Citations

Abstract Chimeric antigen receptor (CAR) T-cell (CAR-T) treatment for B-cell acute lymphoblastic leukemia (ALL) induces high initial response rates, but most patients relapse. Low disease burden (often defined as <5% blasts in the bone marrow) is associated with better outcomes. CAR HEMATOTOX (HT) is a score using prelymphodepletion hematologic and inflammatory parameters to predict outcomes in lymphoma. Here, we assess its prognostic utility in a large multicenter adult B-cell ALL cohort. Patients who received brexucabtagene autoleucel across 33 centers in North America were included as part of the Real-World Outcomes Collaborative of CAR-T in Adult ALL (ROCCA) consortium. An independent cohort of 61 patients with ALL treated with an investigational CD19 CAR-T therapy at 1 center was also described. Among 199 ROCCA consortium patients, 43 (22%) patients with HTlow scores had lower rates of delayed neutrophil recovery than those with HThigh scores (26% vs 52%, P = .002) and fewer severe infections (2.5% vs 18.8%, P = .011). They also had higher response rates, overall survival (OS), and event-free survival (EFS), as well as lower nonrelapse mortality and cumulative incidence of relapse. The survival differences remained significant after multivariable adjustment for disease burden and other covariates. In the investigational cohort of 61 patients, patients with HTlow scores had improved OS and EFS, as well as higher peak CAR-T expansion. In summary, CAR HT score is a prognostic factor independent of disease burden in adult ALL. HTlow score is associated with superior outcomes after CD19 CAR-Ts and higher CAR-T expansion in a single-center cohort. These trials were registered at www.clinicaltrials.gov as #NCT01044069 and #NCT01860937.

Abstract Several complications are associated with total shoulder arthroplasty (TSA), including glenoid loosening and joint instability. These complications are linked to imbalances in glenohumeral muscle forces, which cause eccentric loading that occurs on the outer edge of the glenoid component, rather than in the center of the glenoid, and can be damaging to the implant and destabilizing the joint. The purpose of this study was to develop musculoskeletal models of TSA patients using their skeletal geometry acquired from CT and their kinematics acquired with high-speed stereo radiography (HSSR) to predict glenohumeral joint loading and muscle forces for abduction and flexion and describe how these loads differ from their native contralateral side. CT data was collected for both shoulders of 6 TSA patients (three anatomic and three reverse). Models were developed using CT reconstructions of each patient’s scapula and humerus, and placed implant geometry with CT-derived alignment. Mesh morphing was used to create personalized muscle attachment sites on the scapula. Simulation of abduction and flexion to quantify muscle and joint forces was driven with limb-specific HSSR kinematics. At 90 deg abduction, reverse TSA increased superior shear force by 11.2% bodyweight (BW) and decreased medial compressive force by 27.5%BW compared to each patient’s contralateral shoulder. Lateral deltoid elevation moment arms and stability ratios increased 9.61 mm and 0.58, respectively. At 90 deg abduction, anatomic TSA patients increased humeral internal rotation by 52.7 deg and decreased rotator cuff force by 9.4%BW. Patient-specific musculoskeletal models quantified differences in glenohumeral joint mechanics. This study revealed muscle and kinematic mechanisms that could lead to edge loading and glenoid loosening in TSA and can inform personalized surgical planning for implant alignment with the goal of improving patient outcomes.

Abstract Molecular mechanisms underlying disruptions in brain glucose uptake and metabolism, linked with cognitive decline in Alzheimer’s disease (AD) patients, are only partially understood. This study investigated how soluble amyloid beta (sAβ) peptides affect glucose transport at the blood-brain barrier (BBB), the primary portal for glucose entry into the brain. We demonstrated that [ 18 F]-fluorodeoxyglucose ( 18 FDG) uptake is reduced in sAβ overproducing APP,PS1 transgenic mice compared to wild-type mice. Moreover, the influx rate of 18 FDG decreased in sAβ40 or sAβ42 pre-infused mice, highlighting the inhibitory effect of sAβ peptides on glucose transport at the BBB. Consistently, the expression of GLUT1, the primary glucose transporter at the BBB, is reduced in polarized human cerebral microvascular endothelial cell (hCMEC/D3) monolayers upon exposure to sAβ peptides and in Aβ-laden cerebral vasculature in vivo. The study further examined the influence of sAβ on the insulin-AKT pathway, known to regulate glucose uptake through modulation of thioredoxin-interacting protein (TXNIP) expression. Results showed that sAβ peptides suppress AKT phosphorylation and reduce GLUT1 expression by upregulating TXNIP levels in hCMEC/D3 monolayers. Co-incubation of resveratrol with sAβ peptides reduced TXNIP expression and rectified reductions in GLUT1 expression. In summary, toxic sAβ impairs BBB glucose transport by disrupting the insulin/AKT/TXNIP axis.

Abstract The National Institute on Aging-funded Geroscience Education and Training Network held the “Building an Interdisciplinary Workforce in Geroscience: Aligning Perspectives and Educational Goals” preconference workshop at the 2023 Gerontological Society of America’s Annual Meeting. Parties involved in geroscience education and interested stakeholders addressed the development of didactic educational materials, training, and career development opportunities to equip learners with the skills to meet the demands of the emerging field of geroscience, from research to clinic and industry. Recent successes were presented, existing opportunities, gaps, and challenges identified and discussed, and solutions and future directions described.

Abstract The aging process is universal, and it is characterized by a progressive deterioration and decrease in physiological function leading to decline on the organismal level. Nevertheless, a number of genetic and nongenetic interventions have been described, which successfully extend healthspan and lifespan in different species. Furthermore, a number of clinical trials have been evaluating the feasibility of different interventions to promote human health. The goal of the annual Biological Sciences Section of the Gerontological Society of America meeting was to share current knowledge of different topics in aging research and provide a vision of the future of aging research. The meeting gathered international experts in diverse areas of aging research including basic biology, demography, and clinical and translational studies. Specific topics included metabolism, inflammaging, epigenetic clocks, frailty, senescence, neuroscience, stem cells, reproductive aging, inter-organelle crosstalk, comparative transcriptomics of longevity, circadian clock, metabolomics, and biodemography.

AbstractBackgroundAcute lymphoblastic leukemia (ALL) in adults is aggressive, with long‐term outcomes impacted by treatment resistance and toxicity. CD52 is expressed in most cases of B‐ and T‐lineage ALL. Alemtuzumab, a humanized immunoglobulin G1 monoclonal antibody that targets CD52, was identified as a potential agent to improve treatment efficacy without increasing toxicity.MethodsIn this phase 1/2 study (Cancer and Leukemia Group B [CALGB] 10102, NCT00061945), a course of single‐agent alemtuzumab was intercalated into CALGB 19802 backbone chemotherapy after the third course of intensive chemotherapy in those who were CD52+ at diagnosis. Phase 1 tested three dose levels of subcutaneous alemtuzumab (10, 20, and 30 mg 3 times weekly for 4 weeks/12 doses) and demonstrated that 30 mg was tolerable. Phase 2 established feasibility.ResultsThe study enrolled 295 evaluable patients (115 in phase 1, 180 in phase 2); 206 (69.8%) were CD52+. Among evaluable CD52+ patients, 43.7% (90/206) completed the first three treatment modules; 97.8% (88 of 90) were treated with alemtuzumab. Alemtuzumab was associated with cytomegalovirus viremia, which occurred in 23.3% (14 of 60) of patients during and 29.2% (19 of 65) after alemtuzumab treatment. With a median follow‐up of 101.2 months, median overall survival (OS) was 26.3 months (3‐year rate, 44%; 5‐year rate, 36%; 10‐year rate, 31%). Landmark analysis at the start of the fourth course of treatment demonstrated no difference in OS or disease‐free survival between patients who did and who did not receive alemtuzumab.ConclusionAlemtuzumab was feasible to administer in adults with ALL receiving intensive chemotherapy, but was without evidence of benefit.

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.