Infections in Patients with Myelodysplastic Syndrome/Acute Myeloid Leukemia Treated with Azacitidine: Report from a Single Center
Authors: Quinto Angela Maria , De March Elena , Castelli Monica , Piazza Francesco , Adami Fausto , Semenzato Gianpietro , Binotto Gianni 
Published: October 2019

Abstract
Background and objectives. Infectionsare commonandpotentially fatal events affecting patients with myelodysplastic syndromes (MDS). Predisposing factors that are likely to be associated with increased risk of infections in MDS patients are neutropenia and/or neutrophil functional impairment; B-, T- and NK-cell defects; secondary iron overload related to red blood cell transfusions; comorbidities; treatment toxicity; previous severe infections. Few data are available on the incidence and pathogens involved in infectious events, most of these originating from retrospective studies or clinical trials with primary end points other than infection. An Italian single Center real-life experience assessing the incidence, risk factors and impact of infections on outcome of patients with MDS treated with hypomethylating agents is herein reported.
Design and methods. From March 2008 to October 2013, 50 patients, aged 40 years and older (median age: 69, 40-84 years) with diagnosis of MDS (WHO2008 categories: 22.4% RA/RCMD, 32.6% RAEB-1, 28.5% RAEB-2, 12.2% CMML, 4% AML), were treated with 5-azacitidine (75 mg/m2/die for 7 days every 4 weeks), both in on-label and off-label drug use setting. Forty-four percent of patients had intermediate-2 or high International Prognostic Scoring System, 68% were neutropenic and 12% had high MDS-Comorbidity Index. Prophylactic antibiotics were administered to 12 patients (24%), prophylactic antifungal to 17 patients (34%) and granulocyte colony-stimulating factor was administered to 24 patients (48%).
Results. Median number of cycles received by a single patient was 5 (range 1-21); 48% received more than 6 cycles of therapy. 30.4% of the entire cohort was considered responsive to treatment (14.4% hematologic improvement, 8% partial response, 8% complete response, according to IWG2006 criteria); 24% of patients achieved a stable disease. Out of 50 patients, 25 (50%) developed 25 infectious events (1 for each patient), during 325 treatment cycles (7.7%); 14/25 (56%) events required hospitalization. Only one patient died from an infectious complication. Twenty-two of 25 infectious events (84%) were bacterial, mostly pneumonia; 3 (12%) were fungal (invasive aspergillosis) and 1 (4%) was viral (H1N1). Infectious events did not significantly affect overall survival (27 vs 18 months, p=0.606), progression free survival (6.0 vs 6.1 months, p=0.48) or overall response to therapy (13 vs 17.4%, p=0.693). However, no complete responses were documented in the cohort of patients who suffered from infectious episodes. In a univariate analysis, age, sex, low neutrophil count, high comorbidity index, antibiotic prophylaxis and use of G-CSF were not found to be associated with infections. Only high IPSS and the presence of pancytopenia, seemed to be correlated with an increased risk for infections.
Conclusions. Infectious events, specifically bacterial infections, are one of the most frequent complications during therapy with azacitidine in patients with MDS. These data suggest that there are not predisposing risk factors for infection in patients except those connected with disease severity (high IPSS and pancytopenia). Routine antibiotics, antifungal prophylaxis and/or use of G-CSF appear not to reduce the incidence of infectious events. Moreover, bearing in mind the risk of bacterial and fungal resistance associated with extended use of anti-infective drugs, they should be used with caution in selected subsets of MDS patients.

Disclosures
Off Label Use: Off-label use of azacitidine for low risk MDS patients with severe transfusions dependence after ESAs failure (primary resistance or relapse after a response).