Safety and Efficacy of R-CEEP (Rituximab, Cyclophosphamide, Epirubicin, Etoposide, Prednisolone) in Elderly or Unfit Patients with Diffuse Large B-Cell Lymphoma (DLBCL): A Retrospective Single-Centre Experience
Authors: Yeung James , Campbell Ashlea , Bryant Christian E , Khoo Liane , Dunkley Scott , Iland Harry J , Larsen Stephen R , Moreton Susan , Joshua Douglas E , Vanguru Vinay , McCulloch Derek A , Hsu Danny , Gibson John , Ho P. Joy , Brown Christina 
Published: November 2019

Background
DLBCL is the most common subtype of non-Hodgkin lymphoma in elderly patients (age ≥70). R-CHOP is the standard of care for upfront treatment of fit patients, but may not be tolerated in patients with advanced age and/or comorbidities. There is no established standard of care for this group of patients and dose reduction (R-miniCHOP) or avoidance/replacement of anthracyclines are common strategies, aiming to deliver tolerable immunochemotherapy and provide meaningful outcomes and potential cure. R-CEEP is a dose-reduced regimen that incorporates etoposide and an alternate anthracycline epirubicin. We describe our single-centre experience with R-CEEP for elderly (age ≥70) or unfit patients (CIRS-G >6) with newly-diagnosed or relapsed DLBCL deemed unsuitable for R-CHOP.
Method
All patients receiving R-CEEP for a histological diagnosis of DLBCL at Royal Prince Alfred Hospital from 2000 to 2019 were retrospectively reviewed. R-CEEP (rituximab 375mg/m2 day 1, cyclophosphamide 300mg/m2 day 1, epirubicin 50mg/m2 day 1, etoposide 100mg/m2 day 1 and prednisolone 50mg daily for days 1-5) was delivered every 14 or 21 days at physician discretion planning for 6 cycles. GCSF and antimicrobial prophylaxis were used at physician discretion. The cardiac ejection fraction was assessed as satisfactory (>50%) prior to commencement. Baseline demographics, R-IPI, co-morbidities as assessed by CIRS-G, treatment response and adverse events (AEs) were recorded.
Results
Data from 61 patients were reviewed; 54 received R-CEEP for de novo DLBCL and 7 for DLBCL with a background of previously-treated lymphoma (1 DLBCL; 6 low-grade NHL). The median age at diagnosis was 80 (range 34-93), with 79% aged 75 and 28% aged 85. Thirty-three patients (54%) were female; 87% had Ann Arbor stage III/IV and 52% had R-IPI 3-5. Median CIRS-G was 9 (range 2-20) with 74% of patients having CIRS-G >6. GCSF prophylaxis was used in 67%.
The median follow-up was 2.7 years (range 0.1-10.0 years). Overall response was 54/61 (89%), with complete response (CR) in 42 (69%), partial response (PR) in 12 (20%) and progressive disease (PD) in 1 (2%). Response was not assessed in 6 patients due to early treatment discontinuation for palliation or AEs (4), cerebral palsy (1) and loss to follow-up (1). In patients receiving R-CEEP as upfront therapy, CR was obtained in 38/54 (70%), PR in 10/54 (19%) and 6 were not assessed as above. In the 7 patients receiving R-CEEP as salvage therapy, 4 obtained CR, 2 PR and 1 had PD. Median PFS and OS for the total cohort were 5.2 and 9.4 years respectively; for de novo DLBCL patients, 7.1 and 9.4 years and for patients receiving salvage therapy, 1.1 and 2.0 years. There was no statistically significant difference in PFS or OS when comparing patients aged <80 and ≥80, or with CIRS-G ≤6 and >6, or CIRS-G ≤9 and >9. Relapsed disease was identified in 19 patients (31%) during follow-up.
Of the 75 AEs reported, grade 3/4 AEs accounted for 67%. Infective complications were the most frequent (53%; 40) and febrile neutropenia accounted for 8 AEs. Grade 3/4 haematological toxicity occurred in 19% (14). Despite this, the majority (43/61; 70%) received six cycles of R-CEEP. In the remaining 18 patients, 5 completed 6 cycles with dose-reduction and 13 patients discontinued therapy due to serious AEs (9), treatment intolerance (2) or patient preference (2). Of the 29 deaths recorded during the follow-up period, 18 were due to relapsed/progressive disease; 5 to infection (4 of these in CR, 0.5 to 9 years after the end of treatment, and 1 of urinary sepsis in a patient 3 months after early treatment discontinuation due to toxicity) and 6 to unrelated causes.
Discussion
We demonstrate that R-CEEP is an effective and deliverable immunochemotherapy in elderly or unfit patients with DLBCL. Furthermore, survival outcomes were not impacted by CIRS-G >9 or age ≥80, illustrating efficacy and tolerability even in patients predicted to have a particularly poor prognosis. Our cohort outcomes are not inferior to those reported in elderly fit patients treated with other dose-reduced regimens including R-miniCHOP (Peyrade et al, Lancet Oncology 2011) and R-miniCEOP (with epirubicin; Merli et al, Leukemia and Lymphoma 2012). This data supports the use of R-CEEP as an alternative immunochemotherapy option for patients with DLBCL who may not be candidates for R-CHOP.

Disclosures
Iland: Celgene: Other: Speaker honorarium. Ho:La Jolla: Other: investigator meeting travel costs; Novartis: Other: investigator meeting travel costs; Janssen: Other: investigator meeting travel costs; Celgene: Other: investigator meeting travel costs.