Factors Associated with Overall Survival in Follicular Lymphoma Patients Who Are Eligible for Maintenance Therapy

Background: Follicular lymphoma (FL) is the most common indolent Non-Hodgkin lymphoma. Diagnosed with advanced disease, most patients have an excellent prognosis, but treatment options are not curative and can have significant morbidity. To date, there is no standard of care for first-line (1L) treatment for FL. In fact, current National Comprehensive Care Network (NCCN) guidelines list 11 (including three category 1) 1L treatment options for FL. Following the successful completion of 1L treatment, patients may also receive consolidation or maintenance rituximab (MR) therapy, with the intent of prolonging remission. Although MR has been shown to improve progression free survival, its impact on overall survival (OS) remains controversial. Leveraging electronic healthcare records, we identify and describe the demographics, treatment practices, and associated outcomes of FL patients diagnosed and treated in the nation's largest integrated healthcare system, the Veterans Health Administration (VHA),

Methods: FL patients diagnosed and treated in the VHA between 2006-2014 were identified by linking information from the VA Clinical Cancer Registry (VACCR) and the Corporate Data Warehouse (CDW). Patients were excluded if they had evidence of a prior cancer, documented grade 3b, or stage I disease. Patient demographics, disease characteristics, and treatment history and associated outcomes were extracted. Patients were grouped by 1L treatment(s) which included rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (RCHOP); rituximab, cyclophosphamide, vincristine, and prednisone (RCVP); bendamustine rituximab (BR), single-agent rituximab; and whether or not they received MR. Descriptive statistics were used to describe patient demographics, disease characteristics, and treatment practice patterns. Proportions were used for discrete variables; means and/or medians (with standard deviation or interquartile range, respectively) were used to describe continuous variables. Overall survival (OS) was compared between patients who received MR and those who did not, using an adjusted Cox proportional hazards model.

Results: From 2006-2014, 2290 FL patients were diagnosed at VHA, from all regions of the United States. Median age was 65 years, 95% were male, 81% were non-Hispanic white, 7% were black, 2% were Hispanic, and 8% were other/unknown. At diagnosis, 25% of patients were grade 1, 27% grade 2, and 12% grade 3, and 4% were documented as grade 1-2. More than half (58%) of these patients had disease at stage III or IV at diagnosis, with 13% at stage II, and 21% at stage I. The most common comorbidity was diabetes, present in 27% of patients, followed by pulmonary disease (18%), peripheral vascular disease (8%), and renal disease (8%). Overall, 793 (85%) patients were treated with chemoimmunotherapy, with 341 (15%) patients receiving RCHOP, 253 (11%) receiving RCVP, and 199 (9%) receiving BR; while 132 (6%) patients were treated with single-agent rituximab. Compared to patients treated with chemoimmunotherapy, patients treated with single-agent rituximab were significantly older (77% ≥ 60 vs 67%, p=0.022) and less likely to have elevated LDH (14% vs 24%, p=0.03) or grade 3 disease (9% vs 21%, p= 0.002). Of the 905 patients who were treated with chemoimmunotherapy or single-agent rituximab and showed no evidence of progressive disease (i.e., MR-eligible patients), 319 patients (35%) received MR. On multivariable analysis, the following were independently associated with decreased OS: age at treatment ≥ 60 (HR=2.1, p=0. 0.0003), hemoglobin < 12 g/L (HR=1.5, p=0.041), LDH > ULN (HR=1.6, p=0.013), and Charlson comorbidity index (CCI) ≥ 2 (HR=1.1, p=0.05). Accounting for immortal time bias, MR was associated with a significant improvement in OS (HR = 0.7, p = 0.04).

Conclusions: This nationwide real-world study yields detailed information and new insights into current FL patient characteristics, treatment practices, and associated outcomes. Rituximab maintenance was independently associated with an improvement in overall survival in patients with FL.