has a plethora of potential fusion partners (see Waring and
Cleary15 for review and references therein). In the present
study, t(9;11)(p22;q23) and t(10;11)(p12;q23) were the most common
abnormalities detected, associated with MLL fusion to
AF916 and AF1017 genes,
respectively. Patients with t(9;11) were found to have a relatively
favorable outcome compared with those with t(10;11) (Table 3). Although
this analysis was based on small numbers and the difference did not
reach statistical significance, it is in accordance with previous
reports concerning the prognostic significance of 11q23 abnormalities
in children18 and adults.19
Recently, there has been increasing interest to determine whether the
presence of additional cytogenetic abnormalities, particularly in the
context of the favorable prognosis group, influences outcome. Previous
smaller studies have provided conflicting data as to the significance
of additional changes in the presence of the t(15;17),20-22
while a study that included seven patients with del(9q) advocated that
this additional abnormality predicts a poor prognosis in patients with
t(8;21).23 The MRC AML 10 trial affords the opportunity to
address these issues in much larger groups of patients. Additional
cytogenetic abnormalities, including those associated with the
adverse-risk group were found to have no significant effect on CR
rates, RR, or OS in patients with t(15;17), t(8;21), or inv(16); indeed
the group with t(8;21),del(9q) exhibited the most favorable survival
(Table 3). While the number of patients with t(8;21), del(9q) in the
present study was too small to confidently attach prognostic
significance to this specific abnormality, this result renders the
previous suggestion that this karyotype is associated with poor risk
somewhat questionable. Furthermore, in our study, the presence of
adverse risk abnormalities in patients with intermediate risk changes
was found to have a deleterious effect on outcome (Fig 4). On this
basis, a hierarchical system of karyotype classification was developed
(Table 4) and has been used in the subsequent AML 12 trial to define
prognostic groups and determine treatment approach. This classification
was evaluated in a variety of clinical contexts in AML 10 and found to
retain its predictive value in all age groups examined, in both de novo
and secondary AML, in patients treated with chemotherapy alone, and
among those receiving autologous or allogeneic BMT (Table 6), indeed
cytogenetic risk group was the most important determinant of outcome
following BMT in first CR. The present study confirms previous reports
demonstrating that pretreatment cytogenetics retains its prognostic
significance in the context of BMT in first CR.24-26 The
relative value of each treatment modality to each cytogenetic risk
group requires careful prospective analysis in an intention to treat
manner. We report here the impact of cytogenetics on
treatment delivered, in patients who were all given the same or
equivalent chemotherapy before transplantation.
While it is clear that conventional cytogenetic assessment can assign
patients to distinct prognostic groups in the context of modern
chemotherapy treatment protocols, the challenges of future studies are
to determine whether prognostic significance can be confidently
ascribed to extremely rare cytogenetic abnormalities by consideration
of larger data sets and as to whether targeted molecular screening and
novel techniques such as spectral karyotyping27 may further
enhance determination of risk groups and in particular achieve
stratification within the heterogeneous intermediate group. For many
years progress has been severely hampered by paucity of information
regarding the nature of critical genes disrupted within the adverse
prognostic category, notably those associated with del(5q) and monosomy
5 and 7. However, genes implicated in 3q21 and 3q26 defects have
recently been delineated (reviewed by Nucifora and
Rowley,28 Lopingco and Perkins,29 Zent et al,30 and references therein). The most common reported
abnormality, inv(3)(q21q26),31 is associated with
overexpression of the zinc-finger transcription factor EVI1, postulated
to lead to deregulation of hematopoiesis. EVI1 overexpression has also
been reported in AML cases apparently lacking 3q
abnormalities32; as to whether more widespread
determination of EVI1 expression would be of value to identify
individual patients with poor prognosis among the favorable and
intermediate risk groups remains to be determined.
Recent studies have confirmed MLL as a relatively frequent
target of cryptic rearrangements,33,34 spawning
considerable interest in a multiplex polymerase chain reaction (PCR)
approach to identify an array of potential fusion partners in the
expectation of establishing clinically relevant prognostic differences
over and above those already demonstrated for patients with overt, cytogenetically established 11q23 abnormalities. Indeed, preliminary data suggests that among patients with normal karyotype, the presence of cryptic MLL rearrangements predicts a worse
prognosis.35 Cryptic rearrangements of genes associated
with the favorable risk cytogenetic group have also been
identified.11,36-43 Analysis of material derived from
patients entered into the MRC AML trials has demonstrated that up to
4% harbor CBF /MYH11 rearrangements in the absence of
inv(16) by conventional cytogenetics43; while 8% to 9% of
French-American-British (FAB) AML M2 have molecular
evidence for AML1/ETO fusion without the
t(8;21).41,42 It remains to be established as to whether
patients in whom there is solely molecular evidence for rearrangements
associated with favorable outcome fare as well as those confirmed by
conventional cytogenetics. However, preliminary evidence in relation to
patients with morphologic APL indicates that cases lacking the t(15;17) who have molecular evidence for a PML/RAR rearrangement
share the favorable prognosis of patients with the
t(15;17).44 This is particularly pertinent bearing in mind
that previous work has suggested the merit of adopting differing
treatment approaches according to diagnostic karyotype. In particular,
both high dose daunorubicin45 and ATRA in combination with
chemotherapy46,47 have been found to confer significant
survival advantage in patients with the t(15;17), while consolidation
with high dose Ara-C has been reported to be particularly beneficial
for patients with inv(16) and t(8;21).48
The MRC AML 10 study has clearly established diagnostic karyotype as
one of the most important determinants of outcome in children and
younger adults with AML. While cytogenetic analysis provides a
framework that can clearly distinguish groups of patients with
differing response to treatment and likelihood of relapse suitable for
directing treatment strategy, it lacks the ability to define outcome in
individual patients or to distinguish between cases particularly within
the heterogeneous intermediate risk group, which accounts for 55% of
patients entered into AML 10. There has been increasing interest over
the last few years in attempting to identify further parameters that
might be of independent prognostic value, including immunophenotype,
identification of myelodysplastic features, in vitro growth
characteristics of leukemic blasts, and involvement of molecular
pathways implicated in leukemogenesis such as the presence of ras
mutations, or involved in response to therapy, eg, expression of the
multidrug resistance glycoprotein MDR 1 (reviewed by Rowe and
Liesveld49). However, it is likely that many such factors
are inextricably linked to karyotype. It remains the goal of future
trials to determine whether analysis for various such factors in
addition to targeted screening for cryptic gene rearrangements might
complement diagnostic cytogenetics, thereby providing more accurate
risk assessment, which may ultimately permit a more refined treatment
approach.
| |
FOOTNOTES |
Submitted March 23, 1998;
accepted June 2, 1998.
D.G. was supported by a MRC clinical training fellowship and
subsequently by the Imperial Cancer Research Fund. We are also indebted
to the Kay Kendall Leukaemia Fund for supporting the MRC trials
cytogenetics database.
Address reprint requests to Dr Anthony Goldstone, FRCP, FRC
Path, Department of Haematology, University College
Hospital, Gower St, London, WC1E 6AU, UK.
The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" is accordance with 18 U.S.C. section 1734 solely to indicate this fact.
| |
ACKNOWLEDGMENT |
We thank all of the clinicians participating in the MRC trials,
previously listed in Hann et al,10 and the cytogeneticists involved in performing the karyotype analyses. The following
cytogenetics laboratories participated in the study: EIRE, Dept of
Genetics, Trinity College, Dublin and University College Hospital,
Galway; ENGLAND, Hospital cytogenetic laboratories participating
included: Birmingham Maternity and Heartlands; Southmead, Bristol;
Addenbrooke's, Cambridge; St Richard's, Chichester; Queen's,
Croydon; Northwick Park, Harrow; Ipswich; St James', Leeds; Liverpool
Women's; Christie, Manchester; Middlesbrough General; Norfolk and
Norwich; Nottingham City; Hammersmith, King's College, Royal Free, St
Mary's and University College, London; Churchill, Oxford; Salisbury
District and Royal Marsden, Sutton in addition to Geoffrey Schofield
Laboratories, British Nuclear Fuels plc, Cumbria; Leicester Royal
Infirmary; Department of Human Genetics, University of Newcastle and
Centre for Human Genetics, Sheffield; NEW ZEALAND, the following
centres participated: Auckland, Christchurch, Dunedin, Palmerston,
Waikato, Wellington. NORTHERN IRELAND, Department of Medical Genetics, Belfast City Hospital. SCOTLAND, Medical Genetics Laboratories, Aberdeen; Ninewells Hospital Medical School, Dundee; MRC Human Genetics
Unit, Western General Hospital, Edinburgh; Duncan Guthrie Institute of
Medical Genetics, Yorkhill, Glasgow; Royal Northern Infirmary,
Inverness. WALES, Department of Haematology and Institute of Medical
Genetics, University Hospital of Wales, Cardiff. We are grateful to
Stephen Langabeer for critical reading of the manuscript and to Michael
Neat for helpful discussions. Finally, we thank Kate Grimwade for all
her support.
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Abstract
Introduction
Abstract
