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 - Tập 100 - Trang 1224-1232 - 2002
Maria R. Baer, Stephen L. George, Richard K. Dodge, Kieran L. O'Loughlin, Hans Minderman, Michael A. Caligiuri, John Anastasi, Bayard L. Powell, Jonathan E. Kolitz, Charles A. Schiffer, Clara D. Bloomfield, Richard A. Larson

Tóm tắt

The Cancer and Leukemia Group B conducted a phase 3 trial of the P-glycoprotein modulator PSC-833 in untreated acute myeloid leukemia patients aged 60 years and older. Patients were randomized to 1 of 2 regimens, with doses determined in a prior phase 1 study, consisting of cytarabine 100 mg/m2/d by 7-day infusion, with daunorubicin 60 mg/m2 and etoposide 100 mg/m2 daily for 3 days (ADE), or daunorubicin 40 mg/m2 and etoposide 60 mg/m2 for 3 days with PSC-833, 2.8 mg/kg over 2 hours, and then 10 mg/kg/d by 3-day infusion (ADEP). The ADEP arm was closed after randomization of 120 patients (61 to ADE and 59 to ADEP) because of excessive early mortality. Rates of complete remission, nonresponse, and death were 46%, 34%, and 20% for ADE, versus 39%, 17%, and 44% for ADEP (P = .008). Nevertheless, disease-free survival (median 7 vs 8 months; P = .38) and overall survival (approximately 33% alive at 1 year) did not differ and were similar to historical results. Although the number of patients was limited, ADE patients whose pretreatment cells exhibited PSC-833–modulated dye efflux in vitro (n = 22) had worse outcomes than those without efflux (n = 11) (complete remission, nonresponse, and death rates of 41%, 41%, and 18%, compared with 91%, 9%, and 0%; P = .03), but with ADEP outcomes were nearly identical. Moreover, for patients with PSC-833–modulated efflux, median disease-free survival was 5 months with ADE and 14 months with ADEP (P = .07). Further modulation trials in older patients must await the design of less-toxic regimens.

Tài liệu tham khảo

Mayer, 1994, Intensive postremission chemotherapy in adults with acute myeloid leukemia., Cancer and Leukemia Group B. N Engl J Med., 331, 896, 10.1056/NEJM199410063311402 Stone, 1995, Granulocyte-macrophage colony-stimulating factor after initial chemotherapy for elderly patients with primary acute myelogenous leukemia., Cancer and Leukemia Group B. N Engl J Med., 332, 1671, 10.1056/NEJM199506223322503 Rowe, 1995, A randomized placebo-controlled phase 3 study of granulocyte-macrophage colony-stimulating factor in adult patients (&gt; 55 to 70 years of age) with acute myelogenous leukemia: a study of the Eastern Cooperative Oncology Group (E1490)., Blood., 86, 457, 10.1182/blood.V86.2.457.bloodjournal862457 Lowenberg, 1997, Use of recombinant granulocyte-macrophage colony-stimulating factor during and after remission induction chemotherapy in patients aged 61 years and older with acute myeloid leukemia (AML): final report of AML-11, a phase 3 randomized study of the Leukemia Cooperative Group of European Organisation for the Research and Treatment of Cancer (EORTC-LCG) and the Dutch Belgian Hemato-Oncology Cooperative Group (HOVON)., Blood., 90, 2952 Godwin, 1998, A double-blind placebo-controlled trial of granulocyte colony-stimulating factor in elderly patients with previously untreated acute myeloid leukemia: a Southwest Oncology Group study (9031)., Blood., 91, 3607, 10.1182/blood.V91.10.3607 Leith, 1997, 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, 10.1182/blood.V89.9.3323 Ross, 1993, Enhancement of daunorubicin accumulation, retention, and cytotoxicity by verapamil or cyclosporin A in blast cells from patients with previously untreated acute myeloid leukemia., Blood., 82, 1288, 10.1182/blood.V82.4.1288.1288 Solary, 1996, Combination of quinine as a potential reversing agent with mitoxantrone and cytarabine for the treatment of acute leukemias: a randomized multicenter study., Blood., 88, 1198, 10.1182/blood.V88.4.1198.bloodjournal8841198 Boesch, 1991, In vivo circumvention of P-glycoprotein-mediated multidrug resistance of tumor cells with SDZ PSC 833., Cancer Res., 51, 4226 Tidefelt, 2000, 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., 18, 1837, 10.1200/JCO.2000.18.9.1837 Speeg, 1994, Effect of the nonimmunosuppressive cyclosporin analog SDZ PSC-833 on colchicine and doxorubicin biliary secretion by the rat in vivo., Cancer Chemother Pharmacol., 34, 133, 10.1007/BF00685930 Keller, 1992, Pharmacologic interactions between the resistance-modifying cyclosporine SDZ PSC 833 and etoposide (VP 16-213) enhance in vivo cytostatic activity and toxicity., Int J Cancer., 51, 433, 10.1002/ijc.2910510316 Lee, 1999, Parallel phase 1 studies of daunorubicin given with cytosine arabinoside and etoposide with or without the multidrug resistance modulator PSC-833 in previously untreated patients ≥60 years of age with acute myeloid leukemia: results of Cancer and Leukemia Group B study 9420., J Clin Oncol., 17, 2831, 10.1200/JCO.1999.17.9.2831 Bennett, 1985, Proposed revised criteria for the classification of acute myeloid leukemia: a report of the French-American-British Group., Ann Intern Med., 103, 620, 10.7326/0003-4819-103-4-620 Bennett, 1991, Proposal for the recognition of minimally differentiated acute myeloid leukaemia (AML-MO)., Br J Haematol., 78, 325, 10.1111/j.1365-2141.1991.tb04444.x Giaccone, 1997, A dose-finding and pharmacokinetic study of reversal of multidrug resistance with SDZ PSC 833 in combination with doxorubicin in patients with solid tumors., Clin Cancer Res., 3, 2005 Meropol, 1998, Evaluation of natural killer cell expansion and activation in vivo with daily subcutaneous low-dose interleukin-2 plus periodic intermediate-dose pulsing., Cancer Immunol Immunother., 46, 318, 10.1007/s002620050493 American Society of Clinical Oncology, 1994, Recommendations for the use of hematopoietic colony-stimulating factors: evidence-based, clinical practice guidelines., J Clin Oncol., 12, 2471, 10.1200/JCO.1994.12.11.2471 Weiss, 1993, A successful system of scientific data audits for clinical trials: a report from the Cancer and Leukemia Group B., JAMA., 270, 459, 10.1001/jama.1993.03510040063030 Cheson, 1990, Report of the National Cancer Institute-sponsored workshop on definitions of diagnosis and response in acute myeloid leukemia., J Clin Oncol., 8, 813, 10.1200/JCO.1990.8.5.813 Mitelman, 1995, ISCN 1995: An International System for Human Cytogenetic Nomenclature. Byrd, 2001, Pre-treatment cytogenetics predict initial induction success and overall survival in adult patients with de novo acute myeloid leukemia: results from CALGB 8461 [abstract]., Blood., 98, 457a Leith, 1995, 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., Blood., 86, 2329, 10.1182/blood.V86.6.2329.bloodjournal8662329 Leith, 1999, 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., 94, 1086 Chauncey, 2000, A phase 1 study of induction chemotherapy for older patients with newly diagnosed acute myeloid leukemia (AML) using mitoxantrone, etoposide, and the MDR modulator PSC-833: a Southwest Oncology Group study 9617., Leuk Res., 24, 567, 10.1016/S0145-2126(00)00024-2 Minderman, 1996, DiOC2(3) is not a substrate for multidrug resistance protein (MRP)-mediated drug efflux., Cytometry., 25, 14, 10.1002/(SICI)1097-0320(19960901)25:1<14::AID-CYTO2>3.0.CO;2-E Young, 1977, Proof without prejudice: use of the Kolmogorov-Smirnov test for the analysis of histograms from flow systems and other sources., J Histochem Cytochem., 25, 935, 10.1177/25.7.894009 Dalton, 1986, Characterization of a new drug-resistant human myeloma cell line that expresses p-glycoprotein., Cancer Res., 46, 5125 Armitage, 1971, Statistical Methods in Medical Research. Mehta, 1983, A network algorithm for performing Fisher's exact test in r × c contingency tables., J Am Stat Assoc., 78, 427 Hosmer, 1989, Applied Logistic Regression. Kaplan, 1958, Nonparametric estimation from incomplete observations., J Am Stat Assoc., 53, 457, 10.1080/01621459.1958.10501452 Peto, 1977, Design and analysis of randomized clinical trials requiring prolonged observation of each patient, II: analysis and examples., Br J Cancer., 35, 1, 10.1038/bjc.1977.1 Erlichman, 1994, A phase 1 trial of doxorubicin (D) and PSC833: a modulator of multidrug resistance (MDR)., Proc Am Soc Clin Oncol., 13, A326 Sonneveld, 1996, Reversal of multidrug resistance by SDZ PSC 833, combined with VAD (vincristine, doxorubicin, dexamethasone) in refractory multiple myeloma: a phase 1 study., Leukemia., 10, 1741 Giaccone, 1997, A dose-finding and pharmacokinetic study of reversal of multidrug resistance with SDZ PSC 833 in combination with doxorubicin in patients with solid tumors., Clin Cancer Res., 3, 2005 Boote, 1996, Phase 1 study of etoposide with SDZ PSC 833 as a modulator of multidrug resistance in patients with cancer., J Clin Oncol., 14, 610, 10.1200/JCO.1996.14.2.610 Kornblau, 1997, Phase 1 study of mitoxantrone plus etoposide with multidrug blockade by SDZ PSC-833 in relapsed or refractory acute myelogenous leukemia., J Clin Oncol., 15, 1796, 10.1200/JCO.1997.15.5.1796 Advani, 1999, Treatment of refractory and relapsed acute myelogenous leukemia with combination chemotherapy plus the multidrug resistance modulator PSC 833 (Valspodar)., Blood., 93, 787, 10.1182/blood.V93.3.787 Sonneveld, 1997, Dose-finding study of PSC833, a novel MDR reversing agent, with daunorubicin and ara-C in untreated elderly patients with acute myeloid leukemia [abstract]., Blood., 90, 507a Visani, 2001, Combined action of PSC 833 (Valspodar), a novel MDR reversing agent, with mitoxantrone, etoposide and cytarabine in poor-prognosis acute myeloid leukemia., Leukemia., 15, 764, 10.1038/sj.leu.2402117 Dorr, 2001, Phase 1/2 study of the P-glycoprotein modulator PSC 833 in patients with acute myeloid leukemia., J Clin Oncol., 19, 1589, 10.1200/JCO.2001.19.6.1589 Greenberg, 1999, Treatment of refractory/relapsed AML with PSC833 plus mitoxantrone, etoposide, cytarabine (PSC-MEC) vs. MEC: randomized phase 3 trial (E2995) [abstract]., Blood, 94, 383a List, 1993, Phase 1/2 trial of cyclosporine as a chemotherapy-resistance modifier in acute leukemia., J Clin Oncol., 11, 1652, 10.1200/JCO.1993.11.9.1652 List, 2001, Benefit of cyclosporine modulation of drug resistance in patients with poor-risk acute myeloid leukemia: a Southwest Oncology Group study., Blood., 98, 3212, 10.1182/blood.V98.12.3212 Liu Yin, 2001, Comparison of ‘sequential’ versus ‘standard’ chemotherapy as re-induction treatment, with or without cyclosporine, in refractory/relapsed acute myeloid leukaemia (AML): results of the UK Medical Research Council AML-R trial., Br J Haematol., 113, 713, 10.1046/j.1365-2141.2001.02785.x Tallman, 1999, Mitoxantrone, etoposide, and cytarabine plus cyclosporine for patients with relapsed or refractory acute myeloid leukemia: an Eastern Cooperative Oncology Group pilot study., Cancer., 85, 358, 10.1002/(SICI)1097-0142(19990115)85:2<358::AID-CNCR13>3.0.CO;2-0 Dahl, 2000, Mitoxantrone, etoposide, and cyclosporine therapy in pediatric patients with recurrent or refractory acute myeloid leukemia., J Clin Oncol., 18, 1867, 10.1200/JCO.2000.18.9.1867 Pallis, 2000, P-glycoprotein plays a drug efflux-independent role in augmenting cell sur-vival in acute myeloblastic leukemia and is asso-ciated with modulation of a sphingomyelin-ceramide apoptotic pathway., Blood., 95, 2897, 10.1182/blood.V95.9.2897.009k14_2897_2904 Ross, 2000, Novel mechanisms of drug resistance in leukemia., Leukemia., 14, 467, 10.1038/sj.leu.2401694 Peck, 2001, Phase 1 and pharmacokinetic study of the novel MDR1 and MRP1 inhibitor biricodar administered alone and in combination with doxorubicin., J Clin Oncol., 19, 3130, 10.1200/JCO.2001.19.12.3130 Starling, 1997, Pharmacological characterization of LY335979: a potent cyclopropyldibenzosuberane modulator of P-glycoprotein., Adv Enzyme Regul., 37, 335, 10.1016/S0065-2571(96)00021-0 Bishop, 1990, Etoposide in acute nonlymphocytic leukemia., Blood., 75, 27, 10.1182/blood.V75.1.27.27 Kolitz, 1999, Parallel phase 1 trials of multi-drug resistance (MDR) modulation with PSC-833 (PSC) in untreated patients with acute myeloid leukemia (AML) &lt; 60 years old: preliminary results of CALGB 9621 [abstract]., Blood., 94, 384a