Evidence of bendamustine plus rituximab for old and frail patients with aggressive B-cell lymphoma

Annals of Hematology https://doi.org/10.1007/s00277-023-05166-w LETTER TO THE EDITOR Evidence of bendamustine plus rituximab for old and frail patients with aggressive B‑cell lymphoma Enrico Schalk1 · Kathleen Jentsch‑Ullrich2 Received: 7 February 2023 / Accepted: 6 March 2023 © The Author(s) 2023 Dear Editor, Recently, the largest prospective cohort of old and frail patients with aggressive B-cell lymphoma and bendamustine/rituximab (BR) as first-line treatment was reported (B-R-ENDA trial) [1]. B-R-ENDA was a multi-center, prospective, non-randomized trial on patients > 80 or 61–80 years not qualifying for CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone)-like therapy. Sixty-eight patients were included, with 39 patients (57%) > 80 years (target cohort; Table 1). However, due to slow recruitment, the trial was terminated before the planned target (50 patients > 80 years) was reached [1]. In line with four other bendamustine-based prospective trials (with only 14–49 patients) [1], it shows the difficulty of performing clinical trials in this patients’ population. These difficulties and the fact that standard treatment for old or frail patients not eligible for CHOP(-like) therapy has not been defined [1], retrospective studies are useful to answer important clinical questions [2]. To build more evidence on BR for older patients with aggressive B-cell lymphoma and to compare the results of a prospective clinical trial with real-world data, the aim was to compare the B-R-ENDA data with another study. However, it is difficult to compare different studies, e.g., multicenter vs. single-center analysis, prospective vs. retrospective design, differences in inclusion/exclusion criteria, study endpoints, or sample sizes. A retrospective study on 68 patients treated with BR for aggressive B-cell lymphoma (R-Benda study) [3] is useful for comparison with B-R-ENDA because that was also a multi-center study with the same sample size. * Enrico Schalk 1 Department of Hematology and Oncology, Medical Center, Otto-von-Guericke University Magdeburg, Leipziger Str. 44, 39120 Magdeburg, Germany 2 Practice for Hematology and Oncology, Magdeburg, Germany R-Benda was conducted on older or frail patients ≥ 65 years with ECOG performance score (PS) ≥ 2 or ≥ 75 years regardless of ECOG PS with de novo diffuse large B-cell lymphoma (DLBCL). The aim of this study was to compare the outcome of patients treated with BR vs. rituximab/CHOP. Sixty-eight patients treated with BR were analyzed within this study [3]. For direct comparison of both R-Benda and B-R-ENDA, the same parameters and endpoints, respectively, need to be analyzed. Therefore, the original R-Benda data set had to be re-evaluated according to the B-R-ENDA analyses (Table 1). Regarding age, the whole R-Benda cohort was comparable with the whole B-R-ENDA cohort (median age 80 vs. 81 years). There were also no statistical differences in the portion of patients > 80 years (41% vs. 57%; P = 0.09). However, in R-Benda, in the subgroup of > 80 years (and the whole R-Benda cohort), there were fewer females than in B-R-ENDA. Regarding lymphoma specific parameters, in R-Benda, more patients > 80 years (and in the whole R-Benda cohort) had extranodal involvement compared to B-R-ENDA. According to the International Prognostic Index (IPI) score, in R-Benda, at least numeric more patients > 80 years (and in the whole cohort) had high-risk disease than in B-R-ENDA. The remission rates in the subgroup > 80 years (and in the whole cohort) were comparable between R-Benda and B-R-ENDA (Table 1). However, the overall response rate (sum of complete and partial remission) in the whole R-Benda cohort was higher compared to the whole B-R-ENDA cohort (62% vs. 41%; P = 0.03), caused by the higher complete remission (CR) rate in the cohort 61–80 years in R-Benda (44% vs. 10%; P = 0.005). The lower CR rate in B-R-ENDA, however, was expected based on the inclusion criteria for this age group [1]. The primary endpoint in B-R-ENDA was progressionfree survival at 2 years (2y-PFS) [1]. After re-assessment of the R-Benda data set, it was possible to provide also the 2y-PFS rate. In the subgroup > 80 years, the 2y-PFS in R-Benda was markedly inferior compared to B-R-ENDA 13 Vol.:(0123456789) Annals of Hematology Table 1  Comparison of R-Benda study and B-R-ENDA trial R-Benda study n = 68 B-R-ENDA trial n = 68 Publication year 2019 2022 Study period February 2008–September 2017 July 2012–February 2016 Study sites, n, country 4, Germany 24, Germany Study design Retrospective Prospective, phase 2 Included pathological diagnosis Diffuse large B-cell lymphoma CD20 + aggressive B-cell lymphoma Population/Subgroups > 80 years n = 28 61–80 years n = 40 Total n = 68 > 80 years n = 39 61–80 years n = 29 Total n = 68 P value Patients’ characteristics Females, n/N (%) 10/28 (36) 23/40 (58) 33/68 (49) 28/39 (72) 18/29 (62) 46/68 (68) Age, median, years (range) Age groups, n/N (%) 61–75 years 83.5 (81–91) 77.5 (68–80) 80 (68–91) 84 (81–95) 77 (64–80) 81 (64–95) - 7/40 (18) 7/68 (10) - 8/29 (28) 8/68 (12) 76–80 years - 33/40 (83) 33/68 (49) - 21/29 (72) 21/68 (31) 81–85 years 22/28 (79) - 22/68 (32) 25/39 (64) - 25/68 (37) > 85 years 6/28 (21) - 6/68 (9) 14/39 (36) - 14/68 (21) ECOG PS > 1, n/N (%) 8/26 (31) 16/39a (41) 24/65a (37) 9/39 (23) 15/29 (52) 24/68 (35) Stage III/IV, n/N (%) 20/28 (71) 28/40 (70) 48/68 (71) 20/39 (51) 19/29 (66) 39/68 (57) Extranodal involvement, n/N (%) 24/28 (86) 31/40 (78) 55/68 (81) 21/39 (54) 19/29 (66) 40/68 (59) IPI score (risk), n/N (%) 1 (low) 2/25a (8) 1/37a (3) 3/62a (5) 6/39 (15) 2/29 (7) 8/68 (12) 2 (low-intermediate) 5/25a (20) 9/37a (24) 14/62a (23) 15/39 (38) 5/29 (17) 20/68 (29) 3 (high-intermediate) 7/25a (28) 11/37a (30) 18/62a (29) 11/39 (28) 12/29 (41) 23/68 (34) 4–5 (high) 11/25a (44) 16/37a (43) 27/62a (44) 7/39 (18) 10/29 (34) 17/68 (25) Bulky disease, n/N (%) 11/28 (39) 10/39a (26) 21/67a (31) 8/39 (21) 11/29 (38) 19/68 (28) Bone marrow involvement, n/N (%) 1/22a (5) 7/38a (18) 8/60a (13) 0 2/29 (7) 2/68 (3) Diffuse large B-cell lymphoma, n/N (%) 28/28 (100) 40/40 (100) 68/68 (100) 31/39 (79) 26/29 (90) 57/68 (84) General study overview 13 0.007* 0.90** 0.04*** n/a 0.48** 1.00*** 0.48** 0.05*** 0.31* 0.72*** 0.31* 0.09*** 0.68* 0.53** 0.99*** 0.16* 0.89** 0.15*** 0.01* 0.41** 0.008*** 0.64* 0.82** 0.27*** 0.20* 0.70** 0.49*** 1.00* 0.47** 0.69*** 0.05* 0.64** 0.04*** 0.16* 0.41** 0.81*** 0.72* 0.31** 0.06*** - Annals of Hematology Table 1  (continued) R-Benda study n = 68 B-R-ENDA trial n = 68 Publication year 2019 2022 Study period February 2008–September 2017 July 2012–February 2016 Study sites, n, country 4, Germany 24, Germany Study design Retrospective Prospective, phase 2 Included pathological diagnosis Diffuse large B-cell lymphoma CD20 + aggressive (...truncated)