Reproductive health in patients with primary immune thrombocytopenia (ITP) receiving rilzabrutinib: A subgroup analysis from the Phase 3 LUNA3 multicenter study Free

Introduction: ITP is an immune-mediated disorder characterized by low platelet counts with consequent increased bleeding risk. Additionally, patients with ITP often experience fatigue and impaired health-related quality of life (HRQoL). Women and individuals with the potential to menstruate with ITP experience additional health challenges, particularly heavy and/or prolonged menstrual bleeding and other reproductive impacts. Rilzabrutinib is an oral Bruton tyrosine kinase (BTK) inhibitor with a multi-immune modulation mechanism of action that has demonstrated durable platelet response, reduced bleeding, clinically meaningful improvements in fatigue, and a favorable safety profile in adults with primary ITP in the LUNA3 study (NCT04562766; Kuter, Blood 2025). Here, we present descriptive analyses on self-reported women's reproductive health (WRH) by treatment in the LUNA3 double blind (DB) period.

Methods: Patients were randomized 2:1 to rilzabrutinib 400 mg BID (n=133) or placebo (n=69) for up to 24 weeks. Post-menopausal individuals at baseline were excluded from this analysis. Patients not achieving predefined platelet response by week 12 could either discontinue or enter the 28-week open-label period. The first published LUNA3 report measured HRQoL by ITP-PAQ (scored 0 worst to 100 best), evaluating the WRH domain as an exploratory endpoint (Kuter, Blood 2025). The ITP-PAQ WRH domain is comprised of 6 ITP-related items, including 3 on bleeding/pain during patient's last menstrual period and 3 on reproductive impacts on pregnancy, birth, and adoption. An 8-12–point improvement on the ITP-PAQ WRH domain was considered the minimum important difference (MID), translating to a 3.3-point change/item for menstrual symptoms/fertility (Mathias, CMRO 2009).

Results: Data from 43 rilzabrutinib and 28 placebo at-risk patients treated during the DB period were included. At screening/baseline, respective rilzabrutinib and placebo patients had median ages of 36 and 32 years, platelet counts of 14x10⁹/L and 11x10⁹/L, hemoglobin levels of 125 and 126 g/L, had received a median of 4 and 5.5 unique prior therapies, had median body mass index (BMI) of 27.6 and 23.2, and 23% and 29% were receiving contraceptive medication.

Improvements from baseline on the overall ITP-PAQ WRH domain were observed with rilzabrutinib (baseline mean: 69) with mean changes from baseline at weeks 13 (3.53 point increase, n=39) and 25 (6.63, n=22), but the MID was not met. Change from baseline with placebo (mean: 59) at week 13 was 0.40 (n=25) and at week 25 was –16.67 (n=2).

At the item level, clinically meaningful improvements in respective heavy menstrual bleeding (item 35) and bleeding duration (item 36) were seen with rilzabrutinib at week 13 (7.05 and 4.49) and week 25 (9.09 and 10.23). Improvement in pain (item 37) over MID level was not observed at week 13 (0.64) or week 25 (1.14). The likelihood of getting pregnant (item 38) and giving birth (item 39) improved with rilzabrutinib at weeks 13 (3.85 and 3.21) and 25 (7.95 and 9.09). Likelihood to adopt (item 40) did not substantially change at weeks 13 (1.92) or 25 (2.27). At week 25, durable responders with rilzabrutinib treatment showed improvement from baseline above MID in all 6 items 35-40: 8.93, 14.29, 3.57, 8.93, 8.93, 3.57, respectively. Non-durable responders with rilzabrutinib showed improvements from baseline above MID at week 25 in heavy menstrual bleeding (item 35: 9.38), likelihood of getting pregnant (item 38: 6.25) and giving birth (item 39: 9.38), whereas change from baseline did not reach MID in bleeding duration (item 36: 3.13), pain (item 37: -3.13) and likelihood of adoption (item 40: 0.0). With placebo, the mean change from baseline at week 13 for items 35, 36, 39, and 40 (1.0, -9.0, 2.0, and –2.0) did not reach the item level MID. Meaningful item-level changes at week 13 were only observed for placebo in pain (item 37: 4.0) and likelihood of getting pregnant (item 38: 6.0).Conclusions: Meaningful improvements from baseline were observed in self-reported ITP-PAQ WRH items in at-risk patients treated with rilzabrutinib during the LUNA3 DB period, especially for heavy and prolonged menstrual bleeding. These exploratory findings highlight rilzabrutinib's potential to improve HRQoL and bleeding outcomes for patients with ITP through multi-immune modulation. Larger studies on women's health outcomes and the potential impact of ITP treatments are needed.