Online citations, reference lists, and bibliographies.
← Back to Search

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.

C. Leith, K. Kopecky, J. Godwin, T. McConnell, M. Slovak, I. Chen, D. Head, F. Appelbaum, C. Willman
Published 1997 · Medicine

Save to my Library
Download PDF
Analyze on Scholarcy Visualize in Litmaps
Share
Reduce the time it takes to create your bibliography by a factor of 10 by using the world’s favourite reference manager
Time to take this seriously.
Get Citationsy
Compared with younger patients, elderly patients with acute myeloid leukemia (AML) respond poorly to conventional chemotherapy. To determine if this poor response is due to differences in the biologic characteristics of AML in the elderly, we studied 211 patients (161 de novo, 50 secondary AML) over 55 years of age (median, 68 years) registered to a single clinical trial for previously untreated AML (SWOG 9031, Phase III randomized trial of standard dose cytosine arabinoside and daunomycin + rhG-CSF). Pretreatment leukemic blasts were karyotyped and were also analyzed for intrinsic drug resistance by quantitating expression of the multidrug resistance glycoprotein MDR1 and functional drug efflux using sensitive flow cytometric techniques. Results were correlated with clinical variables and outcome. These elderly AML patients had a high frequency of unfavorable cytogenetics (32%), MDR1 protein expression (71%), and functional drug efflux (58%); each of these factors occurred at high frequencies in both de novo and secondary AML patients and was associated with a significantly poorer complete remission (CR) rate. In multivariate analysis, secondary AML (P = .0035), unfavorable cytogenetics (P = .0031), and MDR1 (P = .0041) were each significantly and independently associated with lower CR rates. Resistant disease was associated with unfavorable cytogenetics (P = .017) and MDR1 expression (P = .0007). Strikingly, elderly MDR1(-) de novo AML patients with favorable/intermediate cytogenetics had a CR rate of 81%; with increasing MDR1 expression, CR rate decreased in this cytogenetic group. MDR1(+) secondary AML patients with unfavorable cytogenetics had a CR rate of only 12%. Thus, AML in the elderly is associated with an increased frequency of unfavorable cytogenetics and MDR1 expression, both of which independently contribute to poor outcomes. The high frequencies of these features in both de novo and secondary elderly AML patients suggest a common biologic mechanism for these leukemias distinct from that in younger patients. Investigation of biologic parameters at diagnosis in AML in the elderly may help identify patients with a high likelihood of achieving CR with conventional regimens, as well as those who may require alternate regimens designed to overcome therapy resistance.
This paper references
10.1007/978-1-4612-4380-9_25
Nonparametric Estimation from Incomplete Observations
E. Kaplan (1958)
Regression models and life tables (with discussion
D. Cox (1972)
10.1111/j.1365-2141.1976.tb03563.x
Proposals for the Classification of the Acute Leukaemias French‐American‐British (FAB) Co‐operative Group
J. Bennett (1976)
10.1177/25.7.894009
Proof without prejudice: use of the Kolmogorov-Smirnov test for the analysis of histograms from flow systems and other sources.
I. T. Young (1977)
10.32388/78qroa
An international system for human cytogenetic nomenclature
Iscn (1978)
10.1002/1097-0142(19850801)56:3<553::AID-CNCR2820560323>3.0.CO;2-Q
Myelodysplastic syndromes. A clinical and pathologic analysis of 109 cases
K. Foucar (1985)
10.1002/1097-0142(19850501)55:9<1979::AID-CNCR2820550925>3.0.CO;2-#
Institutional performance in application of the FAB classification of acute leukemia. The southwest oncology group experience
D. Head (1985)
10.1016/S0140-6736(86)92674-7
PRINCIPAL RESULTS OF THE MEDICAL RESEARCH COUNCIL'S 8th ACUTE MYELOID LEUKAEMIA TRIAL
J. Rees (1986)
Characterization of a new drug-resistant human myeloma cell line that expresses P-glycoprotein.
W. Dalton (1986)
10.1182/BLOOD.V69.6.1551.BLOODJOURNAL6961551
Acute myelogenous leukemia: recent advances in therapy
R. Champlin (1987)
10.1016/0145-2126(87)90017-8
Toward a clinically relevant cytogenetic classification of acute myelogenous leukemia.
M. Keating (1987)
10.1111/j.1365-2141.1988.tb06188.x
Refined chromosome study helps define prognostic subgroups in most patients with primary myelodysplastic syndrome and acute myelogenous leukaemia
J. Yunis (1988)
10.1182/BLOOD.V73.1.263.263
Prognostic impact of cytogenetic abnormalities in patients with de novo acute nonlymphocytic leukemia.
C. Schiffer (1989)
10.1016/0165-4608(89)90025-3
The clinical significance of karyotype in acute myelogenous leukemia.
D. Arthur (1989)
10.1111/j.1365-2141.1989.tb00221.x
Cytogenetics and their prognostic value in de novo acute myeloid leukaemia: a report on 283 cases
P. Fenaux (1989)
10.1200/JCO.1990.8.5.813
Report of the National Cancer Institute-sponsored workshop on definitions of diagnosis and response in acute myeloid leukemia.
B. Cheson (1990)
10.1111/j.1365-2141.1991.tb07947.x
High risk of early resistant relapse for leukaemic patients with presence of multidrug resistance associated P‐glycoprotein positive cells in complete remission
P. Musto (1991)
10.1093/JNCI/83.10.708
MDR1 gene expression and treatment outcome in acute myeloid leukemia.
R. Pirker (1991)
10.1111/j.1365-2141.1991.tb04378.x
Expression of the multidrug resistance gene product (P‐glycoprotein) in myelodysplasia is associated with a stem cell phenotype
A. List (1991)
10.1126/SCIENCE.1360704
Overexpression of a transporter gene in a multidrug-resistant human lung cancer cell line.
S. Cole (1992)
10.1182/BLOOD.V79.2.473.BLOODJOURNAL792473
Clinical significance of multidrug resistance P-glycoprotein expression on acute nonlymphoblastic leukemia cells at diagnosis.
L. Campos (1992)
10.1111/j.1365-2141.1992.tb06430.x
Age‐related incidence and other epidemiological aspects of myelodysplastic syndromes
C. Aul (1992)
10.1200/JCO.1993.11.9.1652
Phase I/II trial of cyclosporine as a chemotherapy-resistance modifier in acute leukemia.
A. List (1993)
High expression of the multidrug resistance P-glycoprotein in high-risk myelodysplasia is associated with immature phenotype.
P. Sonneveld (1993)
A Southwest Oncology Group study
T. Jenkins (1993)
Cyclosporin A as a modifier agent in the salvage treatment of acute leukemia (AL).
J. Marie (1993)
10.1182/BLOOD.V82.4.1288.BLOODJOURNAL8241288
Enhancement of daunorubicin accumulation, retention, and cytotoxicity by verapamil or cyclosporin A in blast cells from patients with previously untreated acute myeloid leukemia.
D. Ross (1993)
10.1111/j.1365-2141.1994.tb08305.x
P‐glycoprotein expression on acute myeloid leukaemia blast cells at diagnosis predicts response to chemotherapy and survival
P. Wood (1994)
10.1056/NEJM199410063311402
Intensive postremission chemotherapy in adults with acute myeloid leukemia. Cancer and Leukemia Group B.
R. Mayer (1994)
P-glycoprotein expression as unfavorable prognostic factor in acute myeloid leukemia.
S. Zoechbauer (1994)
Prognostic significance of karyotype in de novo adult acute myeloid leukemia. The BGMT group.
N. Dastugue (1995)
De novo acute myeloid leukaemia in patients over 55-years-old: a population-based study of incidence, treatment and outcome. Northern Region Haematology Group.
P. Taylor (1995)
10.1038/nm0695-578
The drug resistance-related protein LRP is the human major vault protein
G. Scheffer (1995)
10.1182/BLOOD.V86.9.3542.BLOODJOURNAL8693542
Different genetic pathways in leukemogenesis for patients presenting with therapy-related myelodysplasia and therapy-related acute myeloid leukemia.
J. Pedersen-Bjergaard (1995)
10.1182/BLOOD.V85.8.2147.BLOODJOURNAL8582147
Predictive value for treatment outcome in acute myeloid leukemia of cellular daunorubicin accumulation and P-glycoprotein expression simultaneously determined by flow cytometry.
A. Guerci (1995)
10.1056/NEJM199506223322503
Granulocyte–Macrophage Colony-Stimulating Factor after Initial Chemotherapy for Elderly Patients with Primary Acute Myelogenous Leukemia
R. Stone (1995)
10.1182/BLOOD.V86.6.2329.BLOODJOURNAL8662329
Correlation of multidrug resistance (MDR1) protein expression with functional dye/drug efflux in acute myeloid leukemia by multiparameter flow cytometry: identification of discordant MDR-/efflux+ and MDR1+/efflux- cases.
C. Leith (1995)
10.1056/NEJM199506223322504
A controlled study of recombinant human granulocyte colony-stimulating factor in elderly patients after treatment for acute myelogenous leukemia. AML Cooperative Study Group.
H. Dombret (1995)
Multi-drug resistance (MDR) activity in acute leukemia determined by rhodamine 123 efflux assay.
T. Lamy (1995)
10.1182/BLOOD.V87.5.1710.1710
A randomized study of high-dose cytarabine in induction in acute myeloid leukemia.
J. Bishop (1996)
10.1002/(SICI)1097-0320(19960901)25:1<14::AID-CYTO2>3.0.CO;2-E
DiOC2(3) is not a substrate for multidrug resistance protein (MRP)-mediated drug efflux.
H. Minderman (1996)
Methods to detect P-glycoprotein-associated multidrug resistance in patients' tumors: consensus recommendations.
W. Beck (1996)
10.1182/BLOOD.V87.6.2464.BLOODJOURNAL8762464
Overexpression of the major vault transporter protein lung-resistance protein predicts treatment outcome in acute myeloid leukemia.
A. List (1996)



This paper is referenced by
10.3390/a14020063
Molecular Subtyping and Outlier Detection in Human Disease Using the Paraclique Algorithm
Ronald D. Hagan (2021)
10.1155/2021/6635650
Improved Survival of Leukemic Mice Treated with Sodium Caseinate in Combination with Daunorubicin without Toxicity
I. Aguiñiga-Sánchez (2021)
10.1016/J.YAO.2021.02.019
Focus on Novel Therapies for Older Adults with Acute Myeloid Leukemia and High-Risk Myelodysplastic Syndromes
Kirk Cahill (2021)
10.1042/CS20200309
Interactions between cardiology and oncology drugs in precision cardio-oncology.
S. Kamaraju (2021)
10.1007/978-3-030-53626-8_15
Acute Myeloid Leukemia and Allogeneic Hematopoietic Cell Transplant
Curtis A Lachowiez (2021)
10.1007/978-3-030-72676-8_7
Prognostic Factors in AML
R. Itzykson (2021)
10.1080/10428194.2020.1719093
Liposomal encapsulated cytarabine and daunorubicin (CPX-351) for older patients with acute myeloid leukemia
Hannah Asghari (2020)
10.1080/10428194.2020.1725503
Final safety and efficacy results from the CPX-351 early access program for older patients with high-risk or secondary acute myeloid leukemia
G. Roboz (2020)
10.1111/ijlh.13241
P‐glycoprotein and multidrug resistance‐associated protein‐1 expression in acute myeloid leukemia: Biological and prognosis implications
Lenilton Silva da Silveira Júnior (2020)
10.1016/j.clml.2020.07.002
Usefulness of Charlson Comorbidity Index to Predict Early Mortality and Overall Survival in Older Patients With Acute Myeloid Leukemia.
P. Dhakal (2020)
10.1038/s41408-020-00361-8
CPX-351 treatment in secondary acute myeloblastic leukemia is effective and improves the feasibility of allogeneic stem cell transplantation: results of the Italian compassionate use program
F. Guolo (2020)
10.1016/j.blre.2020.100735
Loss of 5q in myeloid malignancies - A gain in understanding of biological and clinical consequences.
S. Venugopal (2020)
10.31744/einstein_journal/2020AE4530
Brazilian Nutritional Consensus in Hematopoietic Stem Cell Transplantation: Adults
J. B. Barban (2020)
10.1007/s11912-020-0869-0
Myelodysplastic Syndromes: How to Recognize Risk and Avoid Acute Myeloid Leukemia Transformation
M. Hospital (2020)
10.2217/fon-2019-0781
How I treat newly diagnosed acute myeloid leukemia in an outpatient setting: a multidisciplinary team perspective.
Chetasi Talati (2020)
10.3389/fonc.2020.01746
Case Report: Allogeneic Stem Cell Transplantation Following Induction With CPX-351 in Patients With Acute Myeloid Leukemia Is Feasible
V. Vucinic (2020)
10.1002/jcp.30063
The oncogenic potential of NANOG: An important cancer induction mediator
Basira Najafzadeh (2020)
10.1016/j.blre.2020.100670
Older adults in hematologic malignancy trials: Representation, barriers to participation and strategies for addressing underrepresentation.
B. Kanapuru (2020)
10.1016/j.leukres.2020.106367
Comparison of induction strategies and responses for acute myeloid leukemia patients after resistance to hypomethylating agents for antecedent myeloid malignancy.
Chetasi Talati (2020)
10.1038/s41375-020-0916-8
Phase II trial of CPX-351 in patients with acute myeloid leukemia at high risk for induction mortality
Ghayas C. Issa (2020)
10.1007/s12325-020-01310-4
Feasibility and Outcome of a Phase II Study of Intensive Induction Chemotherapy in 91 Elderly Patients with AML Evaluated Using a Simplified Multidimensional Geriatric Assessment
D. Capelli (2020)
10.3390/cancers12010120
Therapeutic Choice in Older Patients with Acute Myeloid Leukemia: A Matter of Fitness
R. Palmieri (2020)
10.1007/978-3-030-53633-6_3
Insights into the Pathobiology of Secondary AML
T. Jain (2020)
10.1002/hon.2755
Epigenetic priming with decitabine followed by low dose idarubicin and cytarabine in acute myeloid leukemia evolving from myelodysplastic syndromes and higher‐risk myelodysplastic syndromes: a prospective multicenter single‐arm trial
Xinping Zhou (2020)
10.1182/bloodadvances.2020002305
Gene expression profile predicts response to the combination of tosedostat and low-dose cytarabine in elderly AML.
G. Visani (2020)
10.1002/hon.2663
Real‐world experience with decitabine as a first‐line treatment in 306 elderly acute myeloid leukaemia patients unfit for intensive chemotherapy
M. Bocchia (2019)
10.1038/s41598-018-36780-8
Lung resistance-related protein (LRP) predicts favorable therapeutic outcome in Acute Myeloid Leukemia
Bibi Kulsoom (2019)
10.1194/jlr.M091876
Acid ceramidase promotes drug resistance in acute myeloid leukemia through NF-κB-dependent P-glycoprotein upregulation
Su-Fern Tan (2019)
10.1111/ijlh.13025
Importance of prognostic stratification via gene mutation analysis in elderly patients with acute myelogenous leukemia
Yusuke Fujiwara (2019)
10.3324/haematol.2018.208637
Comparisons of commonly used front-line regimens on survival outcomes in patients aged 70 years and older with acute myeloid leukemia
Chetasi Talati (2019)
10.1111/ecc.13122
Clinical outcomes in allogeneic haematopoietic stem cell transplantation: A comparison between young and elderly patients. Observational study.
Eduardo Cerello Chapchap (2019)
10.1007/978-3-030-27684-3_8
Molecular Subtyping in Human Disease Using the Paraclique Algorithm
Ronald D. Hagan (2019)
See more
Semantic Scholar Logo Some data provided by SemanticScholar