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Background: Despite the efficacy of covalent (c) Bruton tyrosine kinase inhibitors (BTKi) in R/R MCL, disease relapse arises through evolution of resistance mechanisms or development of cBTKi intolerance. Pirtobrutinib, a highly selective, non-covalent (reversible) BTKi has favorable oral pharmacology that enables continuous BTK inhibition throughout the daily dosing interval regardless of the intrinsic rate of BTK turnover. Pirtobrutinib is the first BTKi to demonstrate durable efficacy following prior cBTKi therapy in heavily pre-treated R/R MCL and was well-tolerated with a low frequency of treatment discontinuation due to toxicity (Wang et al., JCO, 2023). Pirtobrutinib is approved in the USA to treat relapsed or refractory MCL after at least two lines of systemic therapy including a prior cBTKi. Here, we report updated results of pirtobrutinib therapy in all patients (pts), including those with biologically high-risk R/R MCL with a median survival follow-up of 24.2 months (range, 18.2-29.8). Methods: Pts with R/R MCL received pirtobrutinib monotherapy in the multicenter Phase 1/2 BRUIN trial (NCT03740529). Efficacy was assessed in all cBTKi pre-treated pts, as well as in cBTKi treatment-naïve pts. Key endpoints included overall response rate (ORR) as assessed by independent review committee per Lugano 2014 criteria, duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Pts were included across the dose escalation range and expansion (25-300 mg/day) with 93% (n=141) receiving at least one dose of 200 mg/day, the FDA-approved dose. A data cut of 05 May 2023 was utilized. Results: Among all 152 pts with R/R MCL who received a prior cBTKi, the median age was 70 years (range, 46-88), and 52% had intermediate-risk and 28.3% had high-risk sMIPI scores. Median prior lines of therapy were 3 (range, 1-9), including an anti-CD20 antibody (96.7%), chemotherapy (90.1%), immunomodulator (17.1%), stem cell transplant (21.7%), BCL-2 inhibitor (15.8%), CAR-T cell therapy (8.6%), and PI3K inhibitor (3.9%). Among pts with high-risk biomarker data available, 30/60 (50%) had TP53 mutations and 45/63 (71%) had a Ki-67 index of ≥30%. The ORR for cBTKi pre-treated pts was 49.3% (95% CI, 41.1-57.6), including 15.8% complete responses (n=24) and 33.6% partial responses (n=51), whilst cBTKi naïve pts (n=14) had an ORR of 85.7% (95% CI, 57.2-98.2). The ORR among 128 pts who had discontinued a prior cBTKi due to PD and 21 pts who had discontinued for toxicity/other reasons was 43.0% and 90.5%, respectively. Among the 75 responding cBTKi pre-treated pts, the median DOR was 21.6 months (95% CI, 9.2-27.2) at a median follow-up of 24 months. The 18- and 24-month DOR rates were 51.9% (95% CI, 37-64.8) and 38.9% (95% CI, 22.7-54.8), respectively. ORR and DOR by high-risk subgroups (including blastoid/pleomorphic variants, Ki-67 index ≥30%, and TP53 mutations) are shown in Table 1. The 18- and 24-month DOR rates among 12 responding cBTKi naïve pts were both 90.0% (95% CI, 47.3-98.5). The median PFS and OS for cBTKi pre-treated pts was 5.6 months (95% CI, 5.3-9.2), and 23.5 months (95% CI, 17.1-NE), respectively. In the MCL cohort (n=166), the most frequent treatment-emergent adverse events (TEAEs) were fatigue (31.9%), diarrhea (22.3%), and dyspnea (17.5%). The most common Grade ≥3 TEAE was neutropenia/neutrophil count decreased (13.3%) and the rate of Grade ≥3 infections was (19.9%). Grade ≥3 hemorrhage/hematoma (2.4%) and all-grade atrial fibrillation/flutter (3.6%) were infrequent. Overall, 8 pts (5%) had treatment-related AEs leading to dose reductions and 5 (3%) had treatment-related AEs leading to pirtobrutinib discontinuation. Conclusion: Pirtobrutinib continues to demonstrate durable efficacy and a favorable safety profile in heavily pre-treated R/R MCL pts with prior cBTKi therapy. High ORRs were observed in pts who had PD on a prior cBTKi, and in pts with high-risk disease features including blastoid/pleomorphic variants, elevated Ki-67 index, and TP53 mutations.

Introduction: Brexucabtagene autoleucel (brexu-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy approved for adults with relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL). Bridging therapy, defined as anti-leukemia therapy given between apheresis and lymphodepleting chemotherapy, was permitted on the pivotal ZUMA-3 trial. The optimal bridging therapy is unknown in this setting. Here we report patient and disease characteristics in those receiving bridging therapies prior to brexu-cel and the impact of bridging on clinical outcomes in a large multicenter cohort. Methods and Results: ROCCA includes 25 US institutions contributing retrospective data from 152 B-ALL patients treated with standard of care brexu-cel between 2021-2023. Ninety-nine patients (65%) received bridging therapy, while 53 patients (35%) received no bridging therapy. Bridging therapy consisted of cytotoxic chemotherapy ( n=65, 66%), immunotherapy ( n=26, 26%; 23 inotuzumab, 3 blinatumomab), tyrosine kinase inhibitors (TKI) ( n=20, 20%; 16 ponatinib), steroids only ( n=10, 10%), and intrathecal chemotherapy ( n=22, 22%). The median age of the cohort was 46 (IQR 32-61). Patients were heavily pre-treated with a median of 4 prior lines of therapy. The median days from apheresis to infusion was 33 (IQR 26-42). 119 patients had known pre-apheresis blast counts; the bridging group had higher pre-apheresis blast burden, with 21 of 76 patients (28%) having ≥ 50% blasts compared to only 5 of 43 patients (12%) in the no bridging group ( p=0.02). In addition, more patients who received bridging had pre-apheresis extramedullary disease (32% vs. 15%, p=0.02). All other baseline characteristics were similar between the two groups (Table 1). Fifty-four (54%) patients had response assessment after bridging therapy and prior to brexu-cel infusion. In patients who received inotuzumab for pre-apheresis active disease, defined as ≥ 5% blasts, 6 of 13 (46%) who had post-bridging assessment achieved a complete response (CR; 5 measurable residual disease (MRD)+, 1 MRD-), with a mean proportional reduction in blast burden of 46% from baseline. In contrast, after chemotherapy bridging, only 2 of 16 patients (13%) with pre-apheresis active disease had a CR. Patients receiving chemotherapy bridging had a mean proportional increase in blast burden of 4.4%. In recipients of TKI bridging, 2 of 4 patients (50%) with pre-apheresis active disease had a CR. Compared to no bridging, patients in the bridging group had similar rates of grade 3 or 4 CRS (9% bridging vs. 8% no bridging, p=0.73) and grade 3 or 4 ICANS (34% vs. 26%, p=0.32). In univariate analysis, there was no statistically significant difference in day 28 response with 63 patients (72%) achieving MRD- complete response in the bridging group as compared to 36 patients (78%) in the no bridging group ( p=0.60). Non-relapse mortality was similar between the two groups (17% bridging vs. 9% no bridging, p=0.20). Overall survival (OS) and progression-free survival (PFS) were superior in the no bridging group: 1-year OS 74.7% vs 56.8% (log-rank p=0.04), and 1-year PFS 57.3% vs 41.7% (log-rank p=0.04). In a multivariate analysis stratified by bridging and pre-apheresis disease burden, patients with pre-apheresis blasts ≥ 5% and bridging had worse survival than ≥ 5% blasts and no bridging: 1-year OS 45.3% vs. 87.5% and 1-year PFS 27.7% vs. 64.3% (Figure 1). However, patients with < 5% blasts had similar survival regardless of bridging. Conclusions: In our real-world analysis, adults with R/R B-ALL receiving bridging therapy had a higher disease burden at baseline. Despite greater baseline disease, there were no significant differences in toxicity and day 28 response in those receiving bridging therapy vs. not. While survival was inferior in patients with pre-apheresis active disease who received bridging, this may be confounded by the degree of tumor burden. In patients with < 5% blasts pre-apheresis, bridging did not impact survival. Furthermore, inotuzumab bridging demonstrated the most significant disease debulking. However, the comparisons in this study are limited by the variability in practice for post-bridging disease reassessment and the small proportion of patients with active disease who did not receive bridging. A more uniform approach to peri-CAR disease assessment would enable more robust study of optimal bridging strategies.

IMPORTANCEPatients undergoing spine surgery often experience severe pain. The optimal dosage of pregabalin and gabapentin for pain control and safety in these patients has not been well established.OBJECTIVETo evaluate the associations of pain, opioid consumption, and adverse events with different dosages of pregabalin and gabapentin in patients undergoing spine surgery.DATA SOURCESPubMed/MEDLINE, Embase, Web of Science, Cochrane library, and Scopus databases were searched for articles until August 7, 2021.STUDY SELECTIONRandomized clinical trials conducted among patients who received pregabalin or gabapentin while undergoing spine surgery were included.DATA EXTRACTION AND SYNTHESISTwo investigators independently performed data extraction following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) reporting guideline. The network meta-analysis was conducted from August 2022 to February 2023 using a random-effects model.MAIN OUTCOMES AND MEASURESThe primary outcome was pain intensity measured using the Visual Analog Scale (VAS), and secondary outcomes included opioid consumption and adverse events.RESULTSTwenty-seven randomized clinical trials with 1861 patients (median age, 45.99 years [range, 20.00-70.00 years]; 759 women [40.8%]) were included in the systematic review and network meta-analysis. Compared with placebo, the VAS pain score was lowest with gabapentin 900 mg per day, followed by gabapentin 1200 mg per day, gabapentin 600 mg per day, gabapentin 300 mg per day, pregabalin 300 mg per day, pregabalin 150 mg per day, and pregabalin 75 mg per day. Additionally, gabapentin 900 mg per day was found to be associated with the lowest opioid consumption among all dosages of gabapentin and pregabalin, with a mean difference of −22.07% (95% CI, −33.22% to −10.92%) for the surface under the cumulative ranking curve compared with placebo. There was no statistically significant difference in adverse events (nausea, vomiting, and dizziness) among all treatments. No substantial inconsistency between direct and indirect evidence was detected for all outcomes.CONCLUSIONS AND RELEVANCEThese findings suggest that gabapentin 900 mg per day before spine surgery is associated with the lowest VAS pain score among all dosages. In addition, no differences in adverse events were noted among all treatments.

12100 Background: The safety profiles of novel agents are mainly based on clinician-reported adverse events (AEs) from clinical trials. Patient-reported outcomes (PROs) may better represent the treatment burden experienced by patients (pts) compared with clinician-reported AEs. Using data from POLARIX, a double-blind, placebo-controlled, randomized Phase 3 international study (NCT03274492), we previously presented PRO and clinician-reported data showing similar rates of neuropathy (Trněný et al. 2022). Here, we evaluate the reporting of other common symptoms using PRO and clinician-reported data in POLARIX. Methods: POLARIX methods were previously described (Tilly et al. 2022); this analysis included all pts with PRO data. PRO and clinician-reported data described the incidence and severity of fatigue, constipation, diarrhea, nausea, and vomiting. Clinician-reported severity grading was based on the NCI Common Terminology Criteria for Adverse Events (NCI-CTCAE) v4.0. PROs were collected using the European Organisation Research and Treatment of Cancer Quality of Life-Core 30 questionnaire (EORTC QLQ-C30), which was administered to pts at clinic visits on Day 1 of Cycles 1 (baseline), 2, 3, and 5, and end of treatment (EOT). PRO severity scores included ‘A little’, ‘Quite a bit’, and ‘Very much’. Results: Overall, 825 pts were evaluable. From baseline to EOT, PROs showed a higher incidence of symptoms compared with clinicians for fatigue (98% vs 27%), constipation (68% vs 29%), diarrhea (56% vs 26%), nausea (58% vs 40%), and vomiting (24% vs 15%). PRO severity scores of ‘Quite a bit’ or ‘Very much’ were reported in 33% of pts for fatigue, 29% for constipation, 17% for diarrhea, 19% for nausea, and 7% for vomiting. Clinicians reported Grade ≥2 symptoms in 11% of pts for fatigue, 11% for constipation, 11% for diarrhea, 14% for nausea, and 6% for vomiting. Conclusions: In POLARIX, pts reported a higher incidence and severity of symptoms compared with clinicians. Although distinct scales were used, the differences in symptom rates reported by pts and clinicians were clinically meaningful. These data may have implications for symptom management, including physician evaluation and communication of symptom expectations for pts. Reporting of symptoms by PROs should be incorporated into clinical trials as an adjunct to standard AE reporting to better characterize the patient experience. Clinical trial information: NCT03274492 . [Table: see text]

7513 Background: While Bruton tyrosine kinase inhibitors (BTKi) can induce sustained remissions, ongoing response requires continuous treatment and thus long-term safety/tolerability is critical for adherence, maintaining dose intensity, and delivering maximum efficacy. Pirtobrutinib is a highly selective, non-covalent (reversible) BTKi approved by the FDA in January 2023 for R/R mantle cell lymphoma after 2 prior lines of therapy including a BTKi. Pirtobrutinib has demonstrated promising efficacy with low discontinuation and dose reduction rates in patients (pts) with multiple subtypes of R/R B-cell malignancies. However, the long-term safety and tolerability of pirtobrutinib has not yet been reported. Here we report the clinical safety in pts with long-term (≥12 months) pirtobrutinib treatment from the phase 1/2 BRUIN trial. Methods: Pts with R/R B-cell malignancies who received ≥12 months of pirtobrutinib were included. Median time to onset, dose reduction, discontinuation, and cumulative incidence rates were determined for treatment emergent adverse event (TEAE) that occurred in ≥20% of pts and select AE of interest associated with BTKi. Results: As of 29 July 2022, 773 pts were enrolled, and 326 (42%) pts received treatment for ≥12 months. Among these 326 pts, median time on treatment was 19 months (IQR: 16,25), with 231 (71%) remaining on pirtobrutinib. The most common TEAE (all grade, regardless of attribution) in this long-term 326 pt cohort were fatigue (32%), diarrhea (31%), Covid-19 (29%), contusion (26%), cough (25%), and back pain (21%). TEAE leading to dose reduction or discontinuation occurred in 23 (7%) and 11 (3%) pts, respectively. Four (1%) pts discontinued due to a treatment-related AE, and 1 pt had a fatal treatment-related AE (Covid-19 pneumonia). Select AE of interest for the long-term pts are shown in the Table. Comprehensive safety analyses describing the frequency of TEAE over time will be presented. Conclusions: Prolonged pirtobrutinib therapy continues to demonstrate a safety profile amenable to long-term administration at the recommended dose without evidence of new or worsening toxicity signals. The safety and tolerability observed in pts on therapy for ≥12 months was similar to previously published safety analyses on all pts enrolled regardless of follow-up. Clinical trial information: NCT03740529 . [Table: see text]