Current treatments for persistent or chronic immune thrombocytopenia (ITP) are limited by inadequate response, toxicity, and impaired quality of life. The Bruton tyrosine kinase inhibitor rilzabrutinib was evaluated to further characterize safety and durability of platelet response. LUNA2 Part B is a multicenter, phase 1/2 study in adults with ITP (≥ 3 months duration, platelet count < 30 × 109/L) who failed ≥ 1 ITP therapy (NCT03395210, EudraCT 2017-004012-19). Oral rilzabrutinib 400 mg bid was given over 24 weeks, with optional long-term extension (LTE). Primary endpoints were safety and platelet counts ≥ 50 × 109/L on ≥ 8 of the last 12 weeks of main treatment without rescue medication. From 22 March2018 to 31 January2023, 26 patients were enrolled. Patients had baseline median platelet count 13 × 109/L, ITP duration 10.3 years, and six prior ITP therapies (46% splenectomized). Nine (35%) patients achieved the primary endpoint. Platelet counts ≥ 50 × 109/L or ≥ 30 × 109/L and doubling from baseline without rescue therapy were sustained for a mean 9.3 weeks. 11 (42%) LTE-eligible patients were ongoing with median LTE platelet > 80 × 109/L. Three (12%) patients received rescue medication during main treatment, none in LTE. Clinically meaningful improvements were observed in fatigue and women's health. With a median treatment duration of 167 days (main treatment), 16 (62%) patients had ≥ 1 treatment-related adverse event (AE), mainly grade 1, including diarrhea (35%), headache (23%), and nausea (15%). There was no treatment-related grade ≥ 2 bleeding/thrombotic events/infections, serious AE, or death. Rilzabrutinib continues to demonstrate durable platelet responses with favorable safety profile in previously treated ITP patients. Trial Registration: NCT03395210, EudraCT 2017-004012-19.

4th Department of Internal Medicine and Hematology Faculty of Medicine University Hospital of Hradec Králové Hradec Králové Czech Republic

Barts Health NHS Trust The Royal London Hospital London UK

Clinic of Hematology University Hospital Pleven Bulgaria

Department Immunology and Inflammation Imperial College Hammersmith Hospital London UK

Department of Hematology HagaZiekenhuis Den Haag The Netherlands

Erasmus MC University Medical Center Rotterdam The Netherlands

Hematology Division Massachusetts General Hospital Harvard Medical School Boston Massachusetts USA

Leicester Royal Infirmary Leicester UK

Masaryk University Hospital Brno Czech Republic

Princess Alexandra Hospital Woolloongabba Australia

Queen Elizabeth Hospital Birmingham UK

Royal Melbourne Hospital and Peter MacCallum Cancer Centre Parkville Australia

Sanofi Bridgewater New Jersey USA

Sanofi Cambridge Massachusetts USA

Sanofi Rotkreuz Zug Switzerland

St Michael's Hospital Li Ka Shing Knowledge Institute University of Toronto Toronto Ontario Canada

The Bleeding and Clotting Disorders Institute University of Illinois College of Medicine Peoria Peoria Illinois USA

University of Washington and Fred Hutchinson Cancer Center Seattle Washington USA

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