This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kolitz, J. E. Articles by Larson, R. A. Search for Related Content PubMed PubMed Citation Articles by Kolitz, J. E. Articles by Larson, R. A.

Dose Escalation Studies of Cytarabine, Daunorubicin, and Etoposide With and Without Multidrug Resistance Modulation With PSC-833 in Untreated Adults With Acute Myeloid Leukemia Younger Than 60 Years: Final Induction Results of Cancer and Leukemia Group B Study 9621

Jonathan E. Kolitz, Stephen L. George, Richard K. Dodge^,, David D. Hurd, Bayard L. Powell, Steven L. Allen, Enrique Velez-Garcia, Joseph O. Moore, Thomas C. Shea, Eva Hoke, Michael A. Caligiuri, James W. Vardiman, Clara D. Bloomfield, Richard A. Larson

From the North Shore University Hospital, New York University School of Medicine, Manhasset, NY; CALGB Statistical Center; Duke University School of Medicine, Durham; Wake Forest University School of Medicine, Winston-Salem; University of North Carolina, Chapel Hill, NC; University of Puerto Rico School of Medicine, San Juan, Puerto Rico; The Ohio State University, Columbus, OH; and University of Chicago, Chicago, IL

Address reprint requests to Jonathan E. Kolitz, MD, Don Monti Division of Oncology and Division of Hematology, Department of Medicine, North Shore University Hospital, New York University School of Medicine, 300 Community Dr, Manhasset, NY 11030; e-mail: kolitz{at}nshs.edu

PURPOSE: P-glycoprotein (Pgp) is strongly inhibited by PSC-833. A chemotherapy dose-escalation study was performed with PSC-833 in patients younger than 60 years with untreated acute myeloid leukemia. Clinical rather than pharmacokinetic end points were used to develop two induction therapies containing drugs susceptible to Pgp-mediated efflux and associated with comparable toxicities at the maximum-tolerated doses.

PATIENTS AND METHODS: A total of 410 patients were enrolled. Fifteen induction regimens containing variable doses of daunorubicin (DNR) and etoposide (ETOP) and fixed doses of cytarabine were evaluated with (ADEP) or without (ADE) a fixed dose of PSC-833.

RESULTS: Doses selected for phase III testing were DNR 90 mg/m² and ETOP 100 mg/m² in ADE, and DNR and ETOP each 40 mg/m² in ADEP. Intolerable mucosal toxicity occurred at higher doses of ADEP. Although the design of this study precludes direct comparisons, there was an apparent advantage for receiving ADEP with respect to disease-free and overall survival in patients 45 years old, despite the significantly lower doses of DNR and ETOP given in ADEP compared with ADE.

CONCLUSION: A large clinical data set was used to develop induction regimens containing two drugs susceptible to Pgp-mediated efflux, with and without an inhibitor of Pgp function. The chosen doses have comparable antileukemia activity and toxicity, making them suitable for use in a phase III comparative study of induction chemotherapy for patients with acute myeloid leukemia younger than 60 years. That trial will also clarify whether patients 45 years old are especially likely to benefit from Pgp inhibition during induction therapy.

Supported in part by grants from the National Cancer Institute to the Cancer and Leukemia Group B (CA31946, CA101140) and The Leukemia Clinical Research Foundation. J.E.K. and S.L.A. were supported by CA35279; S.L.G. and R.K.D. were supported by CA33601; B.L.P. was supported by CA03927; E.V.-G. was supported by CA32291; J.O.M. was supported by CA47577; T.C.S. was supported by CA47559; M.A.C. was supported by CA77658; and R.A.L. was supported by CA41287.

The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

Deceased.

This article has been cited by other articles:

				C. Langer, M. D. Radmacher, A. S. Ruppert, S. P. Whitman, P. Paschka, K. Mrozek, C. D. Baldus, T. Vukosavljevic, C.-G. Liu, M. E. Ross, et al. High BAALC expression associates with other molecular prognostic markers, poor outcome, and a distinct gene-expression signature in cytogenetically normal patients younger than 60 years with acute myeloid leukemia: a Cancer and Leukemia Group B (CALGB) study Blood, June 1, 2008; 111(11): 5371 - 5379. [Abstract] [Full Text] [PDF]

				G. Marcucci, M. D. Radmacher, K. Maharry, K. Mrozek, A. S. Ruppert, P. Paschka, T. Vukosavljevic, S. P. Whitman, C. D. Baldus, C. Langer, et al. MicroRNA Expression in Cytogenetically Normal Acute Myeloid Leukemia N. Engl. J. Med., May 1, 2008; 358(18): 1919 - 1928. [Abstract] [Full Text] [PDF]

				H. Wandt, U. Schakel, F. Kroschinsky, G. Prange-Krex, B. Mohr, C. Thiede, U. Pascheberg, S. Soucek, M. Schaich, and G. Ehninger MLD according to the WHO classification in AML has no correlation with age and no independent prognostic relevance as analyzed in 1766 patients Blood, February 15, 2008; 111(4): 1855 - 1861. [Abstract] [Full Text] [PDF]

				S. P. Whitman, A. S. Ruppert, M. D. Radmacher, K. Mrozek, P. Paschka, C. Langer, C. D. Baldus, J. Wen, F. Racke, B. L. Powell, et al. FLT3 D835/I836 mutations are associated with poor disease-free survival and a distinct gene-expression signature among younger adults with de novo cytogenetically normal acute myeloid leukemia lacking FLT3 internal tandem duplications Blood, February 1, 2008; 111(3): 1552 - 1559. [Abstract] [Full Text] [PDF]

				G. Marcucci, K. Maharry, S. P. Whitman, T. Vukosavljevic, P. Paschka, C. Langer, K. Mrozek, C. D. Baldus, A. J. Carroll, B. L. Powell, et al. High Expression Levels of the ETS-Related Gene, ERG, Predict Adverse Outcome and Improve Molecular Risk-Based Classification of Cytogenetically Normal Acute Myeloid Leukemia: A Cancer and Leukemia Group B Study J. Clin. Oncol., August 1, 2007; 25(22): 3337 - 3343. [Abstract] [Full Text] [PDF]

				S. P. Whitman, A. S. Ruppert, G. Marcucci, K. Mrozek, P. Paschka, C. Langer, C. D. Baldus, J. Wen, T. Vukosavljevic, B. L. Powell, et al. Long-term disease-free survivors with cytogenetically normal acute myeloid leukemia and MLL partial tandem duplication: a Cancer and Leukemia Group B study Blood, June 15, 2007; 109(12): 5164 - 5167. [Abstract] [Full Text] [PDF]

				H. P. Erba Prognostic Factors in Elderly Patients with AML and the Implications for Treatment Hematology, January 1, 2007; 2007(1): 420 - 428. [Abstract] [Full Text] [PDF]

				L. Ades, S. Chevret, E. Raffoux, S. de Botton, A. Guerci, A. Pigneux, A. M. Stoppa, T. Lamy, F. Rigal-Huguet, A. Vekhoff, et al. Is Cytarabine Useful in the Treatment of Acute Promyelocytic Leukemia? Results of a Randomized Trial From the European Acute Promyelocytic Leukemia Group J. Clin. Oncol., December 20, 2006; 24(36): 5703 - 5710. [Abstract] [Full Text] [PDF]

				M. D. Radmacher, G. Marcucci, A. S. Ruppert, K. Mrozek, S. P. Whitman, J. W. Vardiman, P. Paschka, T. Vukosavljevic, C. D. Baldus, J. E. Kolitz, et al. Independent confirmation of a prognostic gene-expression signature in adult acute myeloid leukemia with a normal karyotype: a Cancer and Leukemia Group B study Blood, September 1, 2006; 108(5): 1677 - 1683. [Abstract] [Full Text] [PDF]

				P. Paschka, G. Marcucci, A. S. Ruppert, K. Mrozek, H. Chen, R. A. Kittles, T. Vukosavljevic, D. Perrotti, J. W. Vardiman, A. J. Carroll, et al. Adverse Prognostic Significance of KIT Mutations in Adult Acute Myeloid Leukemia With inv(16) and t(8;21): A Cancer and Leukemia Group B Study J. Clin. Oncol., August 20, 2006; 24(24): 3904 - 3911. [Abstract] [Full Text] [PDF]

				R. A. Larson, R. M. Stone, R. J. Mayer, and C. A. Schiffer Fifty years of clinical research by the leukemia committee of the cancer and leukemia group B. Clin. Cancer Res., June 1, 2006; 12(11): 3556s - 3563s. [Abstract] [Full Text] [PDF]

				C. D. Bloomfield, K. Mrozek, and M. A. Caligiuri Cancer and Leukemia Group B Leukemia Correlative Science Committee: Major Accomplishments and Future Directions. Clin. Cancer Res., June 1, 2006; 12(11): 3564s - 3571s. [Abstract] [Full Text] [PDF]

				K. Mrozek and C. D. Bloomfield Chromosome Aberrations, Gene Mutations and Expression Changes, and Prognosis in Adult Acute Myeloid Leukemia Hematology, January 1, 2006; 2006(1): 169 - 177. [Abstract] [Full Text] [PDF]

				G. Marcucci, C. D. Baldus, A. S. Ruppert, M. D. Radmacher, K. Mrozek, S. P. Whitman, J. E. Kolitz, C. G. Edwards, J. W. Vardiman, B. L. Powell, et al. Overexpression of the ETS-Related Gene, ERG, Predicts a Worse Outcome in Acute Myeloid Leukemia With Normal Karyotype: A Cancer and Leukemia Group B Study J. Clin. Oncol., December 20, 2005; 23(36): 9234 - 9242. [Abstract] [Full Text] [PDF]

				J. E. Kolitz, S. L. George, G. Marcucci, R. Vij, B. L. Powell, S. L. Allen, D. J. De Angelo, T. Shea, W. Stock, V. Hars, et al. A Randomized Comparison of Induction Therapy for Untreated Acute Myeloid Leukemia (AML) in Patients < 60 Years Using P-Glycoprotein (Pgp) Modulation with Valspodar (PSC833): Preliminary Results of Cancer and Leukemia Group B Study 19808. Blood (ASH Annual Meeting Abstracts), November 16, 2005; 106(11): 407 - 407. [Abstract]

				B. van der Holt, B. Lowenberg, A. K. Burnett, W. U. Knauf, J. Shepherd, P. P. Piccaluga, G. J. Ossenkoppele, G. E. G. Verhoef, A. Ferrant, M. Crump, et al. The value of the MDR1 reversal agent PSC-833 in addition to daunorubicin and cytarabine in the treatment of elderly patients with previously untreated acute myeloid leukemia (AML), in relation to MDR1 status at diagnosis Blood, October 15, 2005; 106(8): 2646 - 2654. [Abstract] [Full Text] [PDF]

				G. Marcucci, K. Mrozek, A. S. Ruppert, K. Maharry, J. E. Kolitz, J. O. Moore, R. J. Mayer, M. J. Pettenati, B. L. Powell, C. G. Edwards, et al. Prognostic Factors and Outcome of Core Binding Factor Acute Myeloid Leukemia Patients With t(8;21) Differ From Those of Patients With inv(16): A Cancer and Leukemia Group B Study J. Clin. Oncol., August 20, 2005; 23(24): 5705 - 5717. [Abstract] [Full Text] [PDF]

				J. O. Moore, S. L. George, R. K. Dodge, P. C. Amrein, B. L. Powell, J. E. Kolitz, M. R. Baer, F. R. Davey, C. D. Bloomfield, R. A. Larson, et al. Sequential multiagent chemotherapy is not superior to high-dose cytarabine alone as postremission intensification therapy for acute myeloid leukemia in adults under 60 years of age: Cancer and Leukemia Group B Study 9222 Blood, May 1, 2005; 105(9): 3420 - 3427. [Abstract] [Full Text] [PDF]

				S. S. Farag, A. S. Ruppert, K. Mrozek, R. J. Mayer, R. M. Stone, A. J. Carroll, B. L. Powell, J. O. Moore, M. J. Pettenati, P. R.K. Koduru, et al. Outcome of Induction and Postremission Therapy in Younger Adults With Acute Myeloid Leukemia With Normal Karyotype: A Cancer and Leukemia Group B Study J. Clin. Oncol., January 20, 2005; 23(3): 482 - 493. [Abstract] [Full Text] [PDF]