SpringerLink
Log in

Low absolute lymphocyte count is a poor prognostic factor for untreated advanced follicular lymphoma treated with rituximab plus bendamustine: results of the prospective phase 2 CONVERT trial

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

Abstract

The aim of this trial is to evaluate the utility of rituximab–bendamustine (R–B) for untreated advanced follicular lymphoma (FL) showing non-optimal response (nOR) to R-CHOP, and to identify clinical prognostic factors for FL patients receiving R–B. Patients who failed to achieve complete response/complete response unconfirmed (CR/CRu) [nOR-group] after 2 cycles of R-CHOP subsequently received 6 cycles of R–B. The primary endpoint was the 3-year progression-free survival (PFS) rate. Secondary endpoints included determination of prognostic factors. Fifty-six patients initially received R-CHOP, 43/56 patients (76.8%) were judged as nOR, and 33/43 patients (76.7%) completed 6 cycles of R–B. At a median follow-up of 50.6 months in the nOR-group, the 3-year PFS rate was 69.0%, and the 3-year overall survival (OS) rate was 92.7%. The most common toxicities associated with R–B were grade 3–4 lymphopenia (93.0%) and neutropenia (74.4%), both of which were manageable. A multivariate analysis including dose intensity, serum soluble interleukin‐2 receptor, and FL international prognostic index-2 revealed low absolute lymphocyte count (<  869/μL) at diagnosis was an independent poor prognostic factor for both PFS and OS in the R–B-treated nOR-group. This result was further confirmed in validation cohorts including R–B-treated de novo (n = 40) and relapsed (n = 49) FL patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (Germany)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Swerdlow SH, Campo E, Pileri SA, Harris NL, Stein H, Siebert R, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016;127:2375–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Tan D, Horning SJ, Hoppe RT, Levy R, Rosenberg SA, Sigal BM, et al. Improvements in observed and relative survival in follicular grade 1–2 lymphoma during 4 decades: the Stanford University experience. Blood. 2013;122:981–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Carbone A, Roulland S, Gloghini A, Younes A, Keudell G, von A López-Guillermo, , et al. Follicular lymphoma. Nat Rev Dis Primers. 2019;5:83.

    Article  PubMed  Google Scholar 

  4. Federico M, Luminari S, Dondi A, Tucci A, Vitolo U, Rigacci L, et al. R-CVP versus R-CHOP versus R-FM for the initial treatment of patients with advanced-stage follicular lymphoma: results of the FOLL05 trial conducted by the Fondazione Italiana Linfomi. J Clin Oncol. 2013;31:1506–13.

    Article  CAS  PubMed  Google Scholar 

  5. Luminari S, Ferrari A, Manni M, Dondi A, Chiarenza A, Merli F, et al. Long-term results of the FOLL05 trial comparing R-CVP versus R-CHOP versus R-FM for the initial treatment of patients with advanced-stage symptomatic follicular lymphoma. J Clin Oncol. 2018;36:689–96.

    Article  CAS  PubMed  Google Scholar 

  6. Rummel MJ, Niederle N, Maschmeyer G, Banat GA, von Grünhagen U, Losem C, et al. Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial. Lancet. 2013;381:1203–10.

    Article  CAS  PubMed  Google Scholar 

  7. Flinn IW, van der Jagt R, Kahl BS, Wood P, Hawkins TE, Macdonald D, et al. Randomized trial of bendamustine-rituximab or R-CHOP/R-CVP in first-line treatment of indolent NHL or MCL: the BRIGHT study. Blood. 2014;123:2944–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Flinn IW, van der Jagt R, Kahl B, Wood P, Hawkins T, MacDonald D, et al. First-line treatment of patients with indolent non-Hodgkin lymphoma or mantle-cell lymphoma with bendamustine plus rituximab versus R-CHOP or R-CVP: results of the bright 5-year follow-up study. J Clin Oncol. 2019;37:984–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Casulo C, Byrtek M, Dawson KL, Zhou X, Farber CM, Flowers CR, et al. Early relapse of follicular lymphoma after rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone defines patients at high risk for death: an analysis from the national lymphocare study. J Clin Oncol. 2015;33:2516–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Sarkozy C, Maurer MJ, Link BK, Ghesquieres H, Nicolas E, Thompson CA, et al. Cause of death in follicular lymphoma in the first decade of the rituximab era: a pooled analysis of French and US cohorts. J Clin Oncol. 2019;37:144–52.

    Article  CAS  PubMed  Google Scholar 

  11. Solal-Céligny P, Roy P, Colombat P, White J, Armitage JO, Arranz-Saez R, et al. Follicular lymphoma international prognostic index. Blood. 2004;104:1258–65.

    Article  PubMed  CAS  Google Scholar 

  12. Federico M, Bellei M, Marcheselli L, Luminari S, Lopez-Guillermo A, Vitolo U, et al. Follicular lymphoma international prognostic index 2: a new prognostic index for follicular lymphoma developed by the international follicular lymphoma prognostic factor project. J Clin Oncol. 2009;27:4555–62.

    Article  PubMed  Google Scholar 

  13. Seymour JF, Marcus R, Davies A, Gallop-Evans E, Grigg A, Haynes A, et al. Association of early disease progression and very poor survival in the GALLIUM study in follicular lymphoma: benefit of obinutuzumab in reducing the rate of early progression. Haematologica. 2019;10:1202–8.

    Article  CAS  Google Scholar 

  14. Jurinovic V, Kridel R, Staiger AM, Szczepanowski M, Horn H, Dreyling MH, et al. Clinicogenetic risk models predict early progression of follicular lymphoma after first-line immunochemotherapy. Blood. 2016;128:1112–20.

    Article  CAS  PubMed  PubMed Central  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 nonHodgkins lymphomas. NCI Sponsored International Working Group. J Clin Oncol. 1999;17:1244.

    Article  CAS  PubMed  Google Scholar 

  16. Cheson BD, Pfistner B, Juweid ME, Gascoyne RD, Specht L, Horning SJ, et al. Revised response criteria for malignant lymphoma. J Clin Oncol. 2007;25:579–86.

    Article  PubMed  Google Scholar 

  17. Juweid ME, Stroobants S, Hoekstra OS, Mottaghy FM, Dietlein M, Guermazi A, et al. Use of positron emission tomography for response assessment of lymphoma: consensus of the Imaging Subcommittee of International Harmonization Project in Lymphoma. J Clin Oncol. 2007;25:571–8.

    Article  PubMed  Google Scholar 

  18. Kanda Y. Investigation of the freely available easy-to-use software “EZR” for medical statistics. Bone Marrow Transplant. 2013;48:452–8.

    Article  CAS  PubMed  Google Scholar 

  19. Brice P, Bastion Y, Lepage E, Brousse N, Haïoun C, Moreau P, et al. Comparison in low-tumoR–Burden follicular lymphomas between an initial no-treatment policy, prednimustine, or interferon alfa: a randomized study from the Groupe d’Etude des Lymphomes Folliculaires. Groupe d’Etude des Lymphomes de l’Adulte. J Clin Oncol. 1997;15:1110–7.

    Article  CAS  PubMed  Google Scholar 

  20. Johnson P, Federico M, Kirkwood A, Fosså A, Berkahn L, Carella A, et al. Adapted treatment guided by interim PET-CT scan in advanced Hodgkin’s lymphoma. N Engl J Med. 2016;374:2419–29.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Gallamini A, Tarella C, Viviani S, Rossi A, Patti C, Mulé A, et al. Early chemotherapy intensification with escalated BEACOPP in patients with advanced-stage Hodgkin lymphoma with a positive interim positron emission tomography/computed tomography scan after two ABVD cycles: long-term results of the GITIL/FIL HD 0607 trial. J Clin Oncol. 2018;36:454–62.

    Article  CAS  PubMed  Google Scholar 

  22. Meignan M, Cottereau AS, Versari A, Chartier L, Dupuis J, Boussetta S, et al. Baseline metabolic tumor volume predicts outcome in high-tumoR–Burden follicular lymphoma: a pooled analysis of three multicenter studies. J Clin Oncol. 2016;34:3618–26.

    Article  PubMed  Google Scholar 

  23. Trotman J, Barrington SF, Belada D, Meignan M, MacEwan R, Owen C, et al. Prognostic value of end-of-induction PET response after first-line immunochemotherapy for follicular lymphoma (GALLIUM): secondary analysis of a randomised, phase 3 trial. Lancet Oncol. 2018;19:1530–42.

    Article  CAS  PubMed  Google Scholar 

  24. Freeman CL, Kridel R, Moccia AA, Savage KJ, Villa DR, Scott DW, et al. Early progression after bendamustine-rituximab is associated with high risk of transformation in advanced stage follicular lymphoma. Blood. 2019;134:761–4.

    Article  CAS  PubMed  Google Scholar 

  25. Mondello P, Steiner N, Willenbacher W, Wasle I, Zaja F, Zambello R, et al. Bendamustine plus rituximab versus R-CHOP as first-line treatment for patients with indolent non-Hodgkin’s lymphoma: evidence from a multicenter, retrospective study. Ann Hematol. 2016;95:1107–14.

    Article  CAS  PubMed  Google Scholar 

  26. Fung M, Jacobsen E, Freedman A, Prestes D, Farmakiotis D, Gu X, et al. Increased risk of infectious complications in older patients with indolent non-Hodgkin lymphoma exposed to bendamustine. Clin Infect Dis. 2019;68:247–55.

    Article  CAS  PubMed  Google Scholar 

  27. Bachy E, Maurer MJ, Habermann TM, Gelas-Dore B, Maucort-Boulch D, Estell JA, et al. A simplified scoring system in de novo follicular lymphoma treated initially with immunochemotherapy. Blood. 2018;132:49–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Pastore A, Jurinovic V, Kridel R, Hoster E, Staiger AM, Szczepanowski M, et al. Integration of gene mutations in risk prognostication for patients receiving first-line immunochemotherapy for follicular lymphoma: a retrospective analysis of a prospective clinical trial and validation in a population-based registry. Lancet Oncol. 2015;16:1111–22.

    Article  CAS  PubMed  Google Scholar 

  29. Hiddemann W, Barbui AM, Canales MA, Cannell PK, Collins GP, Dürig J, et al. Immunochemotherapy with obinutuzumab or rituximab for previously untreated follicular lymphoma in the gallium study: influence of chemotherapy on efficacy and safety. J Clin Oncol. 2018;36:2395–404.

    Article  CAS  PubMed  Google Scholar 

  30. Marcus R, Seymour JF, Hiddemann W. Obinutuzumab treatment of follicular lymphoma. N Engl J Med. 2017;377:2605–6.

    Article  PubMed  Google Scholar 

  31. Jurinovic V, Passerini V, Oestergaard MZ, et al. Evaluation of the m7-FLIPI in patients with follicular lymphoma treated within the gallium trial: EZH2 mutation status may be a predictive marker for differential efficacy of chemotherapy. Blood. 2019;134:122.

    Article  Google Scholar 

  32. Ménétrier-Caux C, Ray-Coquard I, Blay JY, Caux C. Lymphopenia in Cancer Patients and its Effects on Response to Immunotherapy: an opportunity for combination with Cytokines? J Immunother Cancer. 2019;7:85.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Hasenclever D, Diehl VA. prognostic score for advanced Hodgkin’s disease International Prognostic Factors Project on Advanced Hodgkin’s Disease. N Engl J Med. 1998;339:1506–14.

    Article  CAS  PubMed  Google Scholar 

  34. Siddiqui M, Ristow K, Markovic SN, Witzig TE, Habermann TM, Colgan JP, et al. Absolute lymphocyte count predicts overall survival in follicular lymphomas. Br J Haematol. 2006;134:596–601.

    Article  PubMed  Google Scholar 

  35. Behl D, Ristow K, Markovic SN, Witzig TE, Habermann TM, Colgan JP, et al. Absolute lymphocyte count predicts therapeutic efficacy of rituximab therapy in follicular lymphomas. Br J Haematol. 2007;137:409–15.

    Article  CAS  PubMed  Google Scholar 

  36. Mohsen A, Taalab M, Abousamra N, Mabed M. Prognostic Significance of Absolute Lymphocyte Count, Absolute Monocyte Count, and Absolute Lymphocyte Count to Absolute Monocyte Count Ratio in Follicular Non-Hodgkin Lymphoma. Clin Lymphoma Myeloma Leuk. 2020. https://doi.org/10.1016/j.clml.2020.03.007.

    Article  PubMed  Google Scholar 

  37. Blay JY, Chauvin F, Le Cesne A, Anglaret B, Bouhour D, Lasset C, et al. Early lymphopenia after cytotoxic chemotherapy as a risk factor for febrile neutropenia. J Clin Oncol. 1996;14:636–43.

    Article  CAS  PubMed  Google Scholar 

  38. Morschhauser F, Fowler NH, Feugier P, Bouabdallah R, Tilly H, Palomba ML, et al. Rituximab plus Lenalidomide in Advanced Untreated Follicular Lymphoma. N Engl J Med. 2018;379:934–47.

    Article  CAS  PubMed  Google Scholar 

  39. Leonard JP, Trneny M, Izutsu K, Fowler NH, Hong X, Zhu J, et al. AUGMENT: a phase iii study of lenalidomide plus rituximab versus placebo plus rituximab in relapsed or refractory indolent lymphoma. J Clin Oncol. 2019;37:1188–99.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Dave SS, Wright G, Tan B, Rosenwald A, Gascoyne RD, Chan WC, et al. Prediction of survival in follicular lymphoma based on molecular features of tumor-infiltrating immune cells. N Engl J Med. 2004;351:2159–69.

    Article  CAS  PubMed  Google Scholar 

  41. Huet S, Tesson B, Jais JP, Feldman AL, Magnano L, Thomas E, et al. A gene-expression profiling score for prediction of outcome in patients with follicular lymphoma: a retrospective training and validation analysis in three international cohorts. Lancet Oncol. 2018;19:549–61.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Relander T, Johnson NA, Farinha P, Connors JM, Sehn LH, Gascoyne RD. Prognostic factors in follicular lymphoma. J Clin Oncol. 2010;28:2902–13.

    Article  CAS  PubMed  Google Scholar 

  43. Dunn GP, Old LJ, Schreiber RD. The immunobiology of cancer immunosurveillance and immunoediting. Immunity. 2004;21:137–48.

    Article  CAS  PubMed  Google Scholar 

  44. Alvaro T, Lejeune M, Salvadó MT, Lopez C, Jaén J, Bosch R, et al. Immunohistochemical patterns of reactive microenvironment are associated with clinicobiologic behavior in follicular lymphoma patients. J Clin Oncol. 2006;24:5350–7.

    Article  PubMed  Google Scholar 

  45. Strickler JG, Copenhaver CM, Rojas VA, Horning SJ, Warnke RA. Comparison of “host cell infiltrates” in patients with follicular lymphoma with and without spontaneous regression. Am J Clin Pathol. 1988;90(3):257–61.

    Article  CAS  PubMed  Google Scholar 

  46. Tobin JWD, Keane C, Gunawardana J, Mollee P, Birch S, Hoang T, et al. Progression of disease within 24 months in follicular lymphoma is associated with reduced intratumoral immune infiltration. J Clin Oncol. 2019;37:3300–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Inoue H, Rai S, Tanaka H, Espinoza JL, Watatani Y, Kumode T, et al. Tumour-immune microenvironment in duodenal-type follicular lymphoma. Br J Haematol. 2020. https://doi.org/10.1111/bjh.16715.

    Article  PubMed  Google Scholar 

  48. Menter T, Hayoz S, Zucca E, Kimby E, Dirnhofer S, Tzankov A. Immunomodulatory drugs may overcome the negative prognostic role of active Th17 axis in follicular lymphoma: evidence from the SAKK35/10 trial. Br J Haematol. 2020. https://doi.org/10.1111/bjh.16876.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank the pts who participated in the study, their supporters, the investigators, and clinical research staff from the study centers.

Author information

Authors and Affiliations

  1. Department of Hematology and Rheumatology, Faculty of Medicine, Kindai University, 377-2, Ohno-higashi, Osaka-sayama, Osaka, 589-8511, Japan

    Shinya Rai, Hiroaki Inoue, Takahiro Haeno, Yosaku Watatani, Takahiro Kumode, Chikara Hirase, J. Luis Espinoza, Yasuyoshi Morita, Hirokazu Tanaka, Yoichi Tatsumi & Itaru Matsumura

  2. Department of Hematology, Faculty of Medicine, Nara Hospital Kindai University, Ikoma, Japan

    Hitoshi Hanamoto

  3. Department of Hematology, PL General Hospital, Tondabayashi, Japan

    Mitsuhiro Matsuda

  4. Department of Hematology, Minami Sakai Hospital, Sakai, Japan

    Yasuhiro Maeda

  5. Department of Hematology, Izumi City General Hospital, Izumi, Japan

    Yusuke Wada

Authors
  1. Shinya Rai
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hiroaki Inoue
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hitoshi Hanamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mitsuhiro Matsuda
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yasuhiro Maeda
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yusuke Wada
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Takahiro Haeno
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yosaku Watatani
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Takahiro Kumode
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Chikara Hirase
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. J. Luis Espinoza
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Yasuyoshi Morita
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Hirokazu Tanaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Yoichi Tatsumi
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Itaru Matsumura
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

SR and YT designed and supervised the research. SR, HI, HH, MM, YM, YW, CH, YM, TH, TK, and HT contributed to date collection and analysis. SR, and HT performed statistical analysis. SR, HI, HT and IM performed the research and prepared figures and tables. SR, LE and HT wrote the manuscript. HT and IM revised the manuscript. And all authors read and approved the manuscript.

Corresponding author

Correspondence to Shinya Rai.

Ethics declarations

Conflict of interest

Itaru Matsumura has received research funding from Chugai and Eizai Pharmaceuticals. Shinya Rai has received payment for lectures from Chugai Pharmaceuticals. No other potential conflicts of interest were reported.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 194 KB)

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Rai, S., Inoue, H., Hanamoto, H. et al. Low absolute lymphocyte count is a poor prognostic factor for untreated advanced follicular lymphoma treated with rituximab plus bendamustine: results of the prospective phase 2 CONVERT trial. Int J Hematol 114, 205–216 (2021). https://doi.org/10.1007/s12185-021-03148-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12185-021-03148-0

Keywords

Search

Navigation