Evaluation of Infection in Patients with Myelodysplastic Syndromes Treated with Hypomethylating Agents: A Systematic Review

BACKGROUND: Myelodysplastic syndromes (MDS) are a heterogeneous group of disorders associated with cytopenias and risk of febrile neutropenia and infection. Hypomethylating therapy, such as azacitidine and decitabine, form the backbone of outpatient chemotherapy for many patients with MDS. Current literature reports heterogeneous and variable frequency, location, and severity of infections among patients receiving this treatment. Further, the relationship between infection and neutropenia is not well established.

OBJECTIVE: To facilitate evidence-informed supportive care therapy, we evaluated the incidence and severity of infection and neutropenia among patients with MDS treated with hypomethylating therapy. We also aimed to evaluate the relationship between neutropenia and infection (CRD42022339150).

POPULATION: Adult patients (age ≥ 18 years) with MDS (≥80% of the study population) treated with hypomethylating agents.

OUTCOMES: Our primary outcome was febrile neutropenia, as per the National Cancer Institute's Common Toxicity Criteria for Adverse Events (NCI-CTCAE). Secondary outcomes included infection of any grade, grade 3 or 4 infections, death due to infection, microbial and clinical infection subtype, frequency of grade 3 or 4 neutropenia, duration of neutropenia, and use of antimicrobial prophylaxis.

METHODS: We identified randomized controlled trials (RCT) from Medline, Embase, CENTRAL, and CINAHL from inception to April 2021. RCTs were included if they evaluated hypomethylating therapy in patients with MDS and reported at least one outcome of interest. We used Freeman-Tukey transformation to calculate the weighted summary proportion using a random effects model.

RESULTS: We included 21 unique trials enrolling 1380 patients. 14 trials evaluated azacitidine (n=946 patients) and 8 trials studied decitabine (n=434 patients). The median patient age was 70, and 56% were male. 10 trials (n=729 patients) reported risk by International Prognostic Scoring System, of which 5% were low risk, 30% were intermediate-1 risk, 41% were intermediate-2 risk, and 24% were high risk. 49% of patients had grade 3 or 4 neutropenia (95% confidence interval (CI) 34%-63%, n=10 trials, n=697 patients). Febrile neutropenia was reported in 22% of patients (95% confidence interval (CI) 16% to 29%; n=16 trials, n=1124 patients). Grade 3 or 4 infection was reported in 33% of patients (95% CI 0% to 67%; n=3 trials, n=294 patients). Death due to infection occurred in 7% of patients (95% CI 4%-10%; n=9 trials, n=528 patients). Reporting of infection location was inconsistent, and uninterpretable on a per-patient basis. Microbial subtype of infection, duration of neutropenia, and antimicrobial prophylaxis use were not reported.

CONCLUSION: In patients with MDS treated with hypomethylating therapy, grade 3 or 4 neutropenia, febrile neutropenia, and grade 3 or 4 infection were common, yet reported rates were heterogeneous between trials. Limited information was available to define the relationship between neutropenia and infection, as well as the use of antimicrobial prophylaxis. Trials commonly reported infection events in the absence of patient-specific risk estimates. Comprehensive reporting of febrile neutropenia, infection and use of antimicrobial prophylaxis is needed to direct evidence-informed care.

Mozessohn:Abbvie: Current holder of stock options in a privately-held company; Bristol Myers Squibb: Current holder of stock options in a privately-held company; Johnson & Johnson: Current holder of stock options in a privately-held company; Merck and Co: Current holder of stock options in a privately-held company; Novo Nordisk: Current holder of stock options in a privately-held company. Sanford:Abbvie: Other: Advisory Board ; Astellas: Other: Advisory Board ; Pfizer: Research Funding. Buckstein:BMS: Honoraria, Research Funding; Takeda: Research Funding; Taiho: Honoraria, Research Funding. Hay:Merck: Research Funding; Seagen: Research Funding; Karyopharm: Research Funding; Roche: Research Funding; AbbVie: Research Funding.