Rilzabrutinib, an oral Bruton tyrosine kinase inhibitor, in patients with warm autoimmune haemolytic anaemia: a prospective, single-arm, multicentre, phase 2b safety and clinical activity study (LUMINA 2).

Warm autoimmune haemolytic anaemia is a rare blood disorder characterised by haemolysis, anaemia, elevated thromboembolism risk, fatigue, and impaired quality of life. The selective Bruton tyrosine kinase inhibitor, rilzabrutinib, might increase haemoglobin through multi-immune modulatory mechanisms targeting key drivers of warm autoimmune haemolytic anaemia pathophysiology. The aim of the study was to report clinical safety and activity results for rilzabrutinib in patients with warm autoimmune haemolytic anaemia.

LUMINA 2, a multicentre, single-arm, open-label, phase 2b study, evaluated rilzabrutinib (with or without concomitant corticosteroids) in adults aged 18 years or older with primary or systemic lupus erythematosus-associated warm autoimmune haemolytic anaemia who were relapsed, refractory to, or dependent on corticosteroids. Patients were enrolled in 15 clinical research study centres from China, Denmark, Italy, Spain, the UK, and the USA. Patients in part A received oral rilzabrutinib at 400 mg twice a day for 24 weeks. The part A primary endpoint was overall haemoglobin response by week 24: response (haemoglobin increased by ≥2 g/dL from baseline without biochemical resolution of haemolysis) or complete response (haemoglobin ≥11 g/dL for women or ≥12 g/dL for men with no evidence of haemolysis). Responding patients in part A continued into part B with oral rilzabrutinib at 400 mg twice a day until the last patient completed 52 weeks (eligible patients could continue long-term extension for up to 253 weeks). The part B primary endpoint of durable response was haemoglobin at least 10 g/dL with an increase from baseline of at least 2 g/dL on three consecutive visits from after week 24 to week 50. Primary endpoints were without rescue medication or transfusion. The study is registered with ClinicalTrials.gov (NCT05002777) and EU Clinical Trials Register (2023-509441-13-00); enrolment is complete, analyses conducted at the 50-week data cutoff are provided per protocol, and the long-term extension is continuing.

From Jan 24, 2022, to Dec 6, 2023 (50-week data cutoff for ongoing trial was Nov 21, 2024), 22 patients enrolled in part A and 15 entered part B. 14 (64%; 95% CI 41-83) of 22 patients in part A had overall haemoglobin response (13 [59%; 36-79] response and three [14%; 3-35] complete response). 12 (80%) of 15 patients in part B had durable haemoglobin response. Treatment-related adverse events were observed in ten (45%) of 22 patients in part A and four (27%) of 15 patients in part B. The most common treatment-related adverse events in part A were nausea in three (14%) and diarrhoea in two (9%) of 22 patients. Four (18%) of 22 patients in part A had serious adverse events (ie, influenza, pneumonia, haemolytic anaemia, and tenosynovitis); none were treatment related. One patient in part B had severe anaemia considered related to treatment and one patient had a serious adverse event of decreased haemoglobin unrelated to treatment. There were no adverse events of special interest, leading to rilzabrutinib discontinuation, or deaths.