Background The two commonly used second-line strategies for Immune thrombocytopenia (ITP) include rituximab, an anti-CD20 monoclonal antibody, and thrombopoietin receptor agonists (TPO-RAs), such as eltrombopag and romiplostim. While both therapies are effective, they differ in mechanism, duration of response, administration, and risk profile. TPO-RAs often require ongoing treatment and have been associated with thromboembolic risk, whereas rituximab offers the potential for treatment-free remission but carries a risk of immunosuppression-related adverse events. To date, comparative long-term real-world data are lacking. This study aims to compare the clinical outcomes of these two treatment approaches over a five-year period in a large, diverse national cohort.

Methods We conducted a retrospective cohort study using the TriNetX US Collaborative Network, a federated database comprising electronic health records from 68 healthcare organizations. Adult patients (aged ≥18 years) diagnosed with ITP were identified and stratified into two mutually exclusive treatment groups: those who received rituximab (n=5,205) and those treated with either eltrombopag or romiplostim (n=7,890). Patients who had received both treatments at any point were excluded. The observation period extended for five years following treatment initiation. Propensity score matching was performed to balance demographic and clinical covariates, resulting in 1,439 matched patients in each cohort. Primary outcomes included all-cause mortality, platelet count <10,000/μL, and hospitalization. Secondary outcomes included gastrointestinal (GI) bleeding, intracranial hemorrhage (ICH), pulmonary embolism (PE), lower extremity deep vein thrombosis (DVT), splenic vein thrombosis, sepsis, and transaminitis. Hazard ratios (HRs), odds ratios (ORs), and p-values were used to assess differences between groups.

Results Over the 5-year follow-up period, rituximab-treated patients demonstrated significantly improved survival compared to those receiving TPO-RAs, with a 5-year survival rate of 76.8% versus 69.7% (hazard ratio [HR] 0.735, p<0.001). Platelet stabilization was also superior in the rituximab group, with fewer patients experiencing critically low platelet counts (<10,000/μL) than in the TPO-RA group (22.0% vs. 34.5%; HR 0.585, p<0.001). However, hospitalization was more frequent among rituximab users (59.6% vs. 55.1%; HR 1.127, p<0.001), which may reflect closer monitoring, comorbidity burden, or infusion-related care needs. Rituximab was associated with a lower incidence of gastrointestinal bleeding (5.3% vs. 6.1%; odds ratio [OR] 0.855, p=0.044), while rates of intracranial hemorrhage were equivalent across both groups (2.2%; p=0.91). Thrombotic complications were slightly more common in the TPO-RA cohort, with increased risks of pulmonary embolism (HR 1.324, p<0.001) and lower extremity deep vein thrombosis (HR 1.155, p=0.035). Splenic vein thrombosis occurred more frequently in the TPO-RA group, though the difference did not reach statistical significance (p=0.11). No meaningful differences were observed between groups in the rates of sepsis or transaminitis. Overall, rituximab therapy was associated with favorable hematologic outcomes and reduced thrombo-hemorrhagic events but a modestly higher hospitalization burden.

Conclusion In this large, real-world national cohort study, rituximab was associated with lower mortality, improved platelet control, and a reduced incidence of both bleeding and thrombotic complications compared to TPO-RAs. Despite a higher overall hospitalization rate, the hematologic and survival advantages of rituximab suggest it is a favorable second-line option for many patients with ITP. Further prospective studies and randomized controlled trials are needed to confirm these real-world observations and inform clinical guidelines

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2025
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