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Background: Menin, a protein involved in transcriptional regulation, plays a role in the genesis of multiple cancers. Preclinical data from BMF-219, an investigational, highly selective, oral small-molecule inhibitor of menin, show sustained potent abrogation of menin-dependent oncogenic signaling. BMF-219 is the first and only covalent menin inhibitor in clinical development and is being evaluated in multiple hematologic malignancies, solid tumors, and diabetes mellitus. COVALENT-101 (NCT05153330) is a Phase I dose-escalation and -expansion study of BMF-219 in R/R AL (Cohort 1), DLBCL (Cohort 2), MM (Cohort 3), and CLL (Cohort 4). Here we report preliminary safety, PK and anticancer activity data from Cohort 1 (AL). Methods: Doses of BMF-219 are escalated independently for each indication, initially in single-subject cohorts followed by a “3 + 3” design. Eligible patients (pts) include adults with R/R AL ineligible for standard therapy. Initially pts were enrolled agnostic to molecular status. A subsequent amendment introduced quotas for KMT2Ar (MLL1r), NPM1 and other known menin-dependent mutations: CEBP/A, MLL1-PTD, MN1, NUP98, NUP214, PICALM-AF10, SETBP1. Prior exposure to reversible menin inhibitor therapy is permitted. Subjects receive BMF-219 daily for continuous 28-day cycles until progression/intolerability. There are 2 parallel dose-escalation arms: pts not taking (Arm A) or taking (Arm B) moderate or strong CYP3A4 inhibitors. The study is ongoing and accruing in the escalation. Expansion cohorts will enroll pts to obtain further safety and efficacy data at the OBD/RP2D. Results: As of data cutoff of 7/24/2023, 26 pts with R/R AL (24 AML; 2 ALL) are enrolled; 7 remain on study treatment. Baseline characteristics include 17(65%) males and 9(35%) females with a median age of 57.5 years (range 33-84). There is a median of 4 (range 1-8) prior lines of therapy and 11 (42%) with prior HSCT(s). Six pts (23%) had KMT2Ar, 3 (12%) KMT2A-PTD, 4 (15%) NPM1, and 13 (50%) WT for KMT2A and NPM1. Dosing began with single-patient cohorts at 100 mg QD (Arm A) and 25 mg QD (Arm B) and has been escalated through 4 dose levels. Thus far, pts have been dosed up to 500 mg QD (Arm A) and 125 mg QD (Arm B). BMF-219 exposures were comparable between arms, with ~2-4-fold higher exposures observed with co-administration of a moderate or strong CYP3A4 inhibitor. At the highest dose (DL4) in which PK was evaluated, Arm A (500 mg QD) and Arm B (125 mg QD), pts on average achieved ~50% of target exposure (2000 ng*hr/mL) with some pts surpassing it. Higher QD dosing or corresponding BID dosing is expected to achieve desired exposure. BMF-219 has generally been well tolerated with no DLTs observed and no discontinuations due to treatment-related toxicities. No related QTc prolongation was observed. At the time of data cutoff, 23 of 26 pts were included in the safety population. Common TRAEs (≥10%) include vomiting 13% (3) and Differentiation Syndrome (DS) 13% (3). No Grade 5 TRAEs were reported. The only common Grade ≥3 TRAE (≥5%) was DS 13% (3). The efficacy evaluable population includes AML pts who meet the following criteria: dosed at or near predicted efficacious dose (500 mg or above [Arm A]; 125 mg or above [Arm B]), had known menin-dependent mutations, and completed at least one scheduled response assessment (or had a minimum of 7 doses if discontinued prematurely). Thus far, 2 of 5 efficacy evaluable patients achieved a complete remission (1 CR; 1 CRi) and both continue BMF-219 treatment. Patient A: 39/M, NUP98-NSD1, ECOG=0, 500 mg QD, Arm A, 4 prior lines of treatment including intensive chemotherapy and allo-HSCT. At C1D27, marrow blasts were reduced to 6% from 13% at study entry. The patient achieved CR at C2D28 with 0% blasts.Patient B: 70/F, NPM1m, ECOG=1, 125 mg QD, Arm B, 1 prior line of treatment with decitabine and an investigational agent. At C1D28, marrow blasts were reduced to 34% from 52% at study entry. The patient achieved CRi with 3% blasts at C2D28. Conclusion: BMF-219 is generally well tolerated with no DLT observed (and able to be taken with and without CYP3A4 inhibitors) with no pts discontinuing therapy due to toxicity. BMF-219 dose escalation is ongoing and approaching target exposure. BMF-219 demonstrates early signs of clinical activity in different genomic subgroups. The trial is ongoing and includes enrollment for pts diagnosed with AL, DLBCL, MM and CLL.

Introduction HMAs are the only approved therapy for CMML. In order to improve response rates and survival, the addition of VEN has been utilized in both CMML and after blast transformation (CMML-BT) with conflicting results in small single center studies. To clarify the role of upfront HMA+VEN in CMML and CMML-BT, we performed a large multicenter analysis. Methods We included patients with HMA-naïve CMML and CMML-BT treated with combination HMA and VEN from 4 academic centers. The primary outcome was overall survival (OS) with secondary outcomes including overall response rate (ORR) by 2015 MDS/MPN IWG criteria for CMML and 2022 ELN criteria for CMML-BT. To better appreciate the benefit of adding VEN to HMA treatment, we also performed 1:1 propensity score matched (PSM) analysis of patients treated with HMA alone as upfront therapy for CMML or CMML-BT. Matching was based on age, sex, ECOG performance status, CPSS-Mol, blood counts, peripheral and bone marrow blasts. Results Eighty-nine patients were treated with frontline HMA+VEN, 51 CMML and 38 CMML-BT (5 had received HMA alone for prior CMML). The median age was 71 years, 70% were male, and 83% had ECOG 0-1. Among CMML patients, 55% had MP-CMML subtype, 65% had CMML-2 and 12%, 30%, 58% were CPSS-mol intermediate-1, intermediate-2 and high risk, respectively. In the entire cohort, ASXL1 (63%), TET2 (47%), SRSF2 (39%) and RUNX1 (27%) were the most commonly mutated genes and 55% of patients harbored a RAS mutation ( KRAS [20%], NRAS [18%], CBL [13%], NF1 [11%], PTPN11 [9%]). For HMA combination partner, 46 (52%) were treated with azacitidine, 35 (39%) with decitabine, and 8 (9%) with both during their VEN course. During a median follow-up time of 15.8 months (mos) 52 patients (58%) died: 23 (45%) with CMML and 29 (76%) with CMML-BT. Among CMML patients, the ORR was 90%, including complete remission (CR) in 22%, complete cytogenic remission (CCR) in 4%, optimal marrow response (CMR) in 50%, and partial marrow response (PMR) in 6%. The OS of CMML patients was 25.1 mo (95% CI 15.7 - NR). A PSM population of HMA patients matched to HMA+VEN treated patients showing similar baseline characteristics. ORR was significantly higher with HMA+VEN (95%) as compared those treated with HMA alone (46%), p < 0.001. However, there was no significant OS difference between HMA+VEN vs HMA alone (19.1 mos vs 19.1 mos, p = 0.85, Figure 1). For CMML-BT patients, the ORR of HMA+VEN was 81% including CR in 17%, CR with partial hematologic recover (CRh) in 3%, CR with incomplete hematologic recovery (CRi) in 28%, morphologic leukemia-free state (MLFS) in 22% and partial response (PR) in 11%. The OS of CMML-BT patients was 8 mos (95% CI 4.6 - 26.2). A PSM population of CMML-BT patients treated with HMA alone showed a significantly increased ORR with HMA+VEN (82% vs 40%, p = 0.039). However, there was no difference in OS (7.49 mos vs 9.26 mos, p = 0.83, Figure 2). Among HMA-VEN treated patients, achievement of a CR was associated with an improved OS in the CMML (HR 0.31, 95% CI 0.13 - 0.75) and CMML-BT (HR 0.37, 95% CI 0.19 - 0.74). No predictors of response were identified, including the presence of a RAS mutation. In terms of safety, 7 patients (7.9%) had a grade 3/4 (G3/4) neutropenic infection and 2 patients (2.2%) had a G3/4 hemorrhagic event while being treated with HMA+VEN. A total of 29 patients went on to receive allogeneic transplant (alloSCT): 22 (43%) with CMML and 7 (18%) with CMML-BT. CMML patients who underwent alloSCT after HMA+VEN were younger as compared to non-transplanted patients (64 vs 74 years, p < 0.0001), but had otherwise similar baseline characteristics including stage, CPSS-mol category and prevalence of RAS mutations. Similarly, CMML-BT patients bridged to alloSCT were younger (66 vs 74 years, p < 0.002) and had a better ECOG performance status (p = 0.047). Of patients who received alloSCT, 10 patients (34%) died, 5 with CMML and 5 with CMML-BT. The median OS after alloSCT was 26.7 mo. Conclusions Although the use of VEN with HMA in the upfront treatment of CMML and AML secondary to CMML results in higher response rates compared to HMA alone, this combination does not improve survival based on this multi-center PSM analysis. The current sample size of CMML-BT may limit detection of OS differences between treatment groups. The role of VEN to reduce blasts and serve as a bridge to alloSCT, particularly after HMA failure, requires further investigation in larger studies in both the CMML and CMML-BT populations.

Abstract Background Post-discharge culture and susceptibility review has been described in emergency department and urgent care settings, but there is a lack of published literature describing culture review after acute care hospitalizations. Awaiting microbiology results can impede timely patient discharge. However, discharging patients while microbiology results are pending may result in suboptimal therapy or lost opportunity for additional testing/follow up. We implemented an antimicrobial stewardship effort to identify microbiology tests that result post-discharge utilizing a custom report in the electronic medical record (EMR). Methods. This retrospective descriptive study included adult patients ( >18 years of age) at 4 sites within Mayo Clinic from 1/1/2019 to 2/28/2023. Eligible patients had a hospitalization with an ID consult and an abnormal culture that was reviewed by an antimicrobial stewardship pharmacist after discharge. Urine cultures were excluded. The details of pharmacist-initiated antimicrobial stewardship interventions based on the culture review were identified by an EMR based research report. Results A total of 6803 patient encounters with at least 1 microbiology result reviewed post-discharge were identified. Patients were 40% female with a median age of 62 years. Patient race was 89.8% white, 4% black/African American, 1.5% Asian, and < 1% other. Of these patients, 1983 (29%) had at least one pharmacist intervention. A total of 169 (2.5%) of these patients had multiple interventions. Interventions included modification of antimicrobial therapy, addition of susceptibility testing, or additional follow up (labs, imaging, or patient visits). Median time from culture update to pharmacist review was 27.2 hours. Median length of hospital stay was 5 days and discharge disposition was home with self care (65%), home with home health or hospice (22.7%), or discharge to another acute care or skilled nursing facility (12.3%). Conclusion Outpatient review of post-discharge culture updates utilizing EMR reporting led to substantial interventions impacting antimicrobial treatments. Disclosures Christina G. Rivera (O'Connor), Pharm.D, Gilead Sciences: Advisor/Consultant|Gilead Sciences: Board Member|Gilead Sciences: Grant/Research Support|Gilead Sciences: Honoraria

Abstract Background The treatment of invasive fungal infections (IFI) is often complicated by drug-drug interactions, toxicities, and host comorbidities. Isavuconazole (ISA) has a favorable side effect profile and has FDA approval for invasive aspergillosis and mucormycosis, but there are fewer data on its efficacy for other microbes and non-pulmonary infections. We report our experience of ISA in IFI treatment, with a particular focus on non-pulmonary sites and other microbial etiologies. Methods We identified patients who received ISA as part of IFI treatment from 1/1/2015–4/1/2020 at Mayo Clinic. We categorized them by organ involvement and by pathogens, and identified patterns of ISA use and clinical outcomes. Results A total of 131 patients were identified. Similar to the existing literature, the majority were pulmonary infections (60%), with 12% invasive sinus infection, 12% central nervous system (CNS) infection, and 7% fungemia. Aspergillus was the most common pathogen (39%), yeast comprised 19%, dimorphic fungi 15%, Mucormycosis 12%, phaeohyphomycosis 5%, and other molds 3%. ISA was used as secondary/salvage therapy in 89% of cases. The response rate varied by organ involvement and pathogen. ISA had complete/partial resolution or achieved stability in 57% of fungemia cases, 63% of invasive sinus infections, 64% of pulmonary infections, and 73% of CNS infections. Aspergillus species had a 67% response rate, with 72% response in yeast infections, 65% rate in dimorphic fungi, 53% for mucormycosis, and 86% in dematiaceous molds. Conclusion Although limited by a small sample size, the subgroup review based on organ site and microbial etiology did seem to show roughly similar results to approved uses. The CNS infections treated with ISA were particularly of interest, given the limited options available with reliable CNS penetration. The current available literature has little to say on the efficacy of ISA in these off-label uses, with the majority being similar case series. This report highlights the importance of prospective trials comparing ISA to other antifungals in a greater variety of indications to better identify when this better-tolerated agent can be safely used. Disclosures Courtney E. Harris, MD, Dynamed: Advisor/Consultant

Background Neurophysiological coupling between ventilation and locomotor muscle group III/IV muscle afferent fibers during exercise is an important relationship that favorably influences ventilation in young healthy adults. In contrast, we have shown that group III/IV locomotor muscle afferents provoke aberrant ventilation in aging heart failure patients, which is suggested to be a primary effect of heart failure. However, there remains a limited understanding of the effect of aging in the absence of cardiovascular disease on the group III/IV muscle afferent pathway. Subsystolic circulatory occlusion to elicit venous distension has been suggested to stimulate locomotor muscle afferent neurologic feedback. The purpose of this study was to compare ventilatory responses in young vs aging healthy adults during submaximal constant‐load exercise with intermittent bilateral subsystolic occlusion of locomotor muscles. Methods Healthy adults completed 2 visits (10 young [YNG] vs 9 OLD; age 22±1 vs 66±3 yrs, BSA 1.8±0.1 vs 1.9±0.1 m 2 ; % predicted peak VO 2 99±7 vs 115±7 %; peak workload 188±16 vs 144±9 W, respectively; age and workload P <0.05). Visit 1: peak exercise ergometry test. Visit 2: constant‐load cycle ergometry at 30% peak workload (YNG=56±5 vs OLD=43±3 W, P <0.05) with the first 3 min without cuffing (0 mm Hg) and intermittent subsystolic bilateral thigh cuff inflations to 20, 40, 60, 80, or 100 mm Hg for 2 min (randomized), with 2 min deflation between occlusions thereafter. Minute ventilation (V E ), respiratory rate (RR), tidal volume (V T ), oxygen uptake (VO 2 ) indexed to weight, carbon dioxide output (VCO 2 ), respiratory exchange ratio (RER), V E /VCO 2 , and end tidal partial pressure CO 2 (P ET CO 2 ) were measured continuously via breath by breath system. Results At rest, V E , RR, V T , or RER did not differ in YNG vs OLD ( P >0.05); whereas VO 2 (6.3±0.3 vs 3.9±0.2 mL/kg/min) and VCO 2 (0.3±0.0 vs 0.2± 0.0 L/min) were higher in YNG vs OLD (respectively, P <0.05). During all exercise occlusions, V E was higher in YNG vs OLD, with the largest difference at 100 mm Hg (36.7±1.7 vs 30.2±1.6 L/min, respectively, P <0.05). However, the % change from rest to 0 mm Hg or each cuff occlusion resulted in no differences in YNG vs OLD for V E ( P >0.05). In contrast, in YNG vs OLD, the largest % change from 0 mm Hg to the cuff occlusion resulting in between group differences included V E (3.3±3.0 vs 17.3±3.6 at 80 mm Hg, P <0.05), VCO 2 (2.3±2.3 vs 20.8±3.4 at 100 mm Hg, P <0.05) and V E /VCO 2 (7.0±2.6 vs 0.5±1.8 at 100 mm Hg, P <0.05). In addition, there was a trend for significant differences between YNG and OLD for V T (−1.2±4.4 vs 5.9±4.1 % at 80 mm Hg, P =0.15), VO 2 (−2.1±1.5 vs 3.3±1.8 %, at 100 mm Hg, P =0.09) and P ET CO 2 (−6.4±1.9 vs −2.3±1.4 % at 100 mm Hg, P =0.11). Conclusions These data suggest that aging is associated with altered ventilatory responses to venous occlusion of locomotor muscles during constant load submaximal exercise. These changes may be a result of an increased contribution of locomotor muscle afferents on ventilatory control with aging. Support or Funding Information none

Introduction Healthy aging in adults is associated with attenuated cardiac output (Q) for a given exercise workload compared to younger healthy adults. This is important because skeletal muscle perfusion pressure during exercise is dependent on coordinated adjustments between cardiac and vascular hemodynamics. Cardiac power (CP) quantifies the flow and peripheral pressure generating capacity of the heart, and may be the strongest measure of cardiac function during exercise. Group III/IV muscle afferents are suggested to favorably influence Q and arterial pressure during exercise in young healthy adults. However, the influence of group III/IV afferents on cardiac hemodynamic and arterial pressure coupling during exercise remains unclear across the aging spectrum. Venous distension via subsystolic circulatory occlusion of locomotor muscles is suggested to increase group III/IV afferent outflow. The aim of this study was to assess the influence of subsystolic circulatory occlusion of locomotor muscles on CP in young vs aging healthy adults. Methods Healthy adults completed 2 visits (10 young [YNG] vs 9 OLD; age 22±1 vs 66±3 yrs, BSA 1.8±0.1 vs 1.9±0.1 m 2 ; % predicted peak VO 2 99±7 vs 115±7 %; peak workload 188±16 vs 144±9 W, respectively; age and workload P <0.05). Visit 1: peak exercise test. Visit 2: constant load cycle ergometry at 30% peak workload (YNG=56±5 vs OLD=43±3 W, P <0.05) with the first 3 min without cuffing (0 mm Hg), but thereafter included intermittent subsystolic bilateral thigh cuff inflations to 20, 40, 60, 80, or 100 mm Hg for 2 min (randomized), with 2 min deflation between inflations. Non‐invasive Q and mean arterial (MAP) pressure were measured using continuous hemodynamic photoplethysmography. We calculated CP=Q*MAP. Q and CP were indexed to BSA. Results At rest, MAP did not differ in YNG vs OLD, but Q and CP were higher in YNG vs OLD (P<0.05), which persisted throughout each exercise cuff occlusion. In YNG, the greatest increase in CP from 0 mm Hg occurred at 100 mm Hg (754±48 vs 899±48 L/min/m 2 · mm Hg, P <0.05) due to increased MAP (19±4%, P <0.05) but not Q (1±2%, P >0.05). In OLD, Q, MAP, and CP did not differ between 0 mm Hg and any occlusion ( P >0.05). The % increase in Q from rest to 0, 20, 60, 80, and 100 mm Hg was higher in YNG vs OLD ( P <0.05). The % increase in MAP from rest to any occlusion did not differ in YNG vs OLD ( P >0.05). The % increase in CP from rest to occlusions of 60 (130±9 vs 98±11%), 80 (142±9 vs 108±20%), and 100 (158±11 vs 114±14%) were higher in YNG vs OLD (all P <0.05). Within YNG, the % increase in CP from rest to 100 mm Hg was higher than the % increase from rest to 0, 20, 40, or 60 mm Hg ( P <0.05), driven by increased MAP ( P <0.05). Within OLD, these differences for % increase in CP did not occur despite MAP that was similar to YNG ( P >0.05). Conclusions These data suggest that CP is attenuated in OLD vs YNG healthy adults during subsystolic circulatory occlusion of locomotor muscles during submaximal constant load exercise. The reduced CP generation in older adults is related to a blunted increase in Q mediated by attenuated influence of group III/IV muscle afferents on cardiac function during exercise.

Background Shock and preshock are defined on the basis of the presence of hypotension, hypoperfusion, or both. We sought to determine the hemodynamic underpinnings of shock and preshock noninvasively using transthoracic echocardiography (TTE). Methods and Results We included Mayo Clinic cardiac intensive care unit patients from 2007 to 2015 with TTE within 1 day of admission. Hypotension and hypoperfusion at the time of cardiac intensive care unit admission were used to define 4 groups. TTE findings were evaluated across these groups, and in‐hospital mortality was evaluated according to TTE findings in each group. We included 5375 patients with a median age of 69.2 years (36.8% women). The median left ventricular ejection fraction was 50%. Groups based on hypotension and hypoperfusion were assigned as follows: no hypotension or hypoperfusion, 59.7%; isolated hypotension, 15.3%; isolated hypoperfusion, 16.4%; and both hypotension and hypoperfusion, 8.7%. Most TTE variables of interest varied across these groups, with worse biventricular function, lower forward flow, and higher filling pressures as the degree of hemodynamic compromise increased. In‐hospital mortality occurred in 8.2%, and inpatient deaths had more TTE parameter abnormalities. In‐hospital mortality increased with the degree of hemodynamic compromise, and a marked gradient in in‐hospital mortality was observed when the clinical classification of shock and preshock was combined with TTE findings reflecting worse biventricular function, lower forward flow, or higher filling pressures. Conclusions Substantial differences in cardiac function are observed between cardiac intensive care unit patients with preshock and shock using TTE, and the combination of the clinical and TTE hemodynamic assessment provides robust mortality risk stratification.