Clofarabine and cytarabine combination as induction therapy for acute myeloid leukemia (AML) in patients 50 years of age or older

Blood - Tập 108 - Trang 45-51 - 2006
Stefan Faderl1, Srdan Verstovsek1, Jorge Cortes1, Farhad Ravandi1, Miloslav Beran1, Guillermo Garcia-Manero1, Alessandra Ferrajoli1, Zeev Estrov1, Susan O'Brien1, Charles Koller1, Francis J. Giles1, William Wierda1, Monica Kwari1, Hagop M. Kantarjian1
1Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston

Tóm tắt

Outcome of patients with acute myeloid leukemia (AML) who are older than 60 years of age remains unsatisfactory, with low remission rates and poor overall survival. We have previously established the activity of clofarabine plus cytarabine in AML relapse. We have now conducted a phase 2 study of clofarabine plus cytarabine in patients aged 50 years or older with previously untreated AML. Clofarabine was given at 40 mg/m2 as a 1-hour intravenous infusion for 5 days (days 2 to 6) followed 4 hours later by cytarabine at 1 g/m2/d as a 2-hour intravenous infusion for 5 days (days 1 to 5). Of 60 patients, 29 (48%) had secondary AML, 30 (50%) had abnormal karyotypes (monosomy 5 and/or 7 in 15 [25%]), and 11 (21%) showed FLT3 abnormalities. The overall response (OR) rate was 60% (52% CR, 8% CRp). Four patients (7%) died during induction. Adverse events were mainly grade 2 or lower and included diarrhea, nausea, vomiting, mucositis, skin reactions, liver test abnormalities, and infusion-related facial flushing and headaches. Myelosuppression was common. Clofarabine plus cytarabine has activity in adult AML, achieving a good CR rate. However, survival does not appear to be improved compared with other regimens. Modifications of this combination in AML therapy of older patients warrant further evaluation. (Blood. 2006;108:45-51)

Tài liệu tham khảo

Estey E. How I treat older patients with AML. Blood. 2000;96: 1670-1673. 2003, Crit Rev Oncol Hematol, 48, S17 Vey N, Coso D, Bardou VJ, et al. The benefit of induction chemotherapy in patients age > or = 75 years. Cancer. 2004;101: 325-331. Goldstone AH, Burnett AK, Wheatley K, et al. Attempts to improve treatment outcomes in acute myeloid leukemia (AML) in older patients: the results of the United Kingdom Medical Research Council AML11 trial. Blood. 2001;98: 1302-1311. Grimwade D, Walker H, Oliver F, et al. The importance of diagnostic cytogenetics on outcome in AML: analysis of 1,612 patients entered into the MRC AML 10 trial. Blood. 1998;92: 2322-2333. Slovak ML, Kopecky KJ, Cassileth PA, et al. Karyotypic analysis predicts outcome of preremission and postremission therapy in adult acute myeloid leukemia: a Southwest Oncology Group/Eastern Cooperative Oncology Group study. Blood2000;96: 4075-4083. Byrd JC, Mrozek K, Dodge RK, et al. Pretreatment cytogenetic abnormalities are predictive of induction success, cumulative incidence of relapse, and overall survival in adult patients with de novo acute myeloid leukemia: results from Cancer and Leukemia Group B (CALGB 8461). Blood. 2002;100: 4325-4336. Grimwade D, Walker H, Harrison G, et al. The predictive value of hierarchical cytogenetic classification in older adults with acute myeloid leukemia (AML): analysis of 1065 patients entered into the United Kingdom Medical Research Council AML11 trial. Blood. 2001;98: 1312-1320. Baer MR, George SL, Dodge RK, et al. Phase 3 study of the multidrug resistance modulator PSC-833 in previously untreated patients 60 years of age and older with acute myeloid leukemia: Cancer and Leukemia Group B Study 9720. Blood. 2002;100: 1224-1232. Montgomery JA, Shortnacy-Fowler AT, Clayton SD, et al. Synthesis and biologic activity of 2′-fluoro-2-halo derivatives of 9-β-D-arabinofuranosyladenine. J Med Chem. 1992;35: 397-401. Parker WB, Allan PW, Hassan AE, et al. Antitumor activity of 2-fluoro-2′-deoxyadenosine against tumors that express Escherichia coli purine nucleoside phosphorylase. Cancer Gene Ther. 2003;10: 23-29. Carson DA, Wasson DB, Esparza LM, et al. Oral antilymphocyte activity and induction of apoptosis by 2-chloro-2′-arabino-fluoro-2′ deoxyadenosine. Proc Natl Acad Sci U S A. 1992;89: 2970-2974. Xie C, Plunkett W. Metabolism and actions of 2-chloro-9-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)-adenine in human lymphoblastoid cells. Cancer Res. 1995;55: 2847-2852. Xie KC, Plunkett W. Deoxynucleotide pool depletion and sustained inhibition of ribonucleotide reductase and DNA synthesis after treatment of human lymphoblastoid cells with 2-chloro-(2-deoxy-fluoro-β-D-arabinofuranosyl) adenine. Cancer Res. 1996;56: 3030-3037. Kantarjian HM, Gandhi V, Kozuch P, et al. Phase I clinical and pharmacology study of clofarabine in patients with solid and hematologic cancers. J Clin Oncol. 2003;21: 1167-1173. Kantarjian H, Gandhi V, Cortes J, et al. Phase 2 clinical and pharmacologic study of clofarabine in patients with refractory or relapsed acute leukemia. Blood. 2003;102: 2379-2386. Jeha S, Gandhi V, Chan KW, et al. Clofarabine, a novel nucleoside analog, is active in pediatric patients with advanced leukemia. Blood. 2004;103: 784-789. Jeha S, Razzouk BI, Rytting ME, et al. Phase II trials of clofarabine in relapsed or refractory pediatric leukemia [abstract]. Blood. 2004;104: 196a. Parker WB, Shaddix SC, Rose L, et al. Comparison of the mechanism of cytotoxicity of 2-chloro-9-(2-deoxy-2-fluoro-β-D-arabinofuranosyl) adenine, 2-chloro-9-(2-deoxy-2-fluoro-β-D-arabinofuranosyl) adenine, 2-chloro-9-(2-deoxy-2, 2-difluoro-β-D-ribofuranosyl) adenine in CEM cells. Mol Pharmacol. 1999;55: 515-520. Parker WB, Bapat AR, Shen JX, et al. Interaction of 2-halogenated dATP analogs (F, Cl, and Br) with human DNA polymerases, DNA primase, and ribonucleotide reductase. Mol Pharmacol. 1988;34: 485-491. Parker WB, Shaddix SC, Chang CH, et al. Effects of 2-chloro-9-(2-deoxy-2-fluoro-β-D-arabinofuranosyl) adenine on K562 cellular metabolism and the inhibition of human ribonucleotide reductase and DNA polymerases by its 5′-triphosphate. Cancer Res. 1991;51: 2386-2394. Faderl S, Gandhi V, O'Brien S, et al. Results of a phase 1-2 study of clofarabine in combination with cytarabine (ara-C) in relapsed and refractory acute leukemias. Blood. 2005;105: 940-947. Faderl S, Gandhi V, Kantarjian H, Plunkett W. New nucleoside analogues in clinical development. Cancer Chemother Biol Response Modif. 2002;20: 37-58. Rathnasabapathy R, Lancet JE. Management of acute myelogenous leukemia in the elderly. Cancer Control. 2003;10: 469-477. Anderson JE, Kopecky KJ, Willman CL, et al. Outcome after induction chemotherapy for older patients with acute myeloid leukemia is not improved with mitoxantrone and etoposide compared to cytarabine and daunorubicin: a Southwest Oncology Group study. Blood. 2002;100: 3869-3876. Juliusson G, Höglund M, Karlsson K, et al. Increased remissions from one course for intermediate-dose cytosine arabinoside and idarubicin in elderly acute myeloid leukemia when combined with cladribine. A randomized population-based phase II study. Br J Haematol. 2003;123: 810-818. Rowe JM, Neuberg D, Friedenberg W, et al. A phase 3 study of three induction regimens and of priming with GM-CSF in older adults with acute myeloid leukemia: a trial by the Eastern Cooperative Oncology Group. Blood. 2004;103: 479-485. Burnett AK, Russell N, Kell JW, et al. A phase 2 evaluation of single agent clofarabine as first line treatment for older patients with AML who are not considered fit for intensive chemotherapy [abstract]. Blood. 2004;104: 248a. Burnett AK, Milligan D, Prentice AG, et al. Low dose ara-C versus hydroxyurea with or without retinoid in older patients not considered fit for intensive chemotherapy: The UK NCRI AML14 trial [abstract]. Blood. 2004;104: 249a.
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Blood

Tập 108

45-51

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