Low Dose Melphalan and Bortezomib for AML and High-Risk MDS

Summary

The purpose of this study is to determine the response rate of the combination of bortezomib and melphalan in patients with Acute Myelogenous Leukemia (AML) or high-risk Myelodysplastic Syndromes (MDS).

Timeline

Start

2004-09

Primary completion

2008-12

Completion

2008-12

Publications

• Background Phillips GL, Reece DE, Shepherd JD, Barnett MJ, Brown RA, Frei-Lahr DA, Klingemann HG, Bolwell BJ, Spinelli JJ, Herzig RH, et al. High-dose cytarabine and daunorubicin induction and postremission chemotherapy for the treatment of acute myelogenous leukemia in adults. Blood. 1991 Apr 1;77(7):1429-35.
• Background Johnson PR, Yin JA. Prognostic factors in elderly patients with acute myeloid leukaemia. Leuk Lymphoma. 1994 Dec;16(1-2):51-6. doi: 10.3109/10428199409114139.
• Background Maslak PG, Weiss MA, Berman E, Yao TJ, Tyson D, Golde DW, Scheinberg DA. Granulocyte colony-stimulating factor following chemotherapy in elderly patients with newly diagnosed acute myelogenous leukemia. Leukemia. 1996 Jan;10(1):32-9.
• Background Leith CP, Kopecky KJ, Godwin J, McConnell T, Slovak ML, Chen IM, Head DR, Appelbaum FR, Willman CL. 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. 1997 May 1;89(9):3323-9.
• Background Denzlinger C, Bowen D, Benz D, Gelly K, Brugger W, Kanz L. Low-dose melphalan induces favourable responses in elderly patients with high-risk myelodysplastic syndromes or secondary acute myeloid leukaemia. Br J Haematol. 2000 Jan;108(1):93-5. doi: 10.1046/j.1365-2141.2000.01825.x.
• Background Omoto E, Deguchi S, Takaba S, Kojima K, Yano T, Katayama Y, Sunami K, Takeuchi M, Kimura F, Harada M, Kimura I. Low-dose melphalan for treatment of high-risk myelodysplastic syndromes. Leukemia. 1996 Apr;10(4):609-14.
• Background Mitchell BS. The proteasome--an emerging therapeutic target in cancer. N Engl J Med. 2003 Jun 26;348(26):2597-8. doi: 10.1056/NEJMp030092. No abstract available.
• Background King RW, Deshaies RJ, Peters JM, Kirschner MW. How proteolysis drives the cell cycle. Science. 1996 Dec 6;274(5293):1652-9. doi: 10.1126/science.274.5293.1652.
• Background Karin M, Cao Y, Greten FR, Li ZW. NF-kappaB in cancer: from innocent bystander to major culprit. Nat Rev Cancer. 2002 Apr;2(4):301-10. doi: 10.1038/nrc780.
• Background Haefner B. NF-kappa B: arresting a major culprit in cancer. Drug Discov Today. 2002 Jun 15;7(12):653-63. doi: 10.1016/s1359-6446(02)02309-7.
• Background Dokter WH, Tuyt L, Sierdsema SJ, Esselink MT, Vellenga E. The spontaneous expression of interleukin-1 beta and interleukin-6 is associated with spontaneous expression of AP-1 and NF-kappa B transcription factor in acute myeloblastic leukemia cells. Leukemia. 1995 Mar;9(3):425-32.
• Background Felix CA. Secondary leukemias induced by topoisomerase-targeted drugs. Biochim Biophys Acta. 1998 Oct 1;1400(1-3):233-55. doi: 10.1016/s0167-4781(98)00139-0.
• Background Chernov MV, Bean LJ, Lerner N, Stark GR. Regulation of ubiquitination and degradation of p53 in unstressed cells through C-terminal phosphorylation. J Biol Chem. 2001 Aug 24;276(34):31819-24. doi: 10.1074/jbc.M103170200. Epub 2001 Jun 28.
• Background Olsson I, Bergh G, Ehinger M, Gullberg U. Cell differentiation in acute myeloid leukemia. Eur J Haematol. 1996 Jul;57(1):1-16. doi: 10.1111/j.1600-0609.1996.tb00483.x.
• Background Padua RA, Guinn BA, Al-Sabah AI, Smith M, Taylor C, Pettersson T, Ridge S, Carter G, White D, Oscier D, Chevret S, West R. RAS, FMS and p53 mutations and poor clinical outcome in myelodysplasias: a 10-year follow-up. Leukemia. 1998 Jun;12(6):887-92. doi: 10.1038/sj.leu.2401044.
• Background Parry TE. The non-random distribution of point mutations in leukaemia and myelodysplasia--a possible pointer to their aetiology. Leuk Res. 1997 Jun;21(6):559-74. doi: 10.1016/s0145-2126(97)83221-3.
• Background Rosenfeld C, Kantarjian H. Is myelodysplastic related acute myelogenous leukemia a distinct entity from de novo acute myelogenous leukemia? Potential for targeted therapies. Leuk Lymphoma. 2001 May;41(5-6):493-500. doi: 10.3109/10428190109060340.
• Background Slingerland JM, Minden MD, Benchimol S. Mutation of the p53 gene in human acute myelogenous leukemia. Blood. 1991 Apr 1;77(7):1500-7.
• Background Yang, H.H., et al., A phase I/II study of combination treatment with bortezomib and melphalan (Vc+M) in patients with relapsed or refractory multiple myeloma (MM). Proceedings of ASCO, 2003. Abstract 2340.
• Background Richardson PG, Barlogie B, Berenson J, Singhal S, Jagannath S, Irwin D, Rajkumar SV, Srkalovic G, Alsina M, Alexanian R, Siegel D, Orlowski RZ, Kuter D, Limentani SA, Lee S, Hideshima T, Esseltine DL, Kauffman M, Adams J, Schenkein DP, Anderson KC. A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med. 2003 Jun 26;348(26):2609-17. doi: 10.1056/NEJMoa030288.
• Background David P. Schenkein, M., Proteosome Inhibition, D. Jeffrey A. Bubis, Editor. 2003:Lebanon, New Hampshire.
• Background Cheson BD, Bennett JM, Kantarjian H, Pinto A, Schiffer CA, Nimer SD, Lowenberg B, Beran M, de Witte TM, Stone RM, Mittelman M, Sanz GF, Wijermans PW, Gore S, Greenberg PL; World Health Organization(WHO) international working group. Report of an international working group to standardize response criteria for myelodysplastic syndromes. Blood. 2000 Dec 1;96(12):3671-4.
• Background Common Terminology Criteria for Adverse Events. 2003, National Cancer Institute Cancer Therapy Evaluation Program.

Drugs

Indications