Early progression of follicular lymphoma: a view of the problem and personal experience

Follicular lymphoma (FL) refers to indolent mature B-cell lymphomas and, despite the recurrent course, is generally characterized by a favorable prognosis with long-term overall survival. However, in about 20 %, the disease has an aggressive course with early progression and 5-year overall survival of only 50 %, which indicates the biological heterogeneity of FL. Due to the extremely poor prognosis, cases with disease progression within 2 years from the start of treatment represent a major clinical problem.
What predictive risk models of FL early progression are available to us and what regimens of the second and subsequent lines of anticancer therapy should be used? Is high-dose consolidation necessary and when?
Choosing the optimal therapy in early progression of FL is a complex task and depends both on the variant of the previous treatment and the patient’s status, as well as the objectively available therapeutic options. In the case of FL early progression after immunochemotherapy, an alternative regimen is used based on a previously unused anti-CD20 monoclonal antibody (rituximab or obinutuzumab) and non-cross-acting chemotherapeutic agents. For CHOP-like induction therapy, the optimal second-line drug is bendamustine. In addition to cytostatics in combination with anti-CD20 monoclonal antibodies, new agents are currently actively used in FL therapy (such as immunomodulators, inhibitors of B-cell receptor and histone methyltransferase signaling pathways, BCL-2 inhibitors, etc.). Numerous clinical trials continue to actively search for promising therapeutic options for the treatment of FL, with testing of new drugs to other B-cell targets and with different mechanisms of action.
We present a clinical case of FL with early generalized progression, ineffectiveness of subsequent intensification of treatment with autologous hematopoietic stem cell transplantation and the choice of salvage therapy in the realities of 2009–2012.

1. Shadman M., Li H., Rimsza L. et al. Continued excellent outcomes in previously untreated patients with follicular lymphoma after treatment with CHOP plus Rituximab or CHOP plus 131I-Tositumomab: long-term follow-up of Phase III Randomized Study SWOOGS0016. J Clin Oncol 2018;36(7):697–703. DOI:10.1200/JCO.2017.74.5083.

2. Tumyan G.S. Follicular lymphoma: current trends and my choice. Klinicheskaya onkogematologiya = Clinical Oncohematology 2013;6:20–33. (In Russ.).

3. Lipof J.J., Barr P.M. Early Progression of Follicular Lymphoma. Biology and Treatment. Hematol Oncol Clin N Am 2020;34(4):757–69. DOI:10.1016/j.hoc.2020.02.009.

4. Casulo C., Le-Rademacher J., Dixon J. et al. Validation of POD24 as a robust early clinical endpoint of poor survival in follicular lymphoma: results from the Follicular Lymphoma Analysis of Surrogacy Hypothesis (FLASH) investigation using individual data from 5,453 patients on 13 clinical trials. Blood 2017. DOI:10.1182/BLOOD.V130.SUPPL_1.412.412.

5. Casulo C., Byrtek M., Dawson K.L. 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(23):2516–22. DOI:10.1200/JCO.2014.59.7534.

6. Lansigan F., Barak I., Pitcher B. et al. The prognostic significance of PFS24 in follicular lymphoma following firstline immunotherapy: a combined analysis of 3 CALGB trials. Cancer Med 2019;8(1):165–73. DOI:10.1002/cam4.1918.

7. Solal-Celigny P., Roy P., Colombat P. et al. Follicular lymphoma international prognostic index. Blood 2004;104(5):1258–65. DOI:10.1182/blood-2003-12-4434.

8. Federico M., Bellei M., Marcheselli L. 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(27):4555–62. DOI:10.1200/JCO.2008.21.3991.

9. Mondello P. Intrafollicular CD4+ T-cells as an indehendent predictor of early clinical failure in newly diagnosed Follicular lymphoma. Blood 2019;134(Suppl_1):121. DOI:10.1182/blood-2019-126233.

10. Pastore A., Jurinovic V., Kridel R. et al. Integration of gene mutations in risk prognostication for patients receiving firstline immunochemotherapy for follicular lymphoma: a retrospective analysis of a prospective clinical trial and validation in a population-based registry. Lancet Oncol 2015;16(9):1111–22. DOI:10.1016/S1470-2045(15)00169-2.

11. Huet S., Tesson B., Jais J.P. et al. A geneexpression 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(4):549–61. DOI:10.1016/S1470-2045(18)30102-5.

12. Fischer T., Zing, N.P.C., Chiattone C.S. et al. Transformed follicular lymphoma. Ann Hematol 2018;97(1):17–29. DOI:10.1007/s00277-017-3151-2.

13. Link B.K. Transformation of follicular lymphoma – Why does it happen and can it be prevented? Best Pract Res Clin Haematol 2018;31(1):49–56. DOI:10.1016/j.beha.2017.10.005.

14. Babicheva L.G., Kaplanov K.D., Poddubnaya I.V. Modern algorithms for the treatment of recurrent follicular lymphoma. Methodical manual. Moscow: EkonInform, 2021, 29 p. (In Russ.).

15. Salles G., Seymour J.F., Offner F. et al. Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled trial. Lancet 2011;377(9759):42–51. DOI:10.1016/S0140-6736(10)62175-7.

16. Bachy E., Seymour J.F., Feugier P. et al. Sustained progression-free survival benefit of rituximab maintenance in patients with follicular lymphoma: long-term results of the PRIMA study. J Clin Oncol 2019;37(31):2815–24. DOI:10.1200/JCO.19.01073.

17. Marcus R., Davies A., Ando K. et al. Obinutuzumab for the first-line treatment of follicular lymphoma. N Engl J Med 2017;377(14):1331–44. DOI:10.1056/NEJMoa1614598.

18. Sehn L.H., Chua N., Mayer J. et al. Obinutuzumab plus bendamustine versus bendamustine monotherapy in patients with rituximab-refractory indolent nonHodgkin lymphoma (GADOLIN): a randomised, controlled, open-label, multi-centre, phase 3 trial. Lancet Oncol 2016;17(8):1081–93. DOI:10.1016/S1470-2045(16)30097-3.

19. leonard j., trneny m., izutsu k., fowler n. augment phase iii study: lenalidomide/rituximab (r2) improved efficacy over rituximab/placebo in relapsed/refractory follicular patients irrespective of pod24 status. hematol oncol 2019;37(s2):114–5. doi:10.1002/hon.75_2629.

20. Babicheva L.G. New developments in the treatment of follicular lymphoma/ marginal zone lymphoma (according to the Congress of the American Society of Hematology – 2020). Sovremennaya onkologiya = Journal of Modern Oncology 2021;23(1):172–84. (In Russ.). DOI:10.26442/18151434.2021.1.200748.

21. Jurinovic V., Metzner B., Pfreundschuh M. et al. Autologous stem cell transplantation for patients with early progression of follicular lymphoma: a follow-up study of 2 randomized trials from the German Low Grade Lymphoma Study Group. Biol Blood Marrow Transplant 2018;24(6):1172–9. DOI:10.1016/j.bbmt.2018.03.022.

22. Casulo C., Friedberg J.W., Ahn K.W. et al. Autologous transplantation in follicular lymphoma with early therapy failure: a National LymphoCare Study and Center for International Blood and Marrow Transplant Research Analysis. Biol Blood Marrow Transplant 2018;24(6):1163–71. DOI:10.1016/j.bbmt.2017.12.771.

23. Smith S.M., Godfrey J., Ahn K.W. et al. Autologous transplantation versus allogeneic transplantation in patients with follicular lymphoma experiencing early treatment failure. Cancer 2018;124(12):2541–51. DOI:10.1002/cncr.31374.

24. Nath K., Gandhi M.K. Targeted treatment of follicular lymphoma. J Pers Med 2021; 11(2):152. DOI:10.3390/jpm11020152.

25. Instructions for the medical use of the drug Copictra. LP-006892 dated 19.03.2021. According to the State Register of Medicines. Available at: http://grls.rosminzdrav.ru. (In Russ.).