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Presentation Details
| MODIFIED DURABLE PLATELET RESPONSE BY INTERNATIONAL WORKING GROUP CRITERIA: LUNA3 PHASE 3 STUDY OF RILZABRUTINIB VS PLACEBO IN ADULTS WITH PRIMARY IMMUNE THROMBOCYTOPENIA Waleed Ghanima1, Yoshitaka Miyakawa2, Nichola Cooper3, Marie Luise Hütter-Krönke4, Maria Cristina Pascual Izquierdo5, Sylvain Audia6, Meredith C.Foster7, Maria Belen Rodriguez7, Jing Zhao7, Ahmed Daak7, David J.Kuter8, David Farber7. 1Østfold Hospital Trust, Grålum, Norway and Institute of Clinical Medicine, University of Oslo, Oslo, Norway.2Department of Hematology, Saitama Medical University, Saitama, Japan.3Hammersmith Hospital, London, United Kingdom.4Department of Hematology, Oncology and Tumorimmunology, Charité - Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt Universität zu Berlin, Berlin, Germany.5Department of Hematology, Gregorio Marañon Hospital, Madrid, Spain.6CHU Dijon Bourgogne - Hopital Francois Mitterrand, Dijon, France.7Sanofi, Cambridge, MA, USA.8Hematology Division, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA |
Abstract
Background: The International Working Group (IWG)-based definition of platelet response in immune thrombocytopenia (ITP) is clinically meaningful by comprising both a safe platelet count threshold commonly used in clinical practice for treatment decisions and bleeding outcomes (Rodeghiero, Blood 2009), but is rarely used in clinical trials. Target levels for clinically meaningful platelet thresholds that minimize bleeding risk vary across studies, despite published IWG guidelines in ITP. Rilzabrutinib is an oral, covalent, reversible BTK inhibitor acting through multi-immune modulation. Objectives: Analyze modified durable response results based on IWG criteria from the LUNA3 phase 3 study of rilzabrutinib vs placebo in persistent/chronic ITP (NCT04562766; 2020-002063-60). Methods: For the 24-week double-blind period, patients were randomized 2:1 to oral rilzabrutinib 400 mg bid or placebo. After the initial 12 weeks, non-responders could discontinue or receive open-label rilzabrutinib for 28 weeks. Modified durable IWG response was IWG response (platelet count ≥30×109/L and ≥doubled from baseline, absent bleeding) for ≥50% of assessments during the last 12 weeks of the double-blind period with ≥6 non-missing assessments or the last 16 weeks of the open-label period with ≥8 non-missing assessments. Results: In the double-blind period, 133 patients initiated rilzabrutinib and 69 placebo. To date, 180 patients have entered the open-label period on rilzabrutinib (initial double-blind assignment: n=115 rilzabrutinib, n=65 placebo). Modified durable IWG response during the double-blind period was observed in 45/133 (34%) rilzabrutinib vs 2/69 (3%) placebo patients (P<0.0001; Table 1). With open-label rilzabrutinib, 74/180 (41%) patients overall achieved modified durable IWG response, with non-significant differences by initial double-blind assignment (51/115 [44%] rilzabrutinib vs 23/65 [35%] placebo; P=0.24). Among rilzabrutinib-treated patients across periods, 50% achieved modified durable IWG response. Median platelet counts were consistently elevated in rilzabrutinib-treated durable IWG responders during the double-blind period and maintained in the open-label period, with some non-responding patients converting to open-label durable response and showing increased platelet counts (Figure 1). Higher responses to rilzabrutinib were observed in patients who received 1-2 prior unique ITP therapies relative to 3-4 or ≥5 prior therapies. Modified durable IWG response in patients randomized to rilzabrutinib during the double-blind period was achieved in 19 patients receiving 1-2 prior unique ITP therapies, which included 17 (89%) patients receiving prior corticosteroids, 7 (37%) TPO-RA, 2 (11%) IVIg, and 1 (5%) each splenectomy, immunosuppressants and other immunomodulatory agents (including cyclophosphamide), and/or other. The 2 placebo patients with modified durable IWG response during the double-blind period had ≥5 prior unique ITP therapies. Conclusions: Overall, modified durable IWG response was increased in rilzabrutinib-treated patients during the double-blind period; some non-durable responders to either double-blind rilzabrutinib or placebo had improved response during the open-label period. Results also suggest higher responses in patients with fewer prior ITP therapies.
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