Part a Efficacy and Safety of Oral Bruton Tyrosine Kinase Inhibitor (BTKi) Rilzabrutinib in Patients with Warm Autoimmune Hemolytic Anemia (wAIHA): Multicenter, Open-Label, Phase 2b Study

Introduction: wAIHA is a rare form of anemia caused by premature destruction of red blood cells (RBC) mostly due to warm agglutinins (mainly IgG) binding to RBC antigens. Key wAIHA mechanisms are extravascular hemolysis (due to FcγR-mediated RBC phagocytosis, spleen ADCC, liver CDC), intravascular hemolysis (complement cascade activation), and lack of bone marrow (BM) compensation. The clinical picture ranges from BM-compensated to life-threatening anemia and high thromboembolism risk (venous>arterial). Although most patients significantly respond to corticosteroids (CS), CS-dependence, resistance, or intolerance results in extra therapy. The reversible covalent BTKi rilzabrutinib may increase hemoglobin (Hb) levels in wAIHA through multiple mechanisms: decreasing macrophage (FcγR)-mediated RBC destruction in spleen and inhibiting pathogenic autoantibody production. Reported here are final part A results of the open-label multicenter phase 2b study of rilzabrutinib in wAIHA patients (NCT05002777). Methods: Adults ≥18 y with primary wAIHA or SLE-associated wAIHA who were relapsed/refractory to or dependent on CS were enrolled. Patients had Hb level <10 g/dL, ≥1 abnormal hemolytic marker, positive DAT, ECOG PS 0-2, and unsustained response to CS. In this two-part study, part A patients received oral rilzabrutinib 400 mg bid for 24 wks; responding patients completing part A could continue rilzabrutinib in the long-term extension (LTE, part B) until the last patient in completes 52 wks. Stable doses of concomitant CS and rescue therapy were allowed. The primary efficacy endpoint was overall Hb response (including response or complete response) by wk 24. Response was defined as increased Hb by ≥2 g/dL from baseline. Complete response was defined as Hb ≥11 g/dL (women) or ≥12 (men) with no evidence of hemolysis. Responses had to be in the absence of blood transfusion in the last 7 d and no rescue medication during the last 4 wks. Part A secondary endpoints were time to Hb response and durable response (Hb ≥10 g/dL with increase from baseline ≥2 g/dL on 3 consecutive scheduled visits during 24 wks). Fatigue was measured by FACIT-Fatigue scale. Results: 22 patients were enrolled, including 21 with primary wAIHA and 1 erroneously enrolled with cold agglutinin disease. 21 patients completed part A, 1 withdrew due to the patient decision within the first 12 wks, and 15 have entered part B LTE. At baseline, median age was 65 y (range, 33-87; 23% ≥75 y) and 59% were female. For 21 wAIHA patients, median time since diagnosis was 4.9 y (maximum 47 y; 55% ≥3 y). 11 (50%) patients had ≥3 prior medications. Rilzabrutinib monotherapy was given in 9 (41%) patients, and with concomitant CS in 13 (59%) patients. Overall Hb response was achieved in 14 (64%) patients (13 [59%] patients met criteria for response and 3 [14%] for complete response), and 9 (41%) wAIHA patients achieved durable response. Median time to Hb response in 14 responders was 50 d (range, 28-169). Increased Hb levels were associated with reduced hemolysis markers. In all patients at wks 12 and 24 relative to baseline, median LDH levels were reduced by 33% for both, and median reticulocytes reduced by 32% and 51% respectively. Overall mean (SD) baseline FACIT-fatigue scale score of 30.0 (11.1) improved with clinically meaningful increases to 36.4 (10.5) at wk 12 and 37.0 (11.5) at wk 24. Rescue medication was used in 1 patient from wks 1-12 and 3 patients from wks >12-24. 5 (23%) patients (3 responders, 2 non-responders) received blood transfusions during the first 12 wks of treatment. 1 responder, who received more frequent blood transfusions (weekly) pre-study vs others, received them 6x in wks 1-12, and 2x in wks >12-24. Rilzabrutinib was given for a median duration of 24 wks (range, 9-25). 19 (86%) patients had on-treatment adverse events (AEs) due to any cause; 10 (45.5%) patients had treatment-related AEs. The most common any-cause AEs were nausea (32%), diarrhea (23%), and upper abdominal pain (18%), all mild grade. Four (18%) patients had serious AEs; none were treatment related. Part A had no thromboembolic events, AEs leading to discontinuation, or deaths. Conclusion: Rilzabrutinib in previously treated patients with primary wAIHA resulted in robust efficacy based on overall and durable Hb response, decreased hemolysis, and clinically meaningful improvement in fatigue. Rilzabrutinib was well-tolerated with a favorable safety profile in patients with wAIHA.