Early Infectious Complications after Autologous Hematopoietic Cell Transplantation (AHCT) for Lymphoma
Authors: Rahman Shafia , Rybicki Lisa , Cober Eric , Dean Robert M. , Hamilton Betty K. , Jagadeesh Deepa , Hill Brian T. , Pohlman Brad , Sobecks Ronald , Kalaycio Matt , Mossad Sherif , Majhail Navneet S. 
Published: October 2019

Abstract
The spectrum of infectious complications occurring in the first 100 days in lymphoma patients undergoing AHCT has not been well described in the contemporary era of improved supportive care practices and antimicrobial prophylaxis.We conducted a retrospective cohort study to describe early infections in this population and to evaluate the association of early infections with long-term outcomes. From our BMT Program database, we identified 544 consecutive patients (age ≥18 years) who received their first AHCT for lymphoma between 2007 and 2016 and had consented for use of their data for research. Median age was 55 (range, 19-78) years, 63% patients were male, 79% had non-Hodgkin lymphoma (NHL), 96% had KPS ≥80, 39% had AHCT Comorbidity Index score ≥3, and 78% had intermediate/high risk disease. Stem cell mobilization was performed with chemotherapy priming (58%) or G-CSF ± plerixafor (42%). The majority of patients received conditioning regimen consisting of busulfan, cyclophosphamide and etoposide (97%). All patients were hospitalized from start of conditioning chemotherapy until neutrophil engraftment. Routine antimicrobial prophylaxis consisted of ciprofloxacin and fluconazole starting on hospitalization and continued until neutrophil engraftment, and acyclovir for 6 months after transplantation.The following infections were evaluated: all (excluding febrile neutropenia [FN]), bacterial, viral, fungal, C difficile, central line associated blood stream infection (CLABSI), blood stream, pneumonia, and other sites, and FN. Compared to patients without infections, those who had early infections were older (median 57 vs 55 years, P=0.04), more likely to have NHL (86% vs 77%, P=0.04), and had earlier stage disease (P<0.01); there was no difference in the CD34 cell dose or time to neutrophil engraftment. Cumulative incidence of all infections at 100 days (excluding FN) was 19.1% and that of FN was 77.4% (Table). Among bacterial infection episodes (N=114), E coli(18%), C difficile(15%), and S aureus(9%) were the most common organisms identified; the majority of viral infection episodes were caused by respiratory viruses (62%). Compared to no infections, patients with infections had a significantly longer transplant hospitalization and more readmissions, and fewer days alive and out of hospital in first 100 days; there was no difference in 100 day overall mortality between the two groups (3.2% vs 4.8%, P=0.42). In multivariable analyses, older age at AHCT was the only risk factor for any infection (excluding FN; HR 1.21 per 10 year increase, 95% cumulative incidence 1.06-1.39, P=0.006); no association was observed with other risk factors examined, including KPS score, comorbidities, prior therapy, disease risk or time since diagnosis. Disease risk was the only factor independently predictive of FN; compared to low risk disease, patients with intermediate risk (HR 0.78, P=0.01) and high risk (HR 0.71, P=0.05) disease had lower risks of FN. Older age was the only risk factor for C difficilecolitis (HR 2.19 per 10 year increase, P<0.001), while risks for CLABSI increased over time (HR 1.41 per 1 year increase, P=0.002). In a landmark analysis including 100 day survivors (N=525 patients), patients with infections within the first 100 days had higher CI of 1-year non-relapse mortality (4% vs. 1% for no infections, P=0.02) and lower 1-year overall survival (81% vs. 90%, P<0.001), which was confirmed on multivariable analyses (HR 1.92, P=0.02 for non-relapse mortality, HR 1.80, P<0.001 for overall mortality). Although representative of our institutional practices, our study describes the spectrum and incidence of early infectious complications after AHCT for lymphoma in the current era. Early infections are relatively common, impact long-term survival, and have significant resource implications. Notwithstanding advances in supportive care, continued focus in this area is needed to improve outcomes in this population.

Disclosures
Hill: Amgen: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Majhail:Atara: Honoraria; Anthem, Inc.: Consultancy; Incyte: Honoraria.