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

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.