Citations

Background TAILOR‐PCI (Tailored Antiplatelet Initiation to Lessen Outcomes due to decreased Clopidogrel Response After Percutaneous Coronary Intervention) studied genotype‐guided selection of antiplatelet therapy after percutaneous coronary intervention versus conventional therapy with clopidogrel. The presence of CYP2C19 loss‐of‐function alleles in patients treated with clopidogrel may be associated with increased risk for ischemic events. We report a prespecified sex‐specific analysis of genotyping and associated cardiovascular outcomes from this study. Methods and Results Associations between sex and major adverse cardiac events (MACE: cardiovascular death, myocardial infarction, stroke, stent thrombosis, and severe recurrent ischemia) and Bleeding Academic Research Consortium (BARC) bleeding at 12 months were analyzed using Cox proportional‐hazards models. Among 5276 randomized patients, loss‐of‐function carriers were observed in ≈36% of both sexes, and >80% of carriers were heterozygotes. At 12 months, after adjustment for baseline differences, risks of MACE (HR , 1.28 [0.97 to 1.68]; P =0.088) and BARC bleeding (hazard ratio [HR], 1.36 [0.91 to 2.05]; P =0.14) were comparable among women and men. There were no significant interactions between sex and treatment strategy for MACE interaction P value ( P int =0.59) or BARC bleeding ( P int =0.47) nor for sex and genotype (MACE P int =0.15, and BARC bleeding P int =0.60). Conclusions CYP2C19 loss‐of‐function alleles were present in ≈1 in 3 women and men. Women had similar adjusted risks of MACE and bleeding as men following percutaneous coronary intervention. Genotype‐guided therapy did not significantly reduce the risk of MACE or bleeding relative to conventional therapy for both sexes. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01742117.

7556 Background: The majority of R/R NHL progressions after CART involve pre-existing sites, suggesting a promising role for bridging radiotherapy (bRT). We assessed the local control rate of disease sites bridged with radiotherapy prior to CART and identified predictors of in-field recurrence. Methods: We retrospectively reviewed 35 patients with aggressive B-cell NHL who received bRT between leukapheresis and CART infusion between 2018 and 2021 at a multi-site single institution. bRT local control rate (LC), calculated based on the total number of irradiated sites, was defined from bRT end date. Progression-free survival (PFS) and overall-survival (OS) were defined from the date of CART infusion. In-field recurrence was defined as disease relapse occurring within the radiation planning target volume. Kaplan-Meier plots and cox regression modeling were used to estimate the desired output. Results: Median age of the cohort at time of CART infusion was 59 (range 19-73). The median equivalent 2 Gy dose (EQD2) administered was 23.3 Gy (range 4-41 Gy). The median time from end of bRT to CART infusion was 14 days (range 6-42). Five (14%) patients also received bridging chemotherapy with bRT. Among the 34 evaluable patients, 30 (88%) achieved an objective response (59% complete response and 29% partial response). At a median follow-up of 12 months, 1-year PFS was 48% and 1-year OS was 72%. No progression occurred beyond 240 days. On review of treatment plans and pre-treatment PET/CT scans, 59 sites were identified that received bRT prior to CART infusion. The median size and SUVmax of the irradiated sites were 8.7cm (range 1.5-22) and 13 (range 4-46), respectively. Of the 59 irradiated sites, 8 sites (13.6%) in 7 patients had in-field local recurrence, translating to 1-year LC of 84%. No in-field recurrence occurred beyond 180 days. Moreover, no local recurrence occurred in patients who received radiation to all known sites of active disease to EQD2> 30 Gy (n = 4 patients); these patients remained in remission except for 1 who experienced progression outside the bRT field. On univariate analysis, triple hit lymphoma (THL) (OR 22.8, 95% CI: 3.8-138.3; p < 0.001), tumor size (OR 1.25, 95% CI: 1.1-1.4; p < 0.001), specifically ≥ 9cm (OR 9.4, CI: 1.2-77.3; p = 0.036) and SUVmax (OR 1.1, CI: 1.02-1.15; p = 0.008), specifically ≥ 20 (OR 5.6, CI: 1.3-23.7; p = 0.018), were significantly associated with increased risk of in-field recurrence. On multivariate analysis, THL (OR 32.9, CI: 3.2-336.0; p = 0.03) and tumor size (OR 1.3, CI: 1.1-1.6; p = 0.01) retained significant association with in-field recurrence. Conclusions: Bridging radiotherapy prior to CART provides excellent and durable in-field local control for R/R B-cell NHL. Patients with triple hit histology and bulky disease are likely at higher risk of in-field recurrence and may benefit from higher doses of bRT.

e19049 Background: Prognosis of COVID-19 is poor in the setting of immunosuppression. Casirivimab/imdevimab (REGEN-COV), bamlanivimab, and sotrovimab are investigational monoclonal antibodies (MoAbs) authorized for treatment of mild/moderate COVID-19 for patients (pts) 12 years or older and who are at high-risk for progression to severe COVID-19. These neutralizing antibodies, against SARS-CoV-2 spike proteins, have been shown to decrease risk of progression to severe disease. Recipients of allogeneic stem cell transplants (allo-SCT) or chimeric antigen T cell therapy (CAR T cell) represent a high risk population. However, treatment outcomes with these MoAbs in these pts are not well described. Methods: This retrospective study included 33 consecutive adult pts who developed mild/moderate COVID-19 and received anti-spike SARS-CoV-2 MoAbs between December 2020 and November 2021. Allo-SCT (N=27) or CAR T cell (N=6) recipients were included, and outcomes were analyzed separately. Pts received REGEN-COV (N=19), bamlanivimab (N=11), or sotrovimab (N=1), missing (N=2). Results: In the allo-SCT cohort (N=27), median age at time of COVID-19 was 55 (23-76) years. Median time from allo-SCT to COVID-19 was 31 (22-64) months. Two pts received CAR T-cell therapy prior to allo-SCT. Diagnoses included leukemia or myeloid diseases (82%), lymphoma (11%), or myeloma (7%). Transplant characteristics are summarized (Table). Thirteen pts were vaccinated against SARS-CoV-2 prior to breakthrough COVID-19. Events considered included hospitalization due to COVID-19, disease progression, or death from any cause. The 6-month event-free and overall survivals were 81% and 91%, respectively. In the CAR T cell recipients cohort (N=6), 4 pts received axicabtagene ciloleucel for diffuse large B-cell or follicular lymphoma and 2 received brexucabtagene autoleucel for mantle cell lymphoma. The median follow-up was 8 (1-11) months. Two pts received autologous SCT prior to COVID-19. Median time from CAR T cell therapy to COVID-19 was 10 (3-24) months. Three pts were vaccinated prior to COVID-19. Only 1 pt was hospitalized due to severe COVID-19 requiring mechanical ventilation leading to death. Conclusions: These results show a potential benefit of MoAbs in high-risk pts, namely allo-SCT or CAR T cell recipients. Future studies should evaluate the role of prophylactic use MoAbs in these populations. A comparative analysis with a matched control cohort (who did not receive MoAbs) will be provided at the meeting. [Table: see text]

e19007 Background: While clinical outcomes of patients (pts) with TP53 mutated (m) acute myeloid leukemia (AML) are dismal, subsets of pts with eligibility to curative intent therapies can do better. As racial disparities are known to impact outcome in hematological malignancies, we sought to explore disparities in TP53m AML. Methods: We conducted a multicenter study of 304 TP53m AML pts, divided into 2 groups, White (n= 240) and Black/Hispanic (n=64), to compare difference in disease characteristics and clinical outcome. We grouped Black and Hispanic together as the number of pts were small in each group and our aim was to evaluate outcome in under-represented races/ethnicities. Results: Baseline characteristics are summarized in Table. The median age of the pts was comparable between White and Black/Hispanic (p= 0.97). A significantly higher proportion of Black/Hispanic pts (23%) had diabetes mellitus when compared with White (14%) pts (p= 0.02). A higher proportion of Black/Hispanic pts had therapy-related AML (33% vs. 20%, p= 0.03), complex cytogenetics (98% vs. 87%, p= 0.003) and co-mutations (70% vs. 57%, p= 0.02). The proportion of pts who received hypomethylating agent + venetoclax (29% vs 20%, p= 0.20) or CPX-351 (22% vs 20%, p= 0.13) were comparable between White and Black/Hispanic, respectively. A higher proportion of Black/Hispanic pts received supportive care (17% vs. 4%, p= 0.002). White pts had higher rates of complete remission with or without count recovery (25% vs. 19%, p= 0.07). Only 6% of Black/Hispanic pts received allogeneic stem cell transplantation (alloHCT) compared to 16% for White pts (p= 0.01). The median event free survival was 2 months (mo) (95% CI;1.52-2.41) and 2.5 mo (95% CI:1.62-3.31) in White and Black/Hispanic pts, respectively (p= 0.71). The median overall OS was shorter for Black/Hispanic (6.37 mo [95% CI:2.88-9.85]) than for White (6.90 mo [95% CI:5.55-8.24] [p= 0.009]). Conclusions: Our study demonstrates poorer OS in Black/Hispanic pts with TP53m AML. Potential drivers of this disparity include lower alloHCT rates, higher rates of pts receiving supportive care, and higher-risk disease in Black/Hispanic pts.[Table: see text]

e19002 Background: Extramedullary disease in acute myeloid leukemia (AML), also known as myeloid sarcoma (MS), is an uncommon presentation of de novo AML. Clinicopathologic characteristics and optimal treatment strategies of de novo MS remain unclear in both isolated MS without bone marrow (BM) involvement and synchronous MS with BM involvement. Methods: In a single-site retrospective study, medical records of patients with de novo extramedullary AML who received oncological care at any Mayo Clinic site between 1996 and 2021 were analyzed. Using BlueSky Statistics software, survival outcomes were analyzed using Kaplan-Meier and Cox-proportional hazard models for univariate and multivariate analysis, respectively. Results: 83 patients with de novo MS were identified; 49 (59%) presented with synchronous MS and 34 (41%) exhibited isolated MS. Median age at diagnosis was 56 years (range, 17-89); 63% were male. Next-generation sequencing of the blood +/- BM revealed abnormalities in 24/27 (88%) analyzed patients; aberrations included mutations in RTK-RAS pathways (12/27), NPM1 (10/27), TET2 (6/27), and IDH2 (4/27). Median length of follow-up was 1.73 years (95% CI; 0.03-3.0); 53 patients (64%) had expired. Median event free survival was 0.64 years and 0.61 years in isolated and synchronous MS, respectively (p = 0.5). Median overall survival (mOS) in isolated and synchronous MS was 2.1 years and 1.5 years, respectively (p = 0.5). Induction treatment with intensive chemotherapy (IC) was administered in 70 patients (84%). IC regimens included 7+3, MEC, CLAG-M, and hyper-CVAD. Variables associated with improved survival in both groups included treatment with IC +/- allogenic stem cell transplant (alloSCT) (p < 0.001), normal or favorable risk karyotype (p = 0.001), and age less than 60 (p = 0.001). Localized therapy (LT) did not provide an added survival benefit. Patients with synchronous MS were more likely to relapse in the BM and blood than isolated MS (p = 0.02). Conclusions: Enriched with RTK-RAS mutations, de novo MS remains an aggressive form of AML, particularly in patients with intermediate or high-risk genomics or those with skin, soft tissue, or lymphatic involvement. IC should be employed with consideration of alloSCT in eligible patients, particularly in synchronous MS due to a heightened risk for medullary and leukemic relapse.[Table: see text]

TPS7080 Background: Myelodysplastic syndrome/myeloproliferative neoplasms (MDS/MPN) are classified as a distinct category under the World Health Organization (WHO) classification of myeloid neoplasms. MDS/MPN with RS and thrombocytosis (MDS/MPN-RS-T) and MDS/MPN, unclassifiable with > 15% bone marrow ring sideroblasts (MDS/MPN-U-RS) have similar clinical and pathological characteristics with symptomatic or transfusion-dependent anemia as the predominant morbidity. Luspatercept has been approved in myelodysplastic syndromes with ring sideroblasts (MDS-RS) and MDS/MPN overlap syndromes, based on the phase 3 MEDALIST clinical trial which primarily included MDS-RS patients with an objective erythroid response rate of approximately 40 per cent. In this trial, some MDS-RS patients also experienced an increase in neutrophil and platelet counts. This raises a safety concern for MDS/MPN patients with elevated platelet or WBC counts such as MDS/MPN-RS-T and MDS/MPN-U-RS. Previous studies have shown clinical and biological differences between MDS-RS and MDS/MPN-RS-T, with the latter group at a significantly elevated risk for thrombotic events. Additionally, several MDS/MPN-RS-T patients are on hydroxyurea which may blunt the erythroid response of luspatercept. Therefore, it is imperative to establish the safety and efficacy of luspatercept in this patient group. Methods: This is an investigator-initiated, prospective, phase II study of luspatercept in MDS/MPN overlap neoplasms with ring sideroblasts and thrombocytosis or unclassifiable with ring sideroblasts with 2 arms; hydroxyurea-independent (cohort A) and hydroxyurea-dependent (cohort B). Hydroxyurea and/or aspirin use is allowed as per investigator discretion. The primary goal is to study the efficacy and safety of luspatercept in MDS/MPN-RS-T or MDS/MPN-U-RS with symptomatic anemia. The primary endpoint is to assess erythroid response rate as per the 2015 International Working Group MDS/MPN response criteria. Secondary endpoints include response duration, time to acute myeloid leukemia (AML) transformation, thrombosis rate, AML-free and overall survival. Inclusion criteria include newly diagnosed or relapsed/refractory adult patients with WHO-defined diagnosis of MDS/MPN-RS-T or MDS/MPN-U-RS with symptomatic or transfusion-dependent anemia and unlikely to respond (EPO level > 200 IU/L) or intolerant to erythropoiesis stimulating agent (ESA) therapy. Prior therapy with lenalidomide, hypomethylating agents or immunosuppressive therapy is allowed. The overall plan is to enroll 54 patients across the three Mayo Clinic sites, Minnesota, Arizona and Florida. Enrollment to the trial began in January 2022 with 1 patient enrolled at the time of abstract submission. Clinical trial information: NCT05005182.

TPS7070 Background: Outcomes of adults with relapsed/refractory T-cell acute lymphoblastic leukemia (T-ALL) and acute myeloid leukemia (AML) have remained poor. CD38 is a transmembrane glycoprotein with several important functions including its role in immune escape of tumor cells [Chillemi A et al. Front Immunol 2017, Furano A et al. J Immunol 1990]. Several studies have demonstrated that CD38 is expressed in T-ALL and AML and is targetable with CD38 blocking agents [Naik J et al. Haematologica 2019, Bride KL et al. Blood 2018, Tembhare et al. J Immunother Cancer 2020]. XmAb18968 is a novel CD38-CD3 bi-specific T-cell engager with Fc domain modified to minimize Fcγ receptor binding and non-selective T-cell activation resulting in reduced cytokine release without compromising target cell killing. We hypothesize that targeting CD38 in relapsed/refractory T-ALL and AML would be safe and feasible using XmAb18968. Methods: This is an investigator-sponsored multi-institutional phase I study evaluating the safety and tolerability of XmAb18968. Patients aged 18 years or above with relapsed/refractory T-ALL or AML (including measurable residual disease relapse), CD38 expression ≥ 20% by flow cytometry, and adequate organ function will be eligible. Major exclusion criteria are hematopoietic cell transplantation within 6 months of enrollment, active acute graft-versus-host disease, and acute promyelocytic leukemia. The primary objective is to determine the recommended phase 2 dose (RP2D) and toxicity profile of XmAb18968. The secondary objectives include determination of response rates, duration of response, survival and pharmacokinetics. Exploratory objectives include correlation of responses with genomic profile, characterizing changes in serum cytokines and phenotypic expression of activated T-cells and leukemic cells, correlation of the phenotypic expression with changes in the transcriptome at the single-cell level, proteomics evaluation of cytokine secretion at the single-cell level and correlation of response with N-glycan profiling, quantitative site-occupancy and direct glycopeptide analysis. The study will follow 3+3 design. Dose escalation will proceed in two separate groups: Group A for subjects with T-ALL and Group B for subjects with AML. Patients will be entered sequentially to each dose level [0.8mg cohort, 1mg cohort, 1.3mg cohort, 1.5mg cohort). The observation period for dose-escalation will be 28-days. RP2D will be defined as the highest dose level at which none of the 3 treated subjects, or no more than 1 of the 6 treated subjects’ experiences a dose limiting toxicity. A minimum of 24 and a maximum of 60 patients will be enrolled. The study is being conducted at 6 sites in United States and is currently open for enrollment. Clinical trial information: NCT05038644.

Abstract Objective . Arterial dispersion ultrasound vibrometry (ADUV) relies on the use of guided waves in arterial geometries for shear wave elastography measurements. Both the generation of waves through the use of acoustic radiation force (ARF) and the techniques employed to infer the speed of the resulting wave motion affect the spectral content and accuracy of the measurement. In particular, the effects of the shape and location of the ARF beam in ADUV have not been widely studied. In this work, we investigated how such variations of the ARF beam affect the induced motion and the measurements in the dispersive modes that are excited. Approach. The study includes an experimental evaluation on an arterial phantom and an in vivo validation of the observed trends, observing the two walls of the waveguide, simultaneously, when subjected to variations in the ARF beam extension ( F / N ) and focus location. Main results. Relying on the theory of guided waves in cylindrical shells, the shape of the beam controls the selection and nature of the induced modes, while the location affects the measured dispersion curves (i.e. variation of phase velocity with frequency or wavenumber, multiple modes) across the waveguide walls. Significance. This investigation is important to understand the spectral content variations in ADUV measurements and to maximize inversion accuracy by tuning the ARF beam settings in clinical applications.

Abstract We diagnosed 66 peripheral nerve injuries in 34 patients who survived severe coronavirus disease 2019 (COVID-19). We combine our latest data with published case series re-analyzed here (117 nerve injuries; 58 patients) to provide a comprehensive accounting of lesion sites. The most common are ulnar (25.1%), common fibular (15.8%), sciatic (13.1%), median (9.8%), brachial plexus (8.7%) and radial (8.2%) nerves at sites known to be vulnerable to mechanical loading. Protection of peripheral nerves should be prioritized in the care of COVID-19 patients. To this end, we report proof of concept data of a wearable, wireless pressure sensor to provide real time monitoring in the intensive care unit setting.