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S. Storti et al. Introduction
Diffuse large B-cell lymphoma (DLBCL) is the most fre- quent non-Hodgkin lymphoma (NHL) and typically affects elderly patients; approximately 50% of the patients are older than 65 years and 15% are older than 80 years.1 More importantly, life expectancy has markedly improved over the past century and it is expected that the number of people older than 75 years will triple by the year 2030.2 As a consequence, the burden of age-related diseases, including DLBCL, is expected to increase in the near future.
R-CHOP is the undisputed standard for the treatment of elderly patients up to 80 years of age.3 A remaining unmet need, however, is related to the treatment of elderly patients who, due to age or comorbidity, cannot be treated with full-dose standard treatment. In these subjects, the availability of less toxic regimens is strongly warranted but the decision-making process concerning therapeutic intervention should also include an accurate and objective patient selection.4 Bendamustine is an alkylating agent with properties of a purine analog and is approved for the treatment of chronic lymphocytic leukemia (CLL) and indolent NHL. Bendamustine was also studied in aggres- sive lymphomas; several phase II studies of BR (ben- damustine in association with rituximab) in patients with relapsed refractory DLBCL showed promising efficacy with overall good tolerance of this regimen in the salvage setting.5-7 The activity of BR was also tested with promis- ing results in small phase II studies on untreated patients who were generally considered not eligible for standard R-CHOP.8,9
In 2014, the Fondazione Italiana Linfomi (FIL) started a phase II study to investigate the activity and the safety profile of a combination regimen of BR for the initial ther- apy of patients with DLBCL who were not eligible to receive standard anthracycline-based therapy. In contrast to other studies, we included patients who were prospec- tively classified as frail according to the Comprehensive Geriatric Assessment (CGA),10 and we evaluated a modi- fied BR schedule. Based on available evidence, there is still no standard treatment for this subset of patients, complete response to therapy is approximately 15%,11 and, even if rituximab is used, the median OS is approximately 20 months.12
Methods
Study design and objectives
This is a phase II open-label, non-randomized study to inves- tigate activity and safety of BR combination therapy in elderly patients with DLBCL, prospectively defined as frail according to the CGA. The study was approved by the local ethics commit- tees.
Patient eligibility
Eligible patients were elderly frail patients aged 70 years or over with a newly diagnosed, histologically proven DLBCL. All patients were prospectively evaluated by the CGA, as originally reported as part of pre-therapy assessment. Briefly, the CGA used was based on the assessment of Activities of Daily Living (ADL), Instrumental Activities of Daily Living (IADL), and Cumulative Illness Rating Scale-Geriatric (CIRS-G). Patients were classified as frail if the following criteria were met: in
patients aged between 70 and 80 years, ADL<4 or IADL<5 or 1 grade 3 comorbidity or >8 grade 2 comorbidities were required; in patients older than 80 years, ADL>5 or IADL>6 or 5-8 grade 2 comorbidities were required10 (Table 1). A full list of inclusion criteria and study procedures is available in the Online Supplementary Appendix.
Treatment
Patients received bendamustine (90 mg/m2, d1-2) combined with rituximab (375 mg/m2, d1) every 28 days. Patients with age-adjusted International Prognostic Index (aaIPI) equal to 0 and non-bulky disease received 4 cycles of BR followed by 2 cycles of rituximab. All other patients received 6 cycles of BR followed by 2 cycles of rituximab. Bendamustine was supplied for free by Mundipharma. The use of consolidation radiothera- py was allowed. Prophylaxis with valacyclovir and cotrimoxa- zole was mandatory. The use of granulocyte-colony stimulating factor (G-CSF) and erythropoietin was recommended.
Statistical analysis
The main study end point was the complete remission rate (CRR) that was calculated on the efficacy population (EP; i.e. patients receiving at least 2 courses of BR) using Cheson 1999 criteria.13 A further end point was the rate of grade 3-4 extra- hematologic adverse events (eeAEs) calculated on the safety population (SP; i.e. all patients who have received at least one dose of study medication) using CTCAE v.4.0 (Common Terminology Criteria for Adverse Events). Secondary end points were progression-free survival (PFS) and overall survival (OS).14
The study was conducted according to a Simon 2-stage design. The null hypothesis (p0) for CRR was set to 0.15.11 With a type I error of 0.05 and a type II error of 0.10, and considering the alternative hypothesis (p1) at 0.35, at least 4 CRs were required after the enrollment of the first 19 cases. With the full enrollment of the 44 cases, at least 11 patients in CR were required to confirm activity of the combination to be promising. Considering a 10% drop-out rate, the final study enrollment was set at 49 patients.
Maximum tolerated toxicity rate for eeAEs was set at 30%. Considering an alpha error of 0.05, and according to the 2-stage Simon design, the study had to be stopped if grade 3-4 events were observed in 12 or more patients out of the first 19 enrolled. With the enrollment of the planned 44 patients, a maximum number of 20 patients with grade 3-4 eeAEs were allowed.
Results
Patients
From February 2012 to February 2014, 49 patients were enrolled into the study by 24 Italian centers. Three patients
Table 1. Comprehensive Geriatric Assessment criteria for definition of fit, unfit and frail patients.
FIT UNFIT FRAIL
ADL 6 5* ≤4 IADL 8 7-6* ≤5
CIRS** Age
0 score=3-4 < 5 score=2
0 score=3-4 5-8 score=2
1 score=3-4 > 8 score=2
ADL: Activity of Daily Living; IADL: Instrumental Activities of Daily Living; CIRS: Cumulative Illness Rating Scale. *Residual function. **Scores are referred to severity of assessed comorbidities (as reported by Tucci et al.10)
≥ 80 fit
≥ 80 unfit
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