Skip to main content
SpringerLink
Log in

Cellular drug resistance in childhood leukemia

  • First Workshop of CSG-CR
  • Published:
Annals of Hematology Aims and scope Submit manuscript

Summary

The response to chemotherapy is determined essentially by two factors: first, pharmacokinetic factors, determining which concentration of drug reaches the malignant cells, and second, cellular drug resistance of these cells, determining how many of them will be killed by that concentration of drug. The study of cellular drug resistance has been stimulated by the development of short-term ‘total cell kill’ assays, such as the MTT assay, for use on patient samples. The drug resistance profiles differed markedly between ALL and ANLL, between immunophenotypic and karyotypic subgroups within ALL, and between initial and relapsed ALL. The results of the MTT assay showed a significant relation between the antileukemic activity of prednisolone in vitro and the clinical response to systemic monotherapy with that drug. At multivariate analysis including several well-known prognostic factors (WBC, age, immunophenotype) only the in vitro resistance to prednisolone, dexamethasone,l-asparaginase, and daunorubicin was significantly related to clinical outcome. At multiple regression analysis, combination of the results for prednisolone,l-asparaginase, and vincristine made it possible to distinguish between three patient groups with increasing levels of drug resistance and markedly different probabilities of 2-year disease-free survival: 100%, 83%, and 60%. These results show that in vitro drug resistance testing can give a correct prediction of prognosis, superior to that of currently used prognostic factors. Stratification of prognostic groups based on the results of drug resistance testing is feasible and should be introduced into new clinical trials. Many questions now remaining could be answered within carefully designed preclinical and clinical studies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

CSG-CR :

Cooperative Study Group — Cellular Resistance

References

  1. Bosanquet AG (1991) Correlations between therapeutic response of leukaemias and in-vitro drug-sensitivity assay. Lancet 337:711–714

    Google Scholar 

  2. Delmer A, Marie J-P, Thevenin D, Cadiou M, Viguié F, Zittoun R (1989) Multivariate analysis of prognostic factors in acute myeloid leukemia: value of clonogenic leukemic cell properties. J Clin Oncol 7:738–746

    Google Scholar 

  3. Dörffel W, Hartmann R, Schober S, Veerman AJP, Pieters R, Klumper E, Henze G (1993) Drug resistance testing as a basis for tailored therapy in children with refractory or relapsed acute lymphoblastic leukemia. In: Kaspers GJL, Pieters R, Twentyman PR, Weisenthal LM, Veerman AJP (eds) Drug resistance in leukemia and lymphoma. The clinical value of laboratory assays. Harwood Academic, London, pp 353–358

    Google Scholar 

  4. Gazdar A, Steinberg SM, Russell (1990) Correlation of in vitro drug-sensitivity testing results with response to chemotherapy and survival in extensive small cell lung cancer. A prospective clinical trial. J Natl Cancer Inst 82:117–124

    Google Scholar 

  5. Gustavsson A, Olofsson T (1984) Prediction of response to chemotherapy in acute leukemia by in vitro drug sensitivity testing on leukemic stem cells. Cancer Res 44:4648–4652

    Google Scholar 

  6. Hongo T, Fuji Y, Igarashi Y (1990) An in vitro chemosensitivity test for the screening of anticancer drugs in childhood leukemia. Cancer 65:1263–1272

    Google Scholar 

  7. Hongo T, Fujii Y (1991) In vitro chemosensitivity of lymphoblasts at relapse in childhood leukemia using the MTT assay. Int J Hematol 54:219–230

    Google Scholar 

  8. Hwang W-S, Chen L-M, Huang S-H, Wang C-C, Tseng MT (1993) Prediction of chemotherapy response in human leukemia using in vitro chemosensitivity test. Leuk Res 17:685–688

    Google Scholar 

  9. Jones B, Freeman Al, Shuster J, Jacquillat C, Weil M, Pochedly C, Sinks C, Chevalier L, Maurer HM, Koch K, Falkson G, Patterson R, Seligman B, Sartorius J, Kung F, Haurani F, Stuart M, Burgert O, Ruymann F, Sawitsky A, Forman E, Pluess H, Truman J, Hakami N, Glidewell O, Glicksman A, Holland JF (1991) Lower incidence of meningeal leukemia when prednisone is replaced by dexamethasone in the treatment of acute lymphocytic leukemia. Med Pediatr Oncol 19:269–275

    Google Scholar 

  10. Kaspers GJL, Pieters R, Van Zantwijk CH, De Laat PAJM, De Waal FC, Van Wering ER, Veerman AJP (1991) In vitro drug sensitivity of normal peripheral blood lymphocytes and childhood leukaemic cells from bone marrow and peripheral blood. Br J Cancer 64:469–474

    Google Scholar 

  11. Kaspers GJL, Pieters R, Van Zantwijk CH, Klumper E, Hählen K, De Waal FC, Van Wering ER, Veerman AJP (1993) Childhood acute lymphoblastic leukemia and acute nonlymphoblastic leukemia: differences in cellular drug resistance, with emphasis on glucocorticoids — a pilot study. Haematol Blood Transfus 35:452–456

    Google Scholar 

  12. Kaspers GJ (1993) Drug resistance in newly diagnosed childhood leukemia. A prospective in vitro study (thesis). Hofland, Mijdrecht, ISBN 90-9006571-7

  13. Klumper E, Pieters R, Kaspers GJL, Dörffel W, Henze G, Veerman AJP (1993) Treatment of children with poor-prognosis relapsed acute lymphoblastic leukemia based on individual drug resistance profiles: procedure. In: Kaspers GJL, Pieters R, Twentyman PR, Weisenthal LM, Veerman AJP (eds) Drug resistance in leukemia and lymphoma. The clinical value of laboratory assays. Harwood Academic, London, pp 345–352

    Google Scholar 

  14. Klumper E, Pieters R, Kaspers GJL, Loonen AH, Huismans DR, Van Zantwijk CH, Hählen K, Van Wering ER, Henze G, Veerman AJP (1993) Cellular drug resistance in childhood relapsed acute lymphoblastic leukemia. In: Kaspers GJL, Pieters R, Twentyman PR, Weisenthal LM, Veerman AJP (eds) Drug resistance in leukemia and lymphoma. The clinical value of laboratory assays. Harwood Academic, London, pp 337–344

    Google Scholar 

  15. Larsson R, Kristensen J, Sandberg C, Nygren P (1992) Laboratory determination of chemotherapeutic drug resistance in tumor cells from patients with leukemia, using a fluorimetric microculture cytotoxicity assay (FMCA). Int J Cancer 50:177–185

    Google Scholar 

  16. Lathan B, Von Tettau M, Verpoort K, Diehl V (1990) Pretherapeutic drug testing in acute leukemias for prediction of individual prognosis. Haematol Blood Transfus 33:295–298

    Google Scholar 

  17. Park CH, Amare M, Savin MA, Goodwin JW, Newcomb MM, Hooghstraten B (1980) Prediction of chemotherapy response in human leukemia using an in vitro chemotherapy sensitivity test on the leukemic colony-forming cells. Blood (1989) 55:595–601

    Google Scholar 

  18. Pieters R, Huismans DR, Leyva A, Veerman AJP (1989) Comparison of the rapid automated MTT-assay with a dye exclusion assay for chemosensitivity testing in childhood leukemia. Br J Cancer 59:217–220

    Google Scholar 

  19. Pieters R, Huismans DR, Loonen AH, Hählen K, Van Der Does-Van Den Berg A, Van Wering ER, Veerman AJP (1991) Relation of cellular drug resistance to long-term clinical outcome in childhood acute lymphoblastic leukaemia. Lancet 338:399–403

    Google Scholar 

  20. Pieters R, Hongo T, Loonen AH, Huismans DR, Broxterman HJ, Hählen K, Veerman AJP (1992) Non-p-glycoprotein-mediated multiple drag resistance in children with relapsed acute lymphoblastic leukemia. Br J Cancer 65:691–697

    Google Scholar 

  21. Pieters R, Kaspers GJL, Van Wering ER, Huismans DR, Loonen AH, Hählen K, Veerman AJP (1993) Cellular drug resistance profiles that might explain the prognostic value of immunophenotype and age in childhood acute lymphoblastic leukemia. Leukemia 7:392–397

    Google Scholar 

  22. Santini V, Bernabei PA, Silvestro L, Dal Pozzo O, Bezzini R, Viano I, Gattei V, Saccardi R, Rossi Ferrini P (1989) In vitro chemosensitivity testing of leukemic cells: prediction of response to chemotherapy in patients with acute nonlymphocytic leukemia. Hematol Oncol 7:287–293

    Google Scholar 

  23. Sargent JM, Taylor CG (1989) Appraisal of the MTT assay as a rapid test of chemosensitivity in acute myeloid leukaemia. Br J Cancer 60:206–210

    Google Scholar 

  24. Schwarzmeier JD, Paietta E, Mittermayer K, Pirker R (1984) Prediction of the response to chemotherapy in acute leukemia by a short-term test in vitro. Cancer 53:390–395

    Google Scholar 

  25. Tidefelt U, Sundman-Engberg B, Rhedin AS, Paul C (1989) In vitro drug testing in patients mimicking in vivo intracellular drug concentrations. Eur J Haematol 43:374–384

    Google Scholar 

  26. Van Wering ER, Van'T Veer MB, Akkerboom JC, Vissers-Praalder EC, Pinkster T, De Waal FC (1986) The significance of the white blood cell count and of immunological typing for the prognosis of acute lymphatic leukaemia in children. Ned Tijdschr Geneeskd 130:165–169

    Google Scholar 

  27. Van Wering ER, Brederoo P, Van Staalduinen GJ, Van Der Meulen J, Van Der Linden-Schrever BEM, Van Dongen JJM (1993) Contribution of electron microscopy to the classification of minimally differentiated acute leukemias in children. Recent Results Cancer Res 131:77–87

    Google Scholar 

  28. Veerman AJP, Hählen K, Kamps WA, Van Leeuwen EF, De Vaan GAM, Van Wering ER, Van Der Does-Van Den Berg A, Solbu G, Suciu S, Dutch Childhood Leukemia Study Group (1990) Early results of study ALL VI (1984–1988). Haematol Blood Transfus 33:473–477

    Google Scholar 

  29. Veerman AJP, Pieters R (1990) Drug sensitivity assays in leukaemia and lymphoma. Br J Haematol (1990) 74:381–384

    Google Scholar 

  30. Von Hoff DD (1990) He's not going to talk about in vitro predictive assays again, is he? J Natl Cancer Inst 82:96–101

    Google Scholar 

  31. Von Hoff DD, Sandbach JF, Clark GM, Turner JN, Forseth BF, Piccart MJ, Colombo N, Muggia FM (1990) Selection of cancer chemotherapy for a patient by an in vitro assay versus a clinician. J Natl Cancer Inst 82:110–116

    Google Scholar 

  32. Von Hoff DD, Kronmal R, Salmon SE, Turner J, Green JB, Bonorris JS, Moorhead EL, Hynes HE, Pugh RE, Belt RJ, Alberts D (1991) A Southwest Oncology Group Study on the use of a human tumor cloning assay for predicting response in patients with ovarian cancer. Cancer 67:20–27

    Google Scholar 

  33. Weisenthal LM, Dill PL, Finklestein JZ, Duarte TE, Baker JA, Moran EM (1986) Laboratory detection of primary and acquired drug resistance in human lymphatic neoplasms. Cancer Treat Rep 70:1283–1295

    Google Scholar 

  34. Weisenthal LM, Kern DH (1991) Prediction of drug resistance in cancer chemotherapy: the Kern and DiSC assays. Oncology 5:93–113

    Google Scholar 

  35. Welander CE, Morgan TM, Homesly HD (1984) Multiple factors predicting responders to combination chemotherapy in patients with ovarian cancer. In: Salmon SE, Trent JM (eds) Human tumor cloning. Grune and Stratton, Orlando, pp 521–534

    Google Scholar 

  36. Wheeler TK, Dendy PP, Dawson A (1974) Assessment of an in vitro screening test of cytotoxic agents in the treatment of advanced malignant disease. Oncology 3:362–376

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pediatrics, Free University Hospital, Post Box 7057, NL-1007, MB Amsterdam, The Netherlands

    A. J. P. Veerman, G. J. L. Kaspers & R. Pieters

Authors
  1. A. J. P. Veerman
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. G. J. L. Kaspers
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. R. Pieters
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Veerman, A.J.P., Kaspers, G.J.L. & Pieters, R. Cellular drug resistance in childhood leukemia. Ann Hematol 69, S31–S34 (1994). https://doi.org/10.1007/BF01757352

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01757352

Keywords

Search

Navigation