Cancer Chemotherapy and Pharmacology

, Volume 69, Issue 2, pp 387–395 | Cite as

Oral fludarabine in combination with doxorubicin and dexamethasone as first-line therapy for nodal peripheral T-cell lymphomas: early results of a prospective multicenter study

  • Xiao-Jian Liu
  • Ye Guo
  • Yun Fan
  • Kang-Sheng Gu
  • Jun-Ning Cao
  • Xiang-Hua Wu
  • Jian Zhang
  • Xiao-Qiu Li
  • Chao-Fu Wang
  • Xiao-Nan HongEmail author
Original Article



Nodal peripheral T-cell lymphomas (PTCLs) have particularly poor prognoses. Few data enabling establishment of an accepted standard treatment modality for PTCLs are available. We hypothesized that fludarabine-based regimens are tolerable and effective in treatment for nodal PTCLs. Therefore, this study was to analyze the toxicity of, response rate for, and outcome of treatment for nodal PTCLs with oral fludarabine, doxorubicin, and dexamethasone (FAD).


Patients with PTCLs received FAD every 28 days, consisting of oral fludarabine at 40 mg/m2 on days 1–3, doxorubicin at 50 mg/m2 on day 1, and oral dexamethasone at 20 mg/day on days 1–5. Patients who did not exhibit disease progression received at least four courses of treatment.


Thirty-one of 35 patients with previously untreated nodal PTCLs enrolled in the study from 2007 to 2008 were evaluable. The incidence of grade 3–4 neutropenia was 55%. Nine patients had to have dose reductions of fludarabine and doxorubicin, none of whom had grade 3 or 4 toxic effects at the lower dose. Five of 31 patients had pneumonitis. No treatment-related mortality occurred. The response rate for the entire patient population was 71%, and the complete remission rate was 48%. The PFS and OS rates at 2 years were 54.2 and 77.1%, respectively. Four patients had died of cancer progression at the time of this analysis. The serum lactate dehydrogenase level had a significant effect on PFS and OS.


The FAD regimen had encouraging efficacy with an acceptable toxicity profile in patients with nodal PTCLs.


Chemotherapy Fludarabine Peripheral T-cell Lymphoma Toxicity Survival 



We thank Bayer HealthCare for support free Fludarabine for enrolled patients. We thank Mr. Norwood Donald R, who is a scientific editor of department of scientific publications from MD Anderson cancer center of the USA, for her assistance in the language writing of this article.

Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    Harris NL, Swerdlow S, Campo E, Jaffe ES, Stein H, Pileri S, Thiele J, Vardiman J (2008) The World Health Organization (WHO) classification of lymphoid neoplasms: what’s new? Ann Oncol 19:119Google Scholar
  2. 2.
    Vose J, Armitage J, Weisenburger D (2008) International peripheral T-cell and natural killer/T-cell lymphoma study: pathology findings and clinical outcomes. J Clin Oncol 26(25):4124–4130PubMedCrossRefGoogle Scholar
  3. 3.
    Armitage JO, Vose JM, Weisenburger DD (2004) Towards understanding the peripheral T-cell lymphomas. Ann Oncol 15(10):1447–1449PubMedCrossRefGoogle Scholar
  4. 4.
    Savage KJ, Chhanabhai M, Gascoyne RD, Connors JM (2004) Characterization of peripheral T-cell lymphomas in a single North American institution by the WHO classification. Ann Oncol 15(10):1467–1475PubMedCrossRefGoogle Scholar
  5. 5.
    Rodriguez J, Conde E, Gutierrez A, Arranz R, Leon A, Marin J, Bendandi M, Albo C, Caballero MD (2007) Frontline autologous stem cell transplantation in high-risk peripheral T-cell lymphoma: a prospective study from The Gel-Tamo Study Group. Eur J Haematol 79(1):32–38PubMedCrossRefGoogle Scholar
  6. 6.
    Corradini P, Tarella C, Zallio F, Dodero A, Zanni M, Valagussa P, Gianni AM, Rambaldi A, Barbui T, Cortelazzo S (2006) Long-term follow-up of patients with peripheral T-cell lymphomas treated up-front with high-dose chemotherapy followed by autologous stem cell transplantation. Leukemia 20(9):1533–1538PubMedCrossRefGoogle Scholar
  7. 7.
    Laport GG (2010) Peripheral T-cell lymphoma: autologous hematopoietic cell transplantation as first-line therapy. Curr Opin Oncol 22(5):409–413PubMedCrossRefGoogle Scholar
  8. 8.
    Feyler S, Prince H, Pearce R (2007) The role of high-dose therapy and stem cell rescue in the management of T-cell malignant lymphomas: a BSBMT and ABMTRR study Bone Marrow Transplant 40:443–450Google Scholar
  9. 9.
    Corradini P, Dodero A, Zallio F (2004) Graft-versus-lymphoma effect in relapsed peripheral T-cell non-Hodgkin’s lymphomas after reduced-intensity conditioning followed by allogeneic transplantation of hematopoietic cells. J Clin Oncol 22(11):2172–2176PubMedCrossRefGoogle Scholar
  10. 10.
    Hast R, Jacobsson B, Petrescu A, Hjalmar V (1999) Successful treatment with fludarabine in two cases of angioimmunoblastic lymphadenopathy with dysproteinemia. Leuk Lymphoma 34(5–6):597–601PubMedGoogle Scholar
  11. 11.
    Yamaguchi M, Kotani T, Nakamura Y, Ueda M (2006) Successful treatment of refractory peripheral T-cell lymphoma with a combination of fludarabine and cyclophosphamide. Int J Hematol 83(5):450–453PubMedCrossRefGoogle Scholar
  12. 12.
    Rossi JF, van Hoof A, de Boeck K, Johnson SA, Bron D, Foussard C, Lister TA, Berthou C, Kramer MH, Littlewood TJ, Marcus RE, Deconinck E, Montillo M, Guibon O, Tollerfield SM (2004) Efficacy and safety of oral fludarabine phosphate in previously untreated patients with chronic lymphocytic leukemia. J Clin Oncol 22(7):1260–1267PubMedCrossRefGoogle Scholar
  13. 13.
    Tobinai K, Watanabe T, Ogura M, Morishima Y, Ogawa Y, Ishizawa K, Minami H, Utsunomiya A, Taniwaki M, Terauchi T, Nawano S, Matsusako M, Matsuno Y, Nakamura S, Mori S, Ohashi Y, Hayashi M, Seriu T, Hotta T (2006) Phase II study of oral fludarabine phosphate in relapsed indolent B-Cell non-Hodgkin’s lymphoma. J Clin Oncol 24(1):174–180PubMedCrossRefGoogle Scholar
  14. 14.
    Damaraju D, Damaraju VL, Brun M, Mowles D, Kuzma M, Berendt RC, Sawyer MB, Cass CE (2008) Cytotoxic activities of nucleoside and nucleobase analog drugs in malignant mesothelioma: characterization of a novel nucleobase transport activity. Biochem Pharmacol 75(10):1901–1911PubMedCrossRefGoogle Scholar
  15. 15.
    Simon R (1989) Optimal two-stage designs for phase II clinical trials. Control Clin Trials 10(1):1–10PubMedCrossRefGoogle Scholar
  16. 16.
    Savage KJ, Harris NL, Vose JM, Ullrich F, Jaffe ES, Connors JM, Rimsza L, Pileri SA, Chhanabhai M, Gascoyne RD, Armitage JO, Weisenburger DD (2008) ALK- anaplastic large-cell lymphoma is clinically and immunophenotypically different from both ALK + ALCL and peripheral T-cell lymphoma, not otherwise specified: report from the International Peripheral T-Cell Lymphoma Project. Blood 111(12):5496–5504PubMedCrossRefGoogle Scholar
  17. 17.
    Coiffier B, Brousse N, Peuchmaur M, Berger F, Gisselbrecht C, Bryon PA, Diebold J (1990) Peripheral T-cell lymphomas have a worse prognosis than B-cell lymphomas: a prospective study of 361 immunophenotyped patients treated with the LNH-84 regimen. The GELA (Groupe d’Etude des Lymphomes Agressives). Ann Oncol 1(1):45–50PubMedGoogle Scholar
  18. 18.
    Herold M, Hieke K (2002) Costs of toxicity during chemotherapy with CHOP, COP/CVP, and fludarabine. Eur J Health Econ 3(3):166–172PubMedCrossRefGoogle Scholar
  19. 19.
    Disel U, Paydas S, Yavuz S, Karakoc E (2010) Severe pulmonary toxicity associated with fludarabine and possible contribution of rituximab. Chemotherapy 56(2):89–93PubMedCrossRefGoogle Scholar
  20. 20.
    Helman DL Jr, Byrd JC, Ales NC, Shorr AF (2002) Fludarabine-related pulmonary toxicity: a distinct clinical entity in chronic lymphoproliferative syndromes. Chest 122(3):785–790PubMedCrossRefGoogle Scholar
  21. 21.
    Vose JM (2008) Peripheral T-cell non-Hodgkin’s lymphoma. Hematol Oncol Clin North Am 22(5):997–1005, xGoogle Scholar
  22. 22.
    Savage K, Ferreri AJ, Zinzani PL, Pileri SA (2010) Peripheral T-cell lymphoma—not otherwise specified. Crit Rev Oncol Hematol. doi: 10.1016/j.critrevonc.2010.07.007
  23. 23.
    Escalon MP, Liu NS, Yang Y, Hess M, Walker PL, Smith TL, Dang NH (2005) Prognostic factors and treatment of patients with T-cell non-Hodgkin lymphoma: the M. D. Anderson Cancer Center experience. Cancer 103(10):2091–2098PubMedCrossRefGoogle Scholar
  24. 24.
    Yung L, Cunningham D, Hancock B, Smith P, Maclennan K, Linch D, McMillan A (2004) Fludarabine, adriamycin and dexamethasone (FAD) in newly diagnosed advanced follicular lymphoma: a phase II study by the British National Lymphoma Investigation (BNLI). Br J Cancer 91(4):695–698PubMedGoogle Scholar
  25. 25.
    O’Connor OA (2010) Novel agents in development for peripheral T-cell lymphoma. Semin Hematol 47(Suppl 1):S11–S14PubMedCrossRefGoogle Scholar
  26. 26.
    Arkenau HT, Chong G, Cunningham D, Watkins D, Sirohi B, Chau I, Wotherspoon A, Norman A, Horwich A, Matutes E (2007) Gemcitabine, cisplatin and methylprednisolone for the treatment of patients with peripheral T-cell lymphoma: the Royal Marsden Hospital experience. Haematologica 92(2):271–272PubMedCrossRefGoogle Scholar
  27. 27.
    de Totero D, Tazzari PL, Capaia M, Montera MP, Clavio M, Balleari E, Foa R, Gobbi M (2003) CD40 triggering enhances fludarabine-induced apoptosis of chronic lymphocytic leukemia B-cells through autocrine release of tumor necrosis factor-alpha and interferon-gama and tumor necrosis factor receptor-I-II upregulation. Haematologica 88(2):148–158PubMedGoogle Scholar
  28. 28.
    Telek B, Rejto L, Kiss A, Batar P, Remenyi G, Rak K, Udvardy M (2002) Experience with fludarabine treatment and review of the literature. Orv Hetil 143(24):1459–1465PubMedGoogle Scholar
  29. 29.
    Huang HQ, Peng YL, Lin XB, Sun XF, Lin TY, Xia ZJ, Li YH, Cai QQ, He YJ, Jiang WQ, Guan ZZ (2004) Clinical outcomes of 106 patients with peripheral T-cell lymphoma treated by standard CHOP regimen. Ai Zheng 23(11 Suppl):1443–1447PubMedGoogle Scholar
  30. 30.
    Mercadal S, Briones J, Xicoy B, Pedro C, Escoda L, Estany C, Camos M, Colomo L, Espinosa I, Martinez S, Ribera JM, Martino R, Gutierrez-Garcia G, Montserrat E, Lopez-Guillermo A (2008) Intensive chemotherapy (high-dose CHOP/ESHAP regimen) followed by autologous stem-cell transplantation in previously untreated patients with peripheral T-cell lymphoma. Ann Oncol 19(5):958–963PubMedCrossRefGoogle Scholar
  31. 31.
    Zinzani PL, Magagnoli M, Bendandi M, Orcioni GF, Gherlinzoni F, Albertini P, Pileri SA, Tura S (1998) Therapy with gemcitabine in pretreated peripheral T-cell lymphoma patients. Ann Oncol 9(12):1351–1353PubMedCrossRefGoogle Scholar
  32. 32.
    Gallamini A, Zaja F, Patti C, Billio A, Specchia MR, Tucci A, Levis A, Manna A, Secondo V, Rigacci L, Pinto A, Iannitto E, Zoli V, Torchio P, Pileri S, Tarella C (2007) Alemtuzumab (Campath-1H) and CHOP chemotherapy as first-line treatment of peripheral T-cell lymphoma: results of a GITIL (Gruppo Italiano Terapie Innovative nei Linfomi) prospective multicenter trial. Blood 110(7):2316–2323PubMedCrossRefGoogle Scholar
  33. 33.
    Lawlor E, O’Briain DS, Finn T, Ward R, Rogers FM, O’Brien AA, Daly PA (1987) The simultaneous presentation of peripheral T-cell lymphoma and hairy cell leukemia. Cancer 60(7):1537–1544PubMedCrossRefGoogle Scholar
  34. 34.
    Peng YL, Huang HQ, Lin XB, Xia ZJ, Li YH, Wang W, He YJ, Pan ZH, Jiang WQ, Guan ZZ (2004) Clinical outcomes of patients with peripheral T-cell lymphoma (PTCL) treated by EPOCH regimen. Ai Zheng 23(8):943–946PubMedGoogle Scholar
  35. 35.
    Takamatsu Y, Suzumiya J, Utsunomiya A, Maeda K, Matsuoka H, Suzushima H, Tsukada J, Shibata K, Tamura K (2010) THP-COP regimen for the treatment of peripheral T-cell lymphoma and adult T-cell leukemia/lymphoma: a multicenter phase II study. Eur J Haematol 84(5):391–397Google Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Xiao-Jian Liu
    • 1
    • 3
  • Ye Guo
    • 1
    • 3
  • Yun Fan
    • 4
  • Kang-Sheng Gu
    • 5
  • Jun-Ning Cao
    • 1
    • 3
  • Xiang-Hua Wu
    • 1
    • 3
  • Jian Zhang
    • 1
    • 3
  • Xiao-Qiu Li
    • 2
    • 3
  • Chao-Fu Wang
    • 2
    • 3
  • Xiao-Nan Hong
    • 1
    • 3
    Email author
  1. 1.Department of Medical OncologyFudan University Shanghai Cancer centerShanghaiPeople’s Republic of China
  2. 2.Department of PathologyFudan University Shanghai Cancer centerShanghaiPeople’s Republic of China
  3. 3.Department of Oncology, Shanghai Medical CollageFudan UniversityShanghaiPeople’s Republic of China
  4. 4.Department of OncologyZhejiang Provincial Cancer HospitalHangzhouPeople’s Republic of China
  5. 5.Department of Medical OncologyThe First Affiliated Hospital of Anhui Medical UniversityHefeiPeople’s Republic of China

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