Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Keynote Address
  • Published:

Is modulation of multidrug resistance a viable strategy for acute myeloid leukemia?

Leukemia volume 17, pages 488–491 (2003)Cite this article

Multidrug resistance (MDR) is a cause of therapeutic failure in acute myeloid leukemia (AML).1 One mechanism of MDR involves active drug efflux from tumor cells via the membrane-bound P-glycoprotein (Pgp) encoded by MDR1.2,3 Evidence from preclinical studies and from phase I and phase II trials has suggested that blocking Pgp with cyclosporin A (CSA) or its analogue PSC833 (valspodar) would prove beneficial.4,5,6,7,8,9,10,11,12,13 However, at least four randomized phase III trials have been completed, and none of these trials appear to show a benefit from using these drugs in AML patients.14,15,16,17 In contrast, there has been one strikingly positive trial from the Southwest Oncology Group (SWOG), treating patients with poor-risk relapsed AML with cytarabine (ara-C) and concomitant daunorubicin and CSA.18 CSA affects drug resistance by inhibiting Pgp (Mdr1)-mediated efflux of chemotherapeutic drugs, as well as through possible immune and antiapoptotic mechanisms.19,20 When CSA was used after high-dose ara-c and concurrently with daunorubicin in this SWOG phase III trial for relapsed AML, there was a highly significant increase in the complete response (CR) rate, the disease-free survival (DFS), and overall survival (OS).18 The daunorubicin was given by continuous intravenous infusion, which may be one of the important differences between this and most of the other MDR modulation trials.

The frequency of MDR expression in AML increases with age and is predictive of poor outcome with respect to CR, DFS, and OS.21,22,23,24,25 Approximately two out of three patients with AML over the age of 60 years have high levels of MDR1 expression, whereas it is less commonly seen in younger patients. MDR is also overexpressed in AML that follows a myelodysplastic syndrome (MDS). We have been pursuing the hypothesis that MDR1 positive clonogenic AML blasts may form a reservoir of drug-resistant cells that contribute to treatment failure, which means that even when the bulk of AML cells do not appear to express MDR1, the clonogenic AML cell does. Therefore, that minority cell population should be the real target for these studies. If the therapy were successful, the benefit should be seen not necessarily in the CR rate but rather in the DFS or in the time to relapse. One of the difficulties with the first generation of MDR modulation trials was that they were directed toward patients who had high levels of MDR via multiple mechanisms. The benefit of inhibition of Pgp-mediated drug efflux in older patients or those with relapsed AML may have been obscured by other factors associated with drug resistance, including adverse cytogenetics and myelodysplasia. These and other mechanisms of drug resistance are unlikely to be affected by Pgp inhibitors alone.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

References

  1. Leith CP, Kopecky KJ, Godwin J . et al. 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; 89: 3323–3329.

  2. Ross DD, Wooten PJ, Sridhara R, Ordonez JV, Lee EJ, Schiffer CA . Enhancement of daunorubicin accumulation, retention, and cytotoxicity by verapamil or cyclosporin A in blast cells from patients with previously untreated acute myeloid leukemia. Blood 1993; 82: 1288–1299.

    CAS  PubMed  Google Scholar 

  3. Boesch D, Gaveriaux C, Jachez B, Pourtier-Manzanedo A, Bollinger P, Loor F . In vivo circumvention of P-glycoprotein-mediated multidrug resistance of tumor cells with SDZ PSC 833. Cancer Res 1991; 51: 4226–4233.

    CAS  PubMed  Google Scholar 

  4. List AF, Spier C, Greer J, Wolff S, Hutter J, Dorr R, Salmon S, Futscher B, Baier M, Dalton W . Phase I/II trial of cyclosporine as a chemotherapy-resistance modifier in acute leukemia. J Clin Oncol 1993; 11: 1652–1660.

    Article  CAS  PubMed  Google Scholar 

  5. Advani R, Saba HI, Tallman MS, Rowe JM, Wiernik PH, Ramek J, Dugan K, Lum B, Villena J, Davis E, Paietta E, Litchman M, Sikic BI, Greenberg PL . Treatment of refractory and relapsed acute myelogenous leukemia with combination chemotherapy plus the multidrug resistance modulator PSC 833 (Valspodar). Blood 1999; 93: 787–795.

    CAS  PubMed  Google Scholar 

  6. Dahl GV, Lacayo NJ, Brophy N, Dunussi-Joannopoulos K, Weinstein HJ, Chang M, Sikic BI, Arceci RJ . Mitoxantrone, etoposide, and cyclosporine therapy in pediatric patients with recurrent or refractory acute myeloid leukemia. J Clin Oncol 2000; 18: 1867–1875.

    Article  CAS  PubMed  Google Scholar 

  7. Sonneveld P, Lowenberg B, Vossebeld P, Malkhandi J, Covelli A, Dekker AW, Ossenkoppwlw G, Milligan D, Verhoef G, Ferrant A, Yin J, Gratwohl A, Kovacsovis T, Burnett A . Dose-finding study of PSC833, a novel MDR reversing agent, with daunorubicin and ara-C in untreated elderly patients with acute myeloid leukemia. Blood 1997; 90: 566a.

    Google Scholar 

  8. Visani G, Milligan D, Leoni F, Chang J, Kelsey S, Marcus R, Powles R, Schey S, Covelli A, Isidori A, Litchman M, Piccaluga PP, Mayer H, Malagola M, Pfister C . Combined action of PSC 833 (Valspodar), a novel MDR reversing agent, with mitoxantrone, etoposide and cytarabine in poor-prognosis acute myeloid leukemia. Leukemia 2001; 15: 764–771.

    Article  CAS  PubMed  Google Scholar 

  9. Dorr R, Karanes C, Spier C, Grogan T, Greer J, Moore J, Weinberger B, Schiller G, Pearce T, Litchman M, Dalton W, Roe D, List AF . Phase I/II study of the P-glycoprotein modulator PSC 833 in patients with acute myeloid leukemia. J Clin Oncol 2001; 19: 1589–1599.

    Article  CAS  PubMed  Google Scholar 

  10. Chauncey TR, Rankin C, Anderson JE, Chen I, Kopecky KJ, Godwin JE, Kalaycio ME, Moore DF, Shurafa MS, Petersdorf SH, Kraut EH, Leith CP, Head DR, Luthardt FW, Willman CL, Appelbaum FR . A phase I 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 2000; 24: 567–574.

    Article  CAS  PubMed  Google Scholar 

  11. Kornblau SM, Estey E, Madden T, Tran HT, Zhao S, Consoli U, Snell V, Sanchez-Williams G, Kantarjian H, Keating M, Newman RA, Andreeff M . Phase I study of mitoxantrone plus etoposide with multidrug blockade by SDZ PSC-833 in relapsed or refractory acute myelogenous leukemia. J Clin Oncol 1997; 15: 1796–1802.

    Article  CAS  PubMed  Google Scholar 

  12. Tidefelt U, Liliemark J, Gruber A, Liliemark E, Sundman-Engberg B, Juliusson G, Stenke L, Elmhorn-Rosenborg A, Mollgard L, Lehman S, Xu D, Covelli A, Gustavsson B, Paul C . 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 2000; 18: 1837–1844.

    Article  CAS  PubMed  Google Scholar 

  13. Tallman MS, Lee S, Sikic BI, Paietta E, Wiernik PH, Bennett JM, Rowe JM . 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.

    Article  CAS  PubMed  Google Scholar 

  14. Greenberg P, Advani R, Tallman M, Letendre L, Saba H, Dugan K, Lee SJ, Lum B, Sikic BI, Paietta E, Bennett J, Rowe JM . Treatment of refractory/relapsed AML with PSC833 plus mitoxantrone, etoposide, cytarabine (PSC-MEC) vs MEC: randomized Phase III trial (E2995). Blood 1999; 94: 383a.

    Google Scholar 

  15. Solary E, Witz B, Caillot D, Moreau P, Desablens B, Cahn JY, Sadoun A, Pignon B, Berthou C, Maloisel F, Guyotat D, Casassus P, Ifrah N, Lamy Y, Audhuy B, Colombat P, Harousseau JL . Combination of quinine as a potential reversing agent with mitoxantrone and cytarabine for the treatment of acute leukemias: a randomized multicenter study. Blood 1996; 88: 1198–1205.

    CAS  PubMed  Google Scholar 

  16. Liu Yin JA, Wheatley K, Rees JK, Burnett AK . 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 2001; 113: 713–726.

    Article  CAS  PubMed  Google Scholar 

  17. Baer MR, George SL, Dodge RK, O'Loughlin KL, Minderman H, Caligiuri MA, Anastasi J, Powell BL, Kolitz JE, Schiffer CA, Bloomfield CD, Larson RA . 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.

    CAS  PubMed  Google Scholar 

  18. List AF, Kopecky KJ, Willman CL, Head DR, Persons DL, Slovak ML, Dorr R, Karanes C, Hynes HE, Doroshow JH, Shurafa M, Appelbaum FR . 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.

    Article  CAS  PubMed  Google Scholar 

  19. Pilarski LM, Yatscoff RW, Murphy GF, Belch AR . Drug resistance in multiple myeloma: cyclosporin A analogues and their metabolites as potential chemosensitizers. Leukemia 1998; 12: 505–509.

    Article  CAS  PubMed  Google Scholar 

  20. Vogelsang G, Bitton R, Piantadosi S, Altomonte V, Horn T, Jones R, Miller C, Marcellus D, Abrams R, Hess A . Immune modulation in autologous bone marrow transplantation: cyclosporine and gamma-interferon trial. Bone Marrow Transplant 1999; 24: 637–640.

    Article  CAS  PubMed  Google Scholar 

  21. te Boekhorst PA, de Leeuw K, Schoester M, Wittebol S, Nooter K, Hagemeijer A, Lowenberg B, Sonneveld P . Predominance of functional multidrug resistance (MDR-1) phenotype in CD34+ acute myeloid leukemia cells. Blood 1993; 82: 3157–3162.

    CAS  PubMed  Google Scholar 

  22. van den Heuvel-Eibrink MM, van der HB, te Boekhorst PA, Pieters R, Schoester M, Lowenberg B, Sonneveld P . MDR 1 expression is an independent prognostic factor for response and survival in de novo acute myeloid leukaemia. Br J Haematol 1997; 99: 76–83.

    Article  CAS  PubMed  Google Scholar 

  23. Samdani A, Vijapurkar U, Grimm MA, Spier CS, Grogan TM, Glinsmann-Gibson BJ, List AF . Cytogenetics and P-glycoprotein (PGP) are independent predictors of treatment outcome in acute myeloid leukemia (AML). Leuk Res 1996; 20: 175–180.

    Article  CAS  PubMed  Google Scholar 

  24. Wuchter C, Leonid K, Ruppert V, Schrappe M, Buchner T, Schoch C, Haferlach T, Harbott J, Ratei R, Dorken B, Ludwig WD . Clinical significance of P-glycoprotein expression and function for response to induction chemotherapy, relapse rate and overall survival in acute leukemia. Haematologica 2000; 85: 711–721.

    CAS  PubMed  Google Scholar 

  25. Leith CP, Kopecky KJ, Chen IM, Eijdems L, Slovak ML, McConnell TS, Head DR, Weick J, Grever MR, Appelbaum FR, Willman CL . 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 1999; 94: 1086–1099.

    CAS  PubMed  Google Scholar 

  26. Oza AM . Clinical development of P glycoprotein modulators in oncology. Novartis Found Symp 2002; 243: 103–115.

    CAS  PubMed  Google Scholar 

  27. Peck RA, Hewett J, Harding MW, Wang YM, Chaturvedi PR, Bhatnagar A, Ziessman H, Atkins F, Hawkins MJ . Phase I and pharmacokinetic study of the novel MDR1 and MRP1 inhibitor biricodar administered alone and in combination with doxorubicin. J Clin Oncol 2001; 19: 3130–3141.

    Article  CAS  PubMed  Google Scholar 

  28. Slapak CA, Dahlheimer J, Piwnica-Worms D . Reversal of multidrug resistance with LY335979: functional analysis of p-glycoprotein-mediated transport activity and its modulation in vivo. J Clin Pharmacol 2001; (Suppl): 29S–38S.

  29. Kolitz JE, George SL, Hurd DD, Hoke E, Dodge RK, Velez-Garcia E, Powell BL, Moore J, Caligiuri MA, Vardiman JW, Bloomfield CD, Larson RA . Parallel phase I trials of multi-drug resistance (MDR) modulation with PSC-833 (PSC) in untreated patients with acute myeloid leukemia (AML) <60 years old: preliminary results of CALGB 9621. Blood 1999; 94: 384a.

    Google Scholar 

  30. Kolitz JE, George SL, Dodge RK, Hoke E, Hurd DD, Powell BL, Velejz-Garcia E, Caligiuri MA, Moore JO, Vardiman JW, Bloomfield CD, Larson RA . Dose escalation studies of Ara-C (A), daunorubicin (D) and etoposide (E) with and without multidrug resistance (MDR) modulation with PSC-833 (P) in untreated adults with acute myeloid leukemia (AML) <60 years: final induction results of CALGB 9621. Blood 2001; 98: 461a (abstract).

    Google Scholar 

  31. Boote DJ, Dennis IF, Twentyman PR, Osborne RJ, Laburte C, Hensel S, Smyth JF, Brampton MH, Bleehen NM . Phase I study of etoposide with SDZ PSC 833 as a modulator of multidrug resistance in patients with cancer. J Clin Oncol 1996; 14: 610–618.

    Article  CAS  PubMed  Google Scholar 

  32. Kolitz JE, George SL, Dodge RK, Hoke E, Hurd DD, Powell BL, Velez-Garcia E, Caligiuri MA, Moore JO, Vardiman JW, Linker CA, Bloomfield CD, Larson RA . Consolidation therapy by cytogenetic risk in adults with AML <60 years in first complete remission. Blood 2001; 98: 688a.

    Article  Google Scholar 

  33. Linker C, George S, Hurd DD, Larson RA . Autologous stem cell transplantation for acute myeloid leukemia in second remission. Blood 2001; 98: 689a.

    Google Scholar 

  34. Caligiuri MA, Lee EJ, Baer MR, Dodge RK, Cooke K, Szatrowski T, Bloomfield CD, Larson RA . Daily low dose interleukin-2 therapy with or without intermediate dose pulsing in acute myeloid leukemia patients >60 years old in first complete remission: a feasibility study (CALGB 9420). Blood 1999; 95: 76a.

    Google Scholar 

  35. Lee EJ, George SL, Caligiuri M, Szatrowski TP, Powell BL, Lemke S, Dodge RK, Smith R, Baer M, Schiffer CA . Parallel phase I studies of daunorubicin given with cytarabine and etoposide with or without the multidrug resistance modulator PSC-833 in previously untreated patients 60 years of age or older with acute myeloid leukemia: results of cancer and leukemia group B study 9420. J Clin Oncol 1999; 17: 2831–2839.

    Article  CAS  PubMed  Google Scholar 

  36. Mayer RJ, Davis RB, Schiffer CA, Berg DT, Powell BL, Schulman P, Omura GA, Moore JO, McIntyre OR, Frei III E, Intensive postremission chemotherapy in adults with acute myeloid leukemia. Cancer and Leukemia Group B. N Engl J Med 1994; 331: 896–903.

    Article  CAS  PubMed  Google Scholar 

  37. Stone RM, Berg DT, George SL, Dodge RK, Paciucci PA, Schulman P, Lee EJ, Moore JO, Powell BL, Schiffer CA . 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 1995; 332: 1671–1677.

    Article  CAS  PubMed  Google Scholar 

  38. Sekeres MA, Stone RM . The challenge of acute myeloid leukemia in older patients. Curr Opin Oncol 2002; 14: 24–30.

    Article  PubMed  Google Scholar 

  39. Leith CP, Chen IM, Kopecky KJ, Appelbaum FR, Head DR, Godwin JE, Weick JK, Willman CL . 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.

    CAS  PubMed  Google Scholar 

  40. Minderman H, Vanhoefer U, Toth K, Yin MB, Minderman MD, Wrzosek C, Slovak ML, Rustum YM . DiOC2(3) is not a substrate for multidrug resistance protein (MRP)-mediated drug efflux. Cytometry 1996; 25: 14–20.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The CALGB studies described in this report were chaired by Drs Ted Lee, Jonathan E Kolitz, Maria R Baer, and Michael A Caligiuri, and the statistical analyses were performed by Richard K Dodge and Stephen L George.

Author information

Authors and Affiliations

  1. Department of Medicine and Cancer Research Center, Section of Hematology/Oncology, The University of Chicago, Chicago, IL, USA

    R A Larson

Authors
  1. R A Larson
    View author publications

    You can also search for this author in PubMed Google Scholar

Additional information

This paper is part of a series of keynote addresses to be published in Leukemia. They were presented at the Acute Leukemia Forum, San Francisco, 19 April 2002: Supported by an unrestricted educational grant from Immunex Corporation. Supported in part by Grants CA-14599, CA-31946, and CA-33601 from the National Cancer Institute.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Larson, R. Is modulation of multidrug resistance a viable strategy for acute myeloid leukemia?. Leukemia 17, 488–491 (2003). https://doi.org/10.1038/sj.leu.2402809

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.leu.2402809

This article is cited by

Search

Advanced search

Quick links