Abstract Background: Thrombocytopenia in myelodysplastic syndromes (MDS) is associated with an increased risk of bleeding, need for transfusions, and reduced overall survival. Addressing this complication is a major therapeutic goal, particularly in patients who are not candidates for disease-modifying therapies such as hypomethylating agents or stem cell transplantation. Thrombopoietin receptor agonists (TPO-RAs), including eltrombopag and romiplostim, are FDA-approved for chronic immune thrombocytopenia and have been studied in MDS to stimulate platelet production. However, concerns remain about their safety in this population, particularly regarding thrombotic risk and potential disease progression. Rituximab, a chimeric anti-CD20 monoclonal antibody, is commonly used for autoimmune cytopenias and has also been explored in MDS patients—especially when immune-mediated mechanisms are suspected. Despite these therapeutic options, there is limited real-world data comparing the short-term safety and efficacy of TPO-RAs versus rituximab in MDS patients, particularly in the first 90 days of treatment initiation—a critical period for managing cytopenia-related complications. Objective: To compare short-term outcomes between MDS patients treated with TPO-RAs (eltrombopag or romiplostim) versus rituximab, focusing on 90-day rates of thrombocytopenia, bleeding, thromboembolic events, and mortality. Methods: We conducted a retrospective cohort analysis using the TriNetX US Collaborative Network, a large real-world database representing 66 healthcare organizations. Adult patients (≥18 years) with a diagnosis of MDS were included if they had initiated treatment with either a TPO-RA (eltrombopag or romiplostim) or rituximab. Patients who received both agents or had a confounding of ITP were excluded. The final matched cohort included 1,057 patients in each treatment group after applying 1:1 propensity score matching based on age, gender, comorbidities, and baseline laboratory values. The index date was defined as the date of treatment initiation. Outcomes were assessed over a 90-day follow-up period and included hospitalization, severe thrombocytopenia (platelet count 10×10³/μL), all-cause mortality, intracranial hemorrhage (ICH), gastrointestinal (GI) bleeding, pulmonary embolism (PE), deep vein thrombosis (DVT), splenic vein thrombosis, sepsis, and transaminitis. Time-to-event analyses were performed using Kaplan-Meier curves, and comparisons were expressed using hazard ratios (HR), risk differences, and p-values. Results: Hospitalization rates were similar between groups, occurring in 56.1% of the TPO cohort and 58.4% of the rituximab cohort (p=0.54). However, the TPO group experienced significantly higher rates of severe thrombocytopenia, with 44.9% of patients having a platelet count 10×10³/μL compared to 19.5% in the rituximab group (p0.001; HR: 2.80, 95% CI: 2.37–3.32). All-cause mortality within 90 days was also greater in the TPO group (20.0% vs. 13.6%; p0.001; HR: 1.52, 95% CI: 1.22–1.89). Notably, the risk of ICH was markedly elevated among TPO-treated patients (2.6% vs. 0.9%; p0.001; HR: 4.69, 95% CI: 1.94–11.37), whereas GI bleeding rates were not statistically different (4.5% vs. 3.4%; p=0.18). There were no significant differences between cohorts in rates of PE (1.6% vs. 1.9%; p=0.67) or sepsis (8.2% vs. 8.7%; p=0.67). However, the TPO group had a higher incidence of lower extremity DVT (5.4% vs. 2.9%; p=0.007; HR: 0.55, 95% CI: 0.36–0.86). Transaminitis occurred more frequently in the TPO cohort (3.2% vs. 1.6%; p=0.011; HR: 2.08, 95% CI: 1.16–3.73). Conclusion: In this 90-day real-world analysis of propensity-matched MDS patients, those treated with TPO-RAs had significantly higher rates of severe thrombocytopenia, mortality, DVTs and intracranial hemorrhage compared to those receiving rituximab. The overall safety and hematologic outcomes appear to favor rituximab in the short term. These findings suggest that rituximab may offer a safer and potentially more effective option for managing MDS-related thrombocytopenia in selected patients. Further prospective, long-term studies are warranted to validate these results and optimize second-line treatment strategies in MDS.
Lisa A. Duhaime (Mon,) studied this question.