Leukemia Research
Volume 28, Issue 10 , Pages 1057-1067 , October 2004

Addition of cyclosporin A to the combination of mitoxantrone and etoposide to overcome resistance to chemotherapy in refractory or relapsing acute myeloid leukaemia: A randomised phase II trial from HOVON, the Dutch–Belgian Haemato-Oncology Working Group for adults

  • Simon Daenen

      Affiliations

    • Department of Haematology, University Hospital, Hanzeplein 1, 9713 GZ Groningen, The Netherlands
    • Corresponding Author InformationCorresponding author. Tel.: +31-50-3616161; fax: +31-50-3614862.
    • ,
  • Bronno van der Holt

      Affiliations

    • HOVON Data Center, Erasmus Medical Center, Rotterdam, The Netherlands
    • ,
  • Gregor E.G Verhoef

      Affiliations

    • Academic Hospital Gasthuisberg, Leuven, Belgium
    • ,
  • Bob Löwenberg

      Affiliations

    • Erasmus Medical Center, Rotterdam, The Netherlands
    • ,
  • Pierre W Wijermans

      Affiliations

    • Leyenburg Hospital, The Hague, The Netherlands
    • ,
  • Peter C Huijgens

      Affiliations

    • VU University Medical Center, Amsterdam, The Netherlands
    • ,
  • Rien van Marwijk Kooy

      Affiliations

    • Isala Clinics, Zwolle, The Netherlands
    • ,
  • Harry C Schouten

      Affiliations

    • University Hospital, Maastricht, The Netherlands
    • ,
  • Mark H.H Kramer

      Affiliations

    • Eemland Hospital, Amersfoort, The Netherlands
    • ,
  • Augustin Ferrant

      Affiliations

    • Free University Hospital, Brussels, Belgium
    • ,
  • Eva van den Berg

      Affiliations

    • Department of Medical Genetics, Groningen, The Netherlands
    • ,
  • Monique M.C Steijaert

      Affiliations

    • HOVON Data Center, Erasmus Medical Center, Rotterdam, The Netherlands
    • ,
  • Leo F Verdonck

      Affiliations

    • University Hospital, Utrecht, The Netherlands
    • ,
  • Pieter Sonneveld

      Affiliations

    • Erasmus Medical Center, Rotterdam, The Netherlands

Received 27 November 2003 ,Accepted 2 March 2004.

References 

  1. Curt GA, Clendeninn NJ, Chabner BA. Drug resistance in cancer. Cancer Treat. Rep. 1984;68:87–99
  2. Pastan I, Gottesman M. Multiple-drug resistance in human cancer. N. Engl. J. Med. 1987;316:1388–1393
  3. Juliano RL, Ling V. A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants. Biochim. Biophys. Acta. 1976;455:152–162
  4. Cornwell MM, Safa AR, Felsted RL, Gottesman MM, Pastan I. Membrane vesicles from multidrug-resistant human cancer cells contain a specific 150- to 170 kDa protein detected by photoaffinity labeling. Proc. Natl. Acad. Sci. U.S.A. 1986;83:3847–3850
  5. Skovsgaard T. Mechanisms of resistance to daunorubicin in Ehrlich ascites tumor cells. Cancer Res. 1978;38:1785–1791
  6. Cole SPC, Bhardwaj G, Gerlach JH, Mackie JE, Grant CE, Almquist KC, et al.  Overexpression of a transporter gene in a multidrug-resistant human lung cancer cell line. Science. 1992;258:1650–1654
  7. Kool M, de Haas M, Scheffer GL, Scheper RJ, van Eijck MJT, Juijn JA, et al.  Analysis of expression of cMOAT (MRP2), MRP3, MRP4 and MRP5, homologues of the multidrug resistance-associated protein gene (MRP1), in human cancer cell lines. Cancer Res. 1997;57:3537–3547
  8. Ross DD, Karp JE, Chen TT, Doyle LA. Expression of breast cancer resistance protein in blast cells from patients with acute leukemia. Blood. 2000;96:365–368
  9. Scheper RJ, Broxterman HJ, Scheffer GL, Kaaijk P, Dalton WS, van Heijningen THM, et al.  Overexpression of a Mr 110,000 vesicular protein in non-P-glycoprotein-mediated multidrug resistance. Cancer Res. 1993;53:1475–1479
  10. Fojo AT, Ueda K, Slamon DJ, Poplack DG, Gottesman MM, Pastan I. Expression of a multidrug resistance gene in human tumors and tissues. Proc. Natl. Acad. Sci. U.S.A. 1987;84:265–269
  11. Cordon-Cardo C, O’Brien JP, Casals D, Rittman-Grauer L, Biedler JL, Melamed MR, et al.  Multidrug-resistance gene (P-glycoprotein) is expressed by endothelial cells at blood-brain barrier sites. Proc. Natl. Acad. Sci. U.S.A. 1989;86:695–698
  12. Chaudhary PM, Roninson IB. Expression and activity of P-glycoprotein, a multidrug efflux pump, in human hematopoietic stem cells. Cell. 1991;66:85–94
  13. List AF, Spier CM, Cline A, Doll DC, Garewal H, Morgan R, et al.  Expression of the multidrug resistance gene product (P-glycoprotein) in myelodysplasia is associated with a stem cell phenotype. Brit. J. Haematol. 1991;78:28–34
  14. Drach D, Zhao S, Drach J, Mahadevia R, Gattringer C, Huber H, et al.  Subpopulations of normal peripheral blood and bone marrow cells express a functional multidrug resistant phenotype. Blood. 1992;80:2729–2734
  15. Chaudhary PM, Mechetner EB, Roninson IB. Expression and activity of the multidrug resistance P-glycoprotein in human peripheral blood lymphocytes. Blood. 1992;80:2735–2739
  16. Te Boekhorst PAW, de Leeuw K, Schoester M, Wittebol S, Nooter K, Hagemeijer A, et al.  Predominance of functional multidrug resistance (MDR-1) phenotype in CD34+ acute myeloid leukemia cells. Blood. 1993;82:3157–3162
  17. Michieli M, Damiani D, Ermacora A, Masolini P, Raspadori D, Visani G, et al.  P-glycoprotein, lung resistance-related protein and multidrug resistance associated protein in de novo acute non-lymphocytic leukaemias: biological and clinical implications. Brit. J. Haematol. 1999;104:328–335
  18. Leith CP, Chen IM, Kopecky KJ, Appelbaum FR, Head DR, Godwin JE, et al.  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. 1995;86:2329–2342
  19. Willman CL. Immunophenotyping and cytogenetics in older adults with acute myeloid leukemia: significance of expression of the multidrug resistance gene-1 (MDR1). Leukemia. 1996;10(suppl 1):S33–35
  20. Van den Heuvel-Eibrink MM, Wiemer EA, de Boevere MJ, van der Holt B, Vossebeld PJ, Pieters R, et al.  MDR1 gene-related clonal selection and P-glycoprotein function and expression in relapsed or refractory acute myeloid leukemia. Blood. 2001;97:3605–3611
  21. Marie JP, Bastie JN, Coloma F, Faussat Suberville AM, Delmer A, Rio B, et al.  Cyclosporin A as a modifier agent in the salvage treatment of acute leukemia (AL). Leukemia. 1993;7:821–824
  22. Legrand O, Simonin G, Beauchamp-Nicoud A, Zittoun R, Marie JP. 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. 1999;94:1046–1056
  23. Van der Kolk DM, de Vries EG, van Putten WJ, Verdonck LF, Ossenkoppele GJ, Verhoef GE, et al.  P-glycoprotein and multidrug resistance protein activities in relation to treatment outcome in acute myeloid leukemia. Clin. Cancer Res. 2000;6:3205–3214
  24. List AF, Spier CS, Grogan TM, Johnson C, Roe DJ, Greer JP, et al.  Overexpression of the major vault transporter protein lung-resistance protein predicts treatment outcome in acute myeloid leukemia. Blood. 1996;87:2464–2469
  25. Tsuruo T, Iida H, Tsukagoshi S, Sakurai Y. Increased accumulation of vincristine and adriamycin in drug-resistant P388 tumor cells following incubation with calcium antagonists and calmodulin inhibitors. Cancer Res. 1982;42:4730–4733
  26. Slater LM, Sweet P, Stupecky M, Gupta S. Cyclosporin A reverses vincristine and daunorubicin resistance in acute lymphatic leukemia in vitro. J. Clin. Invest. 1986;77:1405–1408
  27. Sonneveld P. Multidrug resistance in haematological malignancies. J. Intern. Med. 2000;247:521–534
  28. List AF, Spier C, Greer J, Wolff S, Hutter J, Dorr R, et al.  Phase I/II trial of cyclosporine as a chemotherapy-resistance modifier in acute leukemia. J. Clin. Oncol. 1993;11:1652–1660
  29. List AF, Kopecky KJ, Willman CL, Head DR, Persons DL, Slovak ML, et al.  Benefit of cyclosporine modulation of drug resistance in patients with poor-risk acute myeloid leukemia: a Southwest Oncology Group study. Blood. 2001;98:3212–3220
  30. Tallman MS, Lee S, Sikic BI, Paietta E, Wiernik PH, Bennett JM, et al.  Mitoxantrone, etoposide, and cytarabine plus cyclosporine for patients with relapsed or refractory acute myeloid leukemia: an Eastern Cooperative Oncology Group pilot study. Cancer. 1999;85:358–367
  31. Liu Yin JA, Wheatley K, Rees JKH, Burnett AK. On behalf of the UK, with or without cyclosporine, in refractory/relapsed acute myeloid leukaemia (AML): results of the UK Medical Research Council AML-R trial. Brit. J. Haematol. 2001;113:713–726
  32. Dahl GV, Lacayo NJ, Brophy N, Dunussi-Joannopoulos K, Weinstein HJ, Chang M, et al.  Mitoxantrone, etoposide, and cyclosporine therapy in pediatric patients with recurrent or refractory acute myeloid leukemia. J. Clin. Oncol. 2000;18:1867–1875
  33. Daenen S, Löwenberg B, Sonneveld P, van Putten WLJ, Verhoef G, Verdonck LF, et al.  on behalf of the Dutch Hematology-Oncology Working Group for Adults (HOVON). Efficacy of etoposide and mitoxantrone in patients with acute myelogenous leukemia refractory to standard induction therapy and intermediate-dose cytarabine with amsidine. Leukemia. 1994;8:6–10
  34. Bow EJ, Sutherland JA, Kilpatrick MG, Williams GJ, Clinch JJ, Shore TB, et al.  Therapy of untreated acute myeloid leukemia in the elderly: remission-induction using a non-cytarabine-containing regimen of mitoxantrone plus etoposide. J. Clin. Oncol. 1996;14:1345–1352
  35. NCI Common Toxicity Criteria. NCI Cancer Treatment Evaluation Program Home Page. http://ctep.cancer.gov/reporting/ctc.html.
  36. Hiddemann W, Aul C, Maschmeyer G, Schonrock-Nabulsi R, Ludwig WD, Bartholomaus A, et al.  High-dose versus intermediate dose cytosine arabinoside combined with mitoxantrone for the treatment of relapsed and refractory acute myeloid leukemia: results of an age adjusted randomized comparison. Leuk. Lymphoma. 1993;10(suppl):133–137
  37. Kern W, Aul C, Maschmeyer G, Schonrock-Nabulsi R, Ludwig WD, Bartholomaus A, et al.  Superiority of high-dose over intermediate-dose cytosine arabinoside in the treatment of patients with high-risk acute myeloid leukemia: results of an age-adjusted prospective randomized comparison. Leukemia. 1998;12:1049–1055
  38. Politi PM, Arnold ST, Felsted RL, Sinha BK. P-glycoprotein-independent mechanism of resistance to VP-16 in multidrug-resistant tumor cell lines: pharmacokinetic and photoaffinity labeling studies. Mol. Pharmacol. 1990;37:790–796
  39. Sehested M, Friche E, Jensen PB, Demant EJ. Relationship of VP-16 to the classical multidrug resistance phenotype. Cancer Res. 1992;52:2874–2879
  40. Maia RC, Carrico MK, Klumb CE, Noronha H, Coelho AM, Vasconcelos FC, et al.  Clinical approach to circumvention of multidrug resistance in refractory leukemic patients: association of cyclosporin A with etoposide. J. Exp. Clin. Cancer Res. 1997;16:419–424
  41. Pastan I, Gottesman MM, Ueda K, Lovelace E, Rutherford AV, Willingham MC. A retrovirus carrying an MDR1 cDNA confers multidrug resistance and polarized expression of P-glycoprotein in MDCK cells. Proc. Natl. Acad. Sci. U.S.A. 1988;85:4486–4490
  42. Hait WN, Choudhary S, Srimatkandala S, Murren JR. Sensitivity of K562 human chronic myelogenous leukemia blast cells transfected with a human multidrug resistance cDNA to cytotoxic drugs and differentiating agents. J. Clin. Invest. 1993;91:2207–2215
  43. Bartlett NL, Lum BL, Fisher GA, Brophy NA, Ehsan MN, Halsey J, et al.  Phase I trial of doxorubicin with cyclosporine as a modulator of multidrug resistance. J Clin Oncol. 1994;12:835–842
  44. Nooter K, Sonneveld P, Oostrum R, Herweijer H, Hagenbeek T, Valerio D. Overexpression of the mdr1 gene in blast cells from patients with acute myelogenous leukemias is associated with decreased anthracycline accumulation that can be restored by cyclosporin-A. Int. J. Cancer. 1990;45:263–268
  45. Larson RA. Is modulation of multidrug resistance a viable strategy for acute myeloid leukemia?. Leukemia. 2003;17:488–491
  46. Baer MC, George SL, Dodge RK, O’Loughlin KL, Minderman H, Caligiuri MA, 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

PII: S0145-2126(04)00063-3

doi: 10.1016/j.leukres.2004.03.001

Leukemia Research
Volume 28, Issue 10 , Pages 1057-1067 , October 2004

Article Tools

* Image Usage & Resolution