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ABSTRACT Introduction Lack of social support negatively impacts medical trainees' wellness. Programmes to educate medical trainees and their support persons (SPs) have been developed to improve resident wellness, but implementation of these programmes at other institutions remains unclear. We aimed to demonstrate the feasibility of implementing the Family Anesthesia Experience (FAX) programme across multiple institutions and to assess the programme's utility. Methods FAX includes didactics on wellness, burnout, substance use disorder and institutional resources; a panel of senior residents and their SPs; and small‐group simulations of airway management, common procedures and a high‐fidelity intraoperative code. We assessed the programme qualitatively using semistructured interviews of 20 first year anaesthesiology residents and 20 SPs. Data analysis was performed via a content analysis approach. Results Twelve anaesthesiology programmes of varying size and geographic locations implemented FAX with minor adaptations. Minimal direct costs were incurred for the virtual programme. Participants enjoyed the event overall. Content analysis showed that FAX improved SPs' understanding of residency and communication between SPs and residents, had minimal impact on SPs' stress, reduced residents' interpersonal stress with SPs and modified perceptions on wellness and burnout. We developed a conceptual model in which we propose SPs' understanding and empathy for their residents would improve through FAX, which may improve communication with and support for residents. Conclusion We demonstrated that FAX can be implemented at varying anaesthesiology residency programmes. Family‐oriented educational events like FAX may be an effective approach to improve SPs' understanding of a resident's role, thereby increasing social support for residents.

Abstract The antiapoptotic protein, myeloid cell leukemia-1 (Mcl-1), contributes to the pathophysiology of acute myeloid leukemia (AML) and certain B-cell malignancies. Tumor dependence on Mcl-1 is associated with resistance to venetoclax. Voruciclib, an oral cyclin-dependent kinase (CDK) inhibitor targeting CDK9, indirectly decreases Mcl-1 protein expression and synergizes with venetoclax in preclinical models. This dose escalation study evaluated voruciclib in patients with previously treated hematologic malignancies. Initially, voruciclib was administered daily, continuously, on a 28-day cycle (group 1). After 2 patients with prior allogeneic stem cell transplantation had a dose-limiting toxicity (DLT) of interstitial pneumonitis at 100 mg, voruciclib administration was changed to days 1 to 14 of a 28-day cycle (group 2). Forty patients, 21 with AML and 19 with B-cell malignancies, were enrolled. Patients had a median of 3 prior lines of therapy (range, 1-8). Dose escalation in group 2 was stopped at 200 mg, a dose that achieved plasma concentrations sufficient for target inhibition, without DLTs observed. The most common adverse events were diarrhea (30%), nausea (25%), anemia (22%), fatigue (22%), constipation (17%), dizziness (15%), and dyspnea (15%). In AML, 1 patient achieved a morphologic leukemia-free state, and 2 had stable disease. Voruciclib treatment led to a decrease in MCL1 messenger RNA expression, downregulation of myelocytomatosis (MYC) and NF-κB transcriptional gene sets, and reduced phosphorylation of RNA polymerase 2. Voruciclib on intermittent dosing was well tolerated, with no DLTs, paving the way for evaluation of the combination of voruciclib with venetoclax for patients with previously treated AML. This trial was registered at www.clinicaltrials.gov as #NCT03547115.

Background and Objectives: The epidemiological data regarding mortality rates of adults with sarcoidosis and non-ischemic cardiovascular disease (CVD) are limited. A retrospective observational analysis was conducted to identify trends and disparities related to sarcoidosis and non-ischemic cardiovascular disease mortality among the adult US population from 1999 to 2022. Methods: We used the Centers for Disease Control and Prevention (CDC) WONDER database to extract death certificate data for the adult US population (≥25 years). The age-adjusted mortality rates (AAMRs) per 100,000 persons were calculated, and annual percent changes (APCs) were determined using Joinpoint. Results: Between 1999 and 2022, 23,642 deaths were identified related to non-ischemic CVD + sarcoidosis. The overall AAMR increased from 0.2 (95% CI, 0.2 to 0.3) in 1999 to 0.5 (95% CI, 0.5 to 0.6) in 2022. Females had a higher AAMR than males (0.6 vs. 0.5). Non-Hispanic (NH) blacks had the highest AAMR, followed by NH whites and Hispanic or Latinos. The southern region had the highest AAMR (0.7: 95% CI, 0.6–0.7), followed by the Midwest (0.6, 95% CI, 0.54–0.669), the Northeast (0.5, 95% CI, 0.5 to 0.6), and the West (0.4; 95% CI, 0.3–0.4). Urban and rural areas had comparable mortality rates (0.5 vs. 0.6). People aged 65+ had the highest AAMRs. Conclusions: The overall mortality rates for non-ischemic CVD and sarcoidosis have increased in the US from 1999 to 2022. Females and NH blacks had higher AAMRs, while a minimal variation was observed based on geographical regions. Early diagnosis and prompt management are the keys to reducing the mortality burden of non-ischemic CVD plus sarcoidosis.

AbstractPurposeOverall there is a lack of evidence on the accuracy and precision of phase‐contrast (PC) MRI in patients with cardiac implantable electronic devices (CIEDs). The purpose of this study is to determine whether aortic velocity measurements are influenced by a CIED.MethodsWe scanned 21 adult patients and 8 pediatric volunteers using clinical standard PC and real‐time PC (rt‐PC) sequences with and without a CIED generator taped on human subjects (below the left clavicle for adults and children; also on the abdomen for children) to mimic image artifacts. Peak and mean velocities above the aortic valve were calculated.ResultsThe Bland–Altman analyses on peak velocity measurements in pediatric subjects showed that both the accuracy and precision worsen as the distance between the CIED and aortic valve decreases (i.e., from abdomen to below the left clavicle). Specifically, both the bias and the coefficient of variation (CV) for both clinical PC and rt‐PC increased from the abdominal position (clinical: bias = −1.1%, CV = 4.3%; rt‐PC: bias = −0.3%, CV = 3.4%) to the clavicle position (clinical: bias = −4.0%, CV = 8.1%; rt‐PC: bias = 8.2%, CV = 7.3%). A similar trend was observed for mean velocity. The mean difference in peak and mean velocity measurements between rt‐PC with CIED (either position) and clinical standard PC with no CIED was within 7.5%. In adult patients, the mean difference between rt‐PC with CIED and clinical standard PC with CIED in peak velocity was 6.9%, and the CV was 7.9%.ConclusionThis study demonstrates that aortic velocity measurements are influenced by CIED in both adult and pediatric subjects.

Background: The BeatAML Master Trial (BAMT) began in 2016 with a goal of determining the feasibility of a precision-medicine approach in treating acute myeloid leukemia (AML) in older adults ≥ 60 years of age where outcomes are poor. At the time, standard of care (SOC) for older patients with AML was intensive 7+3 chemotherapy (cytarabine + daunorubicin) if fit and hypomethylating agents (HMA: azacitidine or decitabine) if unfit. Besides confirming the feasibility, the early results (2019) from the Master Trial suggested that patients who received therapy on one of the sub-studies had a lower early death rate and superior overall survival compared to patients receiving off-protocol SOC, which was primarily single-agent HMA at the time. Since then, the 2019 approval of venetoclax (ven) + azacitidine for older unfit AML patients has been transformative and emerged as the SOC. Using data from the BAMT from 2016-2024, we suggest that knowing the comprehensive genomic profile of AML at the time of diagnosis is still beneficial in determining therapy that would lead to the optimal outcome and that development of targeted therapies and combination regimens with ven/HMA is still needed. Methods: This is a retrospective analysis of 1096 patients who consented and enrolled on the BAMT (NCT03013998) from Nov 2016 through Jun 2024. Patients ≥ 60 years with newly diagnosed AML were included. Patients underwent therapy on a BeatAML sub-study based on their genetics (N=433) or treatment off-protocol (N=663). We divided the patients according to what therapy they received: (1) Non-Intensive (Off-Protocol, N=121), (2) Ven/HMA (Off-Protocol, N=234), (3) Non-Intensive (Sub-Study, N=407), (4) Intensive (Sub-Study, N=26), and (5) Intensive (Off-Protocol, N=155). 94 patients received no treatment and 59 were unknown. Non-intensive therapies included primarily targeted agents or non-ven combinations. We analyzed baseline characteristics and demographics, overall survival (OS), and the impact of allogenic stem cell transplant (SCT). OS, using Kaplan-Meier method, was measured from the start of therapy to all-cause death, censoring patients at last follow-up. Results: Characteristics and demographics were similar between Groups 1, 2 and 3. Group 4 and 5 were treated with intensive chemotherapy and their characteristics are reflective of younger/fit patients appropriate for the intensive regimen. Groups 4 and 5 also had the longest median OS (mOS) of 40.2 months (95% CI: 13.9-not reached (NR)) and 42.3 months (95% CI: 25.1-NR) respectively. Group 3, which included patients treated with a non-intensive, targeted therapy on a sub-study, had an mOS of 14.0 months (95% CI: 12.3-16.7), which was similar to Group 2, treated with Ven/HMA, that had an mOS of 13.2 months (95% CI: 10.9-16.3). Lastly, patients in Group 1, who were treated primarily with HMA monotherapy, did poorly in comparison, with an mOS of 6.0 months (95% CI: 3.3-10.1). Additionally, we looked at the cumulative incidence rate (CIR) of SCT. The CIR in 12 months of Group 1 was 9.8% (95% CI: 6.9-13.4), Group 2: 5.4% (95% CI: 2.2-10.7), Group 3 and 4 combined: 35.0% (95% CI: 628.1-42.1), and Group 5: 13.1% (95% CI: 6.9-13.4). In a multi-variable analysis, after adjusting for typical favorable risk factors like NPM1 mutations and core binding factor, SCT was highly significant (p<0.0001) in improving OS with a hazard ratio of 0.23 (95% CI: 0.16-0.32), and Group 3 performed similarly to Group 2 (p=0.20). Conclusions: First, our results suggest that it is clinically relevant to correctly identify whether an intensive chemotherapy, targeted-therapy, or ven/HMA regimen is best suited for older AML patients, for which a precision-medicine trial is ideal for. Secondly, in this group of patients, our results show that patients treated with a non-intensive targeted therapy (Group 3) has a similar mOS to those treated with ven/HMA (Group 2). Especially after controlling for patient characteristics, patients in Group 2 performed similar to those in Group 3 (p=0.20). Patients in Group 3 were treated on Beat AML sub-studies which included targeted therapy alone or with non-venetoclax combinations, which is a strong rationale for continued development of targeted agents to optimize toxicity and quality of life with similar survival. Lastly, this data also supports the need to improve the ven/HMA SOC by developing combination regimens with targeted agents to further improve outcomes.

Background: Mutations of isocitrate dehydrogenase (IDH) are recurrent in acute myeloid leukemia (AML) and the prevalence increases with age. The prognostic impact of IDH1 and IDH2 mutations remains controversial. IDH inhibitors are small molecules that bind within the IDH enzymatic active site, blocking aberrant 2-hydroxyglutarate production and inducing myeloid differentiation. While they can lead to differentiation syndrome, they generally have a more favorable side-effect profile, making them an attractive option for older patients. We aimed to describe the prevalence and prognostic impact of IDH mutations in newly diagnosed (ND) AML patients ≥ 60 years in a large cohort of patients treated on a Leukemia and Lymphoma Society-sponsored trial. Methods: We performed a retrospective observational analysis including patients ≥ 60 years with ND AML who were enrolled on the Beat AML clinical trial (NCT03013998) before May 10, 2023. Patients were treated with a variety of treatment regimens. Cytogenetic analysis and next-generation sequencing (FoundationOne®Heme) were obtained. Mutations were considered present at any detectable VAF. Cox proportional hazard models were used to describe the relative risk of each variable on death over time from the date of trial inclusion. Results: A total of 1023 patients with ND AML were identified. Patients had a median age of 72 (range 60-92) years and the majority were non-Hispanic White (83.2%), and male (57.6%). Ninety-nine (9.7%) patients were IDH1MUT, 193 (18.9%) patients were IDH2MUT including 10 (1.0%) patients with a co-occurring IDH1 and IDH2 gene mutations. Both IDH1MUT and IDH2MUT were associated with 2022 ELN favorable-risk (26.3% and 22.3% for IDH1 and IDH2 respectively, vs 15.5% overall (P<0.001)). IDH1MUT significantly co-occurred with DNMT3AMUT (42.4%), NPM1MUT (44.4%) and less frequently with TP53MUT (10.1%) (P<0.001 for all). IDH2MUT was associated with DNMT3AMUT (35.8%), NPM1MUT (31.1%), SRSF2MUT (38.3%), and less frequently with TET2MUT (6.7%) and TP53MUT (9.3%) (P<0.001 for all). Normal karyotype was higher in IDH1MUT (P<0.001) and IDH2MUT (P<0.001), whereas complex karyotype (P<0.001 for both) and core-binding factor AML (P=0.047, P=0.015) were lower in IDH1MUT and IDH2MUT. To evaluate the impact of IDH mutations in patients ≥ 60 years, we focused on patients evaluable for outcome treated with lower-intensity therapy (LIT) (N=674), and intensive chemotherapy (IC) (N=178), separately. Among the LIT treated patients, 96 patients received treatment with an IDH inhibitor, and 237 patients received a hypomethylating agent (HMA) plus venetoclax. For patients treated with LIT, the hazard ratios (HRs) of death over time were 0.58 [95% CI 0.47-0.72; P<0.002], 0.81 [95% CI 0.59-1.13; P=0.214] and 0.56 [95% CI 0.44-0.72; P<0.001] for IDHMUT, IDH1MUT, IDH2MUT respectively. Among patients receiving IC, the HRs were 1.05 [95% CI 0.68-1.69; P=0.777], 0.70 [95% CI 0.31-1.61; P=0.406] and 1.27 [95% CI 0.77-2.1; P=0.352] for IDHMUT, IDH1MUT, and IDH2MUT respectively. The HR of death for IDH1MUT patients treated with LIT with the addition of an IDH1 inhibitor (N=24) was significantly lower (HR 0.47 [95% CI 0.24-0.92; P=0.027] vs IDH1MUT patients treated without an IDH1 inhibitor, while an IDH2 inhibitor did not change survivial outcomes in patients with IDH2MUT (N=71). Discussion: To our knowledge this is the largest retrospective study characterizing the prevalence of IDH mutations in patients ≥ 60 years with AML. We demonstrated that IDH mutations were detected in ~27% of older patients with AML. Although there could have been selection bias as the Beat AML study had separate IDHMUT study arms, these findings are concordant with other studies showing an increase in frequency of IDH mutations with age. IDH2MUT was associated with a lower HR of death among patients treated with LIT, which was not seen in patients receiving IC. The high prevalence of IDH mutations suggests that IDH inhibitors used as single agents or in combination with lower-intensity therapies are an important class of drugs for this older patient population as they are generally well tolerated, that need further investigation.

BACKGROUND ELRA is a humanized, BCMA/CD3 bispecific antibody. In the phase 2 registrational MagnetisMM-3 (MM-3) trial, SC ELRA given as 2 step-up priming doses (12 mg on day 1 and 32 mg on day 4 of cycle 1) followed by 76 mg QW in patients (pts) with RRMM naive to BCMA-directed therapy resulted in an ORR of 61.0%. With a median follow-up of 28.4 mos, the median DOR, PFS, and OS were not reached (NR; 2-year rate, 66.9%), 17.2, and 24.6 mos, respectively. Overall, 56.3% of pts had CRS (grade 2, 14.3%; no grade ≥3). Most events occurred after doses 1 (44.5%), 2 (20.2%), and 3 (5.9%); 0.8% (1 pt) had CRS with doses ≥4. Recurrent CRS occurred in 15.1% of pts. The phase 1/2 MagnetisMM-9 (MM-9; NCT05014412) study is examining an alternative priming regimen and longer dosing intervals of ELRA. Here, we present updated MM-9 results. METHODS In MM-9, pts with RRMM and disease refractory to ≥1 IMiD drug, ≥1 PI, and ≥1 anti-CD38 antibody were given SC ELRA as step-up priming doses of 4 and 20 mg on Day 1 and Day 4 of Cycle 1, respectively. After the priming doses, ELRA 76 mg was given QW for the next 6 cycles (Part 1) or for 1 cycle followed by 116 (dose level 1 [DL1]) or 152 (dose level 2 [DL2]) mg Q2W for the next 5 cycles (Part 2A). After 6 cycles, the dosing frequency was decreased from QW to Q2W (Part 1) or from Q2W to Q4W (Part 2) in pts who achieved ≥PR lasting ≥2 months. The recommended phase 2 dose from Part 2A (152 mg, DL2) was evaluated in Part 2B (dose expansion). The primary endpoint for both parts is grade ≥2 CRS rate per ASTCT criteria during Cycle 1. Secondary endpoints include evaluation of efficacy and adverse events. Data cutoff: February 13, 2024. RESULTS Overall, 85 pts (median age, 64.0 y) were treated with ELRA. The majority (72.9%) of pts had R-ISS stage I/II disease (23.5% with R-ISS stage III); 31.8% had high-risk cytogenetics. Median number of prior lines of therapy was 5.0 (range, 1-12). The median treatment duration was 8.6, 2.9, 1.4, and 3.3 mos, in Part 1, Part 2A DL1, Part 2A DL2, and Part 2B, respectively. Median follow-up for pts overall (n=85), in Part 1 (n=33), Part 2A DL1 (n=12), Part 2A DL2 (n=11), and Part 2B (n=29) was 10.4, 23.3, 16.5, 15.2, and 9.3 mos, respectively. Overall, the ORR was 58.8%. For pts in Part 1, Part 2A DL1, Part 2A DL2, or Part 2B, ORR was 66.7%, 58.3%, 36.4%, and 58.6%, respectively; median DOR was NR (9-mo rate: 86.4%), 10.8 mos (9-mo rate: 80.0%), NR (9-mo rate: 100.0%), and NR (9-mo rate: 84.8%); median PFS was 17.1 (9-mo rate: 62.8%), 11.6 (9-mo rate: 50.9%), 1.6 mos (9-mo rate: 40.0%), and NR (9-mo rate: 57.1%); median OS was NR (9-mo rate: 75.8%), 17.4 mos (9-mo rate: 66.7%), NR (9-mo rate: 60.0%), and NR (9-mo rate: 72.4%), respectively. For pts in Part 1, Part 2A DL1, Part 2A DL2, and Part 2B, grade ≥2 CRS rates during Cycle 1 were 15.2%, 16.7%, 27.3%, and 6.9%, respectively. For pts in Part 1, Part 2A DL1, Part 2A DL2, and Part 2B, CRS rates were 30.3%, 33.3%, 36.4%, and 24.1% after dose 1, 27.3%, 25.0%, 36.4%, and 24.1% after dose 2, 15.2%, 33.3%, 27.3%, and 20.7% after dose 3, 6.1%, 8.3%, 0%, and 3.4% after dose 4, and 6.1%, 16.7%, 9.1%, and 0% after doses ≥5. Recurrent CRS occurred in 18.2%, 33.3%, 18.2%, and 17.2% of pts in Part 1, Part 2A DL1, Part 2A DL2, and Part 2B. The most common (>60%) TEAEs (any grade/grade ≥3) were hematologic TEAEs (Part 1, 75.8%/75.8%; Part 2A DL1, 83.3%/83.3%; Part 2A DL2, 81.8%/81.8%; Part 2B, 79.3%/69.0%), infections (Part 1, 78.8%/48.5%; Part 2A DL1, 83.3%/66.7%; Part 2A DL2, 72.7%/63.6%; Part 2B, 62.1%/37.9%), and CRS (Part 1, 60.6%/0%; Part 2A DL1, 83.3%/0%; Part 2A DL2, 90.9%/9.1%; Part 2B, 48.3%/0%). Grade 5 TEAEs not including PD were infection (n=4), fall (n=1), subdural hematoma (n=1), and food poisoning (n=1). CONCLUSIONS The 4/20 mg step-up priming regimen and alternative dosing schedules in MM-9 resulted in similar efficacy vs the step-up regimen used in the registrational MM-3 study (12/32 mg). Responses were durable with encouraging PFS and OS with the alternative step up and longer dosing schedule. While the overall safety signals with the alternative step up regimen are similar to those seen with MM-3, the CRS profile differed with more CRS events after each subsequent dose and a higher prevalence of recurrent CRS. Thus, the optimal ELRA step-up regimen remains 12/32 mg from the original regimen in the MM-3 study. In addition, these early results suggest that reducing the dose frequency of ELRA may not compromise efficacy.

Introduction: Scant data exist on prognostic factors, survival and treatment (Tx)-related outcomes in SCNSL. We conducted a multicenter international analysis to identify prognostic factors and outcomes in SCNSL at diagnosis (de novo), or after frontline Tx (1L) either with (concomitant) or without (isolated) systemic (syst) relapse. Methods: This study collected data from patients (pts) treated between 2001-2023 at 35 centers. Overall (OS) and progression-free survival (PFS) were calculated from SCNSL diagnosis to first event (death for OS, relapse/death for PFS) or last follow-up. Uni- (UVA) and multivariable (MVA) Cox analyses were performed to assess prognostic factors; Kaplan-Meier method was used to estimate survival. Results: 1173 (US: 863, UK: 273, Canada: 37) pts with SCNSL were included. Baseline characteristics were median age: 62 years (interquartile range 52.5-69), male sex: 58.7%, elevated LDH: 71.1%, stage III/IV: 88.6%, HIV: 3%, transformed LBCL (tLBCL): 13.8%, non-germinal center B-cell like (non-GCB) subtype: 52.3%, double expressor (DE): 40%, MYC rearrangement (MYC-R): 28.3%, MYC/BCL2 double hit: 16.6%, MYC/BCL2/BCL6 triple hit (TH): 6.1%. Among 522 pts with de novo SCNSL, 84.2% had involvement of a single CNS compartment (44.7% brain parenchyma; 40.4% leptomeningeal [lepto]). 1L regimens included 36.2% R-CHOP with high-dose methotrexate (HD-MTX), 12.5% MARIETTA-type, and 9.8% R-CODOX-M/IVAC; 54.6% received intrathecal chemotherapy. Consolidation Thiotepa-based autologous stem cell transplant (TT-ASCT) occurred in 15.3%. The majority of pts who underwent TT-ASCT had previously achieved CR or PR in syst (92.5%) and CNS (72.5%) compartments. At median follow-up 25.7 months (mos), subsequent relapse was observed in 27.5% TT-ASCT recipients: 36.3% had isolated CNS, 27.4% syst, and 36.3% concomitant. 588 pts presented with SCNS after 1L (66.2% isolated, 33.8% concomitant). Brain parenchyma involvement was observed in 56.8%, lepto in 22.6%. Tx included 31.6% HD-MTX combination (eg, R-MPV, MTR); 18.4% HD-MTX +/- rituximab; 16.2% MARIETTA-type; and 9.4% platinum-based regimen. Consolidation TT-ASCT occurred in 22.4% (n=132), and 13.8% (n=81) received CAR-T cell therapy (excluding subsequent relapses in de novo group). Syst (65.1%) & CNS (69.1%) responses (CR/PR) were higher before TT-ASCT compared to CAR-T cell (49.5% & 54.5%, respectively). After TT-ASCT, 52 pts (39.3%) relapsed, mainly in the CNS (n=30, 57.7%), with only 4 (7.7%) concomitant. After CAR-T, 48 pts (59.3%) relapsed: 15 (31.2%) isolated in CNS and 15 (31.2%) concomitant. 12-month cumulative incidence of relapse (with death as competing risk) was 21.1% after TT-ASCT and 55.8% after CAR-T. In 63 pts (5.4%), the first CNS event occurred >2 lines of Tx. With median follow-up of the entire cohort of 24.6 mos, median PFS and OS were 11 and 21 mos, respectively. mPFS and mOS were significantly better in pts with de novo SCNSL (13.4 & 47.4 mos) compared to SCNSL after 1L (10.4 & 14.2 mos) and >2 lines of Tx (6.5 & 9.7 mos); P<0.0001. Factors associated with significantly shorter OS in UVA across all presentations were age >60, male sex, GCB subtype, MYC-R, tLBCL, DE, TH, elevated LDH, ECOG PS ≥2, SCNSL after 1L (vs. de novo), and failure to achieve syst/CNS response to 1L. Of these, age >60, male sex, MYC-R, ECOG PS ≥2, and failure to achieve response to 1L remained significant in MVA. In de novo cases, age >60, DE, ECOG PS≥2, and failure to achieve syst/CNS response to 1L were associated with poorer OS; for pts with SCNSL after 1L, age >60, GCB subtype, and ECOG PS ≥2 were significant. Pts treated with HD-MTX-based regimens after 1L experienced longer OS than those treated with platinum regimens or high-dose cytarabine. In de novo cases, TT-ASCT was significantly associated with longer OS (HR=0.58; P=0.025) in MVA after adjusting for significant factors, 1L type, and response. For SCNSL at relapse, TT-ASCT (HR=0.34; P<.0001) and isolated SCNSL presentation (vs. concomitant HR=0.70, P=0.007) were associated with longer OS, adjusting for significant factors, type of second-line Tx, & site of CNS relapse. Conclusions: This study represents the largest analysis of SCNSL inclusive of all modes of presentation. Concomitant SCNSL at relapse was associated with poor outcomes, while TT-ASCT consolidation was associated with improved OS in de novo & relapsed disease. Despite advances in LBCL SCNSL remains an unmet therapeutic need.

Background: Chromosomal rearrangements involving the KMT2A gene and mutations involving the nucleophosmin (NPM1) gene have been associated with response to menin inhibitors in multiple studies of acute myeloid leukemia (AML) patients characterized by these genetic alterations. Both alterations are more common in younger AML patients and those with NPM1 mutations historically perform better. However, the prevalence and outcomes of older (≥60 years) AML patients with these alterations who are treated with current therapies is less well understood. We present results from the Beat AML Master Trial (BAMT) that analyze the outcomes of this large, but less common subset of patients in an older AML population. Methods: Patients were consented and enrolled on this precision medicine-based Beat AML Master Trial (NCT03013998) from November 2016 to June 2024. Patients were included in this analysis if they harbor either the classic NPM1 mutation or a KMT2A rearrangement (over 10 different gene partners). Additionally, 2 patients with a NUP98 rearrangement were included with the KMT2A cohort as they are known to have similar biology in terms of menin dependence. These patients were treated with the following therapies: a sub-study specific targeted therapy for the dominant clone, venetoclax + hypomethylating agent (Ven/HMA), intensive chemotherapy (IC), alternative non-intensive therapy (NIT), or no therapy. Clinical/genetic characteristics and median overall survival (OS) were analyzed in each group separately. Overall survival (OS) was calculated from master consent and estimated using the Kaplan-Meier method. Results: Of 1096 AML patients enrolled on the BAMT, 246 patients had either an NPM1 (N=207, 18.9%) or KMT2A (N=39, 3.6%) genetic alteration. The baseline characteristics for the NPM1 cohort were median age 72 years (range: 60-92), 50% female, and ECOG performance status: 0-16%, 1-58%, 2-25% and 3-1%. Additional disease characteristics include treatment related AML at 11% and complex karyotype (≥3 abnormalities) at 3%. Median OS for the entire NPM1 cohort was 18.4 months (95% CI: 14.2-24.7). Patients were treated on a sub-study (35%), Ven/HMA (19%), IC (26%), NIT (8%) or no treatment (9%). Between treatment groups, median OS was 21 months (95% CI: 12.8-31.7) for those treated on a sub-study, 22 months (95% CI: 12.6-not reached (NR)) for Ven/HMA, 41.6 months (95% CI: 18.2-NR) for IC, and 6.3 months (95% CI: 1.3-23) for NIT, which was significantly different (p<0.0001). The baseline characteristics for the KMT2A cohort were median age 69 years (range: 60-88), 44% female, and ECOG performance status: 0-19%, 1-45%, 2-35% and 3-0%. Treatment related AML occurred in 23% of patients and complex karyotype in 31%. Median OS for the KMT2A cohort was 6.5 months (95% CI: 3.6-31.6). Patients were treated on a sub-study (38%), Ven/HMA (15%), IC (15%), NIT (15%), or no treatment (5%). Between treatment groups, median OS was 31.6 months (95% CI: 3.2-NR) for sub-study, 5.0 months (95% CI: 3.0-NR) for Ven/HMA, 12.7 months (95% CI: 4.9-NR) for IC, and 2.9 months (95% CI: 1.5-NR) for NIT, which was also significantly different (p<0.0001). Conclusions: In this cohort of older AML patients who possess NPM1 or KMT2A mutations, initial demographics and clinical characteristics upon presentation are as expected. Within each cohort and depending on the type of therapy received, there were interesting differences in survival. Median OS was the highest for the NPM1 cohort that received IC while the KMT2A cohort had the highest median OS when enrolled on a KMT2A targeted sub-study; a finding that supports precision-based medicine for this high-risk KMT2A group characterized by poor outcomes. As menin inhibitor combinations with induction chemotherapy or Ven/HMA move to the frontline setting, we anticipate seeing significant improvement in outcomes for AML patients in both of these genomic subsets. Further multivariable analysis will be performed to validate treatment effect on OS. Our analyses for these two cohorts also provide valuable outcome benchmarks for the design of future precision oncology studies that seek to improve survival in these subsets of older AML patients.

Background: There is limited data on the safety and efficacy of ventricular tachycardia (VT) ablation in patients with chronic kidney disease (CKD). We examined the outcomes of patients with CKD undergoing VT ablation in a nationally representative cohort of patients. Methods: The National Inpatient Sample Database (NIS) was analyzed from 2018 to 2021 to identify patients ≥18 years old with VT undergoing ablation. Patients with atrial fibrillation, atrial flutter, supraventricular tachycardia, or pre-excitation syndrome were excluded. Patients were divided into those with CKD and without CKD. A multivariable logistic regression model was utilized to assess the association of CKD with in-hospital mortality and outcomes after adjusting for confounders. Results: Our cohort included 1608 VT ablation procedures, of which 428 (27%) were performed on CKD patients. Mean age was 63 (±13) years, 318 (19%) were female, and 1194 (74%) were White. 1475 (92%) of the procedures were done at an urban teaching hospital, and 1240 (77%) at a private non-profit hospital. On multivariable analysis, CKD was associated with significantly higher odds of death (adjusted odds ration [aOR]: 3.43; 95% confidence interval [CI]: 1.79-6.5; p=0.0002), acute decompensated heart failure (aOR: 3.1; 95% CI 2.24-4.56; p<.0001), bleeding (aOR: 1.53; 95% CI1.02-2.28; p<.03), and acute kidney injury (aOR: 4.49; 95% CI3.42-5.9; p<.0001). There was no difference in the odds of acute myocardial infarction, stroke, cardiogenic shock, vasopressor use, mechanical ventilation, and pericardial tamponade or pericardial procedures Figure . Conclusion: Patients with CKD undergoing VT ablation have an increased risk of mortality and adverse in-hospital outcomes when compared to patients without CKD. These hypothesis-generating findings need validation in future prospective studies for optimal pre-procedural risk stratification.