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Abstract Introduction Rilzabrutinib, a BTK inhibitor that acts through multi-immune modulation, showed rapid and durable platelet response, reduced bleeding, significantly improved physical fatigue, and a well-tolerated safety profile in the double-blind (DB) period of the phase 3 LUNA3 study (NCT04562766; EudraCT 2020-002063-60) in patients with ITP who failed multiple prior therapies. During the OL period, rilzabrutinib treatment showed durable platelet response (platelet counts ≥50x109/L for ≥two-thirds of the last 16 of 28 OL weeks without rescue therapy), including patients initially randomized to placebo and patients who were non-responsive to rilzabrutinib during the DB. We present the effect of treatment with rilzabrutinib on HRQoL and bleeding score in patients who enrolled in the OL period of the LUNA3 study. Methods Previously treated adult ITP patients with baseline platelet counts <30x109/L within 2 weeks of treatment were randomized 2:1 to oral rilzabrutinib 400 mg bid or placebo for up to 24 weeks during DB, then rilzabrutinib 400 mg bid only in the 28-week OL period. After the initial DB 12 weeks, non-responders could join OL or discontinue. Exploratory endpoints assessed at the end of OL (week 53) included change from baseline in physical fatigue (Item 10 of ITP-Patient Assessment Questionnaire [PAQ]), psychological, fear, social activity, women's reproductive health, and work domains of the ITP-PAQ (range, 0-100; higher scores reflect better HRQoL); Idiopathic Thrombocytopenic Purpura Bleeding Scale (IBLS) score (range, 0-2; higher scores reflect increased bleeding). An 8-12–point improvement for symptoms, bother-physical, psychological, overall QoL, social activity, and women's reproductive health and 10-15–point improvement for domains of fatigue/sleep and activity were considered clinically meaningful. Other endpoints included HRQoL measured by the descriptive EuroQOL-Dimensions-5 Level (EQ-5D-5L) and the EuroQol-visual analogue scale (EQ-VAS; range, 0-100; higher scores reflect better health). Results Totally, 180 of 202 DB patients (89%; 115 rilzabrutinib and 65 placebo) entered OL. At baseline, OL patients had a median age of 48 y, 62% were female, patients had median duration of ITP of 7.3 y (range 0.3-52.2 y), and median of 4 (range 1-15) prior ITP therapies (29% prior splenectomy). Durable response was achieved in 49 (27%) patients with rilzabrutinib in OL. An upward trend of improvement of physical fatigue score was seen during OL reaching a maximum mean (SD) increase of 15.6 (28.3), 4.9 (24.5), and 11.7 (27.4) in rilzabrutinib DB, placebo DB, and overall OL patients, respectively, at week 53. As in the DB period, physical fatigue improved in both durable (mean change from baseline [SD], 20.3 [30.4]) and non-durable responders (5.4 [23.2]) by week 53, despite prior worsening in the latter group during DB (-0.4 [23.4]). Rilzabrutinib showed continued improvement of ITP-PAQ domain scores over the OL period. The mean change from baseline at week 53 (SD) was above the published clinically meaningful threshold for bother-physical health (11.15 [22.57]), activity (10.73 [29.73]), overall QoL (10.04 [21.91]), psychological health (9.82 [21.61]), symptoms (9.11 [18.94]), and social activity (8.44 [20.75]). There was improvement in mean change from baseline at week 53 (SD) for fatigue/sleep (6.64 [19.45]), women's reproductive health (5.12 [18.01]), fear (4.15 [19.65]), and work (1.61 [25.24]) domain scores. Patients with prolonged exposure to rilzabrutinib demonstrated greater improvements across domains. Mean (SD) IBLS score at DB baseline was 0.20 (0.21). Reduced mean IBLS score (ie, improvement) was observed during OL, with greatest reduction (SD) of -0.14 (0.19) and -0.10 (0.18) in the rilzabrutinib (DB) and placebo (DB) groups, respectively, at week 53. For EQ-5D-5L, patients were stable throughout the OL period. EQ-VAS scores continued to show improvement at week 53 with mean change from baseline (SD) of 7.1 (16.1). Conclusion Sustained, and in some cases, further improvements in fatigue, HRQoL, and bleeding were seen with continued exposure to rilzabrutinib in the OL period. Additionally, patients who were initially on placebo and switched to rilzabrutinib during OL also experienced improvements in fatigue and HRQoL. These findings further support the use of rilzabrutinib in adults with ITP, highlighting its potential to improve fatigue, HRQoL, and bleeding outcomes through multi-immune modulation.