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Introduction: Patients with TCE RRMM have a high disease burden and often report worsening HRQoL with additional lines of therapy. The single-arm, phase 2 KarMMa study demonstrated that ide-cel, a B-cell maturation antigen (BCMA)-directed chimeric antigen receptor T cell therapy, improved HRQoL from baseline in patients with TCE RRMM who had received ≥ 3 prior regimens (Delforge M, et al. Blood Adv 2022;6:1309-1318). Furthermore, in the phase 3 KarMMa-3 clinical trial (NCT03651128), ide-cel significantly improved progression-free survival and response compared with standard regimens in patients with TCE RRMM who had received 2-4 prior regimens (Rodriguez-Otero P, et al. N Engl J Med 2023;388:1002-1014). Here we assessed the comparative effects of ide-cel versus standard regimens on HRQoL in patients with TCE RRMM who had received 3-4 prior regimens including an immunomodulatory agent, a proteasome inhibitor, and daratumumab (an anti-CD38 monoclonal antibody) using data from the KarMMa-3 study. Methods: Patient-reported outcomes (PROs) were assessed by the European Organization for Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire-Core 30 (QLQ-C30), EORTC Quality of Life Questionnaire Multiple Myeloma Module (QLQ-MY20), and EQ-5D-5L. The pre-specified primary domains of interest included EORTC QLQ-C30 global health status/QoL, physical functioning, cognitive functioning, fatigue, and pain; EORTC QLQ-MY20 disease symptoms and side effects of treatment; and the EQ-5D-5L visual analog scale (EQ-5D VAS). PROs were collected at screening (baseline), the day of ide-cel infusion (ide-cel) or first treatment dose (standard regimens), monthly from 2 to 28 months, and thereafter every 3 months. Comparisons were performed on least squares (LS) mean changes from baseline through 28 months between arms using constrained longitudinal data analysis (cLDA). Effect size was estimated by Hedges' g. The comparative effects of ide-cel versus standard regimens on time to confirmed improvement and time to confirmed deterioration (defined by prespecified change thresholds) were assessed via stratified Cox proportional hazards regression analyses. All P values are nominal and not adjusted for multiple testing. Statistical significance was set at P < 0.05. Results: Baseline characteristics were well balanced among the patients in the ide-cel arm (n = 167) and the standard regimen arm (n = 93), with a median age of 63 years and a median time of 4.7 years from RRMM diagnosis to study screening. Completion rates of HRQoL assessments were high over time for most visits (> 75%). At baseline, mean HRQoL domain scores were similar between arms. Overall LS mean changes from baseline to 28 months showed significant differences in favor of ide-cel versus standard regimens (nominal P < 0.05) for 11 domains (effect sizes of 0.26-0.82), and 7 (4 primary: global health status/QoL, cognitive functioning, pain, EQ-5D VAS; 3 secondary: dyspnea, insomnia, constipation) of them exceeded the prespecified MID thresholds (Table). Time to confirmed improvement was significantly shorter (nominal P < 0.05) in the ide-cel arm than in the standard regimen arm for 10 domains, including all primary domains except pain. Time to confirmed deterioration was longer in the ide-cel arm than the standard regimen arm for most domains, with significant differences in emotional functioning, cognitive functioning, and dyspnea (EORTC QLQ-C30). Finally, side effects of treatment favored the ide-cel versus standard regimen arm (EORTC QLQ-MY20) (Table). Conclusions: These patient-reported findings demonstrate that compared with standard regimens, treatment with ide-cel improved MM-relevant disease symptoms, functioning, and overall health status/HRQoL of patients with TCE RRMM in the KarMMa-3 trial. These data further substantiate the superior treatment outcomes of ide-cel over standard regimens in this patient population. Overall, treatment with ide-cel may help alleviate detriments to HRQoL in these patients with complex disease.

Background: An interim analysis (data cutoff date April 18, 2022) of the international, open-label, phase 3 KarMMa-3 trial (NCT03651128) showed the chimeric antigen receptor T cell therapy idecabtagene vicleucel (ide-cel) significantly improved progression-free survival and treatment response rates, as well as HRQoL, as compared with standard regimens, in patients with triple-class exposed (TCE) RRMM who had received 2-4 prior regimens (Rodriguez-Otero P, et al. N Engl J Med 2023;388:1002-1014; Delforge M, et al., HemaSphere, 2023;7(S3):P905). The aim of the present study was to analyze the effect of ide-cel versus standard regimens (daratumumab [DARA], pomalidomide, and dexamethasone [DEX]; DARA, bortezomib, and DEX; ixazomib, lenalidomide, and DEX; carfilzomib and DEX; or elotuzumab, pomalidomide, and DEX) on HRQoL in KarMMa-3 trial participants with an extended follow-up of patient-reported outcomes (PRO) data collection (data cutoff date April 28, 2023). Methods: In KarMMa-3, HRQoL was assessed using the European Organisation for Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire-Core 30 (QLQ-C30), EORTC Quality of Life Questionnaire Multiple Myeloma Module (QLQ-MY20), and EQ-5D-5L. HRQoL assessments were completed at screening (baseline); the day of ide-cel infusion or the first dose of standard treatment; and monthly from 2 to 28 months; and every 3 months thereafter. The prespecified primary outcomes of interest were EORTC QLQ-C30 global health status/QoL, physical functioning, cognitive functioning, fatigue, and pain; EORTC QLQ-MY20 disease symptoms and side effects of treatment; and the EQ-5D visual analog scale (EQ-VAS). Least squares (LS) mean changes from baseline through month 25 for ide-cel and standard regimens were compared by constrained longitudinal data analysis (cLDA). Effect sizes were estimated by Hedges' g. The effect of ide-cel versus standard regimens on time to confirmed improvement and deterioration in HRQoL (defined by prespecified change thresholds and sustained duration) were compared by stratified Cox proportional hazards regression. There was no adjustment for multiple testing, and all P values reported are nominal. Results: Overall, 254 patients were randomized to the ide-cel arm and 132 to the standard regimens arm. Baseline characteristics were well balanced across treatment arms; both arms had a median age of 63 years, a median of 3 prior anti-myeloma regimens, and median time from MM diagnosis to screening was 4 years. The baseline HRQoL scores were generally comparable between treatment arms. Overall LS mean changes from baseline to month 25 showed significant differences (nominal P value < 0.05) in favor of ide-cel for 18 out of 21 HRQoL domains, with effect sizes (Hedges' g) of 0.27 to 0.82 (Table). For 13 of these domains (including 6 primary domains of interest), the difference in overall LS mean change from baseline exceeded the prespecified minimum important difference (MID) threshold. Time to confirmed improvement was significantly shorter in the ide-cel arm than the standard regimens arm for 19 domains, including all primary domains of interest (Table). Time to confirmed deterioration showed trends of being longer in the ide-cel arm than the standard regimens arm for most domains and was significantly longer for emotional functioning, cognitive functioning, social functioning, dyspnea, and constipation as measured by the EORTC QLQ-C30. The time to confirmed deterioration in side effects of treatment (based on the EORTC QLQ-MY20) was significantly longer for patients in the ide-cel arm and time to confirmed improvement was significantly faster, as compared with the standard regimens arm (Table). Conclusions: In the KarMMa-3 trial, patients with TCE RRMM who had received 2-4 prior regimens, ide-cel significantly and meaningfully improved MM-relevant symptoms, functioning, and overall health status/HRQoL compared with standard regimens. Confirmed HRQoL improvements in the ide-cel arm occurred sooner than standard regimens. PRO improvements were sustained over more than 2 years, which is notable after a single infusion treatment with ide-cel. These patient-reported findings further support the benefit of ide-cel in this patient population.

Background: Chemotherapy in combination with radiotherapy (RT) is the standard for early-stage (ES) Hodgkin lymphoma (cHL). Despite high cure rates (12-year overall survival (OS) >93%), there is room to improve short and long-term outcomes for children and adults with ES cHL. Incorporation of immunotherapy (IO) into front line treatment of ES cHL is an opportunity to both improve progression-free survival (PFS) and maintain OS, while minimizing long-term morbidity and mortality by reducing exposure to RT and high-dose chemotherapy. Study Design and Methods: HL leaders of the NCTN groups, expert HL researchers and physicians, and representatives from the Cancer Therapy Evaluation Program (CTEP) formed a working group in April 2020 with the goals of harmonizing treatment approaches for ES cHL across pediatric and adult patients and reaching consensus regarding the optimal study design for incorporating IO therapy into frontline treatment. Study champions identified from each of the North American cooperative groups [Children's Oncology Group (COG), SWOG, ECOG-ACRIN, Alliance, NRG] and experts in imaging, radiation oncology, lymphoma biology and patient-reported outcomes (PROs) were included. The resulting COG-led clinical trial, AHOD2131, represents the largest ES cHL trial in the history of North American cooperative groups and the first to enroll patients across the age continuum. AHOD2131 (NCT05675410; Figure) is a randomized, phase 3 trial enrolling patients ages 5 to 60 years with newly diagnosed, previously untreated stage I and II cHL and will investigate the addition of the CD30-antibody drug conjugate brentuximab vedotin (Bv) with PD-1 blockade (nivolumab) compared to standard chemotherapy +/- RT. Since the April 2023 activation, 97 North American sites have activated the trial, and 21 participants have enrolled. Target enrollment is 1875 patients over 5 years of accrual, for an estimated 1782 eligible and evaluable patients. The primary objective is to compare the 3-year PFS of patients with ES cHL treated through a response-adapted, superiority design with either standard therapy or with an IO approach (BV + nivolumab). All patients will be stratified as favorable or unfavorable based on disease risk features at enrollment. Based on initial response assessment by PET/CT (via central review) after 2 cycles of ABVD, patients were classified to PET2 positive (SER, defined as 5 Point Score 4 or 5, ~15% of patients) and PET negative (RER). Those who are PET positive will receive involved site RT (ISRT). The SER and RER patients will be randomized to standard chemotherapy vs. IO therapy respectively. In addition to the primary outcome of PFS, there are 11 secondary and 10 exploratory aims. The secondary aims focus on OS, PFS of subgroups, and event-free survival at 12 years, physician-reported treatment-related adverse event (AE) rates, patient-reported AE using pediatric and adult versions of Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE), and the capture of representation by self-report and the use of electronic PRO data collections. The exploratory aims include the assessment of imaging central review as compared to local institutional review and the use of convolutional neural networks through artificial-intelligence machine learning. The study will examine the effect of therapy on acute and long-term adverse effects including health-related quality of life (HRQoL) and OS for up to 12 years. The study will compare patient self-report and provider AE reports and evaluate the associations of self-reported race/ethnicity and social determinants of health (SDOH)and post-progression/post-relapse OS. AHOD2131 strengthens the effort between the North American cooperative groups to conduct collaborative clinical trials and aims to harmonize an improved standard of care for ES cHL across the age continuum.

Background: Event-free survival at 24 months (EFS24) after frontline immunochemotherapy (IC) is an important endpoint in diffuse large B-cell lymphoma and follicular lymphoma, and patients who achieve EFS24 have similar survival compared to age- and sex-matched general population. The role of EFS24 in predicting subsequent survival has not been established in mantle cell lymphoma (MCL), possibly due to perceived poor survival historically. In the last decade, the outcomes of MCL are improving in the evolving treatment landscape. In this international multicenter study, we investigated conditional survival and cause of death in patients with MCL who achieved EFS24 after frontline IC in the older and more recent eras. Methods: Outcomes after frontline IC were evaluated in 5 independent cohorts that included over 3000 patients in total: Mayo/Iowa MER prospective cohort, BC Cancer retrospective population-based cohort, US 12-center retrospective cohort, Swedish Lymphoma Registry, and Danish National Lymphoma Registry. For each cohort, 2 treatment eras were defined based on cohort-specific shifts in treatment patterns (Table 1). Overall survival (OS) after diagnosis and after achieving EFS24 were compared to the background age- and sex-matched general population using a standardized mortality ratio (SMR). Cumulative incidences of cause-specific deaths were analyzed using a competing risk model. Results: In the MER cohort, patients treated in Era M1 (2002-2009; n=147) and Era M2 (2010-2015; n=153) both had inferior OS compared to the general US population. A lower SMR in Era M2 vs M1 (2.25 vs 3.46) suggests a narrower gap in OS compared to the general US population. Lymphoma was the leading cause of death in both eras. In Era M1, patients who achieved EFS24 still had inferior OS compared to the general US population (SMR=2.40, 95% CI 1.76-3.19), and lymphoma remained the leading cause of death. For patients in Era M2 who achieved EFS24, the difference in OS compared to the general US population was not statistically significant with current follow-up (SMR=1.43, 95% CI 0.93-2.09), and lymphoma was no longer the leading cause of death (Table 2). In the BC cohort, patients treated in Era B2 (6/2013-2019; n=188) vs Era B1 (2003-5/2013; n=250) had a narrower gap in OS compared to the general British Columbia population (SMR 4.53 vs 6.69). Lymphoma was the leading cause of death in both eras. For patients achieving EFS24, the gap in OS was narrower in Era B2 vs B1 (SMR 3.56 vs 4.99). After achieving EFS24, lymphoma was the single leading cause of death for patients in Era B1 but not in Era B2 (Table 2). In the US 12-center cohort, patients treated in Era U1 (2002-2011; n=312) and Era U2 (2012-2016; n=417) both had inferior OS compared to the general US population (SMR 2.68 and 2.92, respectively). In patients who achieved EFS24, with current follow up, the difference in OS compared to the general US population was statistically significant in Era U1 (SMR=2.01, 95% CI 1.50-2.64) but not in Era U2 (SMR=1.44, 95% CI 0.82-2.34). Lymphoma was not the leading cause of death after achieving EFS24 (Table 2). In the Swedish cohort, the gap in OS compared to the general Swedish population was narrower in Era S2 (2013-2018; n=439) vs S1 (2006-2012; n=442), both after frontline IC (SMR 4.8 vs 5.4) and after achieving EFS24 (SMR 2.6 vs 3.4). After achieving EFS24, lymphoma was the leading cause of death for patients in Era S1 but not in Era S2 (Table 2). In the Danish cohort, patients treated in Era D2 (2014-2020; n=370) vs Era D1 (2004-2013; n=461) had a slightly narrower gap in OS compared to the general Danish population (SMR 1.90 vs 2.10). For patients who achieved EFS24, those in Era D1 still had inferior OS compared to the general Danish population (SMR=1.44, 95% CI 1.22-1.68), but the OS difference compared to the general Danish population in Era D2 was not statistically significant (SMR=1.27, 95% CI 0.92-1.72) with current follow-up (Table 2). Cause of death data were not available in this cohort. Conclusion: Survival in patients with MCL who achieved EFS24 after frontline IC improved in the more recent treatment era and moved closer to the background expected survival. After achieving EFS24, lymphoma-related mortality was no longer the leading cause of death in the more recent era. EFS24 following frontline treatment may become a critical endpoint for predicting subsequent outcomes in patients with MCL in the modern era.

Background: Bendamustine and rituximab (BR) is a standard-of-care first-line (1L) therapy for older or unfit patients with mantle cell lymphoma (MCL). The SHINE trial compared BR with rituximab maintenance plus ibrutinib vs placebo in patients ≥65 years old and showed that the ibrutinib arm had significantly improved progression-free survival (PFS; median 80.6 vs 52.9 months) but similar overall survival (OS; 57% vs 55% at 7 years) compared to the placebo arm. Whether sequential treatment with BR in 1L and a Bruton's tyrosine kinase inhibitor (BTKi) in second-line (2L) can result in a similar cumulative PFS compared to 1L BR plus BTKi combination therapy is unknown. To provide insight to this question, we modeled observational data to evaluate MCL outcomes after 1L BR and 2L BTKi therapy in the BTKi era. Methods: Patients with MCL who received 1L BR with or without rituximab maintenance in 2014-2020 at one of the 27 participating centers were included. Exclusion criteria included participation in the SHINE or ECHO trials, any additional 1L therapy other than BR (with or without rituximab maintenance), and stem cell transplant consolidation after 1L BR. Baseline characteristics, treatment, and follow-up data were abstracted by chart review. Event-free survival (EFS) was defined as time from index line treatment start to the first event (progression, relapse, retreatment, or death). OS was defined as time from index line treatment start to death. Using an intention-to-treat (ITT) framework, EFS2 was defined as time from 1L BR start to progression, relapse, or retreatment following 2L BTKi treatment or death. Patients who received a non-BTKi treatment at 2L were censored for EFS2 at 2L treatment start; living patients without an event following 1L BR or 2L BTKi were censored for EFS2 at last follow-up. Results: A total of 618 patients with MCL who received 1L BR in 2014-2020 were included. The median age was 71 (IQR 65-76) years, and 447 (72%) were male. 59 (11%) patients had an ECOG PS ≥2, 566 (93%) had stage III-IV disease, and simplified MIPI was low in 105 (21%), intermediate in 200 (39%), and high in 202 (40%) patients. The median follow-up following 1L BR start was 57.4 (95% CI 53.8-63.2) months. Response data were available in 580 patients, and the best ORR was 92% (79% complete response [CR] and 13% partial response [PR]). 258 (42%) patients received rituximab maintenance. As of last follow-up, 255 patients were alive and in remission after 1L BR, 92 patients died without 2L therapy, and 271 patients received a 2L therapy. The median EFS was 34.1 (95% CI 31.0-40.0) months. The median OS was 97.8 (95% CI 81.2-NA) months, the 5-year OS rate was 58.6% (95% CI 54.4-63.2), and the 7-year OS rate was 56.7% (95% CI 52.4-61.5) (Fig 1). Among the 271 patients who started a 2L treatment, 203 (75%) received a BTKi at 2L - 101 (50%) ibrutinib, 76 (37%) acalabrutinib, and 26 (13%) zanubrutinib. The median follow-up following 2L BTKi start was 38.5 (95% CI 31.3-45.1) months. Response data were available in 171 patients, and the best ORR was 64% (36% CR, 28% PR). The median EFS was 10.7 (95% CI 7.7-14.0) months, and the median OS was 24.8 (95% CI 17.3-33.1) months with 2L BTKi therapy (Fig 2). By ITT analysis, the median EFS2 following 1L BR and 2L BTKi was 72.1 (95% CI 56.7-97.8) months (Fig 1). A subset analysis of patients aged ≥65 years (n=471; 198 [42%] received rituximab maintenance) showed similar results. The median EFS with 1L BR was 32.7 (95% CI 29.1-36.3) months. The median OS was 81.5 (95% CI 65.0-NA) months, and the 7-year OS rate was 53.3% (95% CI 48.3-58.7). 208 patients received a 2L therapy, 163 (79%) with a BTKi. The median EFS was 11.5 (95% CI 7.6-15.8) months, and the median OS was 21.0 (95% CI 14.0-29.6) months with 2L BTKi therapy. By ITT analysis, the median EFS2 following 1L BR and 2L BTKi was 58.0 (95% CI 50.2-77.0) months. Conclusion: In this multicenter retrospective study, initiation of 1L BR (with or without rituximab maintenance) resulted in a 7-year OS of 57%. Median EFS2 for sequential 1L BR and 2L BTKi was 72.1 months. In context, the SHINE study reported a median PFS of 80.6 months in the BR (with rituximab maintenance) plus ibrutinib arm and a 7-year OS of 57% in the ibrutinib arm and 55% in the placebo arm, where 39% of patients received a BTKi in 2L. Within the constraints of observational data, our results provide support for sequential use of BR in 1L and BTKi in 2L for patients with MCL.

Introduction A single ide-cel infusion showed significantly longer median progression-free survival (PFS) vs std regimens (13.3 vs 4.4 months [mo], HR 0.49, 95% CI 0.38-0.65, P < 0.001) with deep, durable responses in heavily pretreated TCE RRMM at an interim analysis (IA) of KarMMa-3 (NCT03651128); safety data were consistent with prior studies (Rodríguez-Otero et al. NEJM 2023). Ide-cel benefits were consistent across pts in high-risk subgroups and across 2-4 prior lines of therapy (Tx). Results of the preplanned final PFS analysis of KarMMa-3 with 12.3 mo additional follow-up are reported. Methods In the phase 3 KarMMa-3 trial, pts with RRMM who received 2-4 prior regimens, including an immunomodulatory agent, proteasome inhibitor, and daratumumab, and were refractory to last regimen were randomized 2:1 to ide-cel or a std regimen (DPd, DVd, IRd, Kd, or EPd). In the ide-cel arm, pts could receive ≤ 1 cycle of optional bridging Tx for disease control. Pts in the std regimens arm could receive ide-cel after confirmed disease progression (PD). The primary endpoint was IRC-assessed PFS in the ITT population; final PFS was planned to be analyzed with ~289 events. Key secondary endpoints were IRC-assessed overall response rate (ORR) and overall survival (OS); other secondary endpoints included complete response rate (CRR), duration of response (DOR), minimal residual disease (MRD) status, time to next anti-myeloma Tx (TTNT; time from randomization to next anti-myeloma Tx [MTx]), event-free survival (EFS; time from randomization to first PD, next MTx or any-cause death, whichever is first), PFS2 (time from randomization to second objective PD or any-cause death, whichever is first), safety, and health-related quality of life (QOL). Results Of 386 randomized pts (ide-cel, n = 254; std regimens, n = 132), 225 received ide-cel and 126 received a std regimen. Baseline characteristics were generally balanced. Median follow-up from randomization to data cutoff (April 28, 2023) was 30.9 mo (range 12.7-47.8). Ide-cel significantly improved median PFS (95% CI) vs std regimens (13.8 [11.8-16.1] vs 4.4 [3.4-5.8] mo), representing a 51% reduced risk of PD or death (HR 0.49, 95% CI 0.38-0.63; Figure); 18 mo PFS rates were 41% vs 19%, respectively. Ide-cel significantly improved ORR vs std regimens (71% vs 42%) with deeper (CRR 44% vs 5%; ≥CR and MRD negative status [sensitivity level 10 -5], 22% vs 1%), more durable responses (median DOR 16.6 vs 9.7 mo; Table). PFS and ORR benefits of ide-cel vs std regimens were consistent with the IA. Interim OS will be included in the presentation. In pts who received ide-cel (n = 225) or a std regimen (n = 126), median PFS (95% CI) was 15.7 (12.5-18.9) vs 4.4 (3.4-5.8) mo, respectively. In the ITT population, median TTNT, EFS, and PFS2 were numerically longer with ide-cel vs std regimens. Median (range) TTNT was 20.9 (16.6-24.2) vs 7.0 (5.3-8.5) mo. Median (95% CI) EFS was 13.3 (11.3-15.7) vs 3.9 (3.0-5.3) mo. Median PFS2 (95% CI) was 23.5 (18.4-27.9) vs 16.7 (12.2-20.3) mo; ide-cel was next MTx in 70 (53%) pts in the std regimens arm. In the treated population, grade (gr) 3/4 infections occurred in 66/249 (27%) pts in the ide-cel arm vs 25/126 (20%) in the std regimens arm. In the ide-cel safety population, any gr cytokine release syndrome occurred in 197/225 (88%) pts, gr ≥ 3 in 11 (5%); median time to first onset was 1 d (1-14), median duration was 4 d (1-51). Any gr investigator-identified neurotoxicity occurred in 34/225 (15%) pts, gr ≥ 3 in 7 (3%); median time to onset was 3 d (range 1-317); median duration was 2.5 d (range 1-252). Ide-cel continued to demonstrate durable, clinically meaningful improvements in pt-reported outcomes, including symptoms, functioning, and QOL vs std regimens. Conclusions In this final PFS analysis of KarMMa-3, significantly longer PFS was maintained with ide-cel; PD or death risk reduced by 51%; responses were deeper and more durable vs std regimens. CRR with ide-cel increased since the IA, indicating a deepening response, but were unchanged with std regimens. A single ide-cel infusion vs continuous treatment with std regimens resulted in longer median TTNT and PFS2, indicating improved long-term disease control. The ide-cel safety profile was consistent with previous reports, with no parkinsonism or Guillain-Barré syndrome reported. These data continue to support use of ide-cel in pts with TCE RRMM. Study support 2seventy bio and Celgene, a Bristol-Myers Squibb Company.

Introduction The Ki-67 index has been previously shown to be prognostic, wherein the cut-off of 30% was associated with inferior survival outcomes (Determann O et al, Blood 2008) in newly diagnosed MCL patients (pts). However, this cut-off determination was made in pts treated with CHOP/R-CHOP as the first-line treatment, controlled only for MIPI, and predates the advent of novel agents. Short diagnosis to treatment interval (DTI ≤ 14 days) was recently shown to be prognostic in newly diagnosed MCL but its association with Ki-67 is unknown. We sought to determine the optimal Ki-67 cut-off in MCL and its prognostic relevance in the modern era. Methods This is a pooled analysis of 2 large datasets, one prospective (CALGB 50403) and one retrospective (MCL real world study [MCL-RWS]). CALGB is now part of the Alliance for Clinical Trials in Oncology. CALGB 50403 is a phase II randomized study wherein newly diagnosed MCL pts received intensive induction chemoimmunotherapy (IIC) followed by autologous transplant, and posttransplant rituximab. The MCL-RWS included adult pts (≥18 years [yrs]) with MCL treated from 2000 to 2017 at 12 participating US sites. Pts from sites in the MCL-RWS that enrolled on CALGB 50403 were excluded. Ki-67 was scored by central review in 10% increments in the CALGB 50403 and per institutional standard in the MCL-RWS. We assessed Ki-67 as a continuous variable and used a restricted quadratic spline fit to find an optimal cut-off. We looked at the associations between Ki-67 and other known/ established MCL prognostic markers including MIPI and DTI. The outcome parameters were PFS and OS. Time-to-event endpoints were evaluated by Kaplan-Meier and Cox proportional hazard methods. Results Among the 793 pts (n=666, MCL-RWS and n=127, CALGB 50403) in the pooled analysis, Ki-67 was available in 385 pts (311 from MCL-RWS and 74 from CALGB 50403). The median OS (mOS) and PFS (mPFS) in the entire cohort (n=793) was 11.8 years and 4.7 years, respectively. The two groups (gps), those with and without Ki-67 data, were well balanced including MIPI and DTI. The median age was 62 yrs (range, 32-88), 81% males, 94% with ECOG performance status (PS) 0-1 and 84% with stage 4. We found a Ki-67 cut-off of 50% to be optimal as the relative hazard of death rises after 50%. Pts in the Ki-67 >50% gp had significantly higher proportion with short DTI (36% vs 17%, p<0.001), ECOG PS ≥2 (12% vs 5%, p=0.02), elevated LDH (58% vs 39%, p=0.005), and MIPI ≥6.2 (38% vs 20%, p=0.007) compared to Ki-67 of ≤50%. Ki-67 >50% was associated with significantly inferior PFS with a hazard ratio (HR) of 2.10 (95%CI 1.50-2.92) compared to Ki-67 ≤50% with a mPFS of 2.1 vs 5.3 yrs, respectively, regardless of the age (young [≤65 yrs], 2.6 vs 5.3 yrs or old [>65 yrs], 1.1 vs 5.4 yrs) or receipt of IIC (2.2 vs 5.9 yrs). Figure 1 shows the statistically significant difference in PFS between the Ki-67 gps of ≤10%, >10% to <30%, ≥30 to ≤50%, and >50%. Ki-67 >50% remained prognostic for PFS in multivariable analysis (MVA) after adjusting for significant variables in univariable analysis (UVA) including short DTI, ECOG PS ≥2, stage 4, elevated LDH, and MIPI ≥6.2 with adjusted HR (aHR) 2.19, 95%CI 1.38-3.48, p <0.001. Ki-67 >50% was associated with significantly inferior OS with a HR of 2.10 (95%CI 1.33-3.32) compared to Ki-67 ≤50% with a mOS of 9.4 yrs vs not reached (NR), respectively, regardless of the age or receipt of IIC. Figure 2 shows the statistically significant difference in OS between the Ki-67 gps of ≤10%, >10% to <30%, ≥30 to ≤50%, and >50%. Ki-67 >50% was not prognostic for OS in MVA after adjusting for significant variables in the UVA (MIPI and sex), aHR 1.79, 95% CI 0.92-3.49, p=0.08. Similar findings were seen in multivariable analysis with Ki-67 >30%, which showed no prognostic significance (aHR 1.46, 95%CI 0.82-2.58, p=0.19). Because of disparate datasets, we performed sensitivity analysis looking at the prognostic relevance of in individual datasets (CALGB 50403 and MCL-RWS) and found Ki67 >50% was prognostic for PFS and OS in both of the datasets consistent with the primary analysis. Conclusions This study evaluating the optimal Ki-67 cut off for pts with newly diagnosed MCL in the modern era found that Ki-67 > 50% was prognostic for PFS but not OS in MVA. A potential reason for the lack of prognostic relevance for OS in this more recent dataset is the availability of effective options at relapse. We also found that short DTI was associated with high Ki-67 gp which is a novel finding.

ImportancePrior research has shown differences in postoperative outcomes for patients treated by female and male surgeons. It is important to understand, from a health system and payer perspective, whether surgical health care costs differ according to the surgeon’s sex.ObjectiveTo examine the association between surgeon sex and health care costs among patients undergoing surgery.Design, Setting, and ParticipantsThis population-based, retrospective cohort study included adult patients undergoing 1 of 25 common elective or emergent surgical procedures between January 1, 2007, and December 31, 2019, in Ontario, Canada. Analysis was performed from October 2022 to March 2023.ExposureSurgeon sex.Main Outcome and MeasureThe primary outcome was total health care costs assessed 1 year following surgery. Secondarily, total health care costs at 30 and 90 days, as well as specific cost categories, were assessed. Generalized estimating equations were used with procedure-level clustering to compare costs between patients undergoing equivalent surgeries performed by female and male surgeons, with further adjustment for patient-, surgeon-, anesthesiologist-, hospital-, and procedure-level covariates.ResultsAmong 1 165 711 included patients, 151 054 were treated by a female surgeon and 1 014 657 were treated by a male surgeon. Analyzed at the procedure-specific level and accounting for patient-, surgeon-, anesthesiologist-, and hospital-level covariates, 1-year total health care costs were higher for patients treated by male surgeons ($24 882; 95% CI, $20 780-$29 794) than female surgeons ($18 517; 95% CI, $16 080-$21 324) (adjusted absolute difference, $6365; 95% CI, $3491-9238; adjusted relative risk, 1.10; 95% CI, 1.05-1.14). Similar patterns were observed at 30 days (adjusted absolute difference, $3115; 95% CI, $1682-$4548) and 90 days (adjusted absolute difference, $4228; 95% CI, $2255-$6202).Conclusions and RelevanceThis analysis found lower 30-day, 90-day, and 1-year health care costs for patients treated by female surgeons compared with those treated by male surgeons. These data further underscore the importance of creating inclusive policies and environments supportive of women surgeons to improve recruitment and retention of a more diverse and representative workforce.

Abstract Background Several randomized controlled trials (RCT) have shown that short-course (∼7 days) antibiotic treatment is non-inferior to longer antibiotic courses (∼14 days) in patients with uncomplicated bloodstream infection (BSI) with mostly susceptible Gram-negative bacteria. Here, we evaluate short-course therapy in ceftriaxone-resistant E. coli BSI. Methods In a prospective cohort of 300 patients with E. coli BSI at 14 United States hospitals between November 2020 and April 2021, each patient with ceftriaxone-R E. coli BSI, and the next consecutive patient with a ceftriaxone-S E. coli BSI was included. Patients who received 5-8 days (“short”) or 9-21 days (“long”) of antibiotics were included in this analysis. Patients who died before day 9 were excluded. Primary outcome was a Desirability of Outcome Ranking (DOOR, Table 1) based on disposition at day 30 after collection of the index blood culture. Ceftriaxone susceptibility was centrally determined using broth microdilution for all bacterial isolates. Desirability of outcome ranking (DOOR) categories Results Of 300 patients in the original cohort, 227 were included; 44 patients (24 ceftriaxone-S, 20 ceftriaxone-R) received short (median 8 days, range 5-8 days), and 183 patients (96 ceftriaxone-S, 87 ceftriaxone-R) received long duration (median 15 days, range 9-21 days). Age (median 68 years, IQR 57-77 years), sex (125/227 [55%] female), and Charlson comorbidity index (median 2, IQR 1-4) were similar between groups. Notably, almost all patients (18/19, 95%) with solid organ or stem cell transplant were in the long duration group. The median Pitt bacteremia score was 2 (IQR 1-3) in the short duration group vs. 1 (IQR 0-3) in the long duration group (Wilcoxon Rank Sum p=0.07). DOOR outcomes were similar in both groups (Figure and Table 2). Numerically more patients in the ceftriaxone-resistant group on short treatment were in category 3; 4/20 (20%) vs 5/87 (6%) in the long duration group. These 4 patients all had unsuccessful discharge combined with renal failure (n=2), and/or lack of clinical response (n=3). Desirability of outcome ranking (DOOR) analysesFigure.DOOR outcomes Shown are the percentages of patients in each group with a specific DOOR category outcome. Conclusion Short duration of therapy was less frequently used than long duration of therapy in this prospective cohort of E. coli BSI. Further studies are needed to determine whether short-course therapy is appropriate for ceftriaxone-R E. coli BSI. Disclosures Yohei Doi, MD, PHD, bioMerieux: Advisor/Consultant|FujiFilm: Advisor/Consultant|Gilead: Advisor/Consultant|Gilead: Honoraria|GSK: Advisor/Consultant|Meiji Seika Pharma: Advisor/Consultant|Moderna: Advisor/Consultant|Moderna: Honoraria|MSD: Advisor/Consultant|MSD: Honoraria|Shionogi: Advisor/Consultant|Shionogi: Grant/Research Support|Shionogi: Honoraria Owen Albin, MD, Charles River Laboratories: Advisor/Consultant|Shionogi: Advisor/Consultant Elie Saade, MD, MPH, FIDSA, Envision Pharma: Speaker, Presenter|Johnson and Johnson: Speaker, Travel, Lodging|Protein Sciences Corp: Grant/Research Support|Sanofi Pasteur: Speaker, Travel and Lodging Loren G. Miller, MD MPH, ContraFect: Grant/Research Support|GSK: Grant/Research Support|Medline: Grant/Research Support|Merck: Grant/Research Support|Paratek: Grant/Research Support Michael J. Satlin, MD, AbbVie: IDMC member|Biomerieux: Grant/Research Support|Merck: Grant/Research Support|Shionogi: Advisor/Consultant|SNIPRBiome: Grant/Research Support Martin Krsak, MD, MSc, FASAM, AbbVie: Grant/Research Support|Melinta: Honoraria W. Charles Huskins, MD, MSc, ADMA Biologics: Advisor/Consultant|Bristol Myers Squibb: Stocks/Bonds|Pfizer: Advisor/Consultant|Pfizer: Stocks/Bonds|Zimmer Biomet: Stocks/Bonds Robin Patel, MD, Abbott Laboratories: Advisor/Consultant|Adaptive Phage Therapeutics: Grant/Research Support|Adaptive Phage Therapeutics: Mayo Clinic has a royalty-bearing know-how agreement and equity in Adaptive Phage Therapeutics.|BIOFIRE: Grant/Research Support|CARB-X: Advisor/Consultant|ContraFect: Grant/Research Support|Day Zero Diagnostics: Advisor/Consultant|HealthTrackRx: Advisor/Consultant|Mammoth Biosciences: Advisor/Consultant|Netflix: Advisor/Consultant|Oxford Nanopore Technologies: Advisor/Consultant|PhAST: Advisor/Consultant|See details: Patent on Bordetella pertussis/parapertussis PCR issued, a patent on a device/method for sonication with royalties paid by Samsung to Mayo Clinic|See details: continued, patent on an anti-biofilm substance issued|TenNor Therapeutics Limited: Grant/Research Support|Torus Biosystems: Advisor/Consultant|Trellis Bioscience, Inc.: Advisor/Consultant Vance G. Fowler, MD, MHS, Amphliphi Biosciences, Integrated Biotherapeutics; C3J, Armata, Valanbio; Akagera, Aridis, Roche, Astra Zeneca: Advisor/Consultant|Genentech, Regeneron, Deep Blue, Basilea, Janssen;: Grant/Research Support|Infectious Diseases Society of America: Honoraria|MedImmune, Allergan, Pfizer, Advanced Liquid Logics, Theravance, Novartis, Merck; Medical Biosurfaces; Locus; Affinergy; Contrafect; Karius;: Grant/Research Support|Novartis, Debiopharm, Genentech, Achaogen, Affinium, Medicines Co., MedImmune, Bayer, Basilea, Affinergy, Janssen, Contrafect, Regeneron, Destiny,: Advisor/Consultant|Sepsis diagnostic: Patent pending|UpToDate: Royalties|Valanbio and ArcBio: Stock Options David van Duin, MD, PhD, Entasis: Advisor/Consultant|Merck: Advisor/Consultant|Merck: Grant/Research Support|Pfizer: Advisor/Consultant|Pfizer: Honoraria|Qpex: Advisor/Consultant|Roche: Advisor/Consultant|Shionogi: Advisor/Consultant|Shionogi: Grant/Research Support|Union: Advisor/Consultant|Utility: Advisor/Consultant

Abstract Background Critically ill patients, particularly those treated with extracorporeal devices or at extremes of weight, experience pharmacokinetic variability which can compromise beta-lactam (BL) antibiotic target attainment and treatment response. Therapeutic drug monitoring (TDM) for BL antibiotics can improve precision pharmacotherapy but has had limited implementation. The objective of this study was to evaluate the frequency of BL target attainment among adult intensive care unit (ICU) patients who underwent TDM. Methods This observational study evaluated adults treated with cefepime, piperacillin/tazobactam or meropenem in ICUs at the Mayo Clinic in Rochester, Minnesota who underwent TDM from June-September 2022. During the study timeframe, multidisciplinary teams were encouraged to perform BL TDM on patients requiring extracorporeal membrane oxygenation, continuous kidney replacement therapy, or at an extreme of body weight (weight < 40 kg or >120 kg or BMI < 18 kg/m2 or > 40 kg/m2). Percentage of patients with initial serum trough concentrations within the therapeutic range was calculated (Table 1). Results During the study timeframe, 59 trough concentrations were performed on critically ill patients, of which 5 were excluded due to uninterpretable results. Of the remaining 54 BL trough concentrations analyzed, 49 (91%) were initial troughs during the antibiotic course, and 5 (9%) were repeat troughs. Thirty-six (73%) of the initial trough concentrations were within the therapeutic range. Among the trough concentrations outside the therapeutic range, 10 (77%) were too high, and 3 (23%) were too low (Table 2). Dose adjustment occurred in 19 (39%) of initial trough evaluations, including 6 which were adjusted despite a level within the therapeutic range. All of the repeat trough concentrations drawn during the same antibiotic course were within the therapeutic range (n = 5/5; 100%). Conclusion One-fourth of initial BL trough concentrations were outside of the therapeutic range. BL levels outside the therapeutic range prompted dose adjustment to improve the potential for effectiveness or limit the potential for toxicity. BL TDM appears to be a promising strategy to enhance precision pharmacotherapy in the critically ill. Disclosures Sara Ausman, PharmD, Gilead: Honoraria Christina G. Rivera (O'Connor), Pharm.D, Gilead Sciences: Advisor/Consultant|Gilead Sciences: Board Member|Gilead Sciences: Grant/Research Support|Gilead Sciences: Honoraria