Citations

Abstract Chimeric antigen receptor T‐cell (CAR‐T) therapy, despite being a potentially curative therapy in relapsed or refractory (RR) large B‐cell lymphoma (LBCL), remains underutilized in older patients due to limited clinical data. We therefore studied the safety and efficacy of CAR‐T therapy in older patients with RR LBCL in the real‐world setting. Patients aged ≥65 years with RR LBCL, treated with anti‐CD19 CAR‐T therapy at 7 US institutions were included in this multicenter, retrospective, observational study. In total, 226 patients were included. Median age at infusion was 71 years (range 65–89). Best objective and complete response rates were 86% and 62%, respectively. Median follow‐up after infusion was 18.3 months. The median progression‐free survival (PFS) was 6.9 months, with 6‐ and 12‐month PFS estimates of 54% and 44%, respectively. The nonrelapse mortality (NRM) rate was 10.9% at day 180, primarily due to infections, and not impacted by the age groups. Grade ≥3 cytokine release syndrome and neurotoxicity occurred in 7% and 26%, respectively. In univariate analysis, no significant difference in PFS was seen regardless of the age groups or CAR‐T type, whereas ECOG PS ≥2, elevated LDH, bulky disease, advanced stage, extranodal involvement, the need for bridging therapy, and prior bendamustine exposure were associated with shorter PFS. These findings support the use of CAR‐T in older patients, including those aged ≥80 years. The age at CAR‐T therapy did not influence safety, survival, and NRM outcomes. Older patients should not be excluded from receiving CAR‐T therapy solely based on their chronological age.

12048 Background: Playing music has been an important part of human culture for millennia. Today more than half of American households have at least one person who plays music, and in the UK 43% of adults play an instrument. Despite the overlap between musicians and people diagnosed with cancer, the effect of cancer treatment on musicianship has not been well-studied. We previously reported that 26% of a musician breast cancer survivor cohort reported difficulty with musicianship after treatment, and here we conduct further analysis to identify treatment and disease factors associated with this difficulty, termed acute musical toxicity (AMT). Methods: The Musical Toxicity Questionnaire was distributed to participants who had previously enrolled in the Mayo Clinic Breast Cancer Registry. PROMIS (Patient-Reported Outcomes Measurement Information System) scores were available through the Registry and treatment details were collected retrospectively. Due to the inter-dependency and high correlation between treatment and disease-related variables, a classification tree analysis (CTA) was performed to identify the combination of variables that most accurately classified patients by AMT. Sixteen variables were analyzed by the algorithm. Logistic regression was utilized for examining associations between AMT and continuous variables. Results: Of the 4075 surveys distributed, 1871 were returned and 535 respondents identified as musicians. Median time from diagnosis was 5.2 years, respondents were mostly stage I or II (71%), and 32% were node positive (N+). Over a quarter (26% or 144 respondents) reported AMT. In the final CTA model, being N+ was strongly associated with AMT (42% of those N+ had AMT, 20% of those not N+ had AMT). For respondents who were N+, those who received endocrine therapy were more likely to have AMT than those who did not (46% vs 21% respectively). Subsequent leaves identified not undergoing axillary lymph node dissection (ALND) and receiving chemotherapy as associated with AMT. For respondents who did not receive chemotherapy, breast reconstruction was associated with AMT (60% vs 19%). Variables such as mastectomy, radiation volume, specific chemotherapies, and stage of disease were not selected by the algorithm. The odds of having AMT decreased by 9.7% and 17% with each additional point in the composite mental health (p=0.003) and physical health (p<0.001) PROMIS scores, respectively. The odds of having AMT increased by 3.5% with each lymph node removed (p=0.001). Conclusions: The final model suggests that the group with the largest proportion of AMT was N+, received endocrine therapy, did not have ALND, and received chemotherapy. Both physical and mental health PROMIS scores were associated with AMT, although the directionality of this relationship requires more study. Care teams should counsel patients on potential musical toxicity and engage in shared decision making with musical patients.

11079 Background: Phase 3 randomized clinical trials (RCTs) inform the standard of care in cancer treatment yet have a mixed track record of success. In this study, we sought to 1) determine the overall success rate of phase 3 RCTs; 2) assess whether authorship patterns differ between successful (positive) and unsuccessful (negative) trials; and 3) explore if individual authors have distinct track records of success. Methods: The HemOnc knowledgebase (KB) was queried for initial publications of phase 3 RCTs of systemic anticancer therapy; those without primary outcome described were excluded. RCTs were labeled positive if the primary endpoint was met per HemOnc standard criteria (P value ≤ 0.05 or hazard ratio upper bound ≤ 1 for any experimental arm[s]) and negative if they did not meet these criteria or if the experimental arm was statistically inferior. Trial metadata and author information were extracted from the HemOnc KB. Author positive publication rate (PPR) was defined as % of publications reporting a positive result divided by total number of eligible publications. Prolific authors were defined as those with 6+ eligible publications. Author count for manuscripts reporting positive vs negative results was evaluated with the Mann-Whitney U test; other statistics were descriptive. Results: 3328 studies met criteria as of February 5, 2024; these were associated with 3305 initial publications between 1960-2023, involving 25,412 unique authors. 1474 (44.3%) of the studies were positive. Publications reporting positive trial results had, on average, 3 more authors, median (interquartile range) of 18 (12-23) vs 15 (11-20), p<0.0001. The mean (±SD) PPR for n=1967 prolific authors was 47.7% (±22.3%). The PPR was not related to individual author output; mean PPR for non-prolific authors was 48.0% (SD not reported). Differences in PPR were apparent by the disease under study and the years of publication (Table). Among the 46 prolific authors who had a PPR 2+ SD above the mean, 26 (55%) were from China followed by Italy with 3 (6%). Conclusions: Despite known positive publication bias, the success rate of published phase 3 RCTs remains <50%. Publications reporting positive results had significantly more authors; this finding requires further study including adjustment for trial sample size. Significant variation in PPR amongst fields could be due to watershed therapeutic advances, differential selection of primary endpoints, and/or selective reporting of results. Finally, a signal for geographic association of outlier PPRs suggests the need for further investigation. [Table: see text]

11108 Background: Advances in cancer treatment have led to a growing population of patients living with metastatic cancer. Symptom burden for these patients is understudied. Our objective is to report the prevalence and severity of SPPADE symptoms (sleep disturbance, pain, physical function impairment, anxiety, depression, and low energy /fatigue) in a large cohort of patients with metastatic cancer. Methods: These data are drawn from the Enhanced, EHR-facilitated Cancer Symptom Control (E2C2) stepped wedge pragmatic trial evaluating a symptom management intervention for cancer patients (NCT03892967). This analysis was limited to those identified with metastatic disease using ICD- codes and a natural language processing algorithm prior to or within 30 days of their baseline symptom survey. Symptom severity was measured on a 0-10 scale with scores of 1-3 categorized as “mild”, 4-6 as “moderate”, and ≥7 as “severe.” A SPPADE composite score was calculated by summing six individual symptom scores and is an indicator of total symptom burden. We report descriptive statistics for each symptom by severity category. We also test for differences in SPPADE composite score by race, disability status, employment status, education and cancer type using Kruskal-Wallis tests. Results: 12,824 patients with metastatic disease completed a survey between March 2019 and January 2023. Discretized score distributions for the SPPADE symptoms are reported in the Table. The SPPADE composite mean score for the cohort was 17.6 (SD +/- 12.0). Significant differences were found in total symptom burden by sociodemographic and clinical characteristics ( p<0.01): Higher total symptom burden (Mean [SD])was experienced by individuals who were American Indian/Alaska Native (AI/AN) (23.8[13.5]) or African American (AA) (20.5[14.7]), disabled (24.0[12.8]) or unemployed (21.1[13.0]), and had a high school education (20.0[13.3]) or less than high school education (18.5[12.4]). There were also statistically significant differences ( p<0.01) in symptom burden across cancer types, with patients with metastatic lung cancer reporting the highest symptom burden (20.0[12.2]) and those with metastatic melanoma reporting the lowest (14.7[11.4]). Conclusions: SPPADE symptoms are common in patients with metastatic cancer, especially fatigue, sleep disturbance, and physical function impairment. Symptom burden is especially high in AI/AN, AA, disabled/unemployed, and less educated patients. Further research is needed to tailor symptom interventions among those living with metastatic disease. [Table: see text]

The strength of the shoulder musculature involved with internal rotation and arm extension plays an important role in the overhead throwing motion for baseball athletes, both for throwing-related performance and injury risk. The maintenance of shoulder strength is a high priority for baseball athletes throughout a season; however, little is known in regards to the expected changes in strength throughout a season. To examine pre-post changes in shoulder strength, lower body power, and body composition among collegiate baseball players after the completion of a summer baseball league season. Amateur baseball players (n = 12; age: 20.9 ± 1.0 years.; height: 181.6 ± 5.6 cm; body mass: 86.4 ± 11.1 kg; BMI: 26.0 ± 2.6 kg/m2) participated in the current study. Pre- and post-competitive season, the participants completed shoulder strength assessments and body composition and countermovement vertical jump (CMJ) tests. An upper-body isometric test (athletic shoulder [ASH] test) was used to evaluate shoulder strength for each arm. Each subject completed maximal isometric contractions for both the throwing and non-throwing arms at four separate angles of abduction (180°, ‘I’; 135°, ‘Y’; 90°, ‘T’; and −180°, ‘A’) while lying in a prone position. For shoulder strength, the primary dependent variable of interest was a composite measure that represented the average of the forces produced across all four positions of the ASH test (I, Y, T, A). For the ASH test composite measure, there was a trend toward a significant arm-by-time interaction effect (p = 0.08), as shoulder strength decreased by 9.03% for the throwing arm (ES = 0.72; 95% CI = [−0.27, −0.01]), compared to only 2.03% for the non-throwing arm (ES = 0.15; 95% CI = [−0.16, 0.09]), over the course of the season. The main effects of time (p = 0.16) and arm (p = 0.58) were not significant for the ASH test composite measure. There was no relationship between lower body power and throwing arm strength at baseline (r = 0.20, p = 0.56), and only a non-significant weak relationship at post-test (r = 0.28, p = 0.41). Throughout a season, baseball players may experience reductions in shoulder strength of the throwing arm with minimal changes in shoulder strength in the non-throwing arm.

AbstractProgressive apraxia of speech (PAOS) is a 4R tauopathy characterized by difficulties with motor speech planning. Neurodegeneration in PAOS targets the premotor cortex, particularly the supplementary motor area (SMA), with degeneration of white matter (WM) tracts connecting premotor and motor cortices and Broca's area observed on diffusion tensor imaging (DTI). We aimed to assess flortaucipir uptake across speech‐language‐related WM tracts identified using DTI tractography in PAOS. Twenty‐two patients with PAOS and 26 matched healthy controls were recruited by the Neurodegenerative Research Group (NRG) and underwent MRI and flortaucipir‐PET. The patient population included patients with primary progressive apraxia of speech (PPAOS) and non‐fluent variant/agrammatic primary progressive aphasia (agPPA). Flortaucipir PET scans and DTI were coregistered using rigid registration with a mutual information cost function in subject space. Alignments between DTI and flortaucipir PET were inspected in all cases. Whole‐brain tractography was calculated using deterministic algorithms by a tractography reconstruction tool (DSI‐studio) and specific tracts were identified using an automatic fiber tracking atlas‐based method. Fractional anisotropy (FA) and flortaucipir standardized uptake value ratios (SUVRs) were averaged across the frontal aslant tract, arcuate fasciculi, inferior frontal‐occipital fasciculus, inferior and middle longitudinal fasciculi, as well as the SMA commissural fibers. Reduced FA (p < .0001) and elevated flortaucipir SUVR (p = .0012) were observed in PAOS cases compared to controls across all combined WM tracts. For flortaucipir SUVR, the greatest differentiation of PAOS from controls was achieved with the SMA commissural fibers (area under the receiver operator characteristic curve [AUROC] = 0.83), followed by the left arcuate fasciculus (AUROC = 0.75) and left frontal aslant tract (AUROC = 0.71). Our findings demonstrate that flortaucipir uptake is increased across WM tracts related to speech/language difficulties in PAOS.

Regular, long-term aspirin use may act synergistically with genetic variants, particularly those in mechanistically relevant pathways, to confer a protective effect on colorectal cancer (CRC) risk. We leveraged pooled data from 52 clinical trial, cohort, and case-control studies that included 30,806 CRC cases and 41,861 controls of European ancestry to conduct a genome-wide interaction scan between regular aspirin/nonsteroidal anti-inflammatory drug (NSAID) use and imputed genetic variants. After adjusting for multiple comparisons, we identified statistically significant interactions between regular aspirin/NSAID use and variants in 6q24.1 (top hit rs72833769 ), which has evidence of influencing expression of TBC1D7 (a subunit of the TSC1-TSC2 complex, a key regulator of MTOR activity), and variants in 5p13.1 (top hit rs350047 ), which is associated with expression of PTGER4 (codes a cell surface receptor directly involved in the mode of action of aspirin). Genetic variants with functional impact may modulate the chemopreventive effect of regular aspirin use, and our study identifies putative previously unidentified targets for additional mechanistic interrogation.

1604 Background: Diversity in clinical studies is essential to address health disparities, but racial and ethnic minorities are often underrepresented in clinical studies, especially in precision medicine studies using genetic data (1). BASECAMP-1 (NCT04981119) is an ongoing prescreening study to identify patients with unresectable advanced or metastatic solid tumors and tumor-associated HLA-A*02 LOH for the EVEREST-1 and -2 Tmod chimeric antigen receptor T-cell therapy trials. When enrollment began in 2021, eligibility for Part 1 was restricted to patients with germline HLA-A*02:01 based on preclinical data. Additional analysis revealed the blocker in the Tmod construct had activity across HLA-A*02 subtypes (Mock, et al. Mol Ther Oncolytics.2022). Eligibility for Part 1 was then expanded to all HLA-A*02 subtypes, allowing enrollment of more diverse patient populations. HLA-A*02 allele subtypes vary by ethnicity and race; the frequency of HLA-A*02:01 is 96% in non-Hispanic Whites, but ranges from 53% to 73% in other ethnicities and races. The frequency of all other HLA-A*02 allele subtypes (HLA-A*02:XX) is <5% in non-Hispanic Whites but up to 66% in other ethnicities and races (2,3). Methods: Patients eligible for BASECAMP-1 were identified at United States study sites. All patients screened before January 16, 2024, for Part 1 were included for demographic and central lab HLA-A typing. The % increase in eligibility and % of heterozygous HLA-A*02 patients with HLA-A*02:XX were calculated by ethnicity and race. Results: A total of 1124 patients were screened for germline HLA-A*02 typing; 431 patients were HLA-A*02:01 heterozygous, of whom 37 (9%) were Hispanic, 14 (3%) African American (AA), 2 (<1%) American Indian or Alaska Native, 17 (4%) Asian or Pacific Islander (API), and 324 (75%) non-Hispanic White (Table). The eligibility expansion identified 62 patients with HLA-A*02:XX heterozygosity, of whom 6 (10%) were Hispanic, 6 (10%) AA, 19 (31%) API, and 25 (40%) non-Hispanic White. Conclusions: By expanding enrollment to include HLA-A*02:XX, 16% more Hispanic, 43% more AA, and 112% more API patients were identified, improving the diversity in this trial compared with that of initial enrollment. 1. Aldrighetti, et al. JAMA Netw Open 2021. 2. Ellis, et al. Human Immunol. 2000. 3. Gragert, et al. Human Immunol.2013. Clinical trial information: NCT04981119 . [Table: see text]

530 Background: Robust biomarkers are needed to personalize treatment in early stage HER2-positive breast cancer. The TBCRC026 trial (n=83) demonstrated that early metabolic changes on FDG-PET/CT [>40% decline in SULmax at day 15 post treatment initiation (C1D15); C1D15 SULmax] were associated with response to neoadjuvant trastuzumab/pertuzumab (HP), without chemotherapy, in an ER-negative, HER2-positive cohort (NCT01937117). We investigated the association of RNA sequencing (RNAseq)-based gene expression signatures (GES) at baseline and on-treatment (C1D15), with early metabolic change on PET/CT and clinical outcomes. Methods: RNAseq (664 GES) was performed on baseline (n=56) and C1D15 (n=31) tumor biopsies (25 paired samples available). Association with pCR following HP (secondary), PET/CT parameters and survival (exploratory) was studied. Gene expression changes between baseline and C1D15 samples were tested by Wilcoxon signed-rank test. Association between GES and PET/CT parameters and GES with pCR were evaluated using logistic regression models. Cox regressions were performed to study the association between PET/CT SULmax at C1D15 and a B cell signature and relapse-free survival (RFS). The likelihood ratio test was used to compare the prognostic ability of two nested Cox models. Results: Both RNAseq and clinical outcomes were available in 53/83 patients. HER2-enriched (HER2-E) intrinsic subtype comprised 71% (40/56) of cases at baseline and 61% (19/31) at D15; basal subtype for 27% (15/56) and 39% (12/31), respectively. pCR rate was 19% (10/53) with all but one exhibiting HER2-E subtype. One basal-like sample underwent pCR, with downregulation of HER2 amplicon and IgG signatures slightly more prominent. Gene expression changes from baseline to C1D15 were analyzed; ERBB2was downregulated after HP (p = 0.007), B cell signatures, CD4, CD8, natural killer cells and Treg cells were significantly upregulated at C1D15. GES associated with 40% decline in SULmax at C1D15 included ERBB2 amplicon genes ( ERBB2, GRB7) and correlation to the HER2-E subtype, whereas basal-like signatures were significantly associated with lack of response on PET at C1D15. Univariate logistic regression analysis suggested that FOS-JUN, fibroblast and B cell GES at baseline were significantly associated with pCR (p=<0.05). Finally, the addition of a B cell signature improved the prognostic value of C1D15 SULmax on PET/CT for RFS (p < 0.05). Conclusions: In this unique cohort with ER-negative, HER2-positive breast cancer treated with neoadjuvant HP without chemotherapy, HER2-E tumors and those with increased immune signaling were more likely to respond to HER2-directed therapy. Combining C1D15 SULmax on PET/CT and a B cell signature provided improved prognostic information and should be further explored as candidate biomarkers in this setting. Clinical trial information: NCT01937117 .