Pirtobrutinib Improves Patient-Reported Outcomes in Relapsed/Refractory CLL/SLL

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Pirtobrutinib (Jayprica) demonstrated consistent improvements in patient-reported outcomes (PROs) compared with idelalisib (Zydelig) plus rituximab (Rituxan) or bendamustine plus rituximab (BR) in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) previously treated with a covalent BTK inhibitor, according to findings from an analysis of the randomized phase 3 BRUIN CLL-321 trial (NCT04666038) presented at the 2025 EHA Congress.1

The PRO-evaluable population comprised 91 patients (76.5%) in the pirtobrutinib arm and 88 patients (73.9%) in the idelalisib/rituximab or BR arm who completed baseline assessments, yielding an overall completion rate of 75.2%. PROs were assessed every 4 weeks through week 25 using the EORTC QLQ-C30 for physical function and the EORTC Item Library 87 for CLL/SLL-related symptoms.

Compared with idelalisib/rituximab or BR, patients receiving pirtobrutinib reported more consistent improvements during all visits in CLL/SLL-related symptoms (difference at week 25, 4.72), physical functioning (difference at week 25, 2.77), and fatigue (difference at week 25, 5.27).

“While both groups experienced some improvements in PRO outcomes, compared with idelalisib/rituximab or BR, patients treated with pirtobrutinib had more consistent improvement in CLL/SLL-related symptoms, physical function, and fatigue throughout the assessment period; all pirtobrutinib outcomes met a clinically meaningful threshold,” lead study author Paolo Ghia, MD, PhD, and colleagues noted in a poster presentation of the data. Ghia is a professor at the Università Vita-Salute San Raffaele in Milan, Italy.

In December 2023, the FDA granted an accelerated approval to pirtobrutinib for the treatment of adult patients with CLL or SLL who have received at least 2 prior lines of therapy, including a BTK inhibitor and a BCL2 inhibitor.2 This approval was supported by findings from the phase 1/2 BRUIN trial (NCT03740529).

BRUIN CLL-321 was a randomized trial that evaluated pirtobrutinib in patients with relapsed/refractory CLL/SLL who received prior treatment with a covalent BTK inhibitor.1 Prior data from the phase 3 study showed that pirtobrutinib improved PFS in this patient population compared with idelalisib/rituximab or BR.3

BRUIN-CLL-321 and PRO Analysis Overview

Eligible patients in BRUIN CLL-321 were required to be at least 18 years of age with a confirmed diagnosis of CLL/SLL requiring treatment per International Working Group CLL 2018 criteria. An ECOG performance status of 0 to 2 and prior treatment with a covalent BTK inhibitor were required. There were no limitations on the number of prior therapy lines, and patients with a history of atrial fibrillation were permitted to enroll.

Participants were randomly assigned 1:1 to receive either pirtobrutinib at 200 mg orally once daily or investigator’s choice of idelalisib/rituximab or BR. Stratification was based on 17p deletion status (yes vs no) and prior exposure to venetoclax (Venclexta; yes vs no). Optional crossover to pirtobrutinib was allowed for patients in the comparator arm upon disease progression confirmed by an independent review committee.

Notably, the secondary and exploratory PRO end points were not alpha-controlled. Time to worsening of CLL/SLL-related symptoms and physical function was a secondary end point. Exploratory PRO end points included longitudinal assessments of symptom burden using the EORTC Item Library 87, physical function using the EORTC QLQ-C30, and fatigue.

Additional PRO Data Breakdown and Study Limitations

Differences in mean changes from baseline in CLL/SLL-related symptoms between the pirtobrutinib arm and control arm were 3.08, 7.27, 6.74, 4.61, 6.97, and +4.72 at weeks 5, 9, 13, 17, 21, and 25, respectively. Improvements in physical function were also reported at each time point, with respective mean differences of 1.27, 4.40, 5.63, 3.60, 5.92, and 2.77. Corresponding differences in fatigue scores were 1.70, 9.03, 6.67, 5.16, 6.93, and 5.27 at each respective visit.

Ghia and colleagues noted that the PRO analysis was limited by the lack of data collection beyond week 25 for patients treated with BR. Patients available for PRO assessments also declined over time as patients experienced disease progression or discontinued treatment.

References

1. Ghia P, Rossi D, Ferrant E, et al. Patient-reported outcomes in BRUIN-CLL-321: a phase 3 trial of pirtobrutinib vs idelalisib plus rituximab or bendamustine plus rituximab in BTK inhibitor–pretreated chronic lymphocytic leukemia/small lymphocytic lymphoma. Presented at: 2025 EHA Congress; June 12-15, 2025; Milan, Italy. Abstract PS2282.
2. Jaypirca (pirtobrutinib) now approved by U.S. FDA for the treatment of adult patients with chronic lymphocytic leukemia or small lymphocytic lymphoma who have received at least two lines of therapy, including a BTK inhibitor and a BCL-2 inhibitor. News release. Eli Lilly and Company. December 1, 2023. Accessed June 16, 2025. https://www.prnewswire.com/news-releases/jaypirca-pirtobrutinib-now-approved-by-us-fda-for-the-treatment-of-adult-patients-with-chronic-lymphocytic-leukemia-or-small-lymphocytic-lymphoma-who-have-received-at-least-two-lines-of-therapy-including-a-btk-inhibitor-and--302003695.html#:~:text=INDIANAPOLIS%2C%20Dec.%201%2C%202023,(CLL%2FSLL)%20who%20have
3. Sharman JP, Munir T, Grosicki S, et al. BRUIN CLL-321: Randomized phase III trial of pirtobrutinib versus idelalisib plus rituximab (IdelaR) or bendamustine plus rituximab (BR) in BTK inhibitor pretreated chronic lymphocytic leukemia/small lymphocytic lymphoma. Blood. 2024;144(suppl 1):886-886. doi: 10.1182/blood-2024-198147