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Blood, Vol. 92 No. 2 (July 15), 1998:
pp. 697-699
CORRESPONDENCE
Biological Features of Acute Myeloid Leukemia in the Elderly
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LETTER |
To the Editor:
In a recent report, Leith et al.,1 on behalf of the
Southwest Oncology Group (SWOG), reported on the biologic peculiarities of acute myeloid leukemia (AML) in the elderly. They found that age
greater than 55 years is associated with an increased frequency of
unfavorable cytogenetics [complex karyotypes, t(9;22), anomalies of
chromosome 5/7, abnormalities at 11q], MDR1, and CD34
expression. They conclude that such a pattern may well explain the poor
response to therapy of these leukemias. In addition, striking
similarities with secondary leukemias have been noted by the
investigators, who therefore suggest that de novo and secondary AML in
the elderly may share a common biologic mechanism different from that
of younger patients. We would like to contribute by presenting our
experience in 344 cases of de novo AML diagnosed at our Institution
between January 1987 and June 1997. Cytogenetics, expression of
MDR1, and CD34 were investigated in 201 patients greater
than 55 years of age (median age, 66 years; range, 56 to 81 years) and
143 less than 55 years of age (median age, 41 years; range, 18 to 55 years). CD34 and MDR1 expression were demonstrated by flow
cytometry using HPCA-2, phycoerythrin (PE)-conjugated (Becton
Dickinson, Mountain View, CA) and C219 (CIS Diagnostici, Vercelli,
Italy) monoclonal antibodies (MoAbs), respectively. In addition, in 103 cases, MDR1 expression was also tested using the MoAb
MRK16; no significant differences were observed between C219 and MRK16
in terms of the number of positive cases and the percentage of positive
cells (G. Del Poeta, manuscript in preparation). Sensitive
(Lovo 109) and resistant (Lovo Dx) cells from the LoVo cell line were
used as controls (generous gift from G. Zupi, Istituto Regina Elena, Rome, Italy). Finally, MDR1 was assessed on gated leukemic
cells. Among 225 cases classified cytogenetically, abnormalities were found in 172 (76%). Karyotypic abnormalities were grouped into favorable, intermediate, and unfavorable.2-4 Fifty-eight of
116 evaluable (58%) patients with greater than 55 years of age were classified as unfavorable and 43 (37%) as intermediate, whereas only
15 (13%) showed a favorable karyotype. Among patients with less than
55 years of age, 40 (41%) had an unfavorable karyotype, 37 (46%)
intermediate, and 32 (29%) favorable. The difference was statistically
significant (P = .008; Table 1).
MDR1 expression was assessed in 260 cases, and 136 (52%)
were found positive. No differences were observed between the two
age groups either in terms of the percentage of positive cases or in
terms of intensity of fluorescence as quantified by flow cytometry. In
fact, 56 of 113 (49%) evaluable patients less than 55 years of age
expressed the MDR1 phenotype; among those greater than 55 years of age, 80 of 147 (54%) evaluable were MDR1 positive
(Table 1). The distribution of karyotypic abnormalities among the 260 patients studied for MDR1 was the same as in the overall
group of patients evaluated for cytogenetics. Furthermore, CD34
expression was not correlated with age and no significant differences
were identified between the two groups (Table 1). Additional parameters
such as CD7 and terminaldeoxynucleotidiltransferase (TdT) were
investigated to verify whether they had prognostic implications and
were possibly associated with age. Whereas CD7 and TdT were
significantly associated with a lower rate of complete remission (CR),
no significant correlation was demonstrated with age. In fact,
regardless of age, 41% (40/97) of CD7+ patients achieved a
CR as compared with 56% (115/207) of CD7
(P = .026). Likewise, 33% (26/78) of TdT+
patients entered CR versus 58% (126/216) of those who were
TdT (P < .001). Notably, a significant
correlation was found between the expression of MDR1
protein, unfavorable cytogenetics, and the presence of CD7 and TdT. In
fact, MDR1 phenotype and unfavorable cytogenetics were
observed in 68% (61/90) and 56% (38/68), respectively, of
CD7+ cases (P < .001 and P = .003,
respectively; Fig 1). Similarly, they were
found in 63% (42/67) and 66% (31/47), respectively, of
TdT+ cases (P = .043 and P < .001,
respectively; Fig 1). Overall, 89 of 134 (66%) patients less than 55 years of age assessable for response achieved a CR, whereas only 69 of
179 (40%) elderly patients did the same (P < .001; Table
1). To evaluate the simultaneous impact of different variables on
duration of survival (SV) and CR, a multivariate analysis was performed
using the Cox regression model. A stepwise regression model was used to
assess the effect of different variables on achievement of CR. Age
(P = .001) emerged as an independent factor affecting CR
achievement together with TdT (P = .018), white blood cell
count (P = .001), and FAB (P = .012) karyotype
(P < .001) and MDR1 (P < .001). In
regards to survival, the independent role of MDR1
(P = .001), FAB (P = .001), and unfavorable karyotype (P = .018) was confirmed. Unfavorable karyotype and CD7 were found to adversely affect duration of CR (P = .001
and .037, respectively). In conclusion, in our analysis, age greater than 55 years was significantly correlated with unfavorable
cytogenetics but not with the expression of MDR1, which
seems to occur at similar frequency in elderly and young patients.
However, because in the multivariate model age was significantly and
independently associated with a lower rate of CR, our results confirm
that it represents by itself a poor prognostic factor or,
alternatively, that in some elderly additional mechanisms other than
karyotypic abnormalities may be operating. In addition, we have found
that, regardless of age, the expression of unfavorable cytogenetics and
MDR1 protein is significantly associated with that of CD7
and TdT. Thus, we speculate that the expression of TdT and/or
CD7 may represent the phenotypic counterpart of cytogenetic and
chemoresistance patterns that need to be searched for to deliver
therapies as tailored as possible, even including MDR
modulators, apoptosis-inducers, and stem cell
transplantation.
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| Fig 1.
The correlation between CD7, TdT, cytogenetics, and
MDR1 phenotype is shown. The expression of CD7
and/or TdT increases significantly from a near-lacking of
positivity in favorable cytogenetics to almost 70% in unfavorable
cytogenetics.
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Adriano Venditti
Giovanni Del
Poeta
Francesco Buccisano
Anna Tamburini
Maria Christina
Cox-Froncillo
Antonio Bruno
Beatrice Del Moro
Anna Maria
Epiceno
M. Masi
Sergio Amadori
Catteda di
Ematologia
Università di Roma "Tor Vergata"
Ospedale S. Eugenio
Rome, Italy
Roberto Stasi
Dipartimento di Scienze
Mediche
Ospedale Regina Apostolorum
Albano Laziale, Italy
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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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| |
RESPONSE |
Biologic Features of Acute Myeloid Leukemia in the
Elderly
We were very interested in the comments of Venditti et al on our study
of MDR1 expression and cytogenetics in AML in elderly patients.1 From 344 cases of de novo AML diagnosed at their institution since 1987, they had the opportunity to assess MDR1 expression on 260 cases, including 103 cases in which they used two
different monoclonal antibodies, and cytogenetics on 225 cases as well
as CD7 and TdT expression in 304 and 294 cases, respectively. In our
study on elderly patients, we found a very high frequency of expression
of MDR1 (71%) by leukemic blasts using a highly specific and sensitive
flow cytometric assay.1,2 In multivariate logistic
regression analysis, MDR1 expression was found to be highly and
independently correlated with achievement of complete remission
(P = .0041) and of resistant disease (P = .0007).
We thus postulated that the high frequency of MDR1 expression might be
one reason for the poor response of elderly AML patients to therapy. In
contrast to the high frequency of MDR1 expression found by us,
Venditti et al found that only 54% of their elderly patients had
MDR1+ blasts, a frequency similar to the 49% of younger
patients they found to be MDR1+.
Both biologic and methodologic differences may account for the
differences between the findings of our studies and those of Venditti
et al. First, the patient populations studied may be different: the 211 patients we studied included some with secondary disease, whereas
Venditti et al examined only de novo disease. Secondly, and
surprisingly considering their patients all had de novo AML, Venditti
et al's patients had a much higher frequency of unfavorable
cytogenetics (58%) than that found in our study (32%). This frequency
of unfavorable cytogenetics is significantly higher than what has been
reported by several other groups.1,3,4 Thirdly,
methodologic differences to detect MDR1 likely also play a critical
role in the differences in frequency of MDR1 expression detected.
Venditti et al used the cross-reactive antibody C219 to detect MDR1
expression. C219 is less specific for MDR1 than MRK16, because it
cross-reacts with the related protein, MDR2, and various other
proteins.5-7 In addition, because C219 is directed against
a cytoplasmic epitope of MDR1, technical consistency may be more
problematic than when an antibody directed against a surface epitope is
used.8 Although Venditti et al state that C219 and MRK16
staining were highly correlated when compared on a subset of 103 patients, it is unclear how strong the correlation was or that MRK16 in
their hands gives the same expression data as in ours.1,2,8
A second methodologic factor may be the sensitivity of the assay; we
use a duochrome reagent system to augment the often weak MDR1
expression signal in primary leukemic specimens.2 This step
is essential to detect many MDR1+ primary AML samples;
indeed, in our experience, without this reagent, many false-negative
cases result. Lastly, we analyze the data using the KS statistic,
rather than the percentage of positive cells, because we have found
this, in our hands, to be more reliable in analyzing dimly positive
cell populations. Such methodologic differences are well recognized and
can lead to differences in results between laboratories.2,8
They highlight the need for detailed descriptions of procedures to
detect MDR1 and of using more than one assay (eg, functional studies)
to better detect MDR1.2
Venditti et al found that MDR1 expression was similar among both
younger and elderly patients with AML. Their experience is quite
different from ours; in our recent studies on MDR1 expression among
younger AML patients (median age, 43 years) using similar methodologies, we found that only 35% of patients were
MDR1+, in contrast to the 71% found in our elderly patient
group. In addition, unlike Venditti et al, we found that MDR1
expression frequency increased with patient age
(P = .01).9
Despite these differences in results of MDR1 frequency, it is
interesting that Venditti et al's studies also confirm the prognostic importance of MDR1 expression to clinical outcome in AML. Venditti et
al's observations that CD7 and TdT expression appear to be phenotypic
markers of AML cases with poor prognosis features such as unfavorable
cytogenetics and MDR1 expression are interesting. Analysis of
expression of these markers may thus be a useful initial indicator of
unfavorable prognosis, pending the more lengthy cytogenetic analysis.
Use of these markers to predict for MDR1 expression would be less
helpful, because analysis of MDR1 expression and function can be
performed quite rapidly with the rest of the immunophenotyping profile.
Catherine P. Leith
Kenneth J. Kopecky
Cheryl L. Willman
Southwest Oncology Group Leukemia Biology Program and
Statistical Center
Albuquerque, NM and Seattle, WA
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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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Kopecky KJ,
Appelbaum FR,
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Willman CL:
Correlation of multidrug resistance (MDR1) protein expression with functional dye/drug efflux in acute myeloid leukemia by multiparameter flow cytometry: Identification of discordant CD34+/MDR1 /Efflux+ and MDR1+/Efflux cases.
Blood
86:2329,
1995[Abstract/Free Full Text]
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