Evaluation of Bleeding and Thrombocytopenia in Patients with Myelodysplastic Syndromes Treated with Hypomethylating Agents: A Systematic Review

Abstract

BACKGROUND: Myelodysplastic syndromes (MDS) are a heterogeneous group of disorders associated with significant morbidity, mortality, and quality of life impairment. Hypomethylating therapy, such as azacitidine and decitabine, form the backbone of outpatient chemotherapy for many patients with MDS. Bleeding is primarily due to thrombocytopenia and/or platelet dysfunction, with increased risk among patients with higher risk disease and prolonged disease duration with multiple lines of therapy. Reporting of bleeding and thrombocytopenia among patients treated with hypomethylating therapy are heterogeneous in both frequency and severity, and the exact relationship between bleeding and thrombocytopenia has yet to be comprehensively evaluated. OBJECTIVE: To facilitate evidence-informed patient care and optimize supportive care therapy, we evaluated the incidence and severity of bleeding and thrombocytopenia in patients with MDS treated with hypomethylating therapy. We also aimed to explore the relationship between bleeding and thrombocytopenia and the use of supportive care strategies to prevent bleeding (CRD42022339159). POPULATION: Adult patients (age ≥ 18 years) with MDS (≥80% of the study population) treated with hypomethylating agents. OUTCOMES: Our primary outcome was National Cancer Institute's Common Toxicity Criteria for Adverse Events (NCI-CTCAE) grade 3 or 4 bleeding. Secondary outcomes included bleeding of any grade, deaths due to bleeding, grade 3 or 4 thrombocytopenia using NCI-CTCAE, duration of thrombocytopenia, platelet count at time of bleeding, and number of patients who received tranexamic acid to prevent or treat bleeding. 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 agents 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 17 unique trials enrolling 1153 patients. 13 trials evaluated azacitidine (n=876 patients) and 4 trials evaluated decitabine (n=277 patients). The median patient age was 70, and 55% were male. 11 trials (n=892 patients) reported risk by International Prognostic Scoring System, of which 4% were low risk, 25% were intermediate-1 risk, 42% were intermediate-2 risk, and 29% were high risk. Bleeding events of any grade were reported in 18% of patients (95% confidence interval (CI) 5% to 30%; n=10 trials, n=609 patients); 11% of patients had grade 3 or 4 bleeding events (95% CI 0.4% to 22%; n=4 trials, n=336 patients). Fatal bleeding occurred in 3% of patients (95% CI 2% to 4%; n=6 trials, n=502 patients). Grade 3 or 4 thrombocytopenia occurred in 41% of patients (95% CI 22%-61%; n=10 trials, n=699 patients). Duration of thrombocytopenia, platelet count at time of bleeding event, and number of patients who received tranexamic acid to prevent or treat bleeding was not reported. CONCLUSION: In patients with MDS treated with hypomethylating therapy, grade 3 or 4 thrombocytopenia and bleeding were common yet risk was inconsistently reported and heterogenous among trials. The relationship between bleeding and thrombocytopenia, and the use of supportive care strategies to prevent and treat bleeding were not well characterized in the literature.