Citations

Abstract Background Clinical differences between critical illness from influenza infection vs coronavirus disease 2019 (COVID-19) have not been well characterized in pediatric patients. Methods We compared demographics, clinical characteristics, and outcomes of US children (aged 8 months to 17 years) admitted to the intensive care or high-acuity unit with influenza or COVID-19. Using mixed-effects models, we assessed the odds of death or requiring life support for influenza vs COVID-19 after adjustment for age, sex, race and Hispanic origin, and underlying conditions including obesity. Results Children with influenza (n = 179) were younger than those with COVID-19 (n = 381; median, 5.2 years vs 13.8 years), less likely to be non-Hispanic Black (14.5% vs 27.6%) or Hispanic (24.0% vs 36.2%), and less likely to have ≥1 underlying condition (66.4% vs 78.5%) or be obese (21.4% vs 42.2%), and a shorter hospital stay (median, 5 days vs 7 days). They were similarly likely to require invasive mechanical ventilation (both 30.2%), vasopressor support (19.6% and 19.9%), or extracorporeal membrane oxygenation (2.2% and 2.9%). Four children with influenza (2.2%) and 11 children with COVID-19 (2.9%) died. The odds of death or requiring life support in children with influenza vs COVID-19 were similar (adjusted odds ratio, 1.30; 95% confidence interval, .78–2.15; P = .32). Conclusions Despite differences in demographics and clinical characteristics of children with influenza or COVID-19, the frequency of life-threatening complications was similar. Our findings highlight the importance of implementing prevention measures to reduce transmission and disease severity of influenza and COVID-19.

Patients of African ancestry are not well-represented in cancer clinical trials despite bearing a disproportionate share of mortality both in United States and Africa. We describe key stakeholder perspectives and priorities related to bringing early-stage cancer clinical trials to Africa and outline essential action steps. Increasing Diversity, Market Access, and Capacity in Oncology Registration Trials—Is Africa the Answer? satellite session was organized at 2021 Accelerating Anti-Cancer Agent Development and Validation Workshop. Panelists included representatives of African Organization for Research and Training in Cancer, Uganda Cancer Institute, Uganda Women's Cancer Support Organization, BIO Ventures for Global Health, Bill & Melinda Gates Foundation, the US Food and Drug Administration, Nigeria's National Agency for Food and Drug Administration and Control, Bayer, and Genentech, with moderators from ASCO and American Cancer Society. Key discussion themes and resulting action steps were agreed upon by all participants. Panelists agreed that increasing diversity in cancer clinical trials by including African patients is key to ensuring novel drugs are safe and effective across populations. They underscored the importance of equity in clinical trial access for patients in Africa. Panelists discussed their values related to access and barriers to opening clinical trials in Africa and described innovative solutions from their work aimed at overcoming these obstacles. Multisectoral collaboration efforts that allow leveraging of limited resources and result in sustainable capacity building and mutually beneficial long-term partnerships were discussed as key to outlined action steps. The panel discussion resulted in valuable insights about key stakeholder values and priorities related to bringing early-stage clinical trials to Africa, as well as specific actions for each stakeholder group.

Abstract Gallbladder cancer (GBC) is one of the deadliest cancers, with a 5-year-survival-rate of less than 5 percent for late-stage disease. The response rate to chemotherapy among GBC patients is generally poor. Recent research has attempted to identify diagnostic, prognostic, and predictive biomarkers, however, currently, no biomarkers can accurately diagnose GBC and predict patients’ prognosis. Integrative analysis of molecular and clinical characterization has not been fully established, and minimal improvement has been made to the survival of these patients, in part due to the heterogeneity of GBC. Machine learning techniques have been proven to empower analysis of big data in oncology, allowing for improvement in the generation of biomarkers to predict patient outcomes. Using machine learning, we can utilize high-throughput RNA sequencing with clinicopathologic data to develop a predictive tool for GBC prognosis. Current predictive models for GBC outcomes often utilize clinical data only, with the highest C-statistic reported being 0.71. C-statistic values over 0.7 generally indicate good models, however 0.8 is the threshold for strong predictive models. We aim to build a superior algorithm to predict overall survival in GBC patients with advanced disease, using machine learning approaches to prioritize biomarkers for GBC prognosis. We have identified over 80 fresh frozen GBC tissue samples from Mayo Clinic Rochester, Dongsan Medical Center in Daegu, Korea, University of the Witwatersrand, in Johannesburg, South Africa, Lithuanian University of Health Science in Vilnius, Lithuania, and University of Calgary in Calgary, Canada, from patients enrolled between 2012 and 2021. We will perform next-generation RNA sequencing on these tissue samples. The patients’ clinical, pathologic and survival data will be abstracted from the medical record uniformly across sites. Feature engineering and dimensionality reduction will be performed. Then random forests, support vector machines, and gradient boosting machines will be applied to train the data. Variable importance will prioritize multi-omic markers. Standard 5-fold cross validation will be used to assess performance of each ML algorithm. If overall survival can be better predicted with the addition patients’ transcriptional sequencing data compared to using clinical profiles alone, we can gain a greater understanding of key biomarkers driving the tumor phenotype. Citation Format: Linsey Jackson, Loretta Allotey, Valles Kenneth, Gavin Oliver, Asha Nair, Daniel O'Brien, Rondell Graham, Mitesh Borad, Arjun Athreya, Lewis Roberts. Prognostic biomarkers for gallbladder cancer: A machine learning approach [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1944.

Abstract Pediatric Acute Myeloid Leukemia (AML) with a FLT3 internal tandem duplication (FLT3-ITD) is a challenging disease due to poor outcomes in many patients. The 4-year progression-free survival is still only 31%. Current biomarkers are insufficient to predict why certain patients with FLT3-ITD AML relapse and others do not. The development of prognostic biomarkers in FLT3-ITD pediatric AML may help improve the outcomes and management of these patients. We acquired a panel of 37 diagnostic samples with 18 samples from FLT3-ITD pediatric AML patients with poor outcomes (relapse within 3 years) and 19 from favorable outcome patients that did not exhibit relapse for at least 5 years. Next, we performed FACS to isolate CD34+CD38dim and CD34+CD38+ cells. These two populations were then sequenced using 10x Genomics 3’ end single-cell RNA sequencing (scRNAseq). Using this scRNAseq dataset comprising over 250k single cells, we first investigated if the frequency of specific RNA clusters of AML cells may predict patient outcome. We found 5 clusters had significantly different frequencies between patients with favorable and poor outcomes (p < 0.05). Using these clusters, we performed CIBERSORTx deconvolution on publicly available FLT3-ITD AML bulk RNAseq samples from TCGA (n = 36), BeatAML (n = 47), and the TARGET project (ntrain = 72; ntest = 26) to identify the inferred cluster composition present in each AML patient from these datasets. Next we built LASSO prediction models using the inferred scRNAseq clusters by CIBERSORTx and incorporating clinical features including leukemic blast percentage, bone marrow leukemic blast percentage, and WBC at diagnosis. We found these prediction models to be highly specific as a prognostic biomarker for pediatric AML (p << 0.01). We were unable to train a model directly using genes from the publicly available bulk RNAseq data for pediatric FLT3-ITD AML, highlighting the relevance of using our deconvolution based biomarker. Between the high (> median) and low (< median) LASSO score groups, there was ~50% difference in the number of patients relapsing after 4 years. When we included this LASSO score in a multivariate cox regression (likelihood ratio p value = 0.007), the LASSO score (HR = 6.8, p = 0.026, CI = 1.26 - 37.28) showed additional predictive ability when including FLT3-ITD allelic ratio (HR = 1.83, p = 0.38, CI = 0.47 - 7.15) and MRD (HR = 3.95, p = 0.021 CI = 0.051 - 0.79). These results demonstrate that incorporating rare AML cell populations into a prognostic biomarker could add substantial clinical information to existing biomarkers. This indicates single-cell derived prognostic models can and should be explored further for pediatric FLT3-ITD AML and demonstrates a platform that could be used for other malignancies, including non-hematologic tumors, to create cell-type biomarkers. Citation Format: Robert Schauner, Zachary Jackson, Nethrie Idippily, Grace Lee, Sheela Karunanithi, Shivaprasaad Manjappa, Tae Hyun Hwang, David Wald. New platform for novel biomarker discovery using single-cell RNA sequencing on pediatric acute myeloid leukemia samples [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4080.

Purpose: Prior research has noted similar functional and subjective outcomes between individuals with delayed amputation vs. limb salvage; however, these reports are generally retrospective in nature. Here, we prospectively compare functional and subjective outcomes from an individual with limb salvage to a delayed transtibial amputation using a single-subject design with sequential participation in a fall-prevention program. Materials and Methods: The subject participated in a fall-prevention rehabilitation training program, once before undergoing a delayed transtibial amputation and again after. As part of the fall-prevention program, the participant completed pretraining and post-training assessments which quantified trunk control by 1) trunk flexion and flexion velocity after trip-inducing perturbations on a treadmill and 2) trunk sway parameters during unstable sitting. In addition, the four square step test was administered, and patient-reported outcomes, including pain, prosthetic/orthotic comfort, and walking/running endurance, were collected. Results: In general, the participant demonstrated improved trunk control after amputation, as evidenced by decreases in trunk flexion and flexion velocity after perturbation and sway parameters during unstable sitting. In addition, four square step test times were shorter with amputation vs. limb salvage; the participant also reported reduced pain and greater comfort with amputation (vs. limb salvage). Conclusions: Although just a single participant, within-subject comparisons provide quantitative evidence that, for some individuals, delayed/late (transtibial) amputation after prolonged limb salvage may be beneficial in reducing pain and restoring function.

8028 Background: Ciltacabtagene autoleucel (cilta-cel), a chimeric antigen receptor T (CAR-T) cell therapy with 2 B-cell maturation antigen (BCMA)–targeting single-domain antibodies, led to early, deep, and durable responses in the phase 1b/2 CARTITUDE-1 study (NCT03548207) in heavily pretreated patients (pts) with relapsed/refractory multiple myeloma (RRMM). At ̃1-year (y) median follow-up (MFU), overall response rate (ORR) was 97%; 67% of pts achieved stringent complete response (sCR). 1-y progression-free survival (PFS) and overall survival (OS) rates were 77% and 89%, respectively (Berdeja 2021). Updated results 2-y post last patient in (LPI) will be presented (̃30-month total MFU). Here, we report CARTITUDE-1 results at 21.7-month MFU. Methods: Eligible pts with RRMM received ≥3 prior lines of therapy (LOT) or were refractory to a proteasome inhibitor (PI) and immunomodulatory drug (IMiD) and had received a PI, IMiD, and anti-CD38 antibody. Bridging therapy was permitted after apheresis. Pts received a single cilta-cel infusion (target dose 0.75×106 CAR+ viable T cells/kg) 5–7 days after lymphodepletion. Primary objectives were to evaluate cilta-cel safety and efficacy. Response was assessed per International Myeloma Working Group criteria by independent review committee and minimal residual disease (MRD) negativity at 10-5 by next-generation sequencing. Results: As of July 22, 2021, 97 pts (59% male; median age 61 y) received cilta-cel. Pts had a median of 6 (range 3–18) prior LOT; 84% were penta-drug exposed, 88% were triple-class refractory, 42% were penta-drug refractory, and 99% were refractory to last LOT. ORR was 97.9% (95% CI 92.7–99.7), 94.9% achieved very good partial response, and 82.5% achieved sCR. Median times to first response, best response, and ≥CR were 1.0, 2.6, and 2.9 months (m), respectively; median duration of response was not reached (NR). Of 61 pts evaluable for MRD, 92% were MRD negative (10-5), sustained for ≥6 m in 44% (27/61) and ≥12 m in 18% (11/61). 2-y PFS was 60.5% (95% CI 48.5–70.4). Median PFS and OS were NR. 2-y PFS rates in pts with sustained MRD negativity for ≥6 m and ≥12 m were 91% and 100%, respectively. There were no new safety signals or new events of CAR-T cell neurotoxicity, movement and neurocognitive treatment-emergent adverse events, or treatment-related deaths since 1-y MFU. 15 second primary malignancies were reported in 11 pts over ̃2-y MFU. Conclusions: At ̃2-y MFU, a single cilta-cel infusion led to deepening and durable responses in heavily pretreated pts with RRMM with a manageable safety profile. Follow-up is ongoing, and landmark 2-y post LPI data (̃8 m additional follow-up; ̃30 m total MFU) will be presented. Further investigations of cilta-cel are ongoing in earlier LOT and outpatient settings across the CARTITUDE program (NCT04133636, NCT04181827, NCT04923893). Clinical trial information: NCT03548207.

e13054 Background: Combination therapy with cyclin dependent kinase 4 and 6 inhibitors (CDK4/6i: palbociclib, ribociclib and abemaciclib) and endocrine therapy (ET) has markedly improved treatment of hormone receptor positive (HR+), HER2-negative (-) advanced or metastatic breast cancer (MBC) worldwide.However, data is limited on why patients may discontinue CDK4/6i based therapy and how healthcare providers (HCPs) see their role in educating patients (Px) about side effects and supporting compliance. Objective: This study identifies reasons for suboptimal compliance and early discontinuation of CDK4/6i in US HR+ HER2- MBC Px, with a focus on HCPs and Px educational needs related to on-treatment monitoring, side effects and symptom management. Methods: A sequential mixed-methods design was used; 45-minute phone interviews (n=25) informed the development of an online survey (n=193). Both phases included HCPs comprising medical oncologists (ONCs), oncology registered nurses (RNs), nurse practitioners, and physician assistants (NPs/PAs) in community-based settings. Results: Identified areas of improvement for HCPs included: suboptimal competencies were identified: educating Px adequately regarding potential side effects and engaging them to monitor, report, and address them. Among HCPs surveyed, 26%-48% reported suboptimal knowledge of side effects of specific CDK4/6i [Table]. Interviewees noted that educating Px and setting expectations on potential side effects was critical, but 52% of ONCs reported suboptimal skill doing so. A majority of HCPs (68%-91%) expect Px to be able to report all side effects, with half of ONCs considering compliance with medication entirely Pxs’ responsibility, compared with NPs/PAs and RNs at 16-17%. Conclusions: This study identified areas where HCPs can improve their ability to counsel Px and address concerns that may influence a Px’s decision to prematurely discontinue therapy and should be used to inform future professional development initiatives. [Table: see text]

PURPOSE CARTITUDE-1, a phase Ib/II study evaluating the safety and efficacy of ciltacabtagene autoleucel (cilta-cel) in heavily pretreated patients with relapsed/refractory multiple myeloma, yielded early, deep, and durable responses at 12 months. Here, we present updated results 2 years after last patient in (median follow-up [MFU] approximately 28 months), including analyses of high-risk patient subgroups. METHODS Eligible patients had relapsed/refractory multiple myeloma, had received ≥ 3 prior lines of therapy or were double refractory to a proteasome inhibitor and immunomodulatory drug and had received prior proteasome inhibitor, immunomodulatory drug, and anti-CD38 therapy. Patients received a single cilta-cel infusion 5-7 days after lymphodepletion. Responses were assessed by an independent review committee. RESULTS At a MFU of 27.7 months (N = 97), the overall response rate was 97.9% (95% CI, 92.7 to 99.7); 82.5% (95% CI, 73.4 to 89.4) of patients achieved a stringent complete response. Median duration of response was not estimable. Median progression-free survival (PFS) and overall survival (OS) were not reached; 27-month PFS and OS rates were 54.9% (95% CI, 44.0 to 64.6) and 70.4% (95% CI, 60.1 to 78.6), respectively. Overall response rates were high across all subgroups (95.1%-100%). Duration of response, PFS, and/or OS were shorter in patients with high-risk cytogenetics, International Staging System stage III, high tumor burden, or plasmacytomas. The safety profile was manageable with no new cilta-cel–related cytokine release syndrome and one new case of parkinsonism (day 914 after cilta-cel) since the last report. CONCLUSION At approximately 28 months MFU, patients treated with cilta-cel maintained deep and durable responses, observed in both standard and high-risk subgroups. The risk/benefit profile of cilta-cel remained favorable with longer follow-up.

Abstract Background This study aimed to examine if the association of cerebral perfusion with gait speed differs across systolic blood pressure (SBP) and age. Methods Cerebral perfusion was measured via arterial spin labeled (ASL)-MRI among community-dwelling adults aged 31–94 years in the population-based Mayo Clinic Study of Aging. Usual gait speed was assessed over 5.6 meters on an electronic mat. Sex- and body mass index (BMI)-adjusted linear regression models estimated cross-sectional gait speed associations with ASL and modifying effects of age and SBP using 3-way and 2-way interaction terms between continuous age, SBP, and ASL. Results report estimated differences in gait speed per standard deviation (SD) lower ASL for exemplar SBPs and ages. Results Among 479 participants (mean age 67.6 years; 44% women; mean gait speed 1.17 m/s), ASL relations to gait speed varied by age (ASL-x–age interaction: p = .001) and SBP (ASL-x–SBP interaction: p = .009). At an SBP of 120 mmHg, each SD lower ASL was associated with a 0.04 m/s (95% confidence interval [CI]: 0.01, 0.07) slower gait speed at 65 years, 0.07 m/s (0.04, 0.10) at 75 years, and 0.09 m/s (0.05, 0.13) at 85 years. At an SBP of 140 mmHg, ASL associations with gait speed were attenuated to 0.01 (−0.01, 0.04), 0.04 (0.02, 0.06), and 0.06 (0.04, 0.09) m/s slower gait speed at ages 65, 75, and 85, respectively. Conclusion Poorer cerebral perfusion is associated with clinically meaningful slower gait speeds, particularly with older age, while higher perfusion markedly attenuates age differences in gait speed.

AbstractBackgroundPhysical frailty is associated with increased risk for dementia and other neurologic sequelae. However, the neurobiological changes underlying frailty and frailty risk remain unknown. We examined the association of cerebral white matter structure with current and future frailty.MethodsAtherosclerosis Risk in Communities Study Neurocognitive Study participants who underwent 3T brain MRI were included. Frailty status was classified according to the Fried criteria. Cerebral white matter integrity was defined using white matter hyperintensity (WMH) volume and microstructure, measured using diffusion tensor imaging fractional anisotropy (FA) and mean diffusivity (MD). Multivariable linear regression was used to relate baseline frailty to white matter structure; multivariable logistic regression was used to relate baseline white matter to frailty risk among participants nonfrail at baseline.ResultsIn the cross-sectional analysis (N = 1 754; mean age: 76 years), frailty was associated with greater WMH volume, lower FA, and greater MD. These associations remained consistent after excluding participants with a history of stroke or dementia. Among participants nonfrail at baseline who completed follow-up frailty assessment (N = 1 379; 6.6-year follow-up period), each standard deviation increase in WMH volume was associated with 1.46 higher odds of frailty at follow-up. Composite FA and MD measures were not associated with future frailty; however, secondary analyses found several significant white matter tract-specific associations with frailty risk.ConclusionThe current study demonstrates a robust association of WMH volume with current and future frailty. Although measures of white matter microstructure were altered in frail individuals, these measures were not generally associated with progression from nonfrail to frail status.