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7514 Background: Pirtobrutinib is a highly selective, non-covalent (reversible) BTKi. Here, we report updated results of pirtobrutinib in patients (pts) with cBTKi pre-treated relapsed/refractory (R/R) MCL and more than 3 years follow-up from start of enrollment. Methods: Pts with cBTKi pre-treated R/R MCL received pirtobrutinib monotherapy in a multicenter phase 1/2 BRUIN trial (NCT03740529). Efficacy was assessed in the prespecified primary efficacy cohort that comprised the first 90 enrolled pts who had measurable disease, had received a prior cBTKi, and had no known central nervous system involvement. The primary endpoint was overall response rate (ORR) as assessed by independent review committee. Secondary endpoints included duration of response (DOR) and safety. A data cut of 29 July 2022 was utilized. Results: Among MCL pts who received a prior cBTKi (n=90), median age was 70 years (range, 46-87), median prior lines of therapy were 3 (range, 1-8), 82% discontinued a prior cBTKi due to disease progression, and 78% had intermediate/high risk sMIPI score. Of samples available, 17/36 (47%) had TP53 mutations and 25/34 (74%) had Ki67 ≥30%. The ORR was 57% (95% CI, 46-67), including 19% complete responses (n=17) and 38% partial responses (n=34). At a median follow-up time of 13 months, the median DOR among the 51 responding pts was 17.6 months (95% CI, 7.3-27.2). The 12- and 18-month estimated DOR rates were 58% (95% CI, 41-72) and 45% (95% CI, 27-61), respectively. ORR and DOR by subgroups are shown in the Table. The median progression-free survival was 7.4 months (95% CI, 5.3–13.3). The median overall survival was 23.5 months (95% CI, 15.9-NE). In the MCL safety cohort (n=166), the most frequent treatment-emergent adverse events (TEAE) were fatigue (31%), diarrhea (22%), and anemia (17%). The most common Grade ≥3 TEAE was neutropenia (15%). Grade ≥3 TEAE of hemorrhage (3%) and atrial fibrillation/flutter (2%) were infrequent. Only 5 (3%) pts discontinued due to a treatment-related AE. Conclusions: Pirtobrutinib continues to show durable efficacy and a favorable safety profile in heavily pre-treated R/R MCL pts with prior cBTKi therapy. Responses were observed in pts with high-risk disease features including pts with blastoid/pleomorphic variants, elevated Ki67 index, and TP53 mutations. Clinical trial information: NCT03740529 . [Table: see text]

PURPOSE Pirtobrutinib is a highly selective, noncovalent (reversible) Bruton tyrosine kinase inhibitor (BTKi). We report the safety and efficacy of pirtobrutinib in patients with covalent Bruton tyrosine kinase inhibitor (cBTKi) pretreated mantle-cell lymphoma (MCL), a population with poor prognosis. METHODS Patients with cBTKi pretreated relapsed/refractory (R/R) MCL received pirtobrutinib monotherapy in a multicenter phase I/II trial (BRUIN; ClinicalTrials.gov identifier: NCT03740529 ). Efficacy was assessed in the first 90 consecutively enrolled patients who met criteria for inclusion in the primary efficacy cohort. The primary end point was overall response rate (ORR). Secondary end points included duration of response (DOR) and safety. RESULTS The median patient age was 70 years (range, 46-87), the median prior lines of therapy was 3 (range, 1-8), 82.2% had discontinued a prior cBTKi because of disease progression, and 77.8% had intermediate- or high-risk simplified MCL International Prognostic Index score. The ORR was 57.8% (95% CI, 46.9 to 68.1), including 20.0% complete responses (n = 18). At a median follow-up of 12 months, the median DOR was 21.6 months (95% CI, 7.5 to not reached). The 6- and 12-month estimated DOR rates were 73.6% and 57.1%, respectively. In the MCL safety cohort (n = 164), the most common treatment-emergent adverse events (TEAEs) were fatigue (29.9%), diarrhea (21.3%), and dyspnea (16.5%). Grade ≥3 TEAEs of hemorrhage (3.7%) and atrial fibrillation/flutter (1.2%) were less common. Only 3% of patients discontinued pirtobrutinib because of a treatment-related adverse event. CONCLUSION Pirtobrutinib is a first-in-class novel noncovalent (reversible) BTKi and the first BTKi of any kind to demonstrate durable efficacy after prior cBTKi therapy in heavily pretreated R/R MCL. Pirtobrutinib was well tolerated with low rates of treatment discontinuation because of toxicity.

ImportanceDisparities in treatment initiation may affect outcomes, but data on racially diverse populations with chronic hepatitis B virus (HBV) infection are limited.ObjectiveTo examine whether HBV treatment initiation and outcomes differ among racial groups.Design, Setting, and ParticipantsFrom January 14, 2011, to January 28, 2018, hepatitis B surface antigen—positive adults (age ≥18 years) not receiving anti-HBV therapy were enrolled and followed up at weeks 12, 24, and every 24 weeks thereafter in a multicenter longitudinal cohort study (Hepatitis B Research Network [HBRN] adult cohort study) conducted in North America. The last study visit and data collection were completed January 28, 2019. Data were analyzed from August 27, 2021, to August 25, 2022. All HBRN participants were included unless they had acute HBV, HIV, hepatitis C or D, less than 24-weeks of follow-up after enrollment, initiated treatment at or immediately after enrollment, or had unknown race.ExposuresParticipants had clinical and laboratory assessments and could receive anti-HBV treatment after enrollment.Main Outcomes and MeasuresHepatitis B virus treatment initiation and major adverse liver outcomes (hepatic decompensation, hepatocellular carcinoma, liver transplant, and death).ResultsOf 1550 participants, 193 (12%) were African American or Black, 1157 (75%) were Asian, 157 (10%) were White, and 43 (3%) were other races; 789 (51%) were women, and the median age was 41.2 (IQR, 32.9-51.6) years. Sociodemographic and virologic parameters differed between groups. During 5727 person-years of follow-up, 504 participants initiated treatment, with incidences of 4.8 per 100 person-years in African American or Black individuals, 9.9 per 100 person-years in Asian individuals, 6.6 per 100 person-years in White individuals, and 7.9 per 100 person-years in those of other races (P < .001). A lower proportion (14%) of African American or Black participants met treatment criteria compared with Asian (22%) and White (27%) individuals (P = .01). The cumulative probabilities of treatment initiation after meeting the criteria were not significantly different among racial groups (African American or Black, 0.45; Asian, 0.38; White, 0.40 at 48 weeks and African American or Black, 0.45; Asian, 0.51; White, 0.51 at 72 weeks; P = .68). The incidence of major adverse liver outcomes was 0.1 per 100 person-years and did not differ by race.Conclusions and RelevanceIn this observational study of chronic HBV, African American or Black participants were less likely than individuals of other races to meet treatment criteria, but among those who did, HBV treatment receipt did not differ significantly by race or socioeconomic factors. Not all eligible participants initiated treatment, but adverse liver outcomes were rare. These findings may not be generalizable to patients with chronic HBV receiving care in other settings.

ImportanceChronic hemodynamically significant aortic regurgitation (AR) is associated with excess risk of death, yet data for Asian patients are lacking, and whether Asian patients can abide by Western guidelines as to when aortic valve surgery should be performed is unknown.ObjectiveTo assess AR presentation and cutoffs of left ventricular ejection fraction (LVEF), LV end-systolic dimension index (LVESDi), and LV end-systolic volume index (LVESVi) that are associated with risk of death in Asian patients with AR.Design, Setting, and ParticipantsThis retrospective cohort study included consecutive patients with chronic, moderately severe to severe AR from 3 tertiary referral centers (2 in Japan and 1 in Taiwan) from June 11, 2008, through November 19, 2020, with follow-up through November 11, 2021.ExposuresAortic regurgitation severity, graded by a comprehensive integrated approach.Main Outcomes and MeasuresThe primary outcome was the association between volume-derived LVEF, LVESDi, and LVESVi and all-cause death (ACD). The secondary outcome was the association of these LV indexes with cardiovascular death (CVD). Clinical and echocardiographic data were analyzed retrospectively. A de novo disk-summation method was used to derive LV volumes and volume-derived LVEF.ResultsOf 1259 patients (mean [SD] age, 64 [17] years; 934 [74%] male), 515 (41%) were Japanese and 744 (59%) were Taiwanese. The median follow-up was 4.1 years (IQR, 1.56-7.24 years). The mean (SD) body surface area was 1.67 (0.21) m2; LVEF, 55% (11%); LVESDi, 24.7 (5.7) mm/m2; LVESVi, 50.1 (28.0) mL/m2; and indexed mid–ascending aorta size, 24.7 (5.5) mm/m2. Aortic valve surgery occurred in 483 patients (38%); 240 patients (19%) died during follow-up. Overall mean (SD) 8-year survival was 74% (2%). Separate multivariate models adjusted for covariates demonstrated independent associations of LVEF, LVESDi, and LVESVi with ACD (LVEF: hazard ratio [HR] per 10%, 0.80; 95% CI, 0.70-0.92; P = .002; LVESDi: HR, 1.04; 95% CI, 1.01-1.06; P = .002; LVESVi: HR per 10 mL/m2, 1.11; 95% CI, 1.05-1.17; P < .001) and CVD (LVEF: HR per 10%, 0.69; 95% CI, 0.56-0.85; P < .001; LVESDi: HR, 1.05; 95% CI, 1.01-1.09; P = .01; LVESVi per 10 mL/m2: HR, 1.15; 95% CI, 1.06-1.24; P < .001). In the total cohort, spline curves showed that mortality started to increase for an LVEF of 53% or less, LVESDi of 22 mm/m2 or greater, and LVESVi of 46 mL/m2 or greater for both ACD and CVD. Early surgery was beneficial in 3 strata of LVESDi (<20, 20 to <25, and ≥25 mm/m2) and 2 strata of LVESVi (<46 and ≥46 mL/m2).Conclusions and RelevanceThis multicenter cohort study of Asian patients with hemodynamically significant AR found cutoff values of LVEF, LVESDi, and LVESVi that were associated with increased risk of death. These findings suggest that Western guidelines seem applicable in Asian patients and, most importantly, that indexed LV parameters with a lower cutoff could be used in discriminating patients with excess mortality risk.

AbstractBackgroundData for proton therapy in high‐risk prostate cancer (HRPC) are limited. Using the Proton Collaborative Group prospective registry, we evaluated outcomes for HRPC patients treated with proton therapy.MethodsA totsl of 605 men with localized HRPC treated with proton therapy from 8/2009 to 3/2019 at nine institutions were selected. Outcomes examined included freedom from progression (FFP), metastasis free survival (MFS), overall survival (OS), and toxicity. Multivariable cox/binomial regression models were used to assess predictors of FFP and toxicity.ResultsMedian age was 71 years. Gleason grade groups 4 (49.4%) and 5 (31.7%) were most common, as were clinical stage T1c (46.1%) and cT2 (41.3%). The median pretreatment prostate specific antigen (PSA) was 9.18 and median International Prostate Symptom Score (IPSS) was 6. Androgen deprivation therapy was given in 63.6%. Median dose was 79.2 GyE in 44 fractions. Pelvic lymph nodes were treated in 58.2% of cases. Pencil beam scanning was used in 54.5%, uniform scanning in 38.8%, and a rectal spacer in 14.2%. At a median followup of 22 months, the 3‐ and 5‐year FFP were 90.7% and 81.4%, respectively. Five‐year MFS and OS were 92.8% and 95.9%, respectively. Independent correlates of FFP included Gleason ≥8, PSA > 10, and cT2 (all p < 0.05). No grade 4 or 5 adverse events were reported. There were 23 (5%) grade 2 and 0 grade 3 gastrointestinal events. Prevalence of late grade 3, late grade 2, acute grade 3, and acute grade 2 genitourinary toxicity was 1.7%, 5.8%, 0%, and 21.8%, respectively. Prevalence of grade 2 and 3 erectile dysfunction at 2 years was 48.4% and 8.4%, respectively.ConclusionsIn the largest series published to date, our results suggest early outcomes using proton therapy for HRPC are encouraging for both safety and efficacy. Further evaluation is needed to determine if an advantage exists to use protons over other radiation techniques in this population.

AbstractHaploidentical donors offer a potentially readily available donor, especially for non-White patients, for blood or marrow transplantation (BMT). In this collaboration across North America, we retrospectively analyzed outcomes of first BMT using haploidentical donor and posttransplantation cyclophosphamide (PTCy) in MDS/MPN-overlap neoplasms (MDS/MPN), an otherwise incurable hematological neoplasm. We included 120 patients, 38% of non-White/Caucasian ethnicity, across 15 centers with median age at BMT 62.5 years. The median follow-up is 2.4 years. Graft failure was reported in 6% patients. At 3-years, nonrelapse mortality (NRM) was 25%, relapse 27%, grade 3-4 acute graft versus host disease (GVHD) 12%, chronic GVHD requiring systemic immunosuppression 14%, progression-free survival (PFS) 48% and overall survival (OS) 56%. On multivariable analysis, statistically significant associations included older age at BMT (per decade increment) with NRM (sdHR 3.28, 95%CI 1.30-8.25), PFS (HR 1.98, 95% 1.13-3.45) and OS (HR 2.01, 95% CI 1.11-3.63), presence of mutation in EZH2/RUNX1/SETBP1 with relapse (sdHR 2.61, 95%CI 1.06-6.44), and splenomegaly at BMT/prior splenectomy with OS (HR 2.20, 95%CI 1.04-4.65). Haploidentical donors are a viable option for BMT in MDS/MPN, especially for those disproportionately represented in the unrelated donor registry. Disease-related factors including splenomegaly and high-risk mutations dominate outcomes following BMT.

239 Background: In part, TMB guides therapeutic decisions on the use of immune checkpoint inhibitors (ICIs) in aPC. Most patients (pts) with aPC do not have high TMB (TMB-H) at the time of initial assessment. However, TMB changes over time (from treatment pressure) as pts progress through lines of therapy (LOT) has not been extensively explored in aPC. We describe real world data on changes to blood TMB (bTMB) in pts with aPC exposed to several LOT. Methods: Genomic results from pts with aPC who had ≥1 ctDNA test(s) with TMB analyzed (Guardant360, Guardant Health, Inc) as part of clinical care from Oct 2020 – Jun 2022 were retrospectively queried. Clinical factors were extracted from test requisition forms; pts from Mayo Clinic had additional factors, including intervening treatment, extracted from medical records. High bTMB (TMB-H) was defined as ≥13.4 mut/Mb, as previously reported. Proportions were compared using Fisher’s Exact Test. Results: 316 patients with a median age of 72 (range: 44-91) were analyzed. Initial median TMB for the entire cohort was 8.18 mut/Mb (range: 0.01-268.3). On subsequent test, TMB decreased in 122(40%), increased in 173(55%), of whom 29 (17%) became TMB-H; 21 (7%) had unchanged TMB. Median time between tests was 182 days (range: 21-578). 101 patients with 262 tests and a median age of 71 years (range: 46-87) were clinically annotated in the Mayo cohort of whom 58 had >2 consecutive TMB scores: 25 (43%) had TMB increase, of whom 4 (16%) became TMB-H, 23 (40%) had TMB decrease, 10 (17%) had dynamic changes with increases and decreases. Numeric but not statistically significant differences in clinical factors were observed between groups (p>0.05). Conclusions: In this real world cohort, variation in TMB is seen with increasing LOT. Importantly, nearly 1 in 5 patients with increasing tumor mutational burden develop TMB-H, which may be a clinically actionable finding as these pts become eligible for ICI. Findings underscore the importance of repeat genetic testing with time and LOT. [Table: see text]

Abstract The field of transplant infectious diseases is rapidly evolving, presenting a challenge for clinical practice and trainee education. Here we describe the construction of transplantid.net, a free online library, crowdsourced and continuously updated for the dual purpose of point-of-care evidence-based management and teaching.

Study Design: Case Series and Technical Note, Objective: UBS has been extensively used in open surgery. However, the use of UBS during UBESS has not been reported in the literature. The aim of this study was to describe a new spinal surgical technique using an ultrasonic bone scalpel (UBS) during unilateral biportal endoscopic spine surgery (UBESS) and to report the preliminary results of this technique. Methods: We enrolled patients diagnosed with lumbar spinal stenosis who underwent single-level UBESS. All patients were followed up for more than 12 months. A unilateral laminotomy was performed after bilateral decompression under endoscopy. We used the UBS system after direct visualization of the target for a bone cut. We evaluated the demographic characteristics, diagnosis, operative time, and estimated blood loss of the patients. Clinical outcomes included the visual analog scale (VAS), the Oswestry Disability Index (ODI), the modified MacNab criteria, and postoperative complications. Results: A total of twenty patients (five males and fifteen females) were enrolled in this study. The mean follow-up period was 13.2 months (range 12–17 months). The VAS score, ODI, and modified MacNab criteria classification improved after the surgery. A minimal mean blood loss of 22.1 mL was noted during the operation. Only one patient experienced neuropraxia, which resolved within 2 weeks. There was no durotomy, iatrogenic pars fracture, or infection. Conclusions: In conclusion, our study represents the first report of the use of UBS during UBESS. Our findings demonstrate that this technique is safe and efficient, with improved clinical outcomes and minimal complications. These preliminary results warrant further investigation through larger clinical studies with longer follow-up periods to confirm the effectiveness of this technique in the treatment of lumbar spinal stenosis.

600 Background: Hepatocellular carcinoma (HCC) is the most common primary liver cancer and is associated with a high mortality burden. Lenvatinib is an effective frontline tyrosine kinase inhibitor for HCC but is associated with primary and acquired resistance in most patients. Molecular mechanisms of resistance to lenvatinib remain unclear. Methods: We retrospectively analyzed 227 patients with HCC who underwent baseline ctDNA profiling as a component of routine clinical care, including 46 patients who had serial ctDNA analysis done at baseline and after progression to lenvatinib or ICI. Clinical data including demographics, treatment history, tumor responses, and survival outcomes were abstracted from the electronic medical record. Tumor response was categorized according to RECIST 1.1. A national registry of HCC that underwent ctDNA testing using Guardant360 was analyzed to determine the prevalence of EGFR/ERBB2 alterations in HCC. Results: Nearly a third of patients who progressed on lenvatinib demonstrated a gain in EGFR/ ERBB2 amplifications or activating mutations. No consistent trend in EGFR/ ERBB2 amplifications and alterations was found among ICI refractory HCC. Disease control rates (including complete response, partial response, and stable disease) were 20% in EGFR/ERBB2 altered HCC treated with lenvatinib, 62.5% in EGFR/ERBB2 wildtype HCC treated with lenvatinib (p = 0.05), and 58% in EGFR/ERBB2 altered HCC treated with ICIs (p = 0.09). PFS was also longer in EGFR/ERBB2 wildtype HCC treated with lenvatinib (5.9 months) and EGFR/ERBB2 altered HCC treated with ICIs (7.1 months) compared to EGFR/ERBB2 altered HCC treated with lenvatinib (2.2 months, p = 0.002). In a national cohort of 1739 patients with HCC, EGFR amplifications and activating mutations occurred in 6.5% and 1.5% of cases, respectively, and ERBB2 amplifications and activating mutations occurred in 1.9% and 0.7% of cases, respectively. Among EGFR/ERBB2 mutations, we identified recurrent gatekeeper mutations, including multiple A547T and T790M mutations, in 31% of patients. Conclusions: Our study substantiates EGFR/ERBB2 amplifications and mutations as putative drivers of lenvatinib resistance in patients with HCC and identifies the genetic mechanisms for EGFR pathway activation in refractory cancers. EGFR/ERBB2 alterations may thus represent predictive and pharmacodynamic markers of lenvatinib resistance. These findings lend support to the use of EGFR inhibitors combined with lenvatinib in previously untreated or lenvatinib refractory cancers.