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.

  • Original Manuscript
  • Published:

Therapy

Cyclophosphamide followed by fludarabine for untreated chronic lymphocytic leukemia: a phase II SWOG TRIAL 9706

Abstract

B-cell chronic lymphocytic leukemia (CLL) accounts for 95% of chronic leukemia cases and 25% of all leukemia. Despite the prevalence of CLL, progress in its treatment has been only modest over the past three decades. Based upon the ability of fludarabine to produce high-grade remissions especially among patients with low initial tumor mass, and the ability of alkylators to reduce tumor mass, we hypothesized that sequential administration of a limited number of cycles of intermediate-dose cyclophosphamide followed by fludarabine could result in a larger percentage of patients with complete remissions (CRs). In all, 27 of the 49 eligible patients achieved overall responses of CR, unconfirmed complete remission (UCR), or PR, for a total response rate of 55% (95% confidence interval (CI) 40–69%). Considering the confounding medical issues of this patient population with advanced aggressive disease, the regimen was generally well tolerated. This study demonstrates that high-dose cyclophosphamide followed by fludarabine was relatively well tolerated in this group of advanced CLL patients. The study's criterion for testing whether the regimen is sufficiently effective to warrant further investigation was met: 14 (32%) of the first 44 eligible patients achieved CR or UCR.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 2
Figure 1

Similar content being viewed by others

References

  1. Dighiero G, Maloum K, Desablens B, Cazin B, Navarro M, Leblay R et al. The French Cooperative Group on Chronic Lymphocytic Leukemia. N Engl J Med 1998; 338: 1506–1514.

    Article  CAS  PubMed  Google Scholar 

  2. Rai KR, Sawitsky A, Cronkite EP, Chanana AD, Levy RN, Pastermack BS et al. Clinical staging of chronic lymphocytic leukemia. Blood 1975; 46: 219–234.

    CAS  PubMed  Google Scholar 

  3. Binet JL, Auquier A, Dighiero G, Chastang C, Piguet H, Goasguen H et al. A new prognostic classification of chronic lymphocytic leukemia derived from a multivariate survival analysis. Cancer 1981; 48: 198–206.

    Article  CAS  PubMed  Google Scholar 

  4. Lee JS, Dixon DO, Kantarjian HM, Keating MJ, Talpaz M . Prognosis of chronic lymphocytic leukemia: a multivariate regression analysis of 325 untreated patients. Blood 1987; 69: 929–936.

    CAS  PubMed  Google Scholar 

  5. Rozman C, Montserrat E, Feliu E, Granena A, Marin P, Nomdedeu B et al. Prognosis of chronic lymphocytic leukemia: a multivariate survival analysis of 150 cases. Blood 1982; 59: 1001–1005.

    CAS  PubMed  Google Scholar 

  6. Montserrat E, Sanchez-Bisono J, Vinolas N, Rozman C . Lymphocyte doubling time in chronic lymphocytic leukemia: analysis of prognostic significance. Br J Haematol 1986; 62: 567–575.

    Article  CAS  PubMed  Google Scholar 

  7. Rozman C, Montserrat E, Rodriguez-Fernandez JM, Ayats R, Vallespi T, Parody R et al. Bone marrow histologic pattern – the best single prognostic parameter in chronic lymphocytic leukemia: a multivariate survival analysis of 329 cases. Blood 1984; 64: 642–648.

    CAS  PubMed  Google Scholar 

  8. Juliusson G, Oscier DG, Fitchett M, Ross FM, Stockdill G, Mackie MJ et al. Prognostic subgroups in B-cell chronic lymphocytic leukemia defined by specific cytogenetic abnormalities. N Engl J Med 1990; 323: 720–724.

    Article  CAS  PubMed  Google Scholar 

  9. Han T, Henderson ES, Emrich LJ, Sandberg AA . Prognostic significance of karyotypic abnormalities in B-cell chronic lymphocytic leukemia. Semin Oncol 1987; 24: 257–263.

    CAS  Google Scholar 

  10. Shustik C, Mick R, Silver R, Sawitsky A, Tai K, Shaprio L . Treatment of early chronic lymphocytic leukemia: intermittent chlorambucil versus observation. Hematol Oncol 1988; 6: 7–12.

    Article  CAS  PubMed  Google Scholar 

  11. Hsi ED, Kopecky KJ, Appelbaum FR, Boldt D, Frey T, Loftus M et al. Prognostic significance of CD38 and CD20 expression as assessed by quantitative flow cytometry in chronic lymphocytic leukaemia. Br J Haematol 2003; 120: 1017–1025.

    Article  PubMed  Google Scholar 

  12. Matrai Z, Lin K, Dennis M, Sherrington P, Zuzel M, Pettitt AR et al. CD38 expression and Ig VH gene mutation in B-cell chronic lymphocytic leukemia. Blood 2001; 97: 1902–1903.

    Article  CAS  PubMed  Google Scholar 

  13. French Cooperative Group on Chronic Lymphocytic Leukemia. Prognostic and therapeutic advances in CLL management: the experience of the French Cooperative Group. Semin Hematol 1987; 24: 275–290.

  14. Cheson BD, Bennett JM, Rai KR, Grever MR, Kay NE, Schiffer CA et al. Guidelines for clinical protocols for chronic lymphocytic leukemia: report of the NCI-sponsored Working Group. Am J Hematol 1988; 29: 152–163.

    Article  CAS  PubMed  Google Scholar 

  15. Rai KR, Peterson B, Appelbaum F, Kolitz J, Elias L, Shepherd L et al. Fludarabine compared with chlorambucil as primary therapy for chronic lymphocytic leukemia. N Engl J Med 2000; 343: 1750–1757.

    Article  CAS  PubMed  Google Scholar 

  16. Leporrier M, Chevret S, Boudjerra N, Feugier P, Desablens B, Rapp MJ et al. French Cooperative Group on Chronic Lymphocytic Leukemia. Randomized comparison of fludarabine, CAP and ChOP in 938 previously untreated stage B and C chronic lymphocytic leukemia patients. Blood 2001; 98: 2319–2325.

    Article  CAS  PubMed  Google Scholar 

  17. Bernell P, Pisa P, Hast R, Hansson M, Sandstedt B, Stenke L . Increase of serum interleukin-2 and regression of multiple myeloma after rhGM-CSF treatment of drug induced bone marrow aplasia. Hematol Oncol 1991; 9: 129–135.

    Article  CAS  PubMed  Google Scholar 

  18. Ho AD, Haas R, Wulf G, Knauf W, Erhardt R, Heilig B et al. Activation of lymphocytes induced by recombinant human granulocyte–macrophage colony-stimulating factor in patients with malignant lymphoma. Blood 1990; 75: 203–212.

    CAS  PubMed  Google Scholar 

  19. Baxevanis CN, Tsavaris NB, Papadhimitriou SI, Zarkadis IK . Granulocyte–macrophage colony-stimulating factor improves immunological parameters in patients with refractory solid tumors receiving second-line chemotherapy: correlation with clinical responses. Eur J Cancer 1997; 33: 1202–1208.

    Article  CAS  PubMed  Google Scholar 

  20. Cheson BD, Bennett JM, Grever M, Kay N, Keating MJ, O’Brien S et al. National Cancer Institute-Sponsored working group guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment. Blood 1996; 87: 4990–4997.

    CAS  PubMed  Google Scholar 

  21. Mitelman F ed. An International System for Cytogenetic Nomenclature. Basel, Switzerland: Karger, 1995.

    Google Scholar 

  22. Stilgenbauer S, Lichter P, Dohner H . Genetic features of B-cell chronic lymphocytic leukemia. Rev Clin Exp Hematol 2000; 4: 48–72.

    Article  CAS  PubMed  Google Scholar 

  23. Flinn IW, Byrd JV, Morrison C, Jamison J, Diehl LF, Murphy T et al. Fludarabine and cyclophosphamide with filgrastim support in patients with previously untreated indolent lymphoid malignancies. Blood 2000; 96: 71.

    CAS  PubMed  Google Scholar 

  24. O’Brien SM, Kantarjian HM, Cortes J, Beran M, Koller CA, Giles FJ et al. Results of the fludarabine and cyclophosphamide combination regimen in chronic lymphocytic leukemia. J Clin Oncol 2001; 19: 1414–1420.

    Article  PubMed  Google Scholar 

  25. Weiss MA, Glenn M, Maslak P, Rahman Z, Noy A, Zelents A et al. Consolidation therapy with high-dose cyclophosphamide improves the quality of response in patients with chronic lymphocytic leukemia treated with fludarabine as induction therapy. Leukemia 2000; 14: 1577–1582.

    Article  CAS  PubMed  Google Scholar 

  26. Hallek B, Schmitt M, Wilhelm R, Busch A, Krober HP, Fostitsch O et al. Fludarabine plus cyclophosphamide is an efficient treatment for advanced chronic lymphocytic leukemia (CLL): results of a phase II study of the German CLL Study Group. Br J Haematol 2001; 114: 342–348.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This investigation was supported in part by the following PHS Cooperative Agreement grant numbers awarded by the National Cancer Institute, DHHS: CA38926, CA32102, CA35431, CA04919, CA35176, CA37981, CA46441, CA46282, CA58861, CA45450, CA45807, CA76429, CA35261, CA42777, CA45377, CA35178, CA67663, CA12644, CA27057, CA67575, CA20319, CA63850, CA76462, CA58415, CA35119, CA76447, CA35996, CA14028.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to M A Hussein.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hussein, M., Gundacker, H., Head, D. et al. Cyclophosphamide followed by fludarabine for untreated chronic lymphocytic leukemia: a phase II SWOG TRIAL 9706. Leukemia 19, 1880–1886 (2005). https://doi.org/10.1038/sj.leu.2403940

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.leu.2403940

Keywords

Search

Quick links