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This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Leith, C. P. Articles by Willman, C. L. Search for Related Content PubMed PubMed Citation Articles by Leith, C. P. Articles by Willman, C. L. Related Collections Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  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 CP Leith, KJ Kopecky, J Godwin, T McConnell, ML Slovak, IM Chen, DR Head, FR Appelbaum and CL Willman Department of Pathology, University of New Mexico School of Medicine, Albuquerque, USA. 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. Volume 89, Issue 9, pp. 3323-3329, 05/01/1997 Copyright © 1997 by The American Society of Hematology CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: A. R. Derolf, S. Y. Kristinsson, T. M.-L. Andersson, O. Landgren, P. W. Dickman, and M. 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Sievers, T. A. Gooley, J. M. Bennett, M. S. Berger, L. H. Leopold, F. R. Appelbaum, and I. D. Bernstein Multidrug-resistance phenotype and clinical responses to gemtuzumab ozogamicin Blood, August 15, 2001; 98(4): 988 - 994. [Abstract] [Full Text] [PDF] R. M. Stone, D. T. Berg, S. L. George, R. K. Dodge, P. A. Paciucci, P. P. Schulman, E. J. Lee, J. O. Moore, B. L. Powell, M. R. Baer, et al. Postremission therapy in older patients with de novo acute myeloid leukemia: a randomized trial comparing mitoxantrone and intermediate-dose cytarabine with standard-dose cytarabine Blood, August 1, 2001; 98(3): 548 - 553. [Abstract] [Full Text] [PDF] M. Pallis, M. Grundy, J. Turzanski, R. Kofler, and N. Russell Mitochondrial membrane sensitivity to depolarization in acute myeloblastic leukemia is associated with spontaneous in vitro apoptosis, wild-type TP53, and vicinal thiol/disulfide status Blood, July 15, 2001; 98(2): 405 - 413. [Abstract] [Full Text] [PDF] E. L. Sievers, R. A. Larson, E. A. Stadtmauer, E. Estey, B. Lowenberg, H. Dombret, C. Karanes, M. Theobald, J. M. Bennett, M. L. Sherman, et al. Efficacy and Safety of Gemtuzumab Ozogamicin in Patients With CD33-Positive Acute Myeloid Leukemia in First Relapse J. Clin. Oncol., July 1, 2001; 19(13): 3244 - 3254. [Abstract] [Full Text] [PDF] D. L. Stirewalt, K. J. Kopecky, S. Meshinchi, F. R. Appelbaum, M. L. Slovak, C. L. Willman, and J. P. Radich FLT3, RAS, and TP53 mutations in elderly patients with acute myeloid leukemia Blood, June 1, 2001; 97(11): 3589 - 3595. [Abstract] [Full Text] [PDF] M. M. van den Heuvel-Eibrink, E. A. C. Wiemer, M. J. de Boevere, B. van der Holt, P. J. M. Vossebeld, R. Pieters, and P. Sonneveld MDR1 gene-related clonal selection and P-glycoprotein function and expression in relapsed or refractory acute myeloid leukemia Blood, June 1, 2001; 97(11): 3605 - 3611. [Abstract] [Full Text] [PDF] M. Toyota, K. J. Kopecky, M.-O. Toyota, K.-W. Jair, C. L. Willman, and J.-P. J. Issa Methylation profiling in acute myeloid leukemia Blood, May 1, 2001; 97(9): 2823 - 2829. [Abstract] [Full Text] [PDF] O. Legrand, J.-Y. Perrot, G. Simonin, M. Baudard, and J.-P. Marie JC-1: a very sensitive fluorescent probe to test Pgp activity in adult acute myeloid leukemia Blood, January 15, 2001; 97(2): 502 - 508. [Abstract] [Full Text] [PDF] D. Head Problematic WHO Reclassification of Myelodysplastic Syndromes J. Clin. Oncol., October 19, 2000; 18(19): 3447 - 3452. [Full Text] [PDF] E. H. Estey How I treat older patients with AML Blood, September 1, 2000; 96(5): 1670 - 1673. [Full Text] [PDF] O. Legrand, J.-Y. Perrot, M. Baudard, A. Cordier, R. Lautier, G. Simonin, R. Zittoun, N. Casadevall, and J.-P. Marie The immunophenotype of 177 adults with acute myeloid leukemia: proposal of a prognostic score Blood, August 1, 2000; 96(3): 870 - 877. [Abstract] [Full Text] [PDF] U. Tidefelt, J. Liliemark, A. Gruber, E. Liliemark, B. Sundman-Engberg, G. Juliusson, L. Stenke, A. Elmhorn-Rosenborg, L. Mollgard, S. Lehman, et al. P-Glycoprotein Inhibitor Valspodar (PSC 833) Increases the Intracellular Concentrations of Daunorubicin In Vivo in Patients With P-Glycoprotein-Positive Acute Myeloid Leukemia J. Clin. Oncol., May 9, 2000; 18(9): 1837 - 1844. [Abstract] [Full Text] [PDF] G. V. Dahl, N. J. Lacayo, N. Brophy, K. Dunussi-Joannopoulos, H. J. Weinstein, M. Chang, B. I. Sikic, and R. J. Arceci Mitoxantrone, Etoposide, and Cyclosporine Therapy in Pediatric Patients With Recurrent or Refractory Acute Myeloid Leukemia J. Clin. Oncol., May 9, 2000; 18(9): 1867 - 1875. [Abstract] [Full Text] [PDF] M. Pallis and N. Russell P-glycoprotein plays a drug-efflux-independent role in augmenting cell survival in acute myeloblastic leukemia and is associated with modulation of a sphingomyelin-ceramide apoptotic pathway Blood, May 1, 2000; 95(9): 2897 - 2904. [Abstract] [Full Text] [PDF] E. Hellstrom-Lindberg, C. Willman, A. J. Barrett, and Y. Saunthararajah Achievements in Understanding and Treatment of Myelodysplastic Syndromes Hematology, January 1, 2000; 2000(1): 110 - 132. [Abstract] [Full Text] [PDF] L. F. Hutchins, J. M. Unger, J. J. Crowley, C. A. Coltman, and K. S. Albain Underrepresentation of Patients 65 Years of Age or Older in Cancer-Treatment Trials N. Engl. J. Med., December 30, 1999; 341(27): 2061 - 2067. [Abstract] [Full Text] [PDF] W. Hiddemann, W. Kern, C. Schoch, C. Fonatsch, A. Heinecke, B. Wormann, and T. Buchner Management of Acute Myeloid Leukemia in Elderly Patients J. Clin. Oncol., November 1, 1999; 17(11): 3569 - 3576. [Abstract] [Full Text] [PDF] B. Lowenberg, J. R. Downing, and A. Burnett Acute Myeloid Leukemia N. Engl. J. Med., September 30, 1999; 341(14): 1051 - 1062. [Full Text] [PDF] E. J. Lee, S. L. George, M. Caligiuri, T. P. Szatrowski, B. L. Powell, S. Lemke, R. K. Dodge, R. Smith, M. Baer, and C. A. Schiffer Parallel Phase I Studies of Daunorubicin Given With Cytarabine and Etoposide With or Without the Multidrug Resistance Modulator PSC-833 in Previously Untreated Patients 60 Years of Age or Older With Acute Myeloid Leukemia: Results of Cancer and Leukemia Group B Study 9420 J. Clin. Oncol., September 1, 1999; 17(9): 2831 - 2831. [Abstract] [Full Text] [PDF] O. Legrand, G. Simonin, A. Beauchamp-Nicoud, R. Zittoun, and J.-P. Marie Simultaneous Activity of MRP1 and Pgp Is Correlated With In Vitro Resistance to Daunorubicin and With In Vivo Resistance in Adult Acute Myeloid Leukemia Blood, August 1, 1999; 94(3): 1046 - 1056. [Abstract] [Full Text] [PDF] C. P. Leith, K. J. Kopecky, I-M. Chen, L. Eijdems, M. L. Slovak, T. S. McConnell, D. R. Head, J. Weick, M. R. Grever, F. R. Appelbaum, et al. Frequency and Clinical Significance of the Expression of the Multidrug Resistance Proteins MDR1/P-Glycoprotein, MRP1, and LRP in Acute Myeloid Leukemia. A Southwest Oncology Group Study Blood, August 1, 1999; 94(3): 1086 - 1099. [Abstract] [Full Text] [PDF] Y.-M. Zhu, E.P. Das-Gupta, and N.H. Russell Microsatellite Instability and p53 Mutations Are Associated With Abnormal Expression of the MSH2 Gene in Adult Acute Leukemia Blood, July 15, 1999; 94(2): 733 - 740. [Abstract] [Full Text] [PDF] S. M. Kornblau, P. F. Thall, Z. Estrov, M. Walterscheid, S. Patel, A. Theriault, M. J. Keating, H. Kantarjian, E. Estey, and M. Andreeff The Prognostic Impact of BCL2 Protein Expression in Acute Myelogenous Leukemia Varies with Cytogenetics Clin. Cancer Res., July 1, 1999; 5(7): 1758 - 1766. [Abstract] [Full Text] [PDF] C. McCoy, S. B. McGee, and M. M. Cornwell The Wilms' Tumor Suppressor, WT1, Inhibits 12-O-Tetradecanoylphorbol-13-acetate Activation of the Multidrug Resistance-1 Promoter Cell Growth Differ., June 1, 1999; 10(6): 377 - 386. [Abstract] [Full Text] R. Advani, H. I. Saba, M. S. Tallman, J. M. Rowe, P. H. Wiernik, J. Ramek, K. Dugan, B. Lum, J. Villena, E. Davis, et al. Treatment of Refractory and Relapsed Acute Myelogenous Leukemia With Combination Chemotherapy Plus the Multidrug Resistance Modulator PSC 833 (Valspodar) Blood, February 1, 1999; 93(3): 787 - 795. [Abstract] [Full Text] [PDF] P. A. Cassileth, D. P. Harrington, F. R. Appelbaum, H. M. Lazarus, J. M. Rowe, E. Paietta, C. Willman, D. D. Hurd, J. M. Bennett, K. G. Blume, et al. Chemotherapy Compared with Autologous or Allogeneic Bone Marrow Transplantation in the Management of Acute Myeloid Leukemia in First Remission N. Engl. J. Med., December 3, 1998; 339(23): 1649 - 1656. [Abstract] [Full Text] [PDF] M. Nakayama, M. Wada, T. Harada, J. Nagayama, H. Kusaba, K. Ohshima, M. Kozuru, H. Komatsu, R. Ueda, and M. Kuwano Hypomethylation Status of CpG Sites at the Promoter Region and Overexpression of the Human MDR1 Gene in Acute Myeloid Leukemias Blood, December 1, 1998; 92(11): 4296 - 4307. [Abstract] [Full Text] [PDF] D. E. Hogge, C. L. Willman, R. J. Kreitman, M. Berger, P. D. Hall, K. J. Kopecky, C. McLain, E. P. Tagge, C. J. Eaves, and A. E. Frankel Malignant Progenitors From Patients With Acute Myelogenous Leukemia Are Sensitive to a Diphtheria Toxin-Granulocyte-Macrophage Colony-Stimulating Factor Fusion Protein Blood, July 15, 1998; 92(2): 589 - 595. [Abstract] [Full Text] [PDF] R. Stasi, G. Del Poeta, A. Venditti, M. Masi, E. Stipa, M. Christina Cox, S. Amadori;, F. R. Appelbaum, K. J. Kopecky, and C. L. Willman Prognostic Value of Cytogenetics and Multidrug Resistance (MDR1) in Elderly Patients With Acute Myeloid Leukemia Blood, July 15, 1998; 92(2): 695 - 697. [Full Text] [PDF]

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