Annals of Hematology (2019) 98:2729–2737 https://doi.org/10.1007/s00277-019-03819-3 ORIGINAL ARTICLE Is bendamustine-rituximab a reasonable treatment in selected older patients with diffuse large B cell lymphoma? Results from a multicentre, retrospective study Vanja Zeremski1,2 & Kathleen Jentsch-Ullrich3 & Christoph Kahl4 & Martin Mohren5 & Judith Eberhardt1,2 & Thomas Fischer1,2 & Enrico Schalk1,2 Received: 12 June 2019 /Accepted: 8 October 2019/Published online: 8 November 2019 # Springer-Verlag GmbH Germany, part of Springer Nature 2019 Abstract Despite bendamustine-rituximab (BR) showed disappointing efficacy in diffuse large B cell lymphoma (DLBCL), it is still occasionally used as first-line treatment in older DLBCL patients instead of recommended R-CHOP. This multicentre, retro- spective study was aimed to clarify circumstances in which BR may be justified in this setting. Patients ≥ 65 years with ECOG performance status (PS) ≥ 2or≥ 75 years regardless of PS were included. A total of 140 patients were analysed (BR, 68; R- CHOP, 72). BR patients were older (p < 0.001) and were diagnosed more often with high-risk disease (p = 0.03); no difference regarding comorbidities or PS was seen. Compared with R-CHOP, BR was associated with marked inferior overall survival (OS) (16.3 vs. 75.4 months; p = 0.006) and progression-free survival (PFS) (11.0 vs. 62.3 months; p < 0.001). In multivariate analysis, only high age-adjusted Charlson Comorbidity Index (aaCCI) was associated with inferior PFS in R-CHOP patients (hazard ratio 2.67; p = 0.012). Comparing the subgroup of BR and R-CHOP patients with high aaCCI, there was no difference in OS (p =0.73) or PFS (p = 0.75). Due to the observed non-superiority of R-CHOP in older DLBCL patients with comorbidities, we propose that this subgroup may be treated alternatively with BR, whereas all other older patients are clearly R-CHOP candidates. Keywords Diffuse large B cell lymphoma . Bendamustine . R-CHOP . Older patients . Comorbidities Introduction former definition of ‘older NHL patients’ as patients older than 60 years [3] seems to be abandoned. The age of 75 years Diffuse large B cell lymphoma (DLBCL) is an aggressive was suggested as a new cut-off for ‘older patients’, due to non-Hodgkin lymphoma (NHL) occurring commonly in older higher prevalence of comorbidities and age-related physiolog- patients, with a median age of 70 years at diagnosis [1, 2]. The ical changes in this age group [4, 5]. However, when defining an older patient, other factors in addition to chronological age must be considered, i.e. functional status and comorbidities. * Vanja Zeremski [email protected] Standard treatment with R-CHOP (rituximab, cyclophos- phamide, doxorubicin, vincristine and prednisolone) is ad- vised irrespective of patient’sage[6–8], despite higher toxic- 1 Department of Haematology and Oncology, Otto-von-Guericke ity rates reported in older patients [9, 10]. In order to minimize University Magdeburg, Leipziger Str. 44, 39120 Magdeburg, Germany toxicity and improve quality of life, R-CHOP was often chal- 2 lenged, and diverse reduced-intensity dose regimens with/ Health Campus Immunology, Infectiology and Inflammation – (GC-I3), Medical Centre, Otto-von-Guericke University, without anthracyclines were tested [11 14]. Magdeburg, Germany Bendamustine is a cytotoxic alkylating agent that is world- 3 Private Practice for Haematology and Oncology, wide approved for the treatment of chronic lymphocytic leu- Magdeburg, Germany kaemia and other indolent NHL. In combination with rituxi- 4 Department of Haematology, Oncology and Palliative Care, mab (BR), it was shown not only to be efficient but also well Klinikum Magdeburg, Magdeburg, Germany tolerated in indolent NHL [15, 16]. Consequently, BR was 5 Department of Hematology and Oncology, Johanniter Krankenhaus, tested in DLBCL patients, initially in relapse/refractory set- Stendal, Germany tings and then also as first-line treatment [17–19]. The 2730 Ann Hematol (2019) 98:2729–2737 Table 1 Patients’ baseline characteristics Variables Total (n =140) BR(n = 68) R-CHOP (n =72) p value Age Median (range), years 79 (65–93) 80 (68–91) 77 (65–93) p <0.001 Age ≥ 80 years (n) 56 (40.0%) 36 (52.9%) 20 (27.8%) p <0.001 Sex (n) Male 69/140 (49.3%) 35/68 (51.5%) 34/72 (48.6%) p =0.73 ECOG performance status (n) 0–1 84/132 (63.6%) 41/65 (63.1%) 43/67 (64.2%) p =1.0 2–4 48/132 (36.4%) 24/65 (36.9%) 24/67 (35.8%) n/a 8 3 5 aaCCI score (n) Low (2–3) 30/140 (21.4%) 12/68 (17.6%) 18/72 (25.0%) p =0.36 Intermediate (4–5) 78/140 (55.7%) 42/68 (61.8%) 36/72 (50.0%) High (≥ 6) 32/140 (22.9%) 14/68 (20.6%) 18/72 (25.0%) LVEF ≤ 50% (n) Yes 21/96 (21.9%) 14/48 (29.2%) 7/48 (14.6%) p =0.14 n/a 44 20 24 Ann Arbor stage (n) Limited (I–II) 53/140 (37.9%) 20/68 (29.4%) 33/72 (45.8%) p =0.06 Advanced (III–IV) 87/140 (62.1%) 48/68 (70.6%) 39/72 (54.2%) Extranodal involvement (n) Yes 105/140 (75.0%) 55/68 (80.9%) 50/72 (69.4%) p =0.17 Bulky disease (n) Yes 39/136 (28.7%) 21/67 (31.3%) 18/69 (26.1%) p =0.57 n/a 4 1 3 aaIPI (n) Low (0–1) 51/127 (40.2%) 20/60 (30.0%) 33/67 (49.3%) p =0.03 High (2–3) 76/127 (59.8%) 42/60 (70.0%) 34/67 (50.7%) n/a 13 8 5 BR bendamustine, rituximab; R-CHOP rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone; ECOG: Eastern Cooperative Oncology Group; n/a not available; aaCCI age-adjusted Charlson Comorbidity Index; LVEF left ventricular ejection fraction; aaIPI age-adjusted international prognostic score outcome was rather disappointing. Nevertheless, BR is still diagnosed from February 2008 until September 2017, with occasionally used as first-line treatment in DLBCL [20–22], last follow-up as of January 2019. Of note, older patients were leaving the question whether this is justified as an alternative defined as those ≥ 65 years with Eastern Cooperative to R-CHOP and what are the appropriate candidates for this Oncology Group (ECOG) performance status (PS) ≥2orthose treatment approach. To answer that, we have retrospectively ≥75 years regardless of PS [4, 5, 14]. Only patients that re- analysed clinical characteristics and outcomes of older ceived BR or R-CHOP were included in this analysis. All DLBCL patients treated with BR in first-line and compared other patients treated with best supportive care, radiation or them to other older DLBCL patients treated with R-CHOP surgery treatment only as well as those treated with alternative regimen. regimen (i.e. R-CVP, R-GCVP) were not included in this study. Patients with relapsed/refractory DLBCL, secondary DLBCL and primary central nervous system lymphoma were Materials and Methods excluded. Data regarding patients’ characteristics, diagnosis, therapy and outcome were obtained reviewing patients’ med- Study design ical history. Given the advanced age in this analysed popula- tion, we used the age-adjusted Charlson Comorbidity Index This retrospective study was conducted at four institutions in (aaCCI) in order to assess comorbidities [23]. Other than in Germany on older consecutive patients with de novo DLBCL the original aaCCI, no point was assigned for the presence of Ann Hematol (2019) 98:2729–2737 2731 DLBCL. Due to retrospective nature of the study, comprehen- Results sive geriatric assessment was not possible. The age-adjusted International Prognostic Index (aaIPI) was applied as a prog- Patients’ characteristics nostic score [3]. This study was approved by the institutional Ethical Committees. Written informed consent was not taken Altogether, 140 older patients were identified that met above- due to this retrospective, non-interventional study. All proce- stated inclusion criteria. Median age at the diagnosis was 79 dures were performed in accordance with the general ethical years (range 65–93). About one-third of the patients (36.4%) principles outlined in the Declaration of Helsinki [24]. had poor PS (ECOG 2-4) and 33 patients (22.9%) had severe comorbidities, corresponding aaCCI ≥ 6. Sixty-eight patients Treatment (48.6%) received BR and 72 patients (51.4%) received R- CHOP. Patients that received BR regimen were older (p < Patients were assigned to therapeutic strategy according to 0.001) and had more often high-risk disease (p =0.03).No physicians’ discretions. BR regimen was administered at the difference regarding other clinical parameters was observed. following dose: bendamustine 90 mg/m2 on days 1 and 2 Patients’ baseline characteristics are summarized in Table 1. combined with 375 mg/m2 rituximabonday1every4weeks, forupto6cycles[15]. In case of dose reduction, Treatment and Outcome bendamustine was applied at dose of 70 mg/m2. Alternatively, patients received R-CHOP at standard dose or Treatment pattern and treatment response are shown in reduced dose, for up to 8 cycles. Dose reduction included the Table 2. Data regarding treatment response were missing in so-called R-miniCHOP [12]aswellaseachsingleorcom- 29 patients (18 with BR and 11 with R-CHOP), due to loss to bined dose reduction of cyclophosphamide, doxorubicin or follow-up (8 patients) or death prior to response evaluation vincristine up to 50% at any time of treatment. Patients with (21 patients). bulky disease, defined as tumour mass > 7.5 cm, and/or ad- Overall, median follow-up was 49.9 months (95% confi- vanced disease received consolidation radiotherapy when pos- dence interval [95% CI] 31.4–68.4). Seventy-three deaths sible. In cases of testicular or craniofacial involvement of were documented during treatment and follow-up, of which lymphoma, prophylactic intrathecal chemotherapy with meth- 42 (62.8%) were in the BR group and 31 (43.1%) in the R- otrexate was applied.