PREDICTIVE FACTORS FOR INFECTIOUS ADVERSE EVENTS IN PATIENTS WITH B-CELL NON-HODGKIN LYMPHOMA TREATED WITH BENDAMUSTINE-RITUXIMAB (R)+/- R MAINTENANCE. RESULTS OF A RETROSPECTIVE ANALYSIS

Background The combination of bendamustine (B) and rituximab (R) is an effective and well tolerated treatment for B-cell malignancies. However, previous reports have shown a higher incidence of lymphopenia and secondary infectious complications in patients treated with BR than in patients treated with other chemoimmunotherapy regimens. Aims We performed a retrospective analysis at our institution in patients treated with BR with or without R maintenance, with the aim of determining the incidence of the infectious adverse events (AEs) and of identifying potential predictors factors. Methods We collected data from 65 patients with B-cell non-Hodgkin lymphoma (NHL) who received at least two cycles of BR ± R maintenance between 2010 and 2016 at our institution. The AEs – including neutropenia (N), neutropenic fever (NF), lymphopenia, infections episodes and the occurrence of second tumors - were recorded according to the CTCAE v4.0 grade score. We compared the risk factors of patients who developed infections and those who did not. Univariate analysis with Fisher's exact test was used to evaluate the potential risk factors. Results The median age at the first treatment cycle was 66 years (range 36-89), 33 patients (50%) were ≥65 years, 27 (41%) were male, 53 (82%) had advanced disease and 37 (60%) had bone marrow involvement. Thirty (46%) patients had follicular lymphoma, 17 (26%) mantle cell lymphoma, 11 (17%) marginal lymphoma, 5 (7%) diffuse large B-cell lymphoma and 4% other indolent lymphomas. Thirty two patients (49%) received BR as first line treatment, 51% as second line and above. Bendamustine was administered either at the dosage of 70 or 90 mg/sqm iv on days 1, 2 and R was administered at a dose of 375 mg/sqm iv or sc, on day 1. Therapy was administered every 4 weeks up to 6 courses. Twenty nine patients (46%) received R maintenance every 8-12 weeks for two years. The mean number of cycles administered was 5 (range 2-6), 13 patients (20%) discontinued treatment due to toxicity: 8/13 for non-hematologic toxicity. Primary or secondary G-CSF prophylaxis was administered to 25 patients (38%), while the prophylaxis with trimetropin-sulfametoxazole against Pneumocystis jiroveci pneumonia was given to all patients. Twenty two patients (34%) had at least one infection. Bacterial pneumonia was identified in 6/22 patients, varicella zoster virus infection in 4/22, cytomegalovirus reactivation in 2/22 and other infections in 10 patients. At univariate analysis, the infectious AEs were associated only with lymphopenia during the second cycle (p=0.043) and with neutropenia during the second, third and fourth cycle (p=0.026; p=0.003, p=0.018, respectively). No correlation with age, line of treatment and G-CSF administration was documented. Other AEs were: grade 3/4 neutropenia (49%), neutropenic fever (3%), grade 3/4 lymphopenia (80%). We reported also a 5% incidence of second tumors after treatment (lung cancer in 2 patients and prostate cancer in 1). Conclusion In our analysis, BR ± R maintenance confirms a toxicity profile similar to that reported in previous experiences. According to our results, an early lymphopenia and neutropenia (after two cycles) are predictive factors for infections AEs and for premature treatment discontinuation. Twenty % of patients discontinued treatment mostly because of the early withdrawal due to infectious complications. These data raise the question on the role of antibacterial, antiviral and primary G-CSF prophylaxis in all patients treated with BR.