International Journal of Hematology

, Volume 94, Issue 1, pp 90–96

An effective salvage treatment using ifosfamide, etoposide, cytarabine, dexamethasone, and rituximab (R-IVAD) for patients with relapsed or refractory aggressive B-cell lymphoma

  • Katsuhiro Miura
  • Kazuhiro Takei
  • Sumiko Kobayashi
  • Satomi Kiso
  • Yukio Hirabayashi
  • Atsuko Hojo
  • Hitomi Kodaira
  • Mai Yagi
  • Daisuke Kurita
  • Yujin Kobayashi
  • Toshitake Tanaka
  • Noriyoshi Iriyama
  • Yoshihiro Hatta
  • Yoshimasa Kura
  • Tetsuo Yamazaki
  • Umihiko Sawada
  • Jin Takeuchi
Original Article

Abstract

We evaluated the efficacy and toxicity of a new salvage regimen, consisting of rituximab (375 mg/m2, day 1), ifosfamide (1500 mg/m2 on days 3–7), etoposide (150 mg/m2, days 3–5), cytarabine (100 mg/m2, days 3–5) and dexamethasone (40 mg/body, days 3–5) (R-IVAD) for relapsed or refractory aggressive B-cell lymphoma. In this study, a total of 32 patients with a median age of 64 years (range 38–79) who received an average of 2.6 cycles of R-IVAD from 2001 to 2009 in our institution were retrospectively analyzed. R-IVAD was given every 3 weeks up to a total of three courses with support by granulocyte colony stimulating factor. The overall response rate was 72%, with 56% complete response. On a median follow-up of 16 months (range 2–99), estimated 2-year overall survival (OS) and event-free survival were 55% and 36%, respectively. Of these patients, 10 successfully proceeded to consolidating high-dose chemotherapy followed by autologous stem cell transplantation, accounting for 90% of the 2-year OS. No treatment-related mortality was observed during the investigation. We, therefore, conclude that R-IVAD regimen is a safe and efficacious alternative for patients with relapsed or refractory aggressive B-cell lymphoma.

Keywords

Aggressive B-cell lymphoma Refractory Relapse Rituximab Salvage 

References

  1. 1.
    Fisher RI, Gaynor ER, Dahlberg S, et al. Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin’s lymphoma. N Engl J Med. 1993;328(14):1002–6.PubMedCrossRefGoogle Scholar
  2. 2.
    Coiffier B, Lepage E, Briere J, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med. 2002;346(4):235–42.PubMedCrossRefGoogle Scholar
  3. 3.
    Feugier P, Van Hoof A, Sebban C, et al. Long-term results of the R-CHOP study in the treatment of elderly patients with diffuse large B-cell lymphoma: a study by the Groupe d’Etude des Lymphomes de l’Adulte. J Clin Oncol. 2005;23(18):4117–26.PubMedCrossRefGoogle Scholar
  4. 4.
    Pfreundschuh M, Trumper L, Osterborg A, et al. CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group. Lancet Oncol. 2006;7(5):379–91.PubMedCrossRefGoogle Scholar
  5. 5.
    Niitsu N. Current treatment strategy of diffuse large B-cell lymphomas. Int J Hematol. 2010;92(2):231–7.PubMedCrossRefGoogle Scholar
  6. 6.
    Wilson WH, Bryant G, Bates S, et al. EPOCH chemotherapy: toxicity and efficacy in relapsed and refractory non-Hodgkin’s lymphoma. J Clin Oncol. 1993;11(8):1573–82.PubMedGoogle Scholar
  7. 7.
    Moskowitz CH, Bertino JR, Glassman JR, et al. Ifosfamide, carboplatin, and etoposide: a highly effective cytoreduction and peripheral-blood progenitor-cell mobilization regimen for transplant-eligible patients with non-Hodgkin’s lymphoma. J Clin Oncol. 1999;17(12):3776–85.PubMedGoogle Scholar
  8. 8.
    Velasquez WS, Cabanillas F, Salvador P, et al. Effective salvage therapy for lymphoma with cisplatin in combination with high-dose Ara-C and dexamethasone (DHAP). Blood. 1988;71(1):117–22.PubMedGoogle Scholar
  9. 9.
    Velasquez WS, McLaughlin P, Tucker S, et al. ESHAP—an effective chemotherapy regimen in refractory and relapsing lymphoma: a 4-year follow-up study. J Clin Oncol. 1994;12(6):1169–76.PubMedGoogle Scholar
  10. 10.
    Ogura M, Kagami Y, Taji H, et al. Pilot phase I/II study of new salvage therapy (CHASE) for refractory or relapsed malignant lymphoma. Int J Hematol. 2003;77(5):503–11.PubMedCrossRefGoogle Scholar
  11. 11.
    Jermann M, Jost LM, Taverna C, et al. Rituximab-EPOCH, an effective salvage therapy for relapsed, refractory or transformed B-cell lymphomas: results of a phase II study. Ann Oncol. 2004;15(3):511–6.PubMedCrossRefGoogle Scholar
  12. 12.
    Kewalramani T, Zelenetz AD, Nimer SD, et al. Rituximab and ICE as second-line therapy before autologous stem cell transplantation for relapsed or primary refractory diffuse large B-cell lymphoma. Blood. 2004;103(10):3684–8.PubMedCrossRefGoogle Scholar
  13. 13.
    Mey UJ, Orlopp KS, Flieger D, et al. Dexamethasone, high-dose cytarabine, and cisplatin in combination with rituximab as salvage treatment for patients with relapsed or refractory aggressive non-Hodgkin’s lymphoma. Cancer Invest. 2006;24(6):593–600.PubMedCrossRefGoogle Scholar
  14. 14.
    Harting R, Venugopal P, Gregory SA, O’Brien T, Bogdanova E. Efficacy and safety of rituximab combined with ESHAP chemotherapy for the treatment of relapsed/refractory aggressive B-cell non-Hodgkin lymphoma. Clin Lymphoma Myeloma. 2007;7(6):406–12.PubMedCrossRefGoogle Scholar
  15. 15.
    Oki Y, Ogura M, Kato H, et al. Phase II study of a salvage regimen using cyclophosphamide, high-dose cytarabine, dexamethasone, etoposide, and rituximab in patients with relapsed or refractory B-cell non-Hodgkin’s lymphoma. Cancer Sci. 2008;99(1):179–84.PubMedGoogle Scholar
  16. 16.
    Kobayashi S, Yamazaki T, Uenokawa K, et al. New salvage regimen of IVAD therapy for relapsed diffuse large B cell lymphoma. Rinsho Ketsueki. 2005;46(8):793. (in Japanese).Google Scholar
  17. 17.
    Swerdlow SH, Campo E, Harris NL, et al., editors. WHO classification of tumours of haematopoietic and lymphoid tissues. Lyon, France: IARC; 2008.Google Scholar
  18. 18.
    The International Non-Hodgkin’s Lymphoma Prognostic Factors Project. Project-TIN-HsLPF: a predictive model for aggressive non-Hodgkin’s lymphoma. N Engl J Med. 1993;329(14):987–94.Google Scholar
  19. 19.
    Cheson BD, Horning SJ, Coiffier B, et al. Report of an international workshop to standardize response criteria for non-Hodgkin’s lymphomas. J Clin Oncol. 1999;17(4):1244.PubMedGoogle Scholar
  20. 20.
    Mey UJ, Olivieri A, Orlopp KS, et al. DHAP in combination with rituximab vs DHAP alone as salvage treatment for patients with relapsed or refractory diffuse large B-cell lymphoma: a matched-pair analysis. Leuk Lymphoma. 2006;47(12):2558–66.PubMedCrossRefGoogle Scholar
  21. 21.
    Martin A, Conde E, Arnan M, et al. R-ESHAP as salvage therapy for patients with relapsed or refractory diffuse large B-cell lymphoma: the influence of prior exposure to rituximab on outcome. A GEL/TAMO study. Haematologica. 2008;93(12):1829–36.PubMedCrossRefGoogle Scholar
  22. 22.
    Philip T, Guglielmi C, Hagenbeek A, et al. Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin’s lymphoma. N Engl J Med. 1995;333(23):1540–5.PubMedCrossRefGoogle Scholar
  23. 23.
    Niitsu N, Kohuri M, Higashihara M, Bessho M. Phase II study of the CPT-11, mitoxantrone and dexamethasone regimen in combination with rituximab in elderly patients with relapsed diffuse large B-cell lymphoma. Cancer Sci. 2006;97(9):933–7.PubMedCrossRefGoogle Scholar
  24. 24.
    Kobayashi Y, Miura K, Hojo A, et al. Charlson Comorbidity Index is an independent prognostic factor among elderly patients with diffuse large B-cell lymphoma. J Cancer Res Clin Oncol. 2011;137(7):1079–84.Google Scholar
  25. 25.
    Gisselbrecht C, Glass B, Mounier N, et al. Salvage regimens with autologous transplantation for relapsed large B-cell lymphoma in the rituximab era. J Clin Oncol. 2010;28(27):4184–90.PubMedCrossRefGoogle Scholar
  26. 26.
    Takei K, Yamazaki T, Sawada U, Ishizuka H, Aizawa S. Analysis of changes in CD20, CD55, and CD59 expression on established rituximab-resistant B-lymphoma cell lines. Leuk Res. 2006;30(5):625–31.PubMedCrossRefGoogle Scholar
  27. 27.
    Czuczman MS, Olejniczak S, Gowda A, et al. Acquirement of rituximab resistance in lymphoma cell lines is associated with both global CD20 gene and protein down-regulation regulated at the pretranscriptional and posttranscriptional levels. Clin Cancer Res. 2008;14(5):1561–70.PubMedCrossRefGoogle Scholar
  28. 28.
    Wilson WH. Chemotherapy sensitization by rituximab: experimental and clinical evidence. Semin Oncol. 2000;27(6 Suppl 12):30–6.PubMedGoogle Scholar
  29. 29.
    Ardeshna KM, Kakouros N, Qian W, et al. Conventional second-line salvage chemotherapy regimens are not warranted in patients with malignant lymphomas who have progressive disease after first-line salvage therapy regimens. Br J Haematol. 2005;130(3):363–72.PubMedCrossRefGoogle Scholar

Copyright information

© The Japanese Society of Hematology 2011

Authors and Affiliations

  • Katsuhiro Miura
    • 1
  • Kazuhiro Takei
    • 1
  • Sumiko Kobayashi
    • 1
  • Satomi Kiso
    • 1
  • Yukio Hirabayashi
    • 1
  • Atsuko Hojo
    • 1
  • Hitomi Kodaira
    • 1
  • Mai Yagi
    • 1
  • Daisuke Kurita
    • 1
  • Yujin Kobayashi
    • 1
  • Toshitake Tanaka
    • 1
  • Noriyoshi Iriyama
    • 1
  • Yoshihiro Hatta
    • 1
  • Yoshimasa Kura
    • 1
  • Tetsuo Yamazaki
    • 1
  • Umihiko Sawada
    • 1
  • Jin Takeuchi
    • 1
  1. 1.Division of Medicine, Department of Hematology and RheumatologyNihon University School of MedicineTokyoJapan

Personalised recommendations