Efficacy and safety of bruton tyrosine kinase (BTK) inhibitor zanubrutinib in relapsed/refractory warm autoimmune hemolytic anemia (wAIHA) after multiple lines of therapy: A prospective phase 2 single-arm study

Abstract Objective: To evaluate the efficacy and safety of the Bruton tyrosine kinase (BTK) inhibitor zanubrutinib in patients with relapsed/refractory (R/R) wAIHA who had failed at least two prior lines of immunosuppressive therapy. Methods: This prospective phase 2 single-arm study screened R/R AIHA patients with hemoglobin levels <100 g/L who had received ≥2 prior therapy lines. Patients received zanubrutinib 160 mg twice daily, either alone or with concomitant prednisone ≤15 mg/day. Efficacy and adverse events (AEs) were assessed at 12 weeks. Results: A total of sixteen patients were screened. Three patients were excluded due to NHL-associated AIHA or cold agglutinin disease (CAD). Thirteen patients with wAIHA were enrolled: 8 females and 5 males, with a median age of 59 years (range: 34–91). Among these, 11 patients had primary wAIHA and 2 had Evans syndrome. Eleven cases were idiopathic, while 2 were secondary to connective tissue disease with antiphospholipid syndrome (CTD-APS). Two patients had relapsed disease, and 11 were refractory. The median number of prior treatment lines was 4 (range: 2–7), including glucocorticoids (13/13), rituximab (9/13), sirolimus (9/13), and other immunosuppressants. One patient had undergone prior splenectomy. Nine patients received zanubrutinib for >12 weeks and were efficacy-evaluable. At 12 weeks, the overall response rate (ORR) was 4/9 (44.4%), comprising complete response (CR) in 2/9 and partial response (PR) in 2/9. The four responders continued treatment for 7, 15, 16, and 20 months, respectively. Five non-responders discontinued treatment after 12 weeks; one achieved CR post-splenectomy, two achieved CR and PR with subsequent sirolimus, and two remained on corticosteroids. Four patients discontinued before 12 weeks: two due to AEs (thrombocytopenia, n=1; conjunctival hemorrhage & hematuria, n=1) and one was lost to follow-up. AEs included grade 3 thrombocytopenia (n=1), grade 1 thrombocytopenia (n=1), grade 4 leukopenia (n=1), conjunctival hemorrhage & hematuria (n=1), and night sweats & eyelid edema (n=1). Conclusion: Zanubrutinib demonstrated modest activity at 12 weeks in heavily pre-treated R/R wAIHA patients, with manageable toxicity. Larger studies are warranted to confirm these findings. Ethical Approval: Approved by the Ethics Committee of Peking Union Medical College Hospital (Approval No. K4355).