Skip to main content
SpringerLink
Log in

Oral fludarabine and cyclophosphamide as front-line chemotherapy in patients with chronic lymphocytic leukemia. The impact of biological parameters in the response duration

  • Original Article
  • Published:
Annals of Hematology Aims and scope Submit manuscript

Abstract

We tested the efficacy and safety of oral fludarabine and cyclophosphamide as front-line therapy in chronic lymphocytic leukemia (CLL) and assessed the influence of immunoglobulin variable region heavy chain (IgVH) gene mutation status, interphase cytogenetic abnormalities, and expression of ZAP-70 and CD38 on clinical outcome. Thirty-seven patients with previously untreated CLL received oral fludarabine (30 mg m2) and oral cyclophosphamide (250 mg m2) for three consecutive days every 4 weeks for six cycles. Eighteen patients had unmutated and 15 had mutated IgVH genes. Nine patients had the ‘high risk’ cytogenetic abnormality del(11q22.3) or del(17p13.1). Fifteen patients were ZAP-70-positive and eight patients were CD38-positive. Among the 35 valuable patients, 14 patients (40%) obtained a complete response and 13 (37%) a partial response. The median progression-free survival (PFS) was 23 months and median time to re-treatment (TTR) was 38 months. A significantly lower overall response rate (43% vs. 85%, p = 0.011), a shorter PFS (22 vs. 27 months, p = 0.015), and a shorter TTR (22 vs. 40 months, p = 0.031) were noticed in the ‘high risk’ cytogenetic abnormalities group; TTR was also shorter in IgVH-unmutated than in IgVH-mutated patients (26 vs. 41 months, p = 0.035). Hematologic toxicity included grade IV neutropenia (ten patients) and grade III/IV anemia (three patients). Gastrointestinal toxicity was mild and no patient required hospitalization. The oral combination of fludarabine and cyclophosphamide is an effective, safe, and well-tolerated regimen that, if confirmed with larger series, will be appropriate especially in patients with low risk biological parameters.

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

Fig. 1

Similar content being viewed by others

References

  1. Keating MJ, O’Brien S, Kantarjian H, Plunkett W, Estey E, Koller C et al (1993) Long term follow-up of patients with chronic lymphocytic leukemia treated with fludarabine as single agent. Blood 81:2878–2884

    PubMed  CAS  Google Scholar 

  2. Leporrier M, Chevret S, Cazin B, Boudjerra N, Feugier P, Desablens B et al (2001) Randomized comparison of fludarabine, CAP, and CHOP in 938 previously untreated stage B and C chronic lymphocytic leukemia patients. Blood 98:2319–2325 doi:10.1182/blood.V98.8.2319

    Article  PubMed  CAS  Google Scholar 

  3. Rai KR, Peterson BL, Appelbaum FR, Kolitz J, Elias L, Shepherd L et al (2000) Fludarabine compared with chlorambucil as primary therapy for chronic lymphocytic leukemia. N Engl J Med 343:1750–1757 doi:10.1056/NEJM200012143432402

    Article  PubMed  CAS  Google Scholar 

  4. Johnson S, Smith AG, Loffler H, Osby E, Juliusson G, Emmerich B et al (1996) Multicentre prospective randomized trial of fludarabine versus cyclophosphamide, doxorubicin, and prednisone (CAP) for treatment of advanced-stage chronic lymphocytic leukemia: The French Cooperative Group on CLL. Lancet 347:1432–1438

    PubMed  CAS  Google Scholar 

  5. Bellosillo B, Villamor N, Colomer D, Pons G, Montserrat E, Gil J (1999) In vitro evaluation of fludarabine in combination with cyclophosphamide and/or mitoxantrone in B-cell chronic lymphocytic leukemia. Blood 94:2836–2843

    PubMed  CAS  Google Scholar 

  6. Koehl U, Li L, Nowak B (1997) Fludarabine and cyclophosphamide: synergistic cytotoxicity associated with inhibition of interstrand cross-link removal [abstract]. Proc Am Assoc Cancer Res 38(2):10a

    Google Scholar 

  7. Chronic Lymphocytic Leukemia Trialists’ Collaborative Group (1999) Chemotherapeutic options in chronic lymphocytic leukemia: a meta-analysis of the randomized trials. J Natl Cancer Inst 91:861–868 doi:10.1093/jnci/91.10.861

    Article  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  9. Eichhorst BF, Busch R, Hopfinger G (2006) Fludarabine plus cyclophosphamide versus fludarabine alone in first-line therapy of younger patients with chronic lymphocytic leukemia. Blood 107:885–891 doi:10.1182/blood-2005-06-2395

    Article  PubMed  CAS  Google Scholar 

  10. Plosker GL, Figgit DP (2003) Oral fludarabine. Drugs 63(21):2317–2323 doi:10.2165/00003495-200363210-00004

    Article  PubMed  CAS  Google Scholar 

  11. Foran JM, Oscier D, Orchard J, Johnson SA, Tighe M, Cullen MH et al (1999) Pharmacokinetic study of single doses of oral fludarabine phosphate in patients with low grade non Hodgkin’s lymphoma and B-cell chronic lymphocytic leukemia. J Clin Oncol 17:1574–1579

    PubMed  CAS  Google Scholar 

  12. Rossi J-F, Van Hoof A, De Bock R, Johnson SA, Bron D, Foussard C et al (2004) Efficacy and safety of oral fludarabine phosphate in previously untreated patients with chronic lymphocytic leukemia. J Clin Oncol 22:1260–1267 doi:10.1200/JCO.2004.05.012

    Article  PubMed  CAS  Google Scholar 

  13. Cazin B, Maloum K, Divine M, Lepretre S, Travade P, Delmer A et al (2002) Oral fludarabine and cyclophosphamide in previously untreated CLL: preliminary data on 75 pts. Blood 100:206a [abstract]

    Google Scholar 

  14. Fabbri A, Lenoci M, Gozzetti A, Chitarrelli I, Olcese F, Raspadori D et al (2004) Low-dose oral fludarabine plus cyclophosphamide in elderly patients with chronic lymphoproliferative disorders. Hematol J 5:472–474 doi:10.1038/sj.thj.6200563

    Article  PubMed  CAS  Google Scholar 

  15. Catovsky D, Richards S, Hillmen P (2005) Early results from LRF-CLL4: a UK multicenter randomized trial [abstract]. Blood 106:212a Abstract 716

    Google Scholar 

  16. Damle RN, Wasil T, Fais F, Ghiotto F, Valetto A, Allen SL et al (1999) Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia. Blood 94:1840–1847

    PubMed  CAS  Google Scholar 

  17. Hamblin TJ, Davis Z, Gardiner A, Oscier DG, Stevenson FK (1999) Unmutated IgV(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood 94(6):1948–1954

    Google Scholar 

  18. Rassenti LZ, Huynh L, Toy TL, Chen L, Keating MJ, Gribben JG et al (2004) ZAP-70 compared with immunoglobuline heavy-chain gene mutation status as a predictor of disease progression in chronic lymphocytic leukemia. N Engl J Med 351(9):893–901 doi:10.1056/NEJMoa040857

    Article  PubMed  CAS  Google Scholar 

  19. Del Principe MI, Del Poeta G, Buccisano F, Maurillo L, Venditti A, Zucchetto A et al (2006) Clinical significance of ZAP-70 protein expression in B-cell chronic lymphocytic leukemia. Blood 108:853–861 doi:10.1182/blood-2005-12-4986

    Article  PubMed  CAS  Google Scholar 

  20. Crespo M, Bosh F, Villamor N, Bellosillo B, Colomer D, Rozman, M et al (2003) ZAP-70 expression as a surrogate for immunoglobuline variable region mutations in chronic lymphocytic leukemia. N Engl J Med 348(18):1764–1775 doi:10.1056/NEJMoa023143

    Article  Google Scholar 

  21. Krober A, Seiler T, Benner A, Bullinger L, Bruckle E, Lichter P et al (2002) V(H) mutation status, CD38 expression level, genomic aberration, and survival in chronic lymphocytic leukemia. Blood 100:1410–1416

    PubMed  CAS  Google Scholar 

  22. Wiestner A, Rosenwald A, Barry TS, Wright G, Davis RE, Henrickson SE et al (2003) ZAP-70 expression identifies a chronic lymphocytic leukemia subtype with unmutated immunoglobulin genes, inferior clinical outcome, and distinct gene expression profile. Blood 101(12):4944–4951 doi:10.1182/blood-2002-10-3306

    Article  PubMed  CAS  Google Scholar 

  23. Dohner H, Stilgenbauer S, Benner A, Leupolt E, Krober A, Bullinger L et al (2000) Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med 343:1910–1916 doi:10.1056/NEJM200012283432602

    Article  PubMed  CAS  Google Scholar 

  24. Jelinek DF, Tschumper RC, Geyer SM, Bone ND, Dewald GW, Hanson CA et al (2001) Analysis of clonal B-cell CD38 and immunoglobulin variable region sequence status in relation to clinical outcome for B-chronic lymphocytic leukemia. Br J Haematol 115:854–861 doi:10.1046/j.1365-2141.2001.03149.x

    Article  PubMed  CAS  Google Scholar 

  25. Ritgen M, Lange A, Stilgenbauer S, Dohner H, Bretscher C, Bosse H et al (2003) Unmutated immunoglobuline variable heavy chain gene status remains an adverse prognostic factor after autologous stem cell transplantation for chronic lymphocytic leukemia. Blood 101:2049–2053 doi:10.1182/blood-2002-06-1744

    Article  PubMed  CAS  Google Scholar 

  26. Cazin B, Maloum K, Divine M, Lepretre S, Travade P, Delmer A et al. (2003) Oral Fludarabine and Cyclophosphamide in previously untreated CLL: Final response and Follow-up in 75 Patients. Blood 102 Suppl 1 ABS 1598

  27. Byrd JC, Gribben JG, Peterson BL, Grever MR, Lozanski G, Lucas DM et al (2006) Select high-risk genetic features predict earlier progression following chemoimmunotherapy with fludarabine and rituximab in chronic lymphocytic leukemia: justification for risk-adapted therapy. J Clin Oncol 24:437–443 doi:10.1200/JCO.2005.03.1021

    Article  PubMed  CAS  Google Scholar 

  28. Grever MR, Lucas DM, Dewald GW, Neuberg DS, Reed JC, Kitada S et al (2007) Comprehensive assessment of genetic and molecular features predicting outcome in patients with chronic lymphocytic leukemia. Results from the US Intergroup phase III trial E2997. J Clin Oncol 25(7):799–804 doi:10.1200/JCO.2006.08.3089

    Article  PubMed  CAS  Google Scholar 

  29. Cheson BD, Bennet JM, Grever M, Kay N, Keating MJ, O’Brien S et al (1996) National Cancer Institute-sponsored Working Group guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment. Blood 87(12):4990–4997

    PubMed  CAS  Google Scholar 

  30. Wittes RE (Editorial) (1991) Manual of Oncologic Therapeutics: 1991/1992. Philadelphia, PA, Lippincott

  31. Flinn IW, Neuberg DS, Grever MR, Dewald GW, Bennett JM, Paietta EM et al (2007) Phase III trial of fludarabine plus ciclophosphamide compared with fludarabine for patients with previously untreated chronic lymphocytic leukemia: US Intergroup Trial E2997. J Clin Oncol 25(7):793–798 doi:10.1200/JCO.2006.08.0762

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Istituto di Ematologia, Policlinico A Gemelli, Università Cattolica del Sacro Cuore, Rome, Italy

    Luca Laurenti, Michela Tarnani, Laura De Padua, Gina Zini, Mariagrazia Garzia, Nicola Piccirillo, Patrizia Chiusolo, Federica Sorà, Idanna Innocenti, Simona Sica & Giuseppe Leone

  2. ICGEB Outstation CNR Monterotondo-Roma, Rome, Italy

    Dimitar G. Efremov

  3. Divisione di Ematologia, Istituto di Ematologia, Università Cattolica Sacro Cuore, Largo A Gemelli 8, 00168, Rome, Italy

    Luca Laurenti

Authors
  1. Luca Laurenti
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michela Tarnani
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Laura De Padua
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Dimitar G. Efremov
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Gina Zini
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mariagrazia Garzia
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Nicola Piccirillo
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Patrizia Chiusolo
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Federica Sorà
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Idanna Innocenti
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Simona Sica
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Giuseppe Leone
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Luca Laurenti.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Laurenti, L., Tarnani, M., De Padua, L. et al. Oral fludarabine and cyclophosphamide as front-line chemotherapy in patients with chronic lymphocytic leukemia. The impact of biological parameters in the response duration. Ann Hematol 87, 891–898 (2008). https://doi.org/10.1007/s00277-008-0527-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00277-008-0527-3

Keywords

Search

Navigation