Hematology · Medical Literature
All-Trans Retinoic Acid plus Eltrombopag for Refractory/Relapsed Immune Thrombocytopenia.
Abstract
Eltrombopag is an effective second-line therapy for immune thrombocytopenia (ITP), but its long-term efficacy is limited. All-trans retinoic acid (ATRA) has immunomodulatory effects targeting ITP pathophysiology. We investigated whether combining ATRA with eltrombopag improves long-term outcomes for glucocorticoid-resistant or relapsed ITP. We conducted a multicenter, randomized, open-label trial in adults with glucocorticoid-resistant or relapsed ITP (platelets <30×109/l). Patients were randomly assigned 1:1 to ATRA (12 weeks) plus eltrombopag or eltrombopag monotherapy. The primary outcome was an 18-month sustained response (platelet count ≥30×109/l without clinically significant bleeding or rescue therapy). Ninety-six patients were randomly assigned, 48 per group. At 18 months, 60% (29/48) in the ATRA-plus-eltrombopag group achieved a sustained response, versus 35% (17/48) in the monotherapy group (odds ratio: 2.78; 95% confidence interval [CI]: 1.22-6.37; P=0.014). The combination was associated with a higher complete response rate (79% vs. 58%; 95% CI for difference, 2 to 39 percentage points) and longer median response duration (75 vs. 37 weeks; hazard ratio for relapse, 0.45; 95% CI, 0.23-0.86). Adverse events were comparable between groups, with no grade 3-4 events or treatment-related deaths. However, clinically significant bleeding of World Health Organization grades 2 or 3 was 21% in the combination group at baseline compared with 10% in the monotherapy group. In patients with glucocorticoid-resistant or relapsed ITP, a 12-week ATRA course with eltrombopag significantly enhanced the 18-month sustained response rate compared to eltrombopag alone. (Funded by Capital Health Research and Development of Special Fund and others; ClinicalTrials.gov number, NCT05438875.).
Clinical relevance
Immune thrombocytopenia (ITP) refractory to glucocorticoids or in relapse represents a challenging clinical scenario with limited durable treatment options; eltrombopag, though effective as second-line therapy, has constrained long-term efficacy. This trial addresses the unmet need for sustained remission in adults with platelet counts <30×10⁹/L, a threshold associated with clinically significant bleeding risk. The immunomodulatory mechanism of ATRA—targeting ITP pathophysiology rather than solely stimulating thrombopoiesis—offers a rationale for combination therapy that hematologists managing refractory ITP should now consider.
Key findings
1. Sustained response at 18 months (platelet count ≥30×10⁹/L without clinically significant bleeding or rescue therapy) was achieved in 60% (29/48) of the ATRA-plus-eltrombopag group versus 35% (17/48) in the eltrombopag monotherapy group (OR: 2.78; 95% CI: 1.22–6.37; P=0.014). 2. Complete response rate was higher in the combination arm (79% vs. 58%; 95% CI for difference: 2–39 percentage points), indicating superior depth of hematologic response. 3. Median response duration was significantly longer with combination therapy (75 weeks vs. 37 weeks; HR for relapse: 0.45; 95% CI: 0.23–0.86), representing an approximate doubling of remission duration. 4. The NNT for one additional sustained response at 18 months is approximately 4 (absolute risk difference ~25%). 5. Adverse events were comparable between the two groups, with no grade 3–4 treatment-related adverse events and no treatment-related deaths in either arm. 6. A notable baseline imbalance was observed: clinically significant bleeding (WHO grades 2–3) was present in 21% of the combination group versus 10% in the monotherapy group, which may reflect randomization imbalance and should be considered when interpreting efficacy outcomes.
Practice implications
For adults with glucocorticoid-resistant or relapsed ITP and platelet counts <30×10⁹/L, the addition of a 12-week course of ATRA to standard eltrombopag therapy should be considered as a strategy to meaningfully improve rates of sustained response and complete remission, and to nearly double remission duration. Clinicians should note that ATRA is administered as a time-limited adjunct (12 weeks) rather than continuous therapy, which may limit cumulative toxicity and improve patient acceptability, though the favorable safety profile observed in this relatively small trial (n=96) warrants confirmation in larger cohorts. The baseline bleeding imbalance between arms should prompt careful pre-treatment documentation of bleeding status, and future studies should clarify whether response benefit is consistent across subgroups stratified by baseline bleeding severity and prior lines of therapy.