P1604: impact of thrombopoietin level on platelet response in patients with immune thrombocytopenia treated with rilzabrutinib, an oral bruton tyrosine kinase inhibitor

Topic: 32. Platelet disorders Background: The complex pathophysiology of immune thrombocytopenia (ITP) may contribute to an unpredictable clinical course and response to therapy. Treatment with oral Bruton tyrosine kinase inhibitor rilzabrutinib in adults with ITP in the global phase I/II trial (NCT03395210) showed rapid platelet response and continued durability with longer use, as well as an acceptable safety profile. Rilzabrutinib is known to impact multiple ITP pathways including reducing Fcγ receptor–mediated macrophage function and autoantibody production. Aims: Assess thrombopoietin (TPO) levels at baseline and after rilzabrutinib, and characterize the impact of TPO levels on platelet response following rilzabrutinib. Methods: Eligible ITP phase I/II study patients had 2 baseline platelet counts <30×109/L with required, but inadequate response to ≥1 prior/concomitant ITP therapy. Stable doses of concomitant TPO-receptor agonists (TPO-RA) and/or CS were allowed. Primary endpoints were safety and platelet response (≥2 consecutive platelet counts ≥50×109/L and increased ≥20×109/L from baseline without rescue medication). TPO/platelet levels were evaluated at baseline and weeks 12/24 using bivariate ANCOVA models adjusting for baseline TPO/platelet levels and TPO-RA use. Additionally, the effects of baseline TPO/platelet levels on the odds of being a responder/non-responder were obtained from univariate logistic regression models. Results: At baseline, 50 assessable ITP patients had a median age of 49 y (range, 19-74), 56% were female; n=18 received concomitant TPO-RA. Of 50 evaluable patients, 20 (40%) met the primary platelet response during the main treatment period. Among 32 patients with available data, baseline TPO levels were <100, 100-249, and ≥250 pg/mL in 17, 13, and 2 patients, respectively. Circulating median TPO levels were 94 pg/mL at baseline that decreased following rilzabrutinib to 78 pg/mL (week 12) and 69 pg/mL (week 24). Conversely, median platelet count at baseline of 14×109/L increased following rilzabrutinib at 12 and 24 weeks to 37×109/L and 41×109/L, respectively. Patients not receiving TPO-RA at baseline had lower platelet levels (–68.8×109/L) at week 24 vs those receiving baseline TPO-RA. ANCOVA models showed no relationship between either baseline platelet or TPO levels against platelet levels at either week 12/24 (Table). However, there was a positive relationship with higher baseline TPO levels associated with higher TPO levels at weeks 12/24. The logistic regression model showed that higher baseline platelet levels were associated with significantly greater odds of being a responder for every 1×109/L higher baseline platelet levels (OR=1.08 [95% CI, 1.00, 1.16]; P=0.04). Interestingly, elevated TPO levels were associated with reduced odds of being a responder although not statistically significant, suggesting that TPO levels may have no impact on response to rilzabrutinib. Responders and non-responders showed consistently normal levels of hemoglobin, neutrophils, reticulocytes, and reticulocytes/erythrocytes for a median of 100%, 94%-100%, 88%, 92%-93% of visits, respectively. There were no cases of neutropenia and 5 patients had anemia; none were treatment related and rilzabrutinib dosing was unchanged. Rilzabrutinib treatment was associated with stable B cell levels. All treatment-related adverse events were transient and grade 1/2. Summary/Conclusion: Following rilzabrutinib treatment, platelet levels increased over time, whereas serum TPO levels declined. ITP patients responded to rilzabrutinib irrespective of their baseline TPO levels.Keywords: Bruton’s tyrosine kinase inhibitor (BTKi), Platelet, Immune thrombocytopenia (ITP)