Citations

ABSTRACT Introduction The COVID‐19 pandemic accelerated the shift from in‐person to virtual recruitment, prompting residency and fellowship programs to adopt innovative strategies, such as leveraging social media platforms to attract applicants and enhance visibility. Our aim was to identify and describe the presence of U.S. geriatric medicine fellowship programs on X. Methods We identified all U.S. geriatric medicine fellowship programs using FREIDA, and then located their X accounts through a stepwise process. Data were collected on account creation, number of followers, posts, and activity level, with an analysis of the last 100 posts from the most active accounts. Descriptive statistics were used to analyze the data. Results Among the 147 geriatric medicine fellowship programs identified, 38 (25.9%) had an X account. The majority of accounts were created after the start of the pandemic, reflecting likely the adaptation to virtual recruitment processes. Only a few accounts generated the majority of posts and followers. The accounts primarily posted or reposted educational content, research highlights, and promotional material. Conclusion The use of X by geriatric medicine programs is still significantly underutilized, with only one‐fourth of them having an account. Half of the accounts were created after the COVID‐19 pandemic began. Programs should focus on building a robust social media presence to increase their visibility, especially as virtual interviews have become a permanent part of recruitment.

Abstract Background Temozolomide (TMZ) treatment has demonstrated a variable impact on glioma prognosis. This study examines associations of survival with DNA repair gene germline polymorphisms among glioma patients who did and did not have TMZ treatment. Identifying genetic markers which sensitize tumor cells to TMZ could personalize therapy and improve outcomes. Methods We evaluated TMZ-related survival associations of pathogenic germline SNPs and genetically predicted transcript levels within 34 DNA repair genes among 1504 glioma patients from the University of California San Francisco Adult Glioma Study (UCSF AGS) and Mayo Clinic, whose diagnoses spanned pre- and post-TMZ eras within the major known glioma prognostic molecular subtypes. Results Among those who received TMZ, 5 SNPs were associated with overall survival, but not in those who did not receive TMZ. Only rs2308321-G, in MGMT, was associated with decreased survival (hazard ratio = 1.21, P = .019) for all glioma subtypes. Rs73191162-T (near UNG), rs13076508-C (near PARP3), rs7840433-A (near NEIL2), and rs3130618-A (near MSH5) were only associated with survival and TMZ treatment for certain subtypes, suggesting subtype-specific germline chemosensitization. Genetically predicted elevated expression of PNKP, compared to normal brain expression, was associated with markedly poor survival in TMZ-treated patients with isocitrate dehydrogenase (IDH)-mutant and 1p/19q non-codeleted gliomas (P = .015), with a median difference of over 70 months in overall survival times. Similarly, NEIL2 and TDG expressions were associated with altered TMZ-related survival only among certain subtypes. Conclusions Functional germline alterations within DNA repair genes were associated with TMZ sensitivity, measured by overall survival among adults with glioma. These variants should be evaluated in prospective analyses and functional studies.

The NCCN Guidelines for Survivorship include recommendations for screening, evaluation, and treatment of psychosocial and physical problems resulting from adult-onset cancer and its treatment. They also include recommendations to promote healthy behaviors and immunizations in survivors and provide a framework for care coordination. These NCCN Guidelines Insights summarize the panel’s current recommendations regarding sexual health and fertility.

Multigene panel testing has allowed for the detection of a growing number of inherited pathogenic/likely pathogenic variants in people at high risk of cancer, including endometrial cancer (EC). Hereditary syndromes associated with EC include Lynch syndrome, PTEN hamartoma tumor syndrome, and Peutz-Jeghers syndrome. This manuscript provides the latest recommendations from the NCCN Guidelines for Genetic/Familial High-Risk Assessment: Colorectal, Endometrial, and Gastric on the screening and management of EC in patients at high risk for these syndromes, as well as the advantages and limitations of multigene panel testing. This manuscript also describes recent updates to these guidelines regarding de-implementation of colon cancer screening in individuals with CHEK2 pathogenic/likely pathogenic variants, based on the most up-to-date evidence regarding the association between CHEK2 pathogenic/likely pathogenic variants and colon cancer risk.

PURPOSE SWOG S1815 was a randomized, open label phase III trial, evaluating gemcitabine, nab-paclitaxel, and cisplatin (GAP) versus gemcitabine and cisplatin (GC) in patients with newly diagnosed advanced biliary tract cancers (BTCs). METHODS Patients with newly diagnosed locally advanced unresectable or metastatic BTC, including intrahepatic cholangiocarcinoma (ICC) and extrahepatic cholangiocarcinoma (ECC) and gallbladder carcinoma (GBC), were randomly assigned 2:1 to either GAP (gemcitabine 800 mg/m 2 , cisplatin 25 mg/m 2 , and nab-paclitaxel 100 mg/m 2 intravenously once per day on days 1 and 8 of a 21-day cycle) or GC (gemcitabine 1,000 mg/m 2 and cisplatin 25 mg/m 2 intravenously once per day on days 1 and 8 of a 21-day cycle). RESULTS Among 452 randomly assigned participants, 441 were eligible and analyzable, 67% with ICC, 16% with GBC, and 17% with ECC. There was no significant difference in overall survival (OS) between GAP versus GC. Median OS with GAP was 14.0 months (95% CI, 12.4 to 16.1) and 13.6 months with GC (95% CI, 9.7 to 16.6); hazard ratio (HR), 0.91 (95% CI, 0.72 to 1.14); P = .41. Median progression-free survival (PFS) was similar between groups with median PFS for GAP being 7.5 months (95% CI, 6.4 to 8.5) versus 6.3 months for GC (95% CI, 4.4 to 8.2); HR, 0.89 (95% CI, 0.71 to 1.12); P = .32. In exploratory subset analyses, the OS and PFS benefits of GAP versus GC treatment were greater in locally advanced disease compared with metastatic disease, although not statistically significant (interaction P = .14 for OS and P = .17 for PFS). Moreover, GAP versus GC showed greater improvement in PFS among participants with GBC than those with ICC or ECC (interaction P = .01), but not OS (interaction P = .28). CONCLUSION The addition of a taxane in the GAP regimen to the standard gemcitabine-cisplatin regimen did not improve OS in newly diagnosed BTC. More toxicity was encountered with GAP versus GC.

Abstract Purpose: NFE2L2/KEAP1/CUL3 mutations have been validated for radioresistance in cell-based assays and animal models. However, clinical validation of these biomarkers has been challenging because of multimodality treatment regimens. This study aims to investigate the association between NFE2L2/KEAP1/CUL3 mutations and patient outcomes, including local failure, locoregional failure, disease-free survival (DFS), and overall survival, using samples from a phase III trial in which patients were treated with radiation monotherapy at two controlled doses. Patients and Methods: We investigated NFE2L2/KEAP1/CUL3 mutations in 250 randomized patients with T2N0 glottic squamous cell carcinoma receiving definitive radiotherapy in the NRG/RTOG 9512 trial. A total of 119 patients had available biospecimens that were subjected to amplicon-based next-generation sequencing to assess for the presence of NFE2L2/KEAP1/CUL3 mutations without regard to outcomes. Mutations in NFE2L2/KEAP1/CUL3 were assessed blinded to clinical outcomes. Cox models (two-sided α = 0.05) were used to evaluate the association with clinical outcomes, performed by an independent statistical team. Results: Nineteen of 119 patients (16.0%) had NFE2L2/KEAP1/CUL3 mutations. Patient, treatment, and tumor characteristics were similar between those with and without mutations. Patients with mutation compared with those without had significantly more local failure [HR = 3.50; 95% confidence interval (CI), 1.56–7.89; P = 0.0025] and locoregional failure (HR = 3.80; 95% CI, 1.80–8.03; P = 0.0005). DFS was significantly worse for the mutated compared with the nonmutated group in the first 2 years (HR = 2.88; 95% CI, 1.46–5.66; P = 0.0022). The median DFS was shorter in the mutation group (10.3 months) versus those with intact NFE2L2/KEAP1/CUL3 (4.2 years). Conclusions: NFE2L2/KEAP1/CUL3 mutations may predict radiation treatment failure in T2N0 glottic cancer. See related commentary by Rao, p. 1563

Abstract INTRODUCTION The U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER) is evaluating lifestyle interventions in older adults at risk for cognitive decline and dementia. Here we characterize the baseline data set of the POINTER Imaging ancillary study. METHODS Participants underwent health and cognitive assessments and neuroimaging with multimodal positron emission tomography (PET) (beta‐amyloid [Aβ] and tau) and magnetic resonance imaging (MRI). Framingham risk score (FRS) was used to quantify cardiovascular disease (CVD) risk. RESULTS A total of 1052 participants (31% from underrepresented ethnoracial groups) were enrolled. Compared to Aβ−, Aβ+ (29%) participants were older, had higher apolipoprotein E ( APOE ) ε4 carriage rate and white matter hyperintensity volume, and greater temporal tau. FRS was related to MRI measures, but not AD biomarkers. FRS and tau had independent effects on cognition. DISCUSSION In this heterogenous, at‐risk cohort, CVD risk was related to more abnormal brain structure and poorer cognition, representing a putative non‐AD (Alzheimer's disease) pathway to brain injury and cognitive decline. Highlights The U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER) cohort is enriched for cardiovascular disease (CVD) and poor lifestyle POINTER Imaging collected multimodal neuroimaging data in this unique, at‐risk cohort Amyloid burden was related to age, apolipoprotein E ( APOE ) ε4 carriage, and measures of disease progression Associations between amyloid and tau, and tau and cognition, were relatively weak CVD risk and tau pathology were independently related to memory

*Authors contributed equally. Introduction. Two chimeric antigen receptor (CAR) T-cell therapies have been FDA approved for patients with relapsed/refractory multiple myeloma (RRMM): idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel). Prior work from our consortium identified racial and ethnic differences in safety and response to ide-cel among patients treated in the standard of care (SOC) setting; despite these differences, survival was similar across race and ethnicity. Here, we extend this work to investigate racial and ethnic differences in safety, efficacy, and outcomes in a larger cohort of patients treated with SOC ide-cel with longer follow-up and patients treated with SOC cilta-cel. Methods. Data for RRMM patients who underwent leukapheresis by 12/31/2022 and were treated with SOC ide-cel or cilta-cel were pooled across 19 institutions in the U.S. Multiple Myeloma Immunotherapy Consortium. We compared Non-Hispanic White, Non-Hispanic Black, and Hispanic (any race) patients, excluding other racial and ethnic groups due to small sample sizes that precluded sub-group investigations. Separately for each CAR T-cell therapy, racial and ethnic differences in baseline patient characteristics, safety, and treatment responses were examined using chi-square and Kruskal-Wallis rank sum tests. Kaplan-Meier survival curves and log-rank tests were used to examine progression-free survival (PFS) and overall survival (OS) by race and ethnicity. Results. Among 332 RRMM patients treated with ide-cel, Non-Hispanic Black and Hispanic patients comprised 17% and 10% of the cohort, respectively. Hispanic patients were younger at infusion compared to Non-Hispanic Black and Non-Hispanic White patients (55.5 vs. 63 vs. 66 years, p<0.001). Non-Hispanic Black patients had a higher disease burden (≥ 50% bone marrow plasma cell percentage) compared to Non-Hispanic White and Hispanic patients (35% vs. 20% vs. 19%, p=0.05), while a higher proportion of Non-Hispanic White patients had high-risk cytogenetics compared to Non-Hispanic Black and Hispanic patients (37% vs. 23% vs. 10%, p=0.003). Non-Hispanic Black patients were more likely to develop severe (≥ grade 3) cytopenia at day 30 (p<0.001) and day 90 (p=0.01) post-infusion, and these differences were particularly driven by higher rates of severe neutropenia among Non-Hispanic Black patients at these time points. Non-Hispanic White patients were more likely to achieve a best response of partial response (PR) or better (82%) compared to Non-Hispanic Black (75%) and Hispanic patients (63%, p=0.02). No other racial and ethnic differences in baseline patient characteristics (including cytopenias), safety, PFS, and OS were observed (p>0.05). Among 222 RRMM patients treated with cilta-cel, Non-Hispanic Black and Hispanic patients comprised 12% and 9% of the cohort, respectively. At baseline, Non-Hispanic Black and Hispanic patients were more likely to have anemia (p=0.01), and Non-Hispanic Black patients were more likely to have thrombocytopenia (p=0.02) and neutropenia (p=0.06) compared to Non-Hispanic White patients. No other differences in baseline patient characteristics were observed by race and ethnicity. While not statistically significant, a higher rate of severe (≥ grade 3) cytopenia at day 90 post-infusion was observed among Non-Hispanic Black and Hispanic patients compared to Non-Hispanic White patients (33% vs. 44% vs. 21%, p=0.07), similar to the ide-cel cohort. This finding was primarily driven by higher rates of severe neutropenia among Non-Hispanic Black patients and higher rates of anemia among Hispanic patients. No other racial and ethnic differences in safety, responses to cilta-cel, PFS, or OS were not observed in the cilta-cel cohort (p>0.05). Conclusion. In a large cohort of RRMM patients treated with SOC ide-cel or cilta-cel, we observed a higher rate of cytopenias post-infusion and inferior ide-cel responses among racial and ethnic minority patients compared to Non-Hispanic White patients. Despite these differences, survival was similar across race and ethnicity, suggesting that both available CAR T-cell therapies for RRMM patients can be utilized across all populations. Future studies that include larger patient cohorts of racially and ethnically diverse patients should be conducted to confirm these findings and additionally evaluate long-term outcomes.

Introduction: Patients with chronic lymphocytic leukemia and small lymphocytic lymphoma (CLL/SLL) have a higher risk of developing other malignancies compared to the general population (Greene et al, J NCI 1978). Chemoimmunotherapy has previously been the mainstay of treatment and was associated with increased rates of other cancers (OC) (Thompson et al, Blood 2023). Targeted therapies such as Bruton tyrosine kinase inhibitors (BTKi) and BCL2 inhibitors were approved in the frontline setting in 2016 and 2019, respectively, and are now the standard of care for initial therapy (Shanafelt et al, NEJM 2019; Fischer et al, NEJM 2019). This study aims to compare the incidence of OC in patients with CLL/SLL treated with frontline therapies or managed with active surveillance. Methods: This is a retrospective case-control analysis of patients diagnosed with CLL/SLL during or after 2016 using the Department of US Veteran Affairs Central Cancer Registry (VACCR). Cases were patients with CLL/SLL diagnosed with incident OC, excluding nonmelanoma skin cancers. Frontline treatment with chemoimmunotherapy, monoclonal antibodies alone, or targeted therapies, such as BTKi or BCL2 inhibitor, was the exposure of interest compared to patients on active surveillance. Patients were followed until date of OC, death, or last follow up. Descriptive statistics were used to summarize continuous and categorical variables. Logistic regression was used to analyze the risk of developing OC while adjusting for potential confounders. Results: We identified 5244 patients with CLL/SLL who met inclusion criteria. Median follow up was 3.19 years (interquartile range [IQR] 1.61-5.14). The median age at diagnosis of CLL/SLL was 71.7 years (IQR 66.1-77.3) and most patients were white (78%) and male (97%). 3,460 (66%) patients were managed with active surveillance and 1,784 (34%) patients required frontline treatment: 1,318 (25%) targeted therapy, 329 (6%) chemoimmunotherapy, and 137 (3%) monoclonal antibodies alone. In patients treated with targeted therapies, patients were treated with ibrutinib (776, 59%), acalabrutinib (246, 19%), zanubrutinib (129, 10%), venetoclax (164, 12%), or combination of ibrutinib and venetoclax on a clinical trial (3, <1%). 505 (10%) patients were diagnosed with OC and 4739(90%) patients did not develop OC during the follow up period after diagnosis of CLL/SLL. Types of OC observed included neoplasms of the lung (120, 24%), prostate (105, 21%), gastrointestinal tract (72, 14%), hematologic malignancies (68, 13%), melanoma (45, 9%), kidney and bladder (43, 9%), head and neck (16, 3%), and other/unknown (36, 7%). More patients with OC had a history of tobacco use compared to those diagnosed with CLL/SLL without OC (70% vs 54%, p<0.0001). Fewer patients with OC had a history of alcohol use (60% vs 67%, p<0.0001). In a logistic regression analysis adjusted for age at diagnosis of CLL, race, and tobacco and alcohol use patients treated with chemoimmunotherapy had a higher risk of OC compared to those on observation (OR 2.4, 95% CI: 1.7-3.3, p<0.0001) whereas patients treated with targeted therapies or monoclonal antibodies alone did not have a higher risk of OC (OR 1.1, 95% CI 0.9-1.4 and OR 1.4, 95% CI 0.8-2.6, respectively) compared to the patients on active surveillance. A higher proportion of patients with OC were deceased compared to those without OC, 219/505 (43%) vs 1261/4739 (27%), respectively (p<0.0001) at cutoff date. Similar analyses of occurrence of OC in patients followed at tertiary centers including MD Anderson in Houston, Texas and Mayo Clinic in Rochester, Minnesota are ongoing and will be presented at the meeting. Conclusion: Initial treatment with targeted therapies or monoclonal antibodies alone was not associated with an increased risk of OC in US veterans diagnosed with CLL/SLL during and after 2016. However, initial treatment with chemoimmunotherapy was associated with a significant increase of OC compared to patients with CLL/SLL managed with active surveillance.

Introduction: Teclistamab (Tec) is the first approved BCMA x CD3 bispecific antibody for the treatment of triple-class-exposed patients with relapsed/refractory multiple myeloma (RRMM) based on the pivotal MajesTEC-1 study. Tec was associated with high overall response rate (ORR) of 63% in heavily pretreated patients. After a longer follow-up of 30.4 months, CR rate was 46.1%, median duration of response (DOR) was 24 months (95% CI, 17.0 - not estimable), and median progression-free survival (PFS) was 11.4 months (95% CI, 8.8 - 16.4). Herein, we present updated analysis of real-world outcomes and safety with tec in RRMM with extended follow-up of more than 12 months. Methods: This is an international multicenter retrospective study of patients with RRMM treated with tec on-label at 9 academic centers from 5 countries (United States, United Kingdom, Greece, Spain, and Canada) through the International Myeloma Working Group (IMWG) Immunotherapy Committee. Patients with RRMM treated with commercial tec at the respective institutions between May 24, 2022 to January 4, 2024 were included. Median follow-up was 14 months with data collected until July 15, 2024. High-risk cytogenetic abnormalities (HRCA) was defined as 1q+, t(4;14), t(14;16), t(14;20), and/or del(17p). Response was assessed using the IMWG consensus criteria. Patient characteristics were summarized by frequency (percentage) or median (interquartile range [IQR] or range). PFS, overall survival (OS), DOR were evaluated using the Kaplan-Meier method. Results: There were 223 patients included in this analysis with the following characteristics: median age of 67 (range 33-91) with 24% ≥75 years; 45% female; 74% White, 10% Black, 9% Asian, and 7% other/unknown; 86 of 176 (49%) with high risk cytogenetics, including del(17p), t(4;14), t(14;16), t(14;20), and gain/amp 1q; 29.4% (37/126) with known extramedullary disease; 14% with creatinine clearance ≤30 ml/min. Patients received a median of 6 (IQR, 4-8) prior lines of therapy with 52% (107/206) being penta-drug refractory. Among 212 patients with available data, 161 (75.9%) patients would have been ineligible for MajesTEC-1. There were 94 (42%) patients who received prior BCMA-directed therapy (29.8% antibody-drug conjugate [ADC] alone; 45.7% CART alone; 6.3% bispecific antibody alone; 17.0% ADC and CART). Median time from diagnosis to tec initiation was 6.1 (range 0.6-29.2) years. For the 206 response-evaluable patients, ORR was 66%, including 25.2% ≥CR, 33.5% VGPR, and 7.3% PR. ORR for the 90 response-evaluable patients with prior BCMA-directed therapy was 54.5% (21.1% ≥CR, 26.7% VGPR, 6.7% PR). After a median follow-up of 14 (95%CI, 13-14) months, median PFS and OS were 8.8 (95% CI, 5.5-14) and 20 (95% CI, 18-not reached [NR]) months, respectively. 12-month PFS estimate was 46% (95% CI, 40%-54%), and 12-month OS rate was 65% (95% CI, 59%-72%). Median DOR was 17 (95% CI, 17-NR) months with 12-month estimate of 68% (95% CI, 60%-77%). Tec step-up dosing occurred in the outpatient setting for 57 (25.6%) patients. CRS occurred in 119 out of 222 (53.6%) patients with almost all being grade 1-2, except for 1 grade 4 event. ICANS occurred in 18 out of 216 (8.3%) patients (grade 1-2: 5.1%; grade 3-4: 2.8%). Any grade infection occurred in 130 (58.3%) patients; 25.1% of patients had grade ≥3 infection, including 10 patients with grade 5 infection. While receiving teclistamab, 79 (35.4%) patients had ≥2 infections. IVIG was given in 114 out of 164 (69.5%) patients. Conclusion: In this multicenter international real-world analysis of outcomes and safety associated with tec, ORR was high at 66% with 25.2% of patients achieving ≥CR. CR rates may be underestimated due to infrequent bone marrow confirmation in the real-world datasets. Encouragingly, ORR was 54.5% in BCMA exposed RRMM patients, including 21.1% with ≥CR. After a median follow-up of 14 months, heavily pretreated patients including patients with prior BCMA therapy had durable responses with median PFS of 8.8 months and median DOR of 17 months. There were no new safety signals noted in this real-world study. This is the largest real-world study to date of teclistamab with long-term follow-up of more than 12 months. Additional data including more patients, longer follow-up and results from difficult to treat subgroups will be presented at the meeting.