Risk of Opportunistic Infections in Patients with Bendamustine-Associated Lymphopenia and the Utility of Antimicrobial Prophylaxis
Authors: Krishnan Jayasree , Nachar Victoria , Marini Bernard Lawrence , Perissinotti Anthony J. , Phillips Tycel J. , Kaminski Mark S , Carty Shannon A. , Wilcox Ryan A. 
Published: November 2020

Introduction:
Bendamustine-associated lymphopenia is well-established. However, the risk of opportunistic infections (OI) and the utility of routine antimicrobial prophylaxis in this setting is unclear. In this retrospective analysis, we analyzed the incidence of lymphopenia, the use of antimicrobial prophylaxis, the incidence, type and severity of infections, and risk factors for developing infections in patients that received bendamustine-based therapies.
Methods:
We conducted a retrospective review of patients with lymphoma who were treated with bendamustine between January 2015 and January 2019 at University of Michigan Rogel Cancer Center. Baseline demographics and clinical characteristics such as age, sex, lymphoma diagnosis, absolute lymphocyte count (ALC) and absolute neutrophil count (ANC) at baseline, during treatment and post-treatment, details of infectious events and use of antimicrobial prophylaxis were collected.
Results:
230 patients who received bendamustine were identified. Lymphoma diagnoses included 34% follicular lymphoma, 21% chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), 18% mantle cell lymphoma, 10% marginal zone lymphoma, 9% Hodgkin's lymphoma, 2% diffuse large B cell lymphoma, and 5% Waldenstrom's macroglobulinemia. Median age at the time of treatment was 64.5 years. After excluding CLL and leukemic phase of mantle cell lymphoma, the median ALC count at baseline, during treatment and following the last treatment were 1.4 K/mm3 (range: 0.1-16 K/mm3), 0.6 K/mm3 (range: 0.1-7.2 K/mm3) and 0.4 K/mm3 (range: 0.1-4.4 K/mm3), respectively. At the end of therapy, lymphopenia (ALC &lt; 1 K/mm3) and severe lymphopenia (ALC &lt; 0.5 K/mm3) were noted in 83.5% (n=192, median ALC: 0.3 K/mm3) and 46.5% (n=107, median ALC: 0.4 K/mm3) of patients, respectively. The median time to achieving ALC &gt; 0.5 K/mm3 was 4 months from the end of therapy (range: 2-8 months) and the median time to complete count recovery was 9.5 months from the end of therapy (range: 4-14 months). Of 230 patients, 44.7% did not receive any antimicrobial prophylaxis, 38.3% received antiviral and pneumocystis pneumonia (PJP) prophylaxis, 13.9% received only antiviral prophylaxis, 2.1% received only PJP prophylaxis, 0.4% received antifungal prophylaxis and 0.4% received antibacterial prophylaxis. Fifty-six patients (24%) developed severe infection, defined as any infection requiring hospitalization. OI were relatively rare and were observed in 15 patients (6.5%). Among those 15 patients, 80% did not receive any antimicrobial prophylaxis. OI included PJP pneumonia (n=4), cytomegalovirus pneumonia (n=1), varicella-zoster virus (n=1), aspergillus pneumonia (n=1), disseminated aspergillosis (n=1), cerebral toxoplasmosis (n=1), pulmonary histoplasmosis (n=1), necrotizing otitis externa due to Pseudomonas aeruginosa (n=1) and severe Clostridium difficile colitis (n=4). Risk factors for severe infection and OI that were analyzed included age, underlying disease, pre-treatment severe lymphopenia, post-treatment severe lymphopenia, number of prior therapies, use of rituximab maintenance and G-CSF use. No risk factors for severe infection or OI were identified in our analysis. OI were noted less frequently in patients with severe post-treatment lymphopenia (5/107, 4.7%) compared to those without severe lymphopenia (10/123, 8%) which may have been due to the use of antimicrobial prophylaxis in these patients, as 62% of severely lymphopenic patients received prophylaxis, compared with 49.6% of patients without severe lymphopenia (p=0.06).
Conclusion:
Severe lymphopenia following bendamustine therapy is common. The median 9.5 month time to count recovery in our analysis was similar compared to previous studies. Incidence of OI was lower in patients who received antimicrobial prophylaxis. OI were not limited to patients with severe post-treatment lymphopenia, which may be related to the increased use of prophylaxis in these patients. Further prospective studies are needed to confirm the utility of antimicrobial prophylaxis in the setting of bendamustine-associated severe lymphopenia.

Disclosures
Phillips: Seattle Genetics: Consultancy; BMS: Consultancy; Bayer: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Cardinal Health: Consultancy; Lymphoma Connect: Other; University of Michigan: Current Employment; Beigene: Consultancy; Karyopharm: Consultancy; AstraZeneca: Consultancy; Incyte: Consultancy, Research Funding.