Wang, Michael

Abstract Background: Despite the efficacy of covalent Bruton tyrosine kinase inhibitors (cBTKi) in R/R MCL, patients (pts) ultimately discontinue treatment due to intolerance or development of resistance and disease relapse. Pirtobrutinib is a highly selective, non-covalent BTKi that inhibits BTK with low nM potency throughout the daily dosing interval. Pirtobrutinib was safe and effective in the phase 1/2 BRUIN study in pts with R/R B-cell malignancies, including those previously treated with a BTKi. Pirtobrutinib is approved in the EU for adults with R/R MCL after prior treatment with a BTKi (EMA Conditional Approval, Oct 2023), and in the USA for adults with R/R MCL after ≥ 2 lines of systemic therapy, including a BTKi (FDA Accelerated Approval, Jan 2023).Here, we report the final results from the phase 1/2 BRUIN study (NCT03740529), with a follow-up period of up to 5 yrs, focusing on the efficacy and safety of pirtobrutinib in all R/R MCL pts. Methods: Pts with R/R MCL who received ≥1 prior lines of therapy (including BTKi) were eligible for treatment with pirtobrutinib monotherapy. Key endpoints included overall response rate (ORR), duration of response (DOR) and progression-free survival (PFS), all assessed by independent review committee (IRC) per Lugano 2014 criteria (presented here) and investigator, overall survival (OS), and safety. Pts were included across the range of doses evaluated in dose escalation and expansion (25-300 mg/day). A data cutoff on 27 January 2025 was utilized, with a median study follow-up of 17.5 months (range, 0.5-69.6). Results: Among the 166 pts with R/R MCL, 153 (92%) received the pirtobrutinib approved dose of 200 mg/day, 152 (92%) had received prior cBTKi, of which 128 (84.2%) discontinued any prior cBTKi due to progressive disease (PD), and 15 (9.9%) due to toxicity. The cBTKi-pre-treated pts had a median age of 70 yrs (range, 46-88), 52% had intermediate-risk and 28.3% had high-risk sMIPI scores. The median number of prior lines of therapy was 3 (range 1-9), with most pts having received a prior anti-CD20 antibody (96.7%) and chemotherapy (90.1%). Additional prior therapies included hematopoietic stem cell transplantation (21.7%; 19.7% auto and 4.6% allo), BCL-2 inhibitor (15.8%), CAR-T cell therapy (8.6%). As of the data cutoff, 11 (7.2%) pts who received a prior cBTKi and 6 (42.9%) cBTKi naïve pts remained on treatment. The cBTKi pre-treated pts had an ORR of 49.3% (95% CI, 41.1-57.6), including 15.8% complete responses (CR) (n=24) and 33.6% partial responses (PR) (n=51). The 75 responding pretreated pts had a median DOR of 21.6 months (95% CI, 9.2-27.2) at a median follow-up of 24 months. The ORR among 128 pts who had discontinued any prior cBTKi due to PD and 15 pts who discontinued due to toxicity was 43.0% and 93.3%, respectively. The median PFS and OS for cBTKi pre-treated pts were 5.6 months (95% CI, 5.3-9.2) and 23.9 months (95% CI, 17.3-51.5), respectively. Fourteen pts (9.2%) were censored for PFS due to subsequent anticancer therapy without documented PD, including 8 pts who received CAR-T. The cBTKi naïve pts (n=14) had an ORR of 85.7% (95% CI, 57.2-98.2), including 50.0% CR (n=7) and 35.7% PR (n=5). The 12 responding naïve pts had a median DOR of 42.7 months (95% CI, 25.8-NE) at a median follow-up of 43 months. The median PFS and OS in the cBTKi naïve pts were 44.6 months (95% CI, 16.7-NE) and not reached (95% CI, 33.5-NE), respectively. Among all R/R MCL pts (n=166), the most frequent treatment-emergent adverse events (TEAE), regardless of attribution, were fatigue (31.9%), diarrhea (22.9%), anemia (18.1%), and dyspnea (18.1%). The most common Grade ≥3 TEAE was neutropenia/neutrophil count decreased (13.3%), and the rate of Grade ≥3 infections was 21.1%. Grade ≥3 hemorrhage/hematoma (2.4%) and all-grade atrial fibrillation/flutter (3.6%) were infrequent. In total, 13 (7.8%) pts had a fatal TEAE, with 4 (2.4%) classified as infections. Overall, 8 pts (4.8%) had treatment-related AE leading to dose reductions, and 6 (3.6%) had treatment-related AE leading to pirtobrutinib discontinuation. Conclusion: Pirtobrutinib continues to demonstrate efficacy in pts with heavily pre-treated R/R MCL including both those who previously received a cBTKi and those who were BTKi-naïve. The safety profile of pirtobrutinib remained favorable with a low-rate of dose reductions/discontinuations due to drug-related toxicity. No new safety signals were identified after up to 5 yrs of follow-up.

OBJECTIVE The long-term effects of increased body mass index (BMI) on surgical outcomes are unknown for patients who undergo surgery for low-grade lumbar spondylolisthesis. The goal of this study was to assess long-term outcomes in obese versus nonobese patients after surgery for grade 1 spondylolisthesis. METHODS Patients who underwent surgery for grade 1 spondylolisthesis at the Quality Outcomes Database’s 12 highest enrolling sites (SpineCORe group) were identified. Long-term (5-year) outcomes were compared for patients with BMI ≥ 35 versus BMI < 35. RESULTS In total, 608 patients (57.6% female) were included. Follow-up was 81% (excluding patients who had died) at 5 years. The BMI ≥ 35 cohort (130 patients, 21.4%) was compared to the BMI < 35 cohort (478 patients, 78.6%). At baseline, patients with BMI ≥ 35 were more likely to be younger (58.5 ± 11.4 vs 63.2 ± 12.0 years old, p < 0.001), to present with both back and leg pain (53.8% vs 37.0%, p = 0.002), and to require ambulation assistance (20.8% vs 9.2%, p < 0.001). Furthermore, the cohort with BMI ≥ 35 had worse baseline patient-reported outcomes including visual analog scale (VAS) back (7.6 ± 2.3 vs 6.5 ± 2.8, p < 0.001) and leg (7.1 ± 2.6 vs 6.4 ± 2.9, p = 0.031) pain, disability measured by the Oswestry Disability Index (ODI) (53.7 ± 15.7 vs 44.8 ± 17.0, p < 0.001), and quality of life on EuroQol-5D (EQ-5D) questionnaire (0.47 ± 0.22 vs 0.56 ± 0.22, p < 0.001). Patients with BMI ≥ 35 were more likely to undergo fusion (85.4% vs 74.7%, p = 0.01). There were no significant differences in 30- and 90-day readmission rates (p > 0.05). Five years postoperatively, there were no differences in reoperation rates or the development of adjacent-segment disease for patients in either BMI < 35 or ≥ 35 cohorts who underwent fusion (p > 0.05). On multivariate analysis, BMI ≥ 35 was a significant risk factor for not achieving minimal clinically important differences (MCIDs) for VAS leg pain (OR 0.429, 95% CI 0.209–0.876, p = 0.020), but BMI ≥ 35 was not a predictor for achieving MCID for VAS back pain, ODI, or EQ-5D at 5 years postoperatively. CONCLUSIONS Both obese and nonobese patients benefit from surgery for grade 1 spondylolisthesis. At the 5-year time point, patients with BMI ≥ 35 have similarly low reoperation rates and achieve rates of satisfaction and MCID for back pain (but not leg pain), disability (ODI), and quality of life (EQ-5D) that are similar to those in patients with a BMI < 35.

ObjectivesTo quantify the bias of shear wave speed (SWS) measurements between different commercial ultrasonic shear elasticity systems and a magnetic resonance elastography (MRE) system in elastic and viscoelastic phantoms.MethodsTwo elastic phantoms, representing healthy through fibrotic liver, were measured with 5 different ultrasound platforms, and 3 viscoelastic phantoms, representing healthy through fibrotic liver tissue, were measured with 12 different ultrasound platforms. Measurements were performed with different systems at different sites, at 3 focal depths, and with different appraisers. The SWS bias across the systems was quantified as a function of the system, site, focal depth, and appraiser. A single MRE research system was also used to characterize these phantoms using discrete frequencies from 60 to 500 Hz.ResultsThe SWS from different systems had mean difference 95% confidence intervals of ±0.145 m/s (±9.6%) across both elastic phantoms and ± 0.340 m/s (±15.3%) across the viscoelastic phantoms. The focal depth and appraiser were less significant sources of SWS variability than the system and site. Magnetic resonance elastography best matched the ultrasonic SWS in the viscoelastic phantoms using a 140 Hz source but had a − 0.27 ± 0.027‐m/s (−12.2% ± 1.2%) bias when using the clinically implemented 60‐Hz vibration source.ConclusionsShear wave speed reconstruction across different manufacturer systems is more consistent in elastic than viscoelastic phantoms, with a mean difference bias of < ±10% in all cases. Magnetic resonance elastographic measurements in the elastic and viscoelastic phantoms best match the ultrasound systems with a 140‐Hz excitation but have a significant negative bias operating at 60 Hz. This study establishes a foundation for meaningful comparison of SWS measurements made with different platforms.