Changing Landscape of Management of Warm Autoimmune Hemolytic Anemia Free

STUDY TITLE: Efficacy, Safety and Pharmacokinetics of Rilzabrutinib in Patients with Warm Autoimmune Hemolytic Anemia (wAIHA) (LUMINA 2)

CLINICALTRIALS.GOV IDENTIFIER: NCT05002777

PARTICIPATING CENTERS: 27 international locations, including 11 U.S. sites

SPONSOR: Sanofi

ACCRUAL GOAL: 20 patients, with an actual enrollment of 22

STUDY DESIGN: This multicenter, phase II, open-label, single-arm study is designed to evaluate the efficacy, safety, and pharmacokinetics of rilzabrutinib in adult patients with warm autoimmune hemolytic anemia (wAIHA). LUMINA 2 involves 22 patients across 27 centers globally, including 11 U.S. sites. Patients who failed previous treatments with corticosteroids were enrolled in the study, with rilzabrutinib administered at 400 mg orally twice a day. Participants in Part A of the study were treated for 24 weeks, with primary outcome measures focusing on overall hemoglobin response, as well as avoidance of the need for transfusion and rescue medications. Those able to achieve an overall hemoglobin response were eligible to enroll in Part B (weeks 24 to 50), during which the key primary outcome was durability of response (hemoglobin >10 g/dL) with an increase from baseline of 2 g/dL or more, as well as avoidance of transfusion and rescue medications.

The study’s inclusion criteria specify adult patients with confirmed wAIHA, either primary or due to systemic lupus erythematosus. The study excluded patients with a history of uncontrolled hepatitis B, HIV infection, or underlying hematological malignancy such as lymphoma or leukemia, as well as those with other malignancies in the past five years. Secondary study outcomes included proportion of participants with durable hemoglobin response, median time from baseline to first hemoglobin response, frequency of rescue therapy, change in facet fatigue score from baseline, and incidents of treatment-emergent adverse events.

RATIONALE: wAIHA — the most common type of immune hemolytic anemia — leads to accelerated red cell destruction due to the presence of warm agglutinins (almost always immunoglobulin G antibodies) that bind to antigens on erythrocytes at a temperature of 37 degrees Celsius. Typically, wAIHA causes extravascular hemolysis via Fc gamma receptor (FcγR)-mediated red blood cell phagocytosis and spleen/liver antibody-dependent, cell-mediated cytotoxicity, but it can also lead to intravascular hemolysis via complement cascade activation.¹  Patients present with signs and symptoms related to anemia and thrombotic complications.

For decades, corticosteroids have remained the first-line therapy, with up to 30% of patients having durable remission after initial therapy; however, the remainder of patients experience a chronic, relapsing course. Second-line options include intravenous immunoglobulin, rituximab, immunosuppressive drugs, and splenectomy.^2-4 

Rilzabrutinib is an oral, reversible, covalent Bruton tyrosine kinase (BTK) inhibitor optimized for safety and efficacy in autoimmune and/or inflammatory diseases. Its high degree of selectivity and specificity is thought to contribute to long BTK target engagement while decreasing the off-target risk relative to other BTK inhibitors. Preclinical studies have shown that rilzabrutinib demonstrates its therapeutic effect through multiple mechanisms such as inhibiting B-cell activation, reducing pathogenic autoantibody production, interrupting platelet phagocytosis by FcγR in the spleen and liver, and inhibiting inflammatory pathways.⁵ 

The preliminary results from Part A were presented at the 2024 ASH Annual Meeting, highlighting rilzabrutinib’s clinically meaningful outcomes on disease markers and response rates in patients with the disease.⁶  An overall hemoglobin response was achieved in 14 of 22 enrolled patients (64%), with increased hemoglobin levels associated with reduced hemolysis markers. There were no serious treatment-related adverse events.

COMMENT: The landscape of management of immunohematologic conditions is rapidly evolving. Newer agents such as rilzabrutinib are targeting immune effector cells in a multimodal fashion, thus expanding the therapeutic armamentarium for these rare but complex disorders, which carry a high degree of morbidity and mortality for affected patients. This approach could potentially reduce reliance on corticosteroids and improve patient outcomes, suggesting a promising future for such a therapeutic strategy. Based on published literature from immune thrombocytopenia studies and Lumina 2 Part A, rilzabrutinib has shown a favorable side effect profile, thus making this therapeutic option promising. The ongoing Lumina 3 study aims to further assess whether this medication will prove practice-changing for the management of patients with wAIHA.