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 Article
  • Published:

Lymphoma

Denileukin diftitox in combination with rituximab for previously untreated follicular B-cell non-Hodgkin's lymphoma

Leukemia volume 26, pages 1046–1052 (2012)Cite this article

Abstract

Follicular lymphoma exhibits intratumoral infiltration by non-malignant T lymphocytes, including CD4+CD25+ regulatory T (Treg) cells. We combined denileukin diftitox with rituximab in previously untreated, advanced-stage follicular lymphoma patients anticipating that denileukin diftitox would deplete CD25+ Treg cells while rituximab would deplete malignant B cells. Patients received rituximab 375 mg/m2 weekly for 4 weeks and denileukin diftitox 18 mcg/kg/day for 5 days every 3 weeks for 4 cycles; neither agent was given as maintenance therapy. Between August 2008 and March 2010, 24 patients were enrolled. One patient died before treatment was given and was not included in the analysis. Eleven of 23 patients (48%; 95% confidence interval (CI): 27–69%) responded; 2 (9%) had complete responses and 9 (39%) had partial responses. The progression-free rate at 2 years was 55% (95%CI: 37–82%). Thirteen patients (57%) experienced grade ⩾3 adverse events and one patient (4%) died. In correlative studies, soluble CD25 and the number of CD25+ T cells decreased after treatment; however, there was a compensatory increase in IL-15 and IP-10. We conclude that although the addition of denileukin diftitox to rituximab decreased the number of CD25+ T cells, denileukin diftitox contributed to the toxicity of the combination without an improvement in response rate or time to progression.

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

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

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

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  1. Ansell SM, Stenson M, Habermann TM, Jelinek DF, Witzig TE . CD4+ T-cell immune response to large B- cell non-Hodgkin's lymphoma predicts patient outcome. J Clin Oncol 2001; 19: 720–726.

    Article  CAS  Google Scholar 

  2. Yang ZZ, Novak AJ, Ziesmer SC, Witzig TE, Ansell SM . CD70+ non-Hodgkin lymphoma B cells induce Foxp3 expression and regulatory function in intratumoral CD4+CD25T cells. Blood 2007; 110: 2537–2544.

    Article  CAS  Google Scholar 

  3. Yang ZZ, Novak AJ, Ziesmer SC, Witzig TE, Ansell SM . Malignant B cells skew the balance of regulatory T cells and TH17 cells in B-cell non-Hodgkin's lymphoma. Cancer Res 2009; 69: 5522–5530.

    Article  CAS  Google Scholar 

  4. Yang ZZ, Novak AJ, Stenson MJ, Witzig TE, Ansell SM . Intratumoral CD4+CD25+ regulatory T-cell- mediated suppression of infiltrating CD4+ T-cells in B-cell non-Hodgkin lymphoma. Blood 2006; 107: 3639–3646.

    Article  CAS  Google Scholar 

  5. Yang ZZ, Novak AJ, Ziesmer SC, Witzig TE, Ansell SM . Attenuation of CD8(+) T-cell function by CD4(+)CD25(+) regulatory T cells in B-cell non-Hodgkin's lymphoma. Cancer Res 2006; 66: 10145–10152.

    Article  CAS  Google Scholar 

  6. Shan D, Ledbetter JA, Press OW . Signaling events involved in anti-CD20-induced apoptosis of malignant human B cells. Cancer Immunol Immunother 2000; 48: 673–683.

    Article  CAS  Google Scholar 

  7. Golay J, Zaffaroni L, Vaccari T, Lazzari M, Borleri GM, Bernasconi S et al. Biologic response of B lymphoma cells to anti-CD20 monoclonal antibody rituximab in vitro: CD55 and CD59 regulate complement-mediated cell lysis. Blood 2000; 95: 3900–3908.

    CAS  Google Scholar 

  8. Wurflein D, Dechant M, Stockmeyer B, Tutt AL, Hu P, Repp R et al. Evaluating antibodies for their capacity to induce cell-mediated lysis of malignant B cells. Cancer Res 1998; 58: 3051–3058.

    CAS  Google Scholar 

  9. Hainsworth JD, Litchy S, Burris III HA, Scullin Jr DC, Corso SW, Yardley DA et al. Rituximab as first-line and maintenance therapy for patients with indolent non-hodgkin's lymphoma. J Clin Oncol 2002; 20: 4261–4267.

    Article  CAS  Google Scholar 

  10. Hainsworth JD, Litchy S, Shaffer DW, Lackey VL, Grimaldi M, Greco FA . Maximizing therapeutic benefit of rituximab: Maintenance therapy versus re-treatment at progression in patients with indolent non-Hodgkin's lymphoma–a randomized phase II trial of the Minnie Pearl Cancer Res Network. J Clin Oncol 2005; 23: 1088–1095.

    Article  CAS  Google Scholar 

  11. Martinelli G, Schmitz SF, Utiger U, Cerny T, Hess U, Bassi S et al. Long-term follow-up of patients with follicular lymphoma receiving single-agent rituximab at two different schedules in trial SAKK 35/98. J Clin Oncol 2010; 28: 4480–4484.

    Article  CAS  Google Scholar 

  12. Witzig TE, Vukov AM, Habermann TM, Geyer S, Kurtin PJ, Friedenberg WR et al. Rituximab therapy for patients with newly diagnosed, advanced-stage, follicular grade I non-Hodgkin's lymphoma: a phase II trial in the North Central Cancer Treatment Group. J Clin Oncol. 2005; 23: 1103–1108.

    Article  CAS  Google Scholar 

  13. Dang NH, Hagemeister FB, Pro B, McLaughlin P, Romaguera JE, Jones D et al. Phase II study of denileukin diftitox for relapsed/refractory B-Cell non-Hodgkin's lymphoma. J Clin Oncol 2004; 22: 4095–4102.

    Article  CAS  Google Scholar 

  14. Dang NH, Fayad L, McLaughlin P, Romaguara JE, Hagemeister F, Goy A et al. Phase II trial of the combination of denileukin diftitox and rituximab for relapsed/refractory B-cell non-Hodgkin lymphoma. Br J Haematol 2007; 138: 502–505.

    Article  CAS  Google Scholar 

  15. Cheson BD, Horning SJ, Coiffier B, Shipp MA, Fisher RI, Connors JM et al. Report of an international workshop to standardize response criteria for non-Hodgkin's lymphomas. NCI Sponsored International Working Group. J Clin Oncol 1999; 17: 1244–1253.

    Article  CAS  Google Scholar 

  16. Sargent DJ, Chan V, Goldberg RM . A three-outcome design for phase II clinical trials. Control Clin Trials 2001; 22: 117–125.

    Article  CAS  Google Scholar 

  17. Kaplan E, Meier P . Nonparametric estimation for incomplete observations. J Am Stat Assoc 1958; 53: 457–481.

    Article  Google Scholar 

  18. Solal-Celigny P, Roy P, Colombat P, White J, Armitage JO, Arranz-Saez R et al. Follicular lymphoma international prognostic index. Blood 2004; 104: 1258–1265.

    Article  CAS  Google Scholar 

  19. Shevach EM . CD4+ CD25+ suppressor T cells: more questions than answers. Nat Rev Immunol 2002; 2: 389–400.

    Article  CAS  Google Scholar 

  20. Morse MA, Clay TM, Mosca P, Lyerly HK . Immunoregulatory T cells in cancer immunotherapy. Expert Opin Biol Ther 2002; 2: 827–834.

    Article  CAS  Google Scholar 

  21. Liyanage UK, Moore TT, Joo HG, Tanaka Y, Herrmann V, Doherty G et al. Prevalence of regulatory T cells is increased in peripheral blood and tumor microenvironment of patients with pancreas or breast adenocarcinoma. J Immunol 2002; 169: 2756–2761.

    Article  CAS  Google Scholar 

  22. Woo EY, Yeh H, Chu CS, Schlienger K, Carroll RG, Riley JL et al. Cutting edge: Regulatory T cells from lung cancer patients directly inhibit autologous T cell proliferation. J Immunol 2002; 168: 4272–4276.

    Article  CAS  Google Scholar 

  23. Vang KB, Yang J, Mahmud SA, Burchill MA, Vegoe AL, Farrar MA . IL-2, -7, and -15, but not thymic stromal lymphopoeitin, redundantly govern CD4+Foxp3+ regulatory T cell development. J Immunol 2008; 181: 3285–3290.

    Article  CAS  Google Scholar 

  24. Sarween N, Chodos A, Raykundalia C, Khan M, Abbas AK, Walker LS . CD4+CD25+ cells controlling a pathogenic CD4 response inhibit cytokine differentiation, CXCR-3 expression, and tissue invasion. J Immunol 2004; 173: 2942–2951.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported in part by grants CA92104 and CA25224 from the National Institutes of Health and the Predolin Foundation.

Author information

Authors and Affiliations

  1. Division of Hematology, Mayo Clinic, Rochester, MN, USA

    S M Ansell, G S Nowakowski, Z Yang, D M Grote, S C Ziesmer & T E Witzig

  2. Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA

    H Tang & G D Nelson

  3. Division of Hematopathology, Mayo Clinic, Rochester, MN, USA

    P J Kurtin

  4. North Central Cancer Treatment Group, Rochester, MN, USA

    P A Koenig, D A Nikcevich, P T Silberstein & C Erlichman

Authors
  1. S M Ansell
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. H Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. P J Kurtin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. P A Koenig
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. G S Nowakowski
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. D A Nikcevich
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. G D Nelson
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Z Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. D M Grote
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. S C Ziesmer
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. P T Silberstein
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. C Erlichman
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. T E Witzig
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to S M Ansell.

Ethics declarations

Competing interests

SMA received research funding from Eisai Inc. for this study. The remaining authors declare no conflict of interest.

Additional information

Presented in part at the 52nd Annual Meeting of the American Society of Hematology.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ansell, S., Tang, H., Kurtin, P. et al. Denileukin diftitox in combination with rituximab for previously untreated follicular B-cell non-Hodgkin's lymphoma. Leukemia 26, 1046–1052 (2012). https://doi.org/10.1038/leu.2011.297

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2011.297

Keywords

This article is cited by

Search

Advanced search

Quick links