Evolution of approaches to follicular lymphoma therapy at disease onset and first relapse. Twenty-five-year experience of the National Medical Research Center for Hematology

E. S. Gitelzon; Гительзон Екатерина Сергеевна; Y. K. Mangasarova; Мангасарова Я. К.; I. L. Israilova; Исраилова И. Л.; A. U. Magomedova; Магомедова А. У.; M. O. Bagova; Багова М. О.; E. A. Fastova; Фастова Е. А.; O. V. Margolin; Марголин О. В.; D. S. Belkina; Белкина Д. С.; R. R. Abdurashidova; Абдурашидова Р. Р.; A. S. Khudovekova; Худовекова А. С.; R. V. Dorzhieva; Доржиева Р. В.; M. S. Gulieva; Гулиева М. С.; A. M. Kovrigina; Ковригина А. М.; T. N. Obukhova; Обухова Т. Н.; A. B. Sudarikov; Судариков А. Б.; S. Y.  Smirnova; Смирнова С. Ю.; A. S. Garmash; Гармаш А. С.; M. B. Bidzhieva; Биджиева М. Б.; V. A. Lapin; Лапин В. А.; V. I. Bakhtina; Бахтина В. И.; A. K. Smolyaninova; Смольянинова А. К.; Yu. A. Chabaeva; Чабаева Ю. А.; S. M. Kulikov; Куликов С. М.; E. E. Zvonkov; Звонков Е. Е.; E. N. Parovichnikova; Паровичникова Е. Н.

doi:10.17650/1818-8346-2026-21-1-33-51

Evolution of approaches to follicular lymphoma therapy at disease onset and first relapse. Twenty-five-year experience of the National Medical Research Center for Hematology

Authors: Gitelzon E.S.¹, Mangasarova Y.K.¹, Israilova I.L.¹, Magomedova A.U.¹, Bagova M.O.¹, Fastova E.A.¹, Margolin O.V.¹, Belkina D.S.¹, Abdurashidova R.R.¹, Khudovekova A.S.¹, Dorzhieva R.V.¹, Gulieva M.S.¹, Kovrigina A.M.¹, Obukhova T.N.¹, Sudarikov A.B.¹, Smirnova S.Y.¹, Garmash A.S.¹, Bidzhieva M.B.², Lapin V.A.³, Bakhtina V.I.⁴, Smolyaninova A.K.¹, Chabaeva Y.A.¹, Kulikov S.M.¹, Zvonkov E.E.¹, Parovichnikova E.N.¹
Affiliations:
1. National Medical Research Center for Hematology, Ministry of Health of Russia
2. Moscow Clinical Scientific and Practical Center named after A. S. Loginov, Moscow Healthcare Department
3. Regional Clinical Hospital, Yaroslavl
4. Krasnoyarsk Regional Clinical Hospital
Issue: Vol 21, No 1 (2026)
Pages: 33-51
Section: HEMATOLOGIC MALIGNANCIES: TREATMENT
Published: 23.03.2026
URL: https://oncohematology.eco-vector.com/ongm/article/view/1089
DOI: https://doi.org/10.17650/1818-8346-2026-21-1-33-51
ID: 1089

Cite item

Full Text

Open Access
Restricted Access

Access granted
Restricted Access

Subscription or Fee Access

Abstract
About the authors
References
Supplementary files
Statistics

Abstract

Background. In Russian clinical practice, there is no systematic information on patients with follicular lymphoma (FL) relapses after first-line therapy, and only isolated data are presented regarding the frequency of early and late relapses in the domestic population, first-line therapy regimens used in these patients, the dynamics of treatment response, timing of relapse, and second-line therapy regimens. A detailed analysis of a large cohort of patients with relapsed FL, including detailed clinical, laboratory, morphoimmunohistochemical, and molecular genetic characteristics, the treatments administered at onset and during relapse, as well as the identification of factors correlating with the risk of early progression, is of great scientific and practical interest. This is the focus of this study. Our results will be aimed at optimizing treatment and improving the prognosis of FL patients in Russia who have received second-line therapy.

Aim. To describe changes in the therapeutic landscape of first-line FL therapy from 2001 to 2025 for patients receiving treatment at the National Medical Research Center for Hematology; to analyze the effectiveness of the therapeutic protocols used; to study cases of treatment resistance and identify significant factors influencing the prognosis of the disease; as well as to determine outcomes for patients with the first early relapse of nodal FL.

Materials and methods. A retrospective and prospective study conducted from 2001 to 2025 at the National Medical Research Center of Hematology (Moscow) included 445 patients with newly diagnosed FL of cytological types 1–2 and 3A (World Health Organization, 2017). The median follow-up was 95 (1–251) months. All patients were treated according to the criteria of the Groupe d’Etude des Lymphomes Folliculaires. All patients included in the study were divided into two groups: those who received initial treatment between 2001 and 2022 (the historical control group; n = 374) and those who received initial treatment between 2022 and 2025 according to the new FL-2022 risk-based differentiated treatment protocol for patients with nodal FL (n = 71). Data for the two groups were analyzed separately.

Results. With a median follow-up of 98 (1–251) months, the 2-year, 5-year, and 10-year overall survival of 374 patients from the historical control group (2001–2022) were 93, 90, and 85 %, respectively; 2-year, 5-year, and 10-year event-free survival were 82, 71, and 55 %, respectively. With high-dose chemotherapy, compared with standard regimens, the proportion of progressions / relapses was significantly lower (26 % versus 40 %; p = 0.01), but if events occurred, they were predominantly early (72 % versus 58 %; p = 0.2). According to the results of multivariate analysis, independent prognostic risk factors for disease progression within 24 months after the start of therapy (POD24) were identified: absence of BCL2 gene rearrangement (odds ratio 3.52 (1.89–6.55); p <0.0001) and 3A cytological type (odds ratio 3.8 (1.61–0.16); p = 0.0033). During second-line therapy in the first early relapse / progression after R-B (rituximab + bendamustine), R-CHOP (rituximab + cyclophosphamide + doxorubicin + vincristine + prednisolone) and autologous hematopoietic stem cell transplantation, complete remission was achieved in only 38 % of patients, and after R-DHAP it was not achieved in any case. With therapy according to the FL-2022 protocol (2022–2025), with a median follow-up of 23 months, 2-year overall survival was 100 %, 2-year event-free survival was 97 %. Second-line therapy was required in only 6 % of patients.

Conclusion. The development of early relapse / progression has a critical impact on the survival prognosis of FL patients. The use of a differentiated treatment protocol for patients with nodal FL (FL-2022), based on clinical, morphological, immunohistochemical, and genetic prognostic factors, has significantly improved treatment outcomes and reduced the risk of POD24. When FL first relapses, there is no uniform treatment standard, and the regimens used vary greatly. Treatment outcomes in the first relapse remain modest, especially for the high-risk POD24 group, necessitating a change in the treatment paradigm for this patient group.

Keywords

follicular lymphoma, prognosis, relapse, POD24, BCL2 gene rearrangement

References

Jacobsen E. Follicular lymphoma: 2023 update on diagnosis and management. Am J Hematol 2022;97(12):1638–51. doi: 10.1002/ajh.26737
Junlén H.R., Peterson S., Kimby E. et al. Follicular lymphoma in Sweden: nationwide improved survival in the rituximab era, particularly in elderly women: a Swedish Lymphoma Registry Study. Leukemia 2015;29:668–76. doi: 10.1038/leu.2014.251
Sarkozy C., Maurer M.J., Link B.K. 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(2):144–52. doi: 10.1200/JCO.18.00400
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
Batlevi C.L., Sha F., Alperovich A. et al. Follicular lymphoma in the modern era: survival, treatment outcomes, and identification of high-risk subgroups. Blood Cancer J 2020;10(7):74. doi: 10.1038/s41408-020-00340-z
Kanas G., Ge W., Quek R.G.W. et al. Epidemiology of diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) in the United States and Western Europe: population-level projections for 2020–2025. Leuk Lymphoma 2022;63(1):54–63. doi: 10.1080/10428194.2021.1975188
Link B.K., Day B.M., Zhou X. et al. Second-line and subsequent therapy and outcomes for follicular lymphoma in the United States: data from the observational National LymphoCare Study. Br J Haematol 2019;184(4):660–3. doi: 10.1111/bjh.15149
Dreyling M., Ghielmini M., Rule S. et al. Newly diagnosed and relapsed follicular lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2021;32(3):298–308. doi: 10.1016/j.annonc.2020.11.008
National Institute for Health and Care Excellence. Single technology appraisal – Idelalisib for treating follicular lymphoma refractory to 2 treatments. 2018. Available from: https://www.nice.org.uk/guidance/ta604/evidence/appraisal-consultation-committee-papers-pdf-6906724813
Russian Clinical Guidelines for the Diagnosis and Treatment of Lymphoproliferative Diseases. Eds.: I.V. Poddubnaya, E.N. Parovichnikova. Moscow, 2024. 184 p. (In Russ.).
Zelenetz A.D., Gordon L.I., Abramson J.S. et al. B-cell lymphomas: NCCN Clinical Practice Guidelines in Oncology. Version 1.2026. National Comprehensive Cancer Network® (NCCN)®, 2026.
Guzauskas G.F., Masaquel A., Reyes C. et al. Cost-effectiveness of obinutuzumab plus bendamustine followed by obinutuzumab monotherapy for the treatment of follicular lymphoma patients who relapse after or are refractory to a rituximab-containing regimen in the US. J Med Econ 2018;21(10):960–7. doi: 10.1080/13696998.2018.1489254
Sehn L.H., Chua N.S., Mayer J. et al. GADOLIN: primary results from a Phase III study of obinutuzumab plus bendamustine compared with bendamustine alone in patients with rituximab-refractory indolent non-Hodgkin lymphoma J Clin Oncol 2015;33(18_suppl): LBA8502. doi: 10.1200/jco.2015.33.18_suppl.lba8502
Leonard J.P., Trneny M., Izutsu K. 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(14):1188–99. doi: 10.1200/JCO.19.00010
Montoto S., Corradini P., Dreyling M. et al. Indications for hematopoietic stem cell transplantation in patients with follicular lymphoma: a consensus project of the EBMT Lymphoma Working Party. Haematologica 2013;98(7):1014–21. doi: 10.3324/haematol.2013.084723
Rohatiner A.Z., Nadler L., Davies A.J. et al. Myeloablative therapy with autologous bone marrow transplantation for follicular lymphoma at the time of second or subsequent remission: long-term follow-up. J Clin Oncol 2007;25(18):2554–9. doi: 10.1200/JCO.2006.09.8327
Jiménez- Ubieto A., Grande C., Caballero D. et al. Autologous stem cell transplantation for follicular lymphoma: favorable long-term survival irrespective of pretransplantation rituximab exposure. Biol Blood Marrow Transplant 2017;23(10):1631–40. doi: 10.1016/j.bbmt.2017.05.021
Smolyaninova A.K., Belyaeva A.V., Nesterova E.S., Zvonkov E.E. MRD-controlled “FL-2015” protocol. In: Al-Radi L.S., Bagova M.O., Badmadzhapova D.S. et al. Diagnostic algorithms and treatment protocols for blood diseases. Vol. 2. Moscow, 2024. Pp. 97–101. (In Russ.).
Nesterova E.S., Kravchenko S.K., Baryah E.A. et al. Autologous stem cells transplantation in the first remission of follicular lymphoma as “rescue therapy” in patients with unfavorable prognosis factors. The first prospective study results. Sovremennaya onkologiya = Journal of Modern Oncology 2016;18(5):31–2. (In Russ.).
Nesterova E.S., Kravchenko S.K., Mangasarova Ya.K. et al. Follicular lymphoma. High-dose immunochemotherapy with autologous blood stem cell transplantation: results of the first prospective study in Russia. Terapevticheskiy arkhiv = Therapeutic Archive 2016;88(7):62–71. (In Russ.). doi: 10.17116/terarkh201688762-71
Nesterova E.S., Kravchenko S.K., Kovrigina A.M. et al. Follicular lymphoma: first-line selection criteria of treatment. Terapevticheskiy arkhiv = Therapeutic Archive 2019;91(8):75–83. (In Russ.). doi: 10.26442/00403660.2019.08.000388
Nesterova E.S., Kravchenko S.K., Kovrigina A.M. et al. Follicular lymphoma: results of multicenter study of first-line therapy with bendamustine and rituximab; risk factors for adverse events (FL-RUS-2013 protocol). Onkogematologiya = Oncohematology 2018;13(3):10–24. (In Russ.). doi: 10.17650/1818-8346-2018-13-3-10-24
Abdurakhmanov D.T., Abuzarova G.R., Ageeva T.A. et al. Russian clinical guidelines for the diagnosis and treatment of lymphoproliferative diseases. Eds.: I.V. Poddubnaya. V.G. Savchenko. Russian Society of Oncohematologists, 2018. Available at: https://rusoncohem.ru/klinrec/klin-rekomendatsii-limfoproliferativnykh-zabolevaniy (In Russ.)
Nesterova E.S., Kovrigina A.M., Magomedova A.U. et al. Risk-based differentiated treatment protocol for patients with follicular lymphoma “FL-2022”. Vol. 2. Moscow, 2024. Pp. 102–116. (In Russ.).
Jones K., Savulescu A.F., Brombacher F., Hadebe S. Immunoglobulin M in health and diseases: how far have we come and what next? Front Immunol 2020;11:595535. doi: 10.3389/fimmu.2020.595535
Northend M., Wilson W., Clifton-Hadley L. et al. Long term follow-up of international randomised phase 3 study of rituximab versus a watch and wait approach for patients with asymptomatic, low tumour burden follicular lymphoma shows rituximab is highly effective at delaying time to new treatment without detrimental impact following next line of therapy. Blood 2022;140(S1):1456–8. doi: 10.1182/blood-2022-156790
Kridel R., Sehn L.H., Gascoyne R.D. Can histologic transformation of follicular lymphoma be predicted and prevented? Blood 2017;130(3):258–66. doi: 10.1182/blood-2017-03-691345
Solal-Céligny 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
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
Nesterova E.S., Kravchenko S.K., Gemdzhyan E.G. et al. Results of the 10-year experience gained in the treatment of patients with follicular lymphoma. Gematologiya i transfuziologiya = Russian Journal of Hematology and Transfuziology 2012;57(5):3–8. (In Russ.).
WHO classification of hematolymphoid tumors. 5th edn. IARC, 2024. 930 p.
Hamova I., Maco M., Tkachenko A. et al. Circulating tumor DNA as a powerful tool in diagnostics and treatment outcome prediction – focus on large B-cell lymphomas and follicular lymphomas. Expert Rev Mol Diagn 2025;25(6):275–95. doi: 10.1080/14737159.2025.2500659
Pott C., Jurinovic V., Trotman J. et al. Minimal residual disease status predicts outcome in patients with previously untreated follicular lymphoma: a prospective analysis of the phase III GALLIUM study. J Clin Oncol 2024;42(5):550–61. doi: 10.1200/JCO.23.00838
Barraclough A., Agrawal S., Talaulikar D. et al. Impact and utility of follicular lymphoma GELF criteria in routine care: an Australasian Lymphoma Alliance study. Haematologica 2024;109(10):3338–45. doi: 10.3324/haematol.2023.284538
Jacobson C., Chavez J.C., Sehgal A.R. et al. Primary analysis of Zuma-5: a phase 2 study of Axicabtagene Ciloleucel (Axi-Cel) in patients with relapsed/refractory (R/R) indolent non-Hodgkin lymphoma (iNHL). Blood 2020;136(Suppl 1):40–1. doi: 10.1182/blood-2020-136834
Schuster S.J., Dickinson M.J., Dreyling M.H. et al. Efficacy and safety of tisagenlecleucel (Tisa-cel) in adult patients (Pts) with relapsed/refractory follicular lymphoma (r/r FL): primary analysis of the phase 2 Elara trial. J Clin Oncol 2021;39(15_suppl):7508. doi: 10.1200/JCO.2021.39.15_suppl.7508
Jacobson C.A., Chavez J.C., Sehgal A.R. et al. Axicabtagene ciloleucel in relapsed or refractory indolent non-Hodgkin lymphoma (ZUMA-5): a single-arm, multicentre, phase 2 trial. Lancet Oncol 2022;23(1):91–103. doi: 10.1016/S1470-2045(21)00591-X
Fowler N.H., Dickinson M., Dreyling M. et al. Tisagenlecleucel in adult relapsed or refractory follicular lymphoma: the phase 2 ELARA trial. Nat Med 2021;28(2):325–32. doi: 10.1038/s41591-021-01622-0
Chavez J.C., Locke F.L. CAR T cell therapy for B-cell lymphomas. Best Pract Res Clin Haematol 2018;31(2):135–46. doi: 10.1016/j.beha.2018.04.001
Budde L.E., Sehn L.H., Matasar M. et al. Safety and efficacy of mosunetuzumab, a bispecific antibody, in patients with relapsed or refractory follicular lymphoma: a single-arm, multicentre, phase 2 study. Lancet Oncol 2022;23(8):1055–65. doi: 10.1016/S1470-2045(22)00335-7
Morschhauser F., Le Gouill S., Feugier P. et al. Obinutuzumab combined with lenalidomide for relapsed or refractory follicular B-cell lymphoma (galen): a multicentre, single-arm, phase 2 study. Lancet Haematol 2019;6(8):e429–37. doi: 10.1016/S2352-3026(19)30089-4

Supplementary files

Supplementary Files

Action

1. JATS XML

Download

Username
Password
Remember me

Forgot password?	Register

Username
Password
Remember me

Forgot password?	Register

Evolution of approaches to follicular lymphoma therapy at disease onset and first relapse. Twenty-five-year experience of the National Medical Research Center for Hematology

Full Text

Abstract

Keywords

About the authors

References

Supplementary files