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 others), bone marrow damage, β2-microglobulin (more than 2.2 mg/L), age (over 68 years) and hemoglobin (less than 110 g/dL).

Conclusion 1. The independent negative predictors of OS and PFS in follicular lymphoma were determined. 2. Of the predictors of an adverse event identified, the greatest risk (as a result of a multivariate analysis) is associated with a 3A cytological type of tumor. 3. The FLIPI index has a predictive value not only for the determination of OS, but also for the PFS (moreover, in reduced dichotomous form: 5 points against all the others combined). 4. An increase in the time interval between the first manifestations of follicular lymphoma (lymph node enlargement / appearance of a tumor formation) and the start of therapy beyond a certain threshold value (estimated to be approximately 22 months) is associated (according to the results of univariate analysis) with an increased risk of an adverse event. One of the reasons for the increase in this time interval is associated with expectant medical tactics adopted during the slow development of the clinical picture of the disease. The obtained result shows that the low rate of development of the clinical picture of the disease does not correlate with the low risk of adverse events, and, therefore, cannot be a determining factor when deciding whether to start treatment. 5. The morphology of the tumor is the determining factor in the choice of induction therapy. 6. After achieving full/partial remission of FL, there is a constant risk of recurrence of the disease (by the age of 3 from the termination of treatment, the risk is 11 % (95 % CI 3–19)). 7. The R–B course effectively sanitizes the bone marrow. 8. The R–B allows performing stem cells mobilization and autoSCT that is actual in FL patients with bone marrow involvement. 9. The treatment regimen of R–B is effective and has a relatively low toxicity, so it is advisable in the treatment of elderly patients.

1. Solal-Céligny P., Leconte P., Bardet A. et al. A retrospective study on the management of patients with rituximab refractory follicular lymphoma. Br J Haematol 2018;180(2):217–23. DOI: 10.1111/bjh.15023. PMID: 29230799.

2. Mounier M., Bossard N., Remontet L. et al. Changes in dynamics of excess mortality rates and net survival after diagnosis of follicular lymphoma or diffuse large B-cell lymphoma: comparison between European population-based data (EUROCARE-5). Lancet Haematol 2015;2(11):e481–91. DOI: 10.1016/S2352-3026(15)00155-6. PMID: 26686258.

3. Teras L. R., DeSantis C.E., Cerhan J. R. et al. 2016 US lymphoid malignancy statistics by World Health Organization subtypes. CA Cancer J Clin 2016;66(6): 443–59. DOI: 10.3322/caac.21357. PMID: 27618563.

4. Sancho J. M., García O., Mercadal S. et al. The long term follow-up of early stage follicular lymphoma treated with radiotherapy, chemotherapy or combined modality treatment. Leuk Res 2015;39(8):853–8. DOI: 10.1016/j.

5. leukres. 2015.05.009. PMID: 26122511.

6. 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. PMID: 26124482.

7. Mangasarova Ya. K., Magomedova A. U., Kravchenko S. K. et al. Eight-year experience in treating aggressive mediastinal large B-cell lymphomas. Terapevticheskiy Arkhiv = Therapeutic Archive 2013;85(7):50–6. (In Russ.). PMID: 24137947.

8. Casulo C., Nastoupil L., Fowler N. H. et al. Unmet needs in the first-line treatment of follicular lymphoma. Ann Oncol 2017;28(9):2094–106. DOI: 10.1093/annonc/mdx189. PMID: 28430865.

9. 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. PMID: 26256760.

10. Lopez-Guillermo A. A novel clinicogenetic prognostic score for follicular lymphoma. Lancet Oncol 2015;16(9):1011–2. DOI: 10.1016/S1470-2045(15)00142-4. PMID: 26256759.

11. Kahl B. S. Follicular lymphoma: are we ready for a risk-adapted approach? Hematology Am Soc Hematol Educ Program 2017;2017(1):358–64. DOI: 10.1182/asheducation-2017.1.358. PMID: 29222279.

12. Nastoupil L., Sinha R., Hirschey A., Flowers C. R. Considerations in the initial management of follicular lymphoma. Community Oncol 2012;9(11):S53–60. DOI: 10.1016/j.cmonc.2012.09.015. PMID: 23544009.

13. Dreyling M., Ghielmini M., Marcus R. et al. Newly diagnosed and relapsed follicular lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2014;25(S3):76–82. DOI: 10.1093/annonc/mdx020. PMID: 28327933.

14. Nesterova E.S., Kravсhenko S.K., Gemdzhian E.G. et al. Evaluation of tumor vascularization and microenvironment in follicular lymphoma. Terapevticheskiy Arkhiv = Therapeutic Archive 2013;85(7):57–64. (In Russ.). PMID: 24137948.

15. McNamara C., Davies J., Dyer M. et al. Guidelines on the investigation and management of follicular lymphoma. Br J Haematol 2012;156(4):446–7. DOI: 10.1111/j.1365-2141.2011.08969.x. PMID: 22211428.

16. Swerdlow S. H., Campo E., Pileri S. A. et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood 2016;127(20):2375–90. DOI: 10.1182/blood-2016-01-643569. PMID: 26980727.

17. Khamaganova E. G., Parovichnikova E. N., Kuz’mina L. A. et al. Selection of an unrelated donor for hematopoietic stem cell transplantation. HLA haplotypes in patients with blood system diseases. Terapevticheskiy Arkhiv = Therapeutic Archive 2014;86(7):31–6. (In Russ.). PMID: 25314775.

18. Nesterova E. S., Kravchenko S. K., Baryakh 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 = Modern Oncology 2016;18(5):31–2. (In Russ.).

19. Mondello P., Steiner N., Willenbacher W. et al. Bendamustine plus Rituximab Versus R–CHOP as First-Line Treatment for Patients with Follicular Lymphoma Grade 3A: Evidence from a Multicenter, Retrospective Study. Oncologist 2018;23(4):454–60. DOI: 10.1634/theoncologist.2017-0037. PMID: 29317554.

20. Federico M., Luminari S., Dondi A. et al. R-CVP versus R–CHOP versus R-FM for the initial treatment of patients with advanced-stage follicular lymphoma: results of the FOLL05 trial conducted by the Fondazione Italiana Linfomi. J Clin Oncol 2013;31(12):1506–13. DOI: 10.1200/JCO.2012.45.0866. PMID: 23530110.

21. Flinn I. W., van der Jagt R., Kahl B. S. et al. Randomized trial of bendamustinerituximab or R–CHOP/R-CVP in firstline treatment of indolent NHL or MCL: the BRIGHT study. Blood 2014;123(19):2944–52. DOI: 10.1182/blood-2013-11-531327. PMID: 24591201.

22. Darwish M., Bond M., Hellriegel E. et al. Pharmacokinetic and pharmacodynamic profile of bendamustine and its metabolites. Send to Cancer Chemother Pharmacol 2015;75(6):1143–54. DOI: 10.1007/s00280-015-2727-6. PMID: 25829094.

23. Mondello P., Steiner N., Willenbacher W. et al. Bendamustine plus rituximab versus R–CHOP as first-line treatment for patients with indolent non-Hodgkin’s lymphoma: evidence from a multicenter, retrospective study. Ann Hematol 2016;95(7):1107–14. DOI: 10.1007/s00277-016-2668-0. PMID: 27103007.

24. Cheson B. D., Fisher R. I., Barrington S. F. et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol 2014;32(27):3059–68. DOI: 10.1200/JCO.2013.54.8800. PMID: 25113753.

25. Kaplanov K. D., Shipayeva A. L., Vasilyeva V. A. et al. Experience of application the International Prognostic Index(MPI) in the advanced stages of Hodgkin»s lymphoma in modern therapy. Klinicheskaya Onkogematologiya = Clinical Oncohematology 2013;6(3):294–302. (In Russ.).

26. Kravchenko S. K., Nesterova E. S. A randomized, controlled(comparative), open, prospective study evaluating the effectiveness of R-EPOCH-21, R–CHOP-21 programs and autologous stem cells transplantation in patients with high-risk follicular lymphoma. In: Diagnostic algorithms and treatment protocols of blood system diseases. Ed.: V. G. Savchenko. Moscow: Praktika, 2018. Vol. 2. P. 497–530. (In Russ.).

27. Kravchenko S. K., Nesterova E. S. Prospective multicenter study: first-line combination therapy with bendamustine and rituximab followed by rituximab maintenance therapy in patients with follicular lymphoma (FL-RUS-2013 protocol). In: Diagnostic algorithms and treatment protocols of blood system diseases. Ed.: V. G. Savchenko. Moscow: Praktika, 2018. Vol. 2. P. 101–131. (In Russ.).

28. Kravchenko S. K., Nesterova E. S., Baryakh E. A. The treatment protocol for high-risk follicular lymphoma. In: Collection of Diagnostic algorithms and treatment protocols of blood system diseases. Ed.: V. G. Savchenko. Moscow: Praktika, 2012. P. 595–618. (In Russ.).

29. Nesterova E. S., Kravchenko S. K., Mangasarova Ya. K. et al. Leukemization of follicular lymphoma: The features of diagnostic and clinical course of a rare form of the disease. Terapevticheskiy Arkhiv = Therapeutic Archive 2017;89(7):45–50. (In Russ.). DOI: 10.17116/terarkh201789745-50. PMID: 28766540.

30. 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. Terapevticheskii Arkhiv = Therapeutic Archive 2016;88(7):62–71.(In Russ.) DOI: 10.17116/terarkh201688762–71. PMID: 27459617.

31. Nesterova E. S., Kravchenko S. K., Baryakh E. A., et al. Autologous stem cell transplantation (AutoSCT) in first remission of follicular lymphoma (FL) “save“ patients (pts) with poor prognosis. results of the first Russian prospective study. Blood 2015;126(23):5079.

32. Nesterova E. S., Kravchenko S. K., Gemdzhian E. G. et al. The results of ten years’ experience treating patients with follicular lymphoma. Gematologiya i transfuziologiya = Hematology and Transfusiology 2012;57(5):3–8. (In Russ).

33. Galimberti S., Ciabatti E., Ercolano G. et al. The Combination of Rituximab and Bendamustine as First-Line Treatment Is Highly Effective in the Eradicating Minimal Residual Disease in Follicular Lymphoma: An Italian Retrospective Study. Front Pharmacol 2017;8:413. DOI: 10.3389/fphar. 2017.00413. PMID: 28706485.