Long-term efficacy and safety of rilzabrutinib, an oral bruton tyrosine kinase (BTK) inhibitor in patients with warm autoimmune hemolytic anemia (wAIHA) in the LUMINA Phase 2b part B study: A 74-week follow-up

Abstract Introduction: wAIHA is a rare type of anemia caused by destruction of red blood cells (RBCs) mostly due to IgG (warm antibody) binding to RBC antigens. Treatment goals include raising hemoglobin (Hb) to stable levels, symptom resolution, transfusion independence, and reducing risk of thrombosis. Rilzabrutinib, an oral, covalent, reversible, and highly selective BTK inhibitor that acts through multi-immune modulation, may treat wAIHA by reducing pathogenic autoantibodies directed against RBC, FcγR-mediated phagocytosis, chronic inflammation, and complement activation. In the phase 2B LUMINA2 part A study (NCT05002777), patients (pts) with wAIHA (N=22) receiving rilzabrutinib for 24 weeks (wks) showed robust overall and durable Hb response, reduced fatigue, decreased hemolytic markers and markers of inflammation, and favorable safety (Cooper, ASH 2024). Long-term follow-up in the core part B (Wk 50 assessment) showed sustained efficacy with durable Hb response and stable Hb levels, decreased hemolytic and inflammatory biomarkers, reduced fatigue, and well-tolerated safety profile (Fattizzo, EHA 2025; Cooper, EHA 2025). Here, we examine the efficacy and safety of rilzabrutinib in the continued follow-up of the core part B of the LUMINA2 study, with assessment at 74 wks. Methods: Adult pts with relapsed/refractory or corticosteroid (CS)-dependent primary wAIHA, ECOG PS of 0-2, Hb levels <10 g/dL, ≥1 abnormal marker of hemolysis, positive direct antiglobulin test, and unsustained response to CS were eligible for Part A. To progress to core part B, part A pts had to complete the 24-wk course of oral rilzabrutinib (400 mg bid) and demonstrate overall Hb response by Wk 24. Core part B period lasted until the last pt completed 52 wks in part B. Stable doses of concomitant CS (or dose reduction) and rescue therapy were permitted. Hb levels, hemolytic markers, frequency of blood transfusions, change from baseline in FACIT-Fatigue scores, and safety were evaluated at the 74-wk follow-up. Results: As of 21May2025, 15 of 22 (68%) pts from part A (14 primary wAIHA, 1 erroneously enrolled with cold agglutinin disease) had entered part B and 9 of 15 (60%) have completed core Part B (≥74 wks); 11 (73%) pts received rilzabrutinib for ≥52 wks in part B. At baseline, 15 pts who entered part B had a median age of 68 y (range, 33-87; 27% ≥75 y) and 40% were female. For 14 primary wAIHA pts, median time since diagnosis was 7.1 y (maximum 47 y; 60% ≥3 y). Nine (60%) pts received ≥3 prior medications; 6 (40%) pts received rilzabrutinib monotherapy and 9 (60%) received concomitant CS. Median baseline Hb level was 8.2 g/dL (range: 5.8-11.4) and at Wk 74 was 11.7 g/dL (range: 6.6 to 14.7). Increased Hb levels were associated with reduced hemolytic markers. At Wk 74, median LDH levels decreased by 37%, reticulocytes by 63%, and total bilirubin by 62%. Six (40%) pts received blood transfusions by end of core part B. Clinically meaningful increase in FACIT-Fatigue scale scores was observed with median change from baseline of 5.0 (IQR: 2-11) at Wk 74 (median: 44.4). Two pts (male, 87 y; female, 61 y) opted to discontinue rilzabrutinib due to maintaining durable response at Wks 50 and 58 of part B; both achieved drug-free remission (Hb 14.1 g/dL at Wk 50 and 13.6 g/dL after 5 mo in Pt 1; Hb 11.8 g/dL at Wk 58 and 12.0 g/dL after 4 mo in Pt 2) through Wk 74 (remission for 24 and 16 wks, respectively, after treatment discontinuation) and decreased hemolytic markers. At data cutoff, rilzabrutinib was given for a median duration of 62 wks (range, 26-134) in core part B. Twelve (80%) pts had adverse events (AEs) due to any cause, 5 (33%) with treatment-related AEs. The most common any-cause AEs were diarrhea (33%), upper respiratory tract infection (27%), back pain (20%), and headache (20%). Six pts (40%) had any-cause serious AEs (none were treatment related). There was one treatment-emergent AE that led to treatment discontinuation in a pt with relapsed wAIHA, per investigator judgement. There were no AEs of special interest or deaths. Conclusion: Extended follow-up of pts treated with rilzabrutinib showed continued efficacy with sustained Hb response, with some pts achieving drug-free remission; decreased hemolytic markers; clinically meaningful improvement in fatigue score; and a favorable safety profile in pts with wAIHA. Efficacy and safety of rilzabrutinib will be further evaluated in a phase 3, randomized, placebo-controlled study (LUMINA3).