A multi-center retrospective analysis of patients with relapsed/refractory follicular lymphoma after third-line chemotherapy

Abstract

The overall outcome of patients with advanced-stage follicular lymphoma (FL) has improved significantly. However, some patients still develop multiple relapsed/refractory FL (RRFL). To address the still-limited data on this population, we performed this multi-center retrospective study. We analyzed 41 patients who received third-line treatment for RRFL at 8 institutes. The median age at diagnosis was 59 years (range, 38–70). The median progression-free survival (PFS) and probability of PFS at 2 years were 1.61 years and 39.4%, respectively, after third-line chemotherapy, and 0.45 years and 19.0%, respectively, after fourth-line chemotherapy. Objective response (OR) after third-line chemotherapy was achieved in 24 patients (53.7%). Bendamustine (Ben)-based regimens were associated with a significantly higher OR rate than other regimens (77.8% vs. 40.0%, respectively, P = 0.025). The median overall survival (OS) and probability of OS at 2 years were 4.71 years and 65.9%, respectively, after third-line chemotherapy, and 1.01 year and 45.1%, respectively, after fourth-line chemotherapy. In conclusion, this study had a small sample size and retrospective design, but it was able to demonstrate poor response rate and duration in patients with multiple RRFL, particularly after fourth-line chemotherapy. The optimal treatment strategy in this population should be clarified, including possibly hematopoietic stem cell transplantation.

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References

  1. 1.

    Tan D, Horning SJ, Hoppe RT, Levy R, Rosenberg SA, Sigal BM, Warnke RA, Natkunam Y, Han SS, Yuen A, Plevritis SK, Advani RH (2013) Improvements in observed and relative survival in follicular grade 1-2 lymphoma during 4 decades: the Stanford University experience. Blood 122(6):981–987. https://doi.org/10.1182/blood-2013-03-491514

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  2. 2.

    Casulo C, Byrtek M, Dawson KL, Zhou X, Farber CM, Flowers CR, Hainsworth JD, Maurer MJ, Cerhan JR, Link BK, Zelenetz AD, Friedberg JW (2015) 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 33(23):2516–2522. https://doi.org/10.1200/JCO.2014.59.7534

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Link BK, Day BM, Zhou X, Zelenetz AD, Dawson KL, Cerhan JR, Flowers CR, Friedberg JW (2019) Second-line and subsequent therapy and outcomes for follicular lymphoma in the United States: data from the observational National LymphoCare Study. Br J Haematol 184(4):660–663. https://doi.org/10.1111/bjh.15149

    Article  PubMed  Google Scholar 

  4. 4.

    Rivas-Delgado A, Magnano L, Moreno-Velazquez M, Garcia O, Nadeu F, Mozas P, Dlouhy I, Baumann T, Rovira J, Gonzalez-Farre B, Martinez A, Balague O, Delgado J, Villamor N, Gine E, Campo E, Sancho-Cia JM, Lopez-Guillermo A (2019) Response duration and survival shorten after each relapse in patients with follicular lymphoma treated in the rituximab era. Br J Haematol 184(5):753–759. https://doi.org/10.1111/bjh.15708

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Welaya K, Casulo C (2019) Follicular lymphoma: redefining prognosis, current treatment options, and unmet needs. Hematol Oncol Clin North Am 33(4):627–638. https://doi.org/10.1016/j.hoc.2019.03.003

    Article  PubMed  Google Scholar 

  6. 6.

    Casulo C, Barr PM (2019) How I treat early-relapsing follicular lymphoma. Blood 133(14):1540–1547. https://doi.org/10.1182/blood-2018-08-822148

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    Seymour JF, Marcus R, Davies A, Gallop-Evans E, Grigg A, Haynes A, Herold M, Illmer T, Nilsson-Ehle H, Sokler M, Dunzinger U, Nielsen T, Launonen A, Hiddemann W (2019) 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 104(6):1202–1208. https://doi.org/10.3324/haematol.2018.209015

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Hamadani M, Horowitz MM (2017) Allogeneic transplantation for follicular lymphoma: does one size fit all? J Oncol Pract 13(12):798–806. https://doi.org/10.1200/JOP.2017.026336

    Article  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Norman JE, Schouten HC, Dreger P, Robinson SP (2019) The role of stem cell transplantation in the management of relapsed follicular lymphoma in the era of targeted therapies. Bone Marrow Transplant 54(6):787–797. https://doi.org/10.1038/s41409-018-0372-5

    Article  PubMed  Google Scholar 

  10. 10.

    Vose JM, Bierman PJ, Loberiza FR, Lynch JC, Bociek GR, Weisenburger DD, Armitage JO (2008) Long-term outcomes of autologous stem cell transplantation for follicular non-Hodgkin lymphoma: effect of histological grade and Follicular International Prognostic Index. Biol Blood Marrow Transplant 14(1):36–42. https://doi.org/10.1016/j.bbmt.2007.06.016

    Article  PubMed  Google Scholar 

  11. 11.

    Kothari J, Peggs KS, Bird A, Thomson KJ, Morris E, Virchis AE, Lambert J, Goldstone AH, Linch DC, Ardeshna KM (2014) Autologous stem cell transplantation for follicular lymphoma is of most benefit early in the disease course and can result in durable remissions, irrespective of prior rituximab exposure. Br J Haematol 165(3):334–340. https://doi.org/10.1111/bjh.12741

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    Tada K, Kim SW, Asakura Y, Hiramoto N, Yakushijin K, Kurosawa S, Tajima K, Mori S, Heike Y, Tanosaki R, Maeshima AM, Taniguchi H, Furuta K, Kagami Y, Matsuno Y, Tobinai K, Takaue Y, Fukuda T (2012) Comparison of outcomes after allogeneic hematopoietic stem cell transplantation in patients with follicular lymphoma, diffuse large B-cell lymphoma associated with follicular lymphoma, or de novo diffuse large B-cell lymphoma. Am J Hematol 87(8):770–775. https://doi.org/10.1002/ajh.23246

    Article  PubMed  Google Scholar 

  13. 13.

    Heinzelmann F, Bethge W, Beelen DW, Engelhard M, Kroger N, Dreger P, Niederwieser D, Finke J, Bunjes D, Tischer J, Kobbe G, Holler E, Bornhauser M, Stelljes M, Baurmann H, Muller A, Haubitz I, Schrezenmeier H, Muller C, Ottinger H (2016) Allogeneic hematopoietic cell transplantation as curative therapy for non-transformed follicular lymphomas. Bone Marrow Transplant 51(5):654–662. https://doi.org/10.1038/bmt.2015.348

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Klyuchnikov E, Bacher U, Woo Ahn K, Carreras J, Kroger NM, Hari PN, Ku GH, Ayala E, Chen AI, Chen YB, Cohen JB, Freytes CO, Gale RP, Kamble RT, Kharfan-Dabaja MA, Lazarus HM, Martino R, Mussetti A, Savani BN, Schouten HC, Usmani SZ, Wiernik PH, Wirk B, Smith SM, Sureda A, Hamadani M (2016) Long-term survival outcomes of reduced-intensity allogeneic or autologous transplantation in relapsed grade 3 follicular lymphoma. Bone Marrow Transplant 51(1):58–66. https://doi.org/10.1038/bmt.2015.223

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    Sureda A, Zhang MJ, Dreger P, Carreras J, Fenske T, Finel H, Schouten H, Montoto S, Robinson S, Smith SM, Boumedil A, Hamadani M, Pasquini MC (2018) Allogeneic hematopoietic stem cell transplantation for relapsed follicular lymphoma: a combined analysis on behalf of the Lymphoma Working Party of the EBMT and the Lymphoma Committee of the CIBMTR. Cancer 124(8):1733–1742. https://doi.org/10.1002/cncr.31264

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Kanda Y (2013) Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Transplant 48(3):452–458. https://doi.org/10.1038/bmt.2012.244

    CAS  Article  Google Scholar 

  17. 17.

    Oki Y, Ogura M, Kato H, Kikuchi A, Taji H, Kagami Y, Oshiro A, Tsujimura A, Yamamoto K, Morishima Y (2008) 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 99(1):179–184. https://doi.org/10.1111/j.1349-7006.2007.00662.x

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Casulo C, Nastoupil L, Fowler NH, Friedberg JW, Flowers CR (2017) Unmet needs in the first-line treatment of follicular lymphoma. Ann Oncol 28(9):2094–2106. https://doi.org/10.1093/annonc/mdx189

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Freeman CL, Kridel R, Moccia AA, Savage KJ, Villa DR, Scott DW, Gerrie AS, Ferguson D, Cafferty F, Slack GW, Farinha P, Skinnider B, Connors JM, Sehn LH (2019) Early progression after bendamustine-rituximab is associated with high risk of transformation in advanced stage follicular lymphoma. Blood 134(9):761–764. https://doi.org/10.1182/blood.2019000258

    CAS  Article  PubMed  Google Scholar 

  20. 20.

    Schouten HC, Qian W, Kvaloy S, Porcellini A, Hagberg H, Johnsen HE, Doorduijn JK, Sydes MR, Kvalheim G (2003) High-dose therapy improves progression-free survival and survival in relapsed follicular non-Hodgkin’s lymphoma: results from the randomized European CUP trial. J Clin Oncol 21(21):3918–3927. https://doi.org/10.1200/jco.2003.10.023

    CAS  Article  PubMed  Google Scholar 

  21. 21.

    Tomblyn MR, Ewell M, Bredeson C, Kahl BS, Goodman SA, Horowitz MM, Vose JM, Negrin RS, Laport GG (2011) Autologous versus reduced-intensity allogeneic hematopoietic cell transplantation for patients with chemosensitive follicular non-Hodgkin lymphoma beyond first complete response or first partial response. Biol Blood Marrow Transplant 17(7):1051–1057. https://doi.org/10.1016/j.bbmt.2010.11.004

    Article  PubMed  Google Scholar 

  22. 22.

    Montoto S, Davies AJ, Matthews J, Calaminici M, Norton AJ, Amess J, Vinnicombe S, Waters R, Rohatiner AZ, Lister TA (2007) Risk and clinical implications of transformation of follicular lymphoma to diffuse large B-cell lymphoma. J Clin Oncol 25(17):2426–2433. https://doi.org/10.1200/JCO.2006.09.3260

    Article  PubMed  Google Scholar 

  23. 23.

    Montoto S, Fitzgibbon J (2011) Transformation of indolent B-cell lymphomas. J Clin Oncol 29(14):1827–1834. https://doi.org/10.1200/JCO.2010.32.7577

    Article  PubMed  Google Scholar 

  24. 24.

    Umino K, Fujiwara SI, Ito S, Mashima K, Minakata D, Nakano H, Yamasaki R, Kawasaki Y, Sugimoto M, Ashizawa M, Hatano K, Okazuka K, Sato K, Oh I, Ohmine K, Suzuki T, Muroi K, Kanda Y (2017) Serum soluble interleukin-2 receptor level at diagnosis predicts transformation in patients with follicular lymphoma. Leuk Lymphoma 58(2):316–323. https://doi.org/10.1080/10428194.2016.1190975

    CAS  Article  PubMed  Google Scholar 

  25. 25.

    Jurinovic V, Kridel R, Staiger AM, Szczepanowski M, Horn H, Dreyling MH, Rosenwald A, Ott G, Klapper W, Zelenetz AD, Barr PM, Friedberg JW, Ansell S, Sehn LH, Connors JM, Gascoyne RD, Hiddemann W, Unterhalt M, Weinstock DM, Weigert O (2016) Clinicogenetic risk models predict early progression of follicular lymphoma after first-line immunochemotherapy. Blood 128(8):1112–1120. https://doi.org/10.1182/blood-2016-05-717355

    CAS  Article  PubMed  PubMed Central  Google Scholar 

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Funding

This study was supported by Health, Labour, and Welfare Science Grants for Research on Measures for Rare and Intractable Diseases from the Japanese Government.

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Correspondence to Shigeo Fuji.

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The study was approved by the institutional review board of the Osaka International Cancer Institute in Osaka, Japan.

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Informed consent was obtained from all individual participants included in the study.

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Fuji, S., Tada, Y., Nozaki, K. et al. A multi-center retrospective analysis of patients with relapsed/refractory follicular lymphoma after third-line chemotherapy. Ann Hematol (2020). https://doi.org/10.1007/s00277-020-04126-y

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Keywords

  • Follicular lymphoma
  • Relapse
  • Hematopoietic stem cell transplantation
  • Bendamustine