Follicular lymphoma: results of multicenter study of first-line therapy with bendamustine and rituximab, risk factors for adverse events (fl-rus-2013 protocol)
Background. Follicular lymphoma (FL) is the most common type of indolent lymphomas and accounts for 20–30 % of all non-Hodgkin's lymphomas detected. High risk of recurrence and elderly patients make it difficult to choose induction therapy for FL. The R–B course in comparison with the R–CHOP course increases the progressive free survival (PFS) of FL patients and is less toxic. International studies have not studied the efficacy and toxicity of the R–B course due to various cytological types of FL.Aim of the study – assessment of the effectiveness and toxicity of the R–B course (with R support) in general and depending on the different cytological types of FL, the assessment of overall survival (OS) and PFS (adverse events: progression, relapse, death); identification of risk factors for an adverse event in general and death, in particular. The main endpoint of this study is selected BPV.Materials and methods. We performed a prospective, multicenter, open-label trial in Russia since June 1, 2013 till June 1, 2018. The study included 74 patients with FL. Median age of patients was 59 years (from 30 to 78 years). Treatment was completed in 66 patients, so this group of patients was analyzed. Ratio between men and women was 1:2. 32/66 of patients (48 %) were older than 60 years old. Patients received rituximab 375 mg/m2 on day 1 and bendamustine 90 mg/m2 on days 1 and 2 of a 4-week cycle (6 cycles). 49/66 (74 %) of patients were diagnosed with FL grade 1, 10/66 (15 %) – grade 2, 7/66 (11 %) – grade 3A. 34/66 (52 %) patients had nodular tumor growth type, 28/66 (42 %) – nodular-diffuse, 4/66 (6 %) – diffuse. High risk according to FLIPI had 25/59 (42 %) of patients with cytologic grade of FL 1–2 and 7/7 (100 %) of patients with FL grade 3A. Extranodal lesions were revealed in 26/66 (39 %) of cases: in 4/66 of cases – orbit, in 2/66 – parotid gland, in 5/66 – lungs, in 4/66 – intestines, in 2/66 – stomach, 2/66 – pancreas, 2/66 – uterus, 2/66 – skin, 1/66 – subcutaneous tissue, 3/66 – vertebrae, in 1/66 – latticed maze and nasal passages, 1/66 – kidneys, 1/66 – root of the tongue. In 23/26 (88 %) of cases extranodal lesion was revealed in generalized stage of FL (including lymph nodes and bone marrow). Extranodal lesions were found in 37 % of patients with FL grade 1–2, and 57 % with FL grade 3A. Bulky also was observed more frequently in pts with FL grade 3 3/7 (43 %) than in patients with FL grade 1–2 20/59 (34 %). (The risk factors of an adverse event are also its predictors in this study.)Results. Complete remission of disease was achieved in 40/66 (61 %) patients, partial remission – 13/66 (19 %) patients. Tumor progression observed in 11/66 (17 %) cases, patients were withdrawn from the protocol. А partial tumor response was achieved in 2/66 cases (3 %) and patients received high-dose therapy after 4 courses of R–B. Five-year (as well as the 3-year) overall survival (OS) of all patients (n = 66) in R–B was 90 % (95 % confidence interval (CI) 78–96), 5-year PFS – 70 % (95 % CI 55–85) and a 3-year PFS – 75 % (95 % CI 60–89). The cumulative incidence of relapse (considering competing risks of progression and death) at the 3th year after initiation of treatment was 11 % (95 % CI 3–19). The following independent statistically significant (p ≤0.05) predictors of PFS (measured in the onset of the disease) were determined (as a result of a stepwise multivariate cox regression analysis): 1) cytological type of tumor (only type 3A is significant); 2) involvement of nodal zones (more than 4); 3) presence of a conglomerate of tumor lymph nodes larger than 6 cm (bulky); 4) Ki-67 protein expression (more than 35 %). The first 3 characteristics (as well as the sign «presence of extranodal foci», close to the level of significance) are independent statistically significant predictors of OS. In the single factor analysis the following characteristics (besides the above) were significant: index FLIPI (significant only 5 points against all other