Blood, Vol. 92 No. 2 (July 15), 1998:
pp. 695-697
CORRESPONDENCE
Prognostic Value of Cytogenetics and Multidrug Resistance (MDR1)
in Elderly Patients With Acute Myeloid Leukemia
 |
LETTER |
To the Editor:
In a recent article, Leith et al of the Southwest Oncology
Group1 investigated the prognostic value of cytogenetics
and MDR1 in patients with previously untreated acute myeloid leukemia (AML; de novo + secondary) and age greater than 55 years. The investigators concluded that AML in the elderly is characterized by an
increased frequency of unfavorable karyotypic abnormalities and MDR1
expression, both of which independently contribute to poor outcomes. We
would like to focus on some points of this report that, in our opinion,
deserve further elucidation and contribute our own results.
(1) In this SWOG trial, patients were presumably selected according to
their performance status, but no data are given about noneligible
cases. It is essential to verify whether these patients had biological
characteristics similar to those actually recruited to rule out
selection biases. In our series of 159 consecutive patients greater
than 60 years of age with AML, only 101 were deemed suitable for
aggressive chemotherapy. It is noteworthy that eligible patients had a
median age of 67 years, as compared with a median age of 71 years of
those who received conservative or supportive therapy only. On
the other hand, the biological characteristics, most notably MDR
expression and cytogenetic patterns, did not exhibit significant
differences between the two groups.2
(2) To assess whether unfavorable cytogenetics and MDR1 expression
really varied with age, the investigators should have compared the
frequencies of these variables with those of consecutive individuals less than 55 years of age with AML treated in the same institutions in
the same lap of time. In our studies, we found no
significant differences in the frequency distribution of the MDR1
phenotype and abnormal karyotypes between the elderly population and
younger adults with AML admitted at the S. Eugenio University Hospital of Rome between January 1987 and June 1993. However, when looking at
favorable and unfavorable cytogenetic patterns, a significant difference between age groups was observed
(P = .002).2,3
(3) Although intrinsic differences in the biology of the disease are
important in partly explaining the poorer prognosis observed in the
elderly, there is considerable evidence in the literature to suggest
that age-related host factors, particularly increased susceptibility to
the stress of infectious episodes, play a relevant role.2,4-7 In our study, the overall complete remission
(CR) rate was 52.3%, decreasing from 65.3% in individuals 60 to 67 years of age to 37.2% in the group 68 to 79 years of age
(P = .007), a difference determined essentially by a reduced
ability to cope with infections.2 Conversely, in the SWOG
study, the major determinant of induction treatment failure was
resistant disease. However, it should be underlined that the CR rate
(45%) is among the lowest reported in recent trials, being
significantly affected by the poor outcome of secondary AMLs. Because
most de novo and secondary AMLs share similar features, resistant
disease in patients with secondary AMLs may not be determined by
abnormal cytogenetics and MDR1 expression alone, but by the presence of
other biological abnormalities. This corroborates the notion that
secondary AML is a distinct disease entity and that experimental
protocols different from those of de novo AML should be
adopted.8,9
(4) It is relevant that, in the SWOG study, the multivariate analysis
showed two independent prognostic factors for overall survival, ie,
unfavorable cytogenetics and age, that were also identified in our own
series, whereas we did not confirm the prognostic value of the white
blood cell count found by the SWOG group. In our study, patients could
be stratified into discrete groups with different prognosis according
to their age and cytogenetic pattern (Fig 1). Patients
67 years of age with favorable cytogenetics had a good prognosis,
those either greater than 67 years of age with favorable
karyotype or 67 years of age with unfavorable karyotype had an
intermediate prognosis, whereas individuals with 67 years of age with
unfavorable cytogenetics had a poor outlook. Previously, we have also
demonstrated that stratification into age groups significantly enhances
the prognostic value of the MDR1 phenotype, although the most
discriminant cut-off point in that study was age 45 years.10
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| Fig 1.
Kaplan-Meier plot of overall survival duration according
to age and cytogenetic pattern. FC, favorable cytogenetics; UC,
unfavorable cytogenetics.
|
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(5) It is notorious that data from the literature are extremely
variable and highly dependent on methodological factors. By using two
separate primary monoclonal antibodies (C219 and JSB1), the same
procedure of cell fixation-permeabilization, and histogram subtraction
analysis, cytofluorimetric detection of the multidrug resistance
P-glycoprotein varied from 43% (C219) to 73% (JSB1) in 158 patients
with newly diagnosed AML.10 This might account for the
differences in frequency distribution between the various studies and
for the different prognostic impact of this variable. The lower MDR
expression in the M4 and M5 FAB categories reported in the SWOG paper
is peculiar. In our series, we found strict correlations
between C219 negativity and M3 subtype and between JSB1 positivity and
M0-M4-M5 subtypes.10 Methodological factors or
age-related differences might also explain the considerable discrepancy
between the percentage of cases with karyotypic abnormalities (86.6%)
in our study2 as compared with the SWOG report (55%).
(6) Although the use of chronological age as a differentiating
parameter is controversial and has brought about a whole variety of cut-off points, in a time when allogeneic bone marrow
transplantation has been extended to patients up to 60 years of age and
high-dose chemotherapy with peripheral blood stem cell or autologous
bone marrow support is used in patients aged 60 to 70 years,11 the definition of elderly applied to individuals
greater than 55 years of age does not seem entirely
appropriate.
In conclusion, AML in elderly patients is not a homogenous disease and
careful evaluation of clinical and biological features of single
individuals is essential for a judicious treatment planning. Certain
subgroups of patients can be defined who are characterized by age,
cytogenetics, MDR1 phenotype, and secondary AML, who are likely to fail
conventional standard chemotherapy. These patients, as well as those
who are not eligible for aggressive chemotherapy because of a poor
performance status, may better be served by alternative treatment
approaches that have yet to be developed.
Roberto Stasi
Department of Medical Sciences
Regina Apostolorum
Hospital
Albano Laziale, Italy
Giovanni Del Poeta
Adriano Venditti
Mario Masi
Elisa Stipa
Maria Christina Cox
Sergio Amadori
Division of Hematology
University of Rome "Tor
Vergata"
S. Eugenio Hospital
Rome, Italy
| |
REFERENCES |
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Leith CP,
Kopecky KJ,
Godwin J,
McConnell T,
Slovak ML,
Chen I-M,
Head DR,
Appelbaum FR,
Willman CL:
Acute myeloid leukemia in the elderly: Assessment of multidrug resistance (MDR1) and cytogenetics distinguishes biologic subgroups with remarkably distinct responses to standard chemotherapy. A Southwest Oncology Group study.
Blood
89:3323,
1997[Abstract/Free Full Text]
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Stasi R,
Venditti A,
Del Poeta G,
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| |
RESPONSE |
Sensitive and Specific Assessment of MDR1 Is Essential
to Determine Prognostic Impact in AML
We have read the letter by Stasi et al and would like to offer the
following comments to each of the points raised.
(1) The Southwest Oncology Group (SWOG) does not collect data on
patients seen at our cooperating institutions who are not entered onto
SWOG clinical trials, in this case, SWOG 9031. We are gratified to
learn that, according to the experience of Stasi et al, the biologic
characteristics (most notably MDR expression and cytogenetic patterns)
did not differ between patients receiving induction chemotherapy and
those receiving only supportive care.
(2) We are very surprised that Stasi et al did not find a
significant difference in the frequency of MDR1 expression between younger versus older AML patients in their single institutional study.
We have now examined the incidence of MDR1 expression (using the
MDR1-specific antibodies MRK16 and MM4.17) and functional dye efflux
(assessing rhodamine efflux and its inhibition by the MDR1-specific
inhibitor cyclosporine or PSC833) in more than 1,500 cases of AML using
multiparameter flow cytometric techniques in a single reference
laboratory. In our experience, the frequency of MDR1 expression and
functional drug efflux increases dramatically with age. In our initial
study,1 we reported an MDR1 incidence of 71% in de novo
and 77% in secondary AML cases arising in individuals greater than 55 years of age. These results have now been confirmed in a second ongoing
study (SWOG 9333) in which the frequency of MDR1 expression in elderly
patients is 73%. In contrast, in both a retrospective (SWOG 8600) and
a prospective (SWOG 9500) study of younger AML patients using identical
laboratory techniques, we find the incidence of MDR1 expression to be
only 25% to 35%.
(3) The lower 45% overall complete remission (CR) rate reported for
SWOG 9031 was likely due in part to the inclusion of patients with
secondary AML in our study. If we limit our analysis to the type of
patients reported by Stasi et al (patients who were 60 to 79 years of
age with de novo AML), then we achieved a CR rate of 54%, highly
similar to the rate of 52% reported by Stasi et al. Secondly, we agree
that older patients may be less able to cope with infection, which is
why in SWOG 9031, we studied the use of granulocyte colony-stimulating
factor (G-CSF) support after induction chemotherapy. Although G-CSF
accelerated myeloid recovery, it did not increase the complete
remission (CR) rate. However, it is often difficult to distinguish the
cause of remission induction failure and, particularly, to determine if
patients who die with infection after prolonged neutropenia would have
survived had they had more responsive leukemia and entered into a more
rapid CR. For years, physicians have assumed that older patients cannot cope with infection. However, the 81% CR rate seen in SWOG 9031 in
elderly patients with leukemia characterized by a lack of MDR1 expression and favorable or intermediate cytogenetics argues that this
inability to cope may more reflect the resistant nature of the
underlying disease.1 Finally, we agree that
"... resistant disease in patients with secondary AMLs may not
be determined by abnormal cytogenetics and MDR expression alone, but by
the presence of other biologic abnormalities." As indicated in our multiple logistic regression analysis,1 a patient with
secondary AML has a lower probability of achieving CR than does a
patient with de novo AML who is otherwise comparable, ie, who has the same level of MDR1 expression and the same cytogenetic status (favorable, intermediate, or unfavorable). This implies that there must
be some other biological mechanism related to disease onset that
operates separately from MDR1 and cytogenetics.
(4) We are surprised that Stasi et al failed to find peripheral white
blood cell count as a prognostic factor, because in five consecutive
SWOG clinical trials, each reporting more than 250 patients, the
peripheral white blood cell count was in every case a significant
prognostic factor for achievement of CR. The magnitude of the effect of
peripheral white blood cell count is not immense; therefore, large
numbers of patients may be necessary to see the effect. This may
explain why Stasi et al failed to see this relationship.
(5) We completely agree that many studies of the incidence and clinical
significance of MDR1 expression in leukemia (and other cancers)
previously reported in the literature are fraught with numerous
methodologic problems and frequently lack sufficient sensitivity and
specificity. In particular, the use of the C219 antibody as reported by
Stasi et al and many others is extremely problematic, because this
antibody lacks specificity for MDR1 detection.2-4 The C219
antibody cross-reacts with the related MDR2 gene and other unrelated
cytoplasmic epitopes. In fact, we have found that C219 will frequently
stain more differentiated myelomonocytic leukemias that in fact lack
MDR1 transcripts using specific reverse transcription-polymerase chain
reaction techniques. Thus, for the most specific
assessment of MDR1, it is essential to use only MDR1-specific
antibodies and to correlate MDR1 protein expression with a functional
assay.3,4 This specific and sensitive approach has been
used in all of our laboratory assays, and we consistently detect lower
levels of MDR1 expression in FAB M4 and M5 AML cases as compared with
the FAB M0, M1, and M2 subgroups.
(6) We whole-heartedly agree with Stasi et al that the definition of
patients greater than 55 years of age as elderly is inappropriate, particularly as our own age increases. However, the median age of our
patients registered to SWOG 9031 was 68 years.
Frederick R. Appelbaum
Kenneth J. Kopecky
Cheryl L. Willman
The Southwest
Oncology Group Leukemia and Leukemia Biology Committees
| |
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Head DR,
Appelbaum FR,
Willman CL:
Acute myeloid leukemia in the elderly: Assessment of multidrug resistance (MDR1) and cytogenetics distinguishes biologic subgroups with remarkably distinct responses to standard chemotherapy: A Southwest Oncology Group Study.
Blood
89:3323,
1997
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