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BACKGROUND Among antiretroviral therapy–suppressed (ART-suppressed) people with HIV (PWH), women have higher levels of some inflammatory markers than men, but the effect of sex on the inflammatory proteome, and whether age modifies these differences, remain unclear. METHODS Plasma inflammatory protein levels were assessed in ART-suppressed PWH from the Center for AIDS Research Network of Integrated Clinical Systems. The relationship between sex and plasma proteins — including 22 interferon-α response pathway proteins — was assessed, adjusting for confounders and assessing interactions by age. RESULTS Of 922 participants, 162 (18%) were female. The median age was 47, above which the majority of women had undetectable plasma anti-Müllerian hormone levels, a biomarker of ovarian reserve. Age modified the influence of sex on the inflammatory proteome. Older age (>47) was associated with greater increases among women than men in 194 proteins. Interferon-α response proteins were higher in men in those ≤ 47 but higher in women in those > 47 (interaction P < 0.001). Among the 131 proteins associated with mortality risk ( q < 0.05), only 5 differed by sex among those ≤ 47, while 79 differed by sex in those > 47, with nearly all being higher in women. Women had decreased mortality than men ≤ 47 ( P < 0.001) but had similar mortality > 47 ( P = 0.84). CONCLUSION The menopausal transition appears to increase systemic type I interferon responses and inflammation in women with HIV, which may contribute to a loss of female advantage in mortality. FUNDING NIH National Heart, Lung, and Blood Institute; National Institute of Neurological Disorders and Stroke; National Institute of Allergy and Infectious Diseases.

This practice guideline addresses perioperative pain management using local and regional anesthesia for cardiothoracic, mastectomy, and abdominal surgery in adults and children. For adults, the American Society of Anesthesiologists (Schaumburg, Illinois) Task Force on Perioperative Pain Management strongly recommends fascial plane blocks to reduce pain and/or opioid requirements in the first 24 h postoperatively for open cardiothoracic, abdominal, retroperitoneal, and pelvic surgeries and mastectomy. Fascial plane blocks are also recommended in adults to reduce pain and/or opioid requirements after minimally invasive abdominal procedures. The Task Force conditionally recommends use of fascial plane blocks for minimally invasive cardiothoracic surgeries and open hernia repair to reduce pain in the first 24 h postoperatively. For children, the Task Force strongly recommends use of fascial plane blocks to reduce pain/and or opioid use after open cardiac or thoracic surgeries. Fascial plane blocks are conditionally recommended to reduce pain the first 24 h in children undergoing open hernia repair. Overall, data analysis for this practice guideline was limited by low methodologic quality, inconsistencies in outcome measurements, and small sample sizes from individual centers. Future research in regional anesthesia and analgesia needs to address these pervasive limitations.

Abstract Chimeric Antigen Receptor (CAR) T cell therapy is a transformative treatment for hematologic malignancies. However, ex vivo autologous CAR T cell manufacturing presents substantial logistical and clinical challenges. Direct in vivo CAR-T cell engineering offers a new paradigm for CAR T delivery. We recently developed the CD3-targeted lentiviral vector LV-169 which can deliver a CAR transgene to resting niche-resident T cells in lymphoid tissues. LV169 is pseudotyped with a mix of chimeric and nonchimeric VSV-G proteins detargeted (blinded) from the natural LDL receptor and re-targeted to T cells through the display of a CD3-specific scFv. Here we demonstrate that LV169 can specifically deliver a functional aBCMA-CAR transgene to resting human T cells in PBMC cultures from the healthy volunteers and from multiple myeloma patients. For clinical translation, we selected an αBCMA-CAR construct comprising a fully human single heavy chain nanobody linked to 41BB and CD3z cytoplasmic signaling domains. Human T cells expressing this CAR construct have low tonic signaling and efficiently kill BCMA-positive myeloma target cells with similar or lower associated cytokine release compared to a clinically relevant benchmark BCMA-CAR. To further improve LV169 and to minimize CAR protein incorporation in the LV envelope which may lead undesirably to myeloma cell transduction, we placed the CAR transgene under a T-cell specific Lck promoter in reverse orientation relative to the 5' LTR. The transcriptional activity of the Lck promoter was comparable to that of a constitutive EF1a promoter in primary T cells and, in contrast to EF1a had minimal activity in a variety of other tested cell types including the HEK293T producer cell line and the THP-1 monocytic cell line. Western blotting confirmed the absence of CAR protein in LV particles (LVP) generated using the Lck promoter-driven reverse orientation construct. In contrast, high levels of CAR protein were detected in LVP generated using the parental EF1a promoter-driven construct. The LV-incorporated CAR protein mediated off-target gene delivery to BCMA-positive myeloma cells. The therapeutic efficacy of intravenously administered LV169 LV particles carrying BCMA-CAR constructs was tested in the OPM-2 human multiple myeloma xenograft model. NSG mice with knockout of MHC-I and MHC-II, and with advanced disseminated OPM-2-Luc tumors were engrafted with human PBMC one week prior to intravenous LV169-BCMA-CAR administration. Mice were treated with single intravenous injection of LV169 at different doses 3 weeks after tumor engraftment. OPM-2-Luc tumor burden was monitored by regular luciferase imaging. All treated mice cleared their tumors within 28-days following LV administration and the rate of clearance was correlated to the LV particle dose. Even at the 4e8 dose level (by p24) tumors were completely cleared. Eighty four days post-treatment the treated mice remained tumor-free and resisted re-challenge with OPM-2 tumor cells. Circulating CAR-T cells, monitored by flow cytometry, became detectable by 14 dpi and peaked between 21-35 dpi. Following tumor clearance, the number of circulating CAR-T cells declined dramatically. The treatment was well tolerated and analysis of cytokines associated with CAR-T cell cytotoxicity confirmed the absence of a severe cytokine storm. IFNγ was the only cytokine which was elevated during the expansion period of CAR-T cells, while IL-2, IL-6, TNFα and GM-CSF were barely detectable. In summary the characteristics of our new developed LV169-based platform make it suitable for further clinical translation which is underway.

Abstract Background: Undetectable minimal residual disease (uMRD) at the end of first-line (1L) treatment (tx) with 12-cycles (C) of venetoclax (ven) + obinutuzumab (obin) is associated with prolonged survival for patients (pts) with chronic lymphocytic leukemia (CLL, Al Sawaf et al. Blood 2024). We hypothesized that MRD may be used to guide ven tx duration for CLL pts treated with 1L ven + obin. Methods In this ongoing phase II, multicenter investigator-initiated study, pts receive ven + obin for 1L tx of CLL/small lymphocytic lymphoma (NCT04447768). Eligible pts have a CIRS score of ≤ 6 and require 1L tx per iwCLL 2018 criteria. Pts receive 6 x 28-day C of obin and initiate ven on C1D22. Ven duration is dependent on peripheral blood (PB) MRD status measured by ClonoSeq next generation sequencing. At C7, pts undergo MRD testing. Pts uMRD6 (&lt;10-6 sensitivity) at both C7 and C9 dc ven after 9C and enter treatment free observation (TFO). Pts with detectable MRD6 (dMRD6) at C7 undergo repeat testing at C12; if uMRD5 (&lt;10-5) pts dc ven after 12C. Pts dMRD5 at C12 continue ven for an additional 12C (24C total) prior to TFO. The primary study endpoint is 36-month PFS; the unpromising rate is set at 82% and will be tested by a nonparametric survival estimate (Kaplan-Meier) along with Greenwood's formula. RNA sequencing (RNAseq) was performed pre-tx on patient bone marrow (or PB if inaspirable) samples. Unsupervised clustering using machine learning (ML) based on consensus nonnegative matrix factorization was applied to the most variable genes to identify patient clusters. Clusters were then biologically characterized by gene signature scoring using xCell algorithm and assessed for association with uMRD6 at C7 using a Fisher exact test. Results Baseline characteristics of the 100 pts who initiated tx include: median age 58 (range 34-81); 71% male, 90% White, 3% Black and 2% Asian, 5% unknown; 49% IGHV unmutated, 16% TP53 mutation, 8% del17p (previously reported, Roeker et al. ASH 2024). 3 pts stopped tx prior to C7. 51 pts were uMRD6 at C7 and C9 and completed 9C ven. 46 pts were dMRD6 at C7; 6 pts stopped tx outside of meeting protocol requirements and are included in intention-to-treat (IIT) analyses. 32 pts were uMRD5 at C12 and dc ven after 12C. 8 pts were dMRD5 at C12: 5 continued ven per protocol (3 completed 24C ven, 2 ongoing tx as of 15 May 2025 data cut-off), 2 stopped ven outside of protocol requirements (included in ITT analyses), and 1 pt withdrew consent. At a median follow-up of 35 months, the 36-month PFS rate is 90% (95% CI: 84%, 97%). 36-month OS is 94% (95% CI: 89%, 99%). Landmark PFS analyses from EOT were performed for pts who dc ven after 9C due to uMRD6 (24-month PFS 92%, 95% CI: 85, 100%, n=51) and pts who dc ven after 12C due to uMRD5 (24-month PFS 96%, 95% CI: 89%, 100%, n=32). For pts dc ven after 9C due to uMRD6 (n=51), PB MRD at 12C after EOT was: 59% uMRD6, 12% uMRD5, 4% uMRD4, 8% dMRD4 and 18% unknown. For pts dc ven after 12C due to uMRD5 status (n=32), PB MRD at 12C following EOT was: 9% uMRD6, 31% uMRD5, 9% uMRD4, 25% dMRD4 and 25% unknown. Of the 5 pts with PD, 3 pts have had Richter Transformation to diffuse large B-cell lymphoma (all uMRD6 at C7 / 9). Two pts with PD have not met iwCLL tx criteria and remain in TFO. Five pts have died (suicide, West Nile encephalitis, COVID-19, complications of glioblastoma and RT DLBCL). Five C12 dMRD5 pts who continued ven have reached C18, with only 1 of 5 converting to uMRD5 in PB. However, all 5 maintained uMRD4 (&lt;10-4). Of 3 pts that completed 24C ven (2 ongoing tx), 1 pt had deepening of response to uMRD5 at C24, and 2 pts had rising MRD on ven (dMRD4 at C24). To investigate patient heterogeneity at baseline and its relationship to uMRD, we clustered patient RNAseq samples into two clusters using artificial intelligence/ML based unsupervised clustering. The clusters associated with uMRD6 at C7 (Fisher exact test p=0.038), and patients in the cluster with significantly higher immunosuppressive cells such as T-regulatory cells and M2 macrophages were less likely to be uMRD6 at C7. Conclusions At a median follow-up of 35 months, the estimated 36-month PFS rate is 90%. RNAseq transcriptomic analyses identified that patients with enriched immunosuppressive cells were less likely to be uMRD6 at C7. Additional follow-up is required to confirm the durability of this MRD-guided ven + obin tx strategy.

Abstract Background: Venetoclax (VEN)+obinutuzumab (VO) is an effective therapy for CLL/SLL requiring regular monitoring for tumor lysis syndrome (TLS) during VEN ramp-up. The CLL14 trial of VO reported no TLS during VEN ramp-up; however, there are limited real-world data on monitoring practices and TLS outcomes for different dose levels and monitoring timepoints. This study assessed VEN initiation prophylaxis and monitoring outcomes for patients (pts) with CLL/SLL starting VO in first line (1L) in an outpatient, real-world setting. Methods This interim analysis relied onretrospective observational data from 4 US sites of the CLL Collaborative Study of Real-World Evidence (CORE). Adult pts with CLL/SLL were eligible if they: (1) started VO per-label outside of a clinical trial in 1L, or immediately after exposure in 1L to agents with different mechanisms of action (i.e., BTKi, anti-CD20 only) of &lt;30 days; (2) prior to VEN start, had either (i) low physician-determined tumor burden (TB) (i.e., all lymph nodes [LN] &lt;5 cm and ALC &lt;25 x 109/L), or (ii) medium physician-determined TB (i.e., any LN ≥5-&lt;10 cm or ALC ≥25 x 109/L) with creatinine clearance ≥80 mL/min; (3) had no strong CYP3A inhibitors or prophylactic rasburicase from 3 days prior to VEN start until end of VEN ramp-up; and (4) had VEN ramp-up in an outpatient setting. TB-related labs/imaging was assessed from 2 months prior to obinutuzumab initiation (i.e., index date) until VEN start. VEN characteristics (i.e., dosing, duration), prophylaxis measures (i.e., antihyperuricemics and IV hydration), and TLS-related monitoring and management (i.e., lab results and interventions received) were collected per ramp-up week and TLS monitoring timepoint. Results Of 128 pts in CORE who initiated VO in any line, 72 pts met inclusion criteria (low TB: 57 [79.2%]; medium TB: 15 [20.8%]). Median (IQR) age was 62 (56.0, 68.5) years, 58.3% were male, and 81.9% had ECOG grade ≤1. Among pts tested, 7/68 (10.3%) had del(17p)/TP53 mutation and 43/66 (65.2%) had unmutated IGHV. Median (IQR) time from index to VEN start was 23.0 (22.0, 30.0) days. Most pts completed ramp-up (98.6% [71/72]) and followed a per-label regular dosing schedule (93.1% [67/72]). Prior to VEN ramp-up, all pts received prophylactic antihyperuricemics (allopurinol: 71 [98.6%]; febuxostat: 2 [2.8%]) and prophylactic hydration. In the 2 days prior to a dose escalation for at least 1 week of ramp-up, prophylactic IV hydration was reported for 27 (37.5%) pts based on physician determination. One pt stopped VEN after week 2 due to neutropenia (grade 3+). During ramp-up (median [IQR] of 9 [8, 12] blood tests per pt), no lab or clinical TLS was reported. Of 21 (29.2%) pts who received an intervention following a lab assessment, most had low TB at VEN start (16 [76.2%]). All interventions were either prophylactic or non-TLS-related. Following a lab assessment for at least 1 week of ramp-up, prophylactic IV or escalated oral hydration intervention was reported in 17/21 pts (81.0%) based on physician determination (e.g., to manage impaired baseline renal function in those with low TB, patient request, or institutional practice) (IV hydration: 15 pts; escalated oral hydration: 2 pts). By per-label monitoring timepoints, hydration intervention was given prophylactically following pre-dose lab tests for 7 pts (across weeks 1-5), 6-8 hours post-dose for 5 pts (weeks 1-2), and 24 hours post-dose for 10 pts (weeks 1-2). By per-label monitoring timepoints, other non-TLS-related interventions (i.e., blood transfusion for anemia, insulin for hyperglycemia, and potassium for non-TLS-related hypokalemia) were given following pre-dose lab tests for 2 pts (weeks 1-5) and 24 hours post-dose for 4 pts (weeks 1-2). Conclusion Consistent with the CLL14 trial, no TLS was reported in this real-world, interim analysis of pts with mostly low TB and good renal function at 1L VO initation. All interventions during VEN ramp-up were prophylactic or non-TLS-related, with prophylactic hydration commonly given based on physician preference. These results suggest that VO initiation is manageable in an outpatient setting. Consideration should be given for simplified monitoring requirements including potential removal of 6-8 hour post-dose lab in this population and be further explored in prospective studies. Data collection for this study is ongoing to further contextualize real-world VEN initiation prophylaxis and monitoring outcomes in a larger cohort.

Abstract Introduction Elevated levels of fetal hemoglobin (HbF) ameliorate sickle cell disease (SCD) manifestations. BEAM-101 is an investigational cell therapy comprising ex vivo base-edited autologous CD34+ hematopoietic stem and progenitor cells (HSPCs) that directly target the HBG1/2 promoters to disrupt BCL11A binding, switching production from sickle (HbS) to majority anti-sickling HbF. We present ongoing data from the BEACON study (NCT05456880), a Phase 1/2, single-arm, open-label study evaluating a single dose of BEAM-101 in individuals with SCD and severe vaso-occlusive crises (sVOCs). Methods Eligible patients were aged 12–35 years with SCD and ≥4 sVOCs in the 2-year period prior to informed consent. After mobilization with weight-based or tiered fixed-dose plerixafor, autologous CD34+ HSPCs were collected by leukapheresis and genetically modified with an adenine base editor. Following conditioning with pharmacokinetically adjusted myeloablative busulfan (target cumulative AUC 80 hr*mg/L), patients received a single dose of BEAM-101 (≥3.0×106 viable CD34+ cells/kg). Patients were then monitored for neutrophil and platelet engraftment, adverse events (AEs), total Hb, Hb fractions, % F-cells, hemolysis markers, sVOCs, and additional protocol endpoints for up to 24 months. Results As of June 16, 2025, enrollment has been completed and 46 patients have initiated mobilization. Of the 26 patients who have received BEAM-101, mean duration of follow-up was 6.2 (range 1.0–18.7) months. Baseline demographics were: age 18–34 years, 24 βS/βS genotype, 21 self-reported Black/African American, and 11 female. One patient, who successfully engrafted and obtained stable HbF levels &gt;60%, withdrew consent 5 months post-infusion. For the 26 treated patients, the median number of stem cell collection cycles was 1 (range 1–4); 18 (69.2%) required a single cycle, 4 required 2 cycles, and 4 required &gt;2 cycles. Target cell dose was achieved with a median of 3 (1–12) collection days. Patients received a mean BEAM-101 dose of 8.4 (range 3.2–23.4) ×106 viable CD34+ cells/kg. By the data cut, patients achieved neutrophil (n=26) and platelet (n=24) engraftment at a median of 18 (12–30) days and 19 (11–50) days, respectively, with a median duration of 7 (4–17) days of neutropenia. Of the 24 evaluable patients, 9 (37.5%) achieved platelet engraftment without requiring platelet transfusion through the transplant process. No patients had ≥Grade 3 AEs or serious AEs related to BEAM-101. One patient died due to respiratory failure, assessed as likely related to busulfan conditioning, 4 months post-infusion as previously reported. Mean total Hb increased to 12.1 (range 9.0–14.7) g/dL by Month (M) 1 (n=24), 15.6 (11.9–18.6) g/dL by M6 (n=11), and was sustained through follow-up. Four patients had total Hb levels above the normal range beyond M6 without any associated clinical manifestations or need for therapeutic intervention. Erythropoietin levels trended towards normal in all patients, including those with elevated total Hb. Mean endogenous HbF (HbF/[HbF+HbS]) was &gt;60% and HbS was &lt;40% by M1, which was sustained through last follow-up. At M6, mean % F-cells were 99.2% (97.0–99.9; n=10) and mean HbF/F-cell was 20.8 (18.0–23.9; n=9) pg, exceeding the protective threshold of 10 pg against sickling. Peripheral blood editing was at a mean of 68.5% by M3 (n=16), 69.6% by M6 (n=10), and 72.8% by M12 (n=5). Hemolysis markers and sickling parameters normalized or improved for all patients. No patients experienced any investigator-reported sVOCs post-engraftment. Conclusions The BEAM-101 treatment process is characterized by a low number of mobilization and collection cycles and high editing efficiency, resulting in rapid neutrophil and platelet engraftment and robust pancellular HbF expression, with durability observed up to 18 months. Additionally, there is a corresponding reduction in HbS levels to &lt;40%, and improvements or resolution of hemolysis parameters and anemia, along with resolution of investigator-reported sVOCs post-engraftment. The safety profile of the BEAM-101 treatment regimen is consistent with busulfan conditioning, autologous HSCT, and underlying SCD. These results demonstrate the potential for base editing of the HBG1/2 promoters as a safe and effective therapeutic modality for the treatment of SCD that also has the potential to minimize hospitalization and treatment process burden for patients, families, and sites.

Abstract Introduction: Patients diagnosed with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) exhibit an elevated risk of developing other cancers (OC) relative to the general population. Historically, chemoimmunotherapy (CIT) represented the cornerstone of CLL/SLL management. A systematic review of clinical trials of CIT for CLL that included 28 studies reported 352/3297 (12.6%) patients developed OC (Csanadi 2022). The introduction of targeted agents beginning in the mid-2010's, including Bruton tyrosine kinase inhibitors (BTKi) and BCL2 inhibitors, has shifted the standard of care toward these novel therapies. In this study, we determined the risk of OC in newly diagnosed CLL/SLL patients cared for at the US Department of Veteran Affairs (VA), The University of Texas MD Anderson Cancer Center, and Mayo Clinic in Rochester, MN. Methods: We identified patients with newly diagnosed CLL/SLL after 1/1/2016 using the VA Central Cancer Registry, MD Anderson, and the Mayo Clinic CLL Databases. The baseline clinical characteristics, CLL treatments, and the occurrence of OC were abstracted by electronic health record (EHR) review. Receipt of CLL directed therapy was categorized into a) CIT only; b) targeted therapy only; c) CIT and targeted therapy; and d) other (including monotherapy with monoclonal antibody therapy). The occurrence of OC was modeled using CLL treatment as a time-dependent variable. Prior and concurrent OC diagnosed within 3 months of CLL/SLL were excluded from analyses, to reduce ascertainment bias. Results: We identified 6844 patients with CLL/SLL who met inclusion criteria. Median follow up was 3.6 years (interquartile range [IQR] 1.9-5.8). The median age at diagnosis of CLL/SLL was 71 years (range, 23 - 102); most patients were white (81%) and male (90%). Although many patients had missing values, among those with available information, IGHV genes were unmutated in 884 (51%), CLL FISH panel showed del17 in 213 (7%), del11q in 389 (13%), trisomy 12 in 674 (23%), and del13q in 1508 patients (50%). A total of 2344 patients received CLL directed therapy during follow-up: 278 (12%) received CIT only, 1809 (77%) received targeted therapy (+/- monoclonal antibody), only 99 (4%) received CIT and targeted therapy and 150 (6%) monoclonal antibody therapy only. Among patients treated with targeted therapies, 950 (50%) received ibrutinib, 381 (20%) received acalabrutinib, 164 (9%) received zanubrutinib, 4 (&lt;1%) received orelabrutinib, 280 (15%) received venetoclax, and 3 (&lt;1%) received sonrotoclax. Other treatments included combinations of a covalent BTKi (cBTKi) and BCL2i in 52 (3%) patients, among others. A total of 583 patients were diagnosed with OC during the study period. Types of OC observed included neoplasms of the prostate (n=129, 22%), lung (n=118, 20%), hematologic malignancies (n=91, 16%), gastrointestinal tract (n=68, 12%), melanoma (n=66, 11%), kidney and bladder (n=44, 8%), head and neck (n=19, 3%), and other/unknown (n=48, 8%). Estimated risk of occurrence of OC was 4.2% (95%CI 3.8-4.8%) at 24 months and 9.7% (95%CI 8.9-10.6%) at 60 months after a diagnosis of CLL/SLL. Multivariable analyses demonstrated that older age (HR: 1.013, 95%CI: 1.00-1.021), male sex (HR: 1.6, 95%CI: 1.1-2.3), and receipt of CLL directed therapy (HR: 1.4, 95%CI: 1.2-1.7) were associated with an increased risk of OC. When considering different types of CLL directed treatments, those who received CIT with or without targeted therapies had the highest risk of development of OC (HR: 1.6, 95%CI: 1.2-2.1). Risk of OC were also increased for those who received CIT only (HR: 1.41, 95%CI: 0.97-2.05) and those who received targeted treatments alone (HR: 1.27, 95%CI: 1.02-1.58). Conclusion: In this large dataset of newly diagnosed patients with CLL/SLL in the past ten years, approximately 10% patients developed OC at 5 years. Receipt of CLL directed therapy was associated with a 40% increased risk of development of OC compared to those patients who did not receive therapy. The risk was highest among patients who received CIT with or without targeted therapy and was still elevated in those who received CIT only or targeted therapy only.

Abstract Background Translocation of chromosomes 4 and 14 (t(4;14)) results in overexpression of MMSET and has been associated with poor clinical outcomes in patients (pts) with multiple myeloma (MM). KTX-1001 is a first-in-class, potent, and selective oral inhibitor of MMSET (also known as NSD2) developed as the first investigational therapy to directly target the high-risk t(4;14) translocation, a key molecular driver in MM. KTX-1001 binds to and inhibits the catalytic SET domain of MMSET, thereby suppressing the deposition of dimethylated histone H3 lysine 36 (H3K36me2), leading to downregulation of oncogenic histone modifications and epigenetic reprogramming of malignant plasma cells. Preclinically, KTX-1001 synergistically inhibited cell viability in MM cell lines when combined with a proteasome inhibitor (PI), immunomodulatory drug (IMiD), or cereblon E3 ligase modulator (CELMoD™). Preliminary findings were previously reported from the initial cohort of 18 pts enrolled in a first-in-human phase 1 trial evaluating KTX-1001 in relapsed/refractory multiple myeloma (RRMM; NCT05651932; Bories et al. Blood. 2024;144[Suppl 1]:3370). Here, we present updated results from this study. Methods RRMM pts who received ≥3 prior therapies, including PI, IMiD and anti-CD38 monoclonal antibody (anti-CD38 mAb), received oral KTX-1001 across 9 dose levels using a 3+3 dose-escalation design. Primary objective was to determine the recommended Phase 2 dose (RP2D) and the maximum tolerated dose (MTD). Secondary objectives included pharmacokinetics, pharmacodynamics (PD), and primary efficacy. The dose expansion phase has been initiated to evaluate KTX-1001 in combination with either carfilzomib or the investigational CELMoD™ mezigdomide in t(4;14) RRMM pts. Results As of 13 June 2025, 40 pts have been treated in the monotherapy dose-escalation phase. The maximum tolerated dose (MTD) was exceeded due to dose-limiting toxicities (DLTs) in 2 pts: two Grade (Gr) 4 thrombocytopenia and one Gr 3 epistaxis. Backfill at selected dose levels is ongoing to further characterize safety profile and refine dose optimization. The median time from initial MM diagnosis was 8 years (range:2-20) with a median of 6.5 prior lines of therapy (range: 3-25). This included stem cell transplant (70%), BCMA CAR-T (42.5%), and non-CAR-T BCMA targeted drugs such as antibody-drug conjugates and bispecific antibodies (57.5%). The median age was69 years (range:50-83); 21 were female and 19 were male. Extra-medullary disease was present in 13 (32.5%) pts. Nineteen (47.5%) pts had t(4;14) translocation, 5 (12.5%) had 1q21 gain and 4 (10%) had deletion 17p. A total of 16 (40%) pts have shown a treatment response according to IMWG criteria or have achieved stable disease: 1 VGPR (10+ months), 1 PR (4+ months), 2 MR (3+ and 12 months), 12 SD (2-20+ months). KTX-1001 has demonstrated a favorable tolerability profile. Grade 3 or higher treatment-emergent adverse events (TEAEs) were reported in 31 (77.5%) pts. The most frequent (≥20% pts) Gr 3/4 TEAEs were thrombocytopenia in 12 pts (30%; grade 4 in 8 [20%]), neutropenia in 12 pts (30%; febrile neutropenia in 2 [5%]), anemia in 10 (25%) pts. Gr 3 infections were observed in 5 (12.5%) pts and fatigue in 5 (10%) pts. The main reason for treatment discontinuation was progressive disease (57.5%), other pts discontinued due to physician decision (5%), consent withdrawal (5%), and one pt due to adverse event. Twelve (30%) pts remain on treatment. At Cycle 1 Day 15, drug exposure and steady-state concentrations of KTX-1001 increased with dose. A dose-dependent reduction in H3K36me2, the primary PD marker of KTX-1001 activity, was observed in peripheral blood at Cycle 2 Day 1 and beyond, which plateaued above dose-level 4. Paired bone marrow samples further confirmed on-target PD effects, with a marked reduction in H3K36me2 levels in MM cells at Cycle 2 Day 1 with observed anti-MM effect of reduced proliferation of MM cells with concomitant increased proliferation in immune cells in pts achieving clinical benefit. ConclusionsKTX-1001 is a novel agent showing tolerable safety profile in RRMM and demonstrating promising single agent activity in heavily pretreated, triple class refractory RRMM including those with high-risk features. KTX is currently evaluated in ongoing study in combination with carfilzomib and the investigational CELMoD™ mezigdomide in t(4;14) RRMM pts.

ABSTRACT Background Intracranial and extracranial hemorrhages are significant causes of morbidity and mortality. Emergency medicine pharmacists (EMPs) can play a crucial role in anticoagulation reversal by identifying patients on anticoagulation, selecting the optimal anticoagulation reversal agent, and ensuring adequate dosing and prompt administration. The goal of this systematic review and meta‐analysis was to determine the impact EMPs have on time to anticoagulation reversal and patient outcomes in anticoagulation‐associated hemorrhages. Methods A medical librarian performed a literature search in EBSCO CINAHL, Ovid Cochrane Central Register of Controlled Trials, Ovid Embase, Ovid Medline, Scopus, and Web of Science Core Collection from inception to January 2025 for all types of oral anticoagulants and for life‐threatening bleeding that required emergent reversal. Newcastle‐Ottawa was used to assess the risk of bias, and Grading of Recommendations Assessment, Development, and Evaluation (GRADE) was used to assess the level of certainty of the evidence. Random effects models estimating mean differences and 95% confidence intervals are reported. Results There were 2445 titles and abstracts screened, with 44 undergoing full‐text evaluation. Six observational studies including 219 patients who received an anticoagulation reversal agent with the presence of an EMP and 198 patients who received a reversal agent without an EMP were included. Time from emergency department (ED) presentation to anticoagulation reversal agent administration (75.60 min, 95% confidence interval [CI]: −101.7 to −49.5) and time from medication order to administration were faster with an EMP (−18.7 min, 95% CI: −23.5 to −14.0). There was no difference in short‐term mortality. The included studies had a high risk of bias and were deemed very low quality of evidence. Conclusion EMP involvement in patient care during anticoagulation reversal of acute hemorrhages improved time to anticoagulation reversal agent administration. Larger scale, higher‐quality studies are necessary to assess the value of EMPs in improving patient‐centered outcomes.