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Abstract Background Although CAR T-cell therapy has achieved remarkable response in patients (pts) with B-cell non-Hodgkin’s lymphoma (NHL), 20-30% of pts still have primary refractory disease (PD1), and another 30-40% relapse (PD2). We and others have shown that monocytes can modulate T-cell functions and impact clinical response to chemoimmunotherapy in NHL. Given that monocytes nadir and recovery kinetics differ from lymphocytes post lymphodepletion chemotherapy, we hypothesize that monocyte phenotype at peak CAR-T expansion and in the early month post CAR-T can modulate immune responses. Methods scRNAseq were performed on peripheral blood mononuclear cells of NHL pts prior to lymphodepletion chemotherapy (pre), at peak CAR-T expansion (peak), and one month following CAR-T (M1). Seurat v4.3.0 was used for unsupervised hierarchical clustering analysis. Lugano criteria was used to determine clinical responses which were categorized as CR (complete remission), PD1, or PD2. Results We analyzed 129,981 monocytes from 77 samples of 32 pts (16 CR, 4 PD1, 12 PD2) and 5 healthy controls. Unsupervised hierarchical clustering analysis identified 13 monocyte clusters: 4 classical monocyte (CM) clusters with transcriptome profiles for enriched signaling in IL-6, TGFβ, EMT, and p53; 2 intermediate monocyte (IM) clusters enriched for IL-1 or CD38 signaling; 2 non-classical monocytes (NM), one with increased CD36 expression; 3 monocytic MDSC clusters with enrichment of TGFβ, SIRPα, and HIF1α signaling; and 2 lymphoma-associated monocytes, expressing CD163 or CD169. At Pre and Peak, the distribution of the monocyte clusters was similar in pts with CR, PD2, or PD1, with only a slight decrease in the percent of NM in the PD2 group at Pre and slight increase of CD36 NM in PD1 at Peak. Compared to Pre, all pts had increased percent of CD36 NM and IL-1 IM at Peak. Interestingly, while the distribution of monocyte clusters was similar at Pre and Peak across clinical responses, GSEA showed that monocytes in CR pts, compared to PD1 and PD2, had gene expression enrichment of MYC target V2 pathway at Pre and TGFβ pathway at Peak. At M1, pts in PD1 had increased percent of p53 and TGFβ CM and decreased percent of NM. In contrast, pts with CR had decreased percent of IL-6 CM, p53 CM, TGFβ CM, IL-1 IM and increased percent of NM. Notably, as pts with CR and PD2 may appear similar clinically at M1, pts with PD2, compared to CR, have increased IL-6 CM, IL-1 IM, and decreased NM. In addition, GSEA showed that PD2 pts had increased IFNα response. Our results demonstrate that monocyte phenotype differences at Pre and Peak could be associated with CAR-T clinical response, and that persistent inflammatory monocyte signaling at M1 in pts with clinical response is associated with relapse. These data suggest a role for development of monocyte biomarkers to predict response and therapeutic targeting. Citation Format: Andre de Menezes Silva Corraes, Panwen Wang, Radhika Bansal, Henan Zhang, Zuoyi Shao, Kevin Regan, Eider Moreno Cortes, Arushi Khurana, Nora Bennani, Yucai Wang, Paul Hampel, Jonas Paludo, Patrick Johnston, Hemant Murthy, Madiha Iqbal, Stephen Ansell, Javier Munoz, Allison Rosenthal, Mohamed Kharfan-Dabaja, Januario Castro, Saad Kenderian, Haidong Dong, Ying Li, Yi Lin. Monocyte transcriptome profiles associated with clinical response in patients with B-cell non-Hodgkin’s lymphoma receiving CD19-directed CAR-T therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4001.

Abstract Background: Although CAR T-cell therapy has achieved remarkable response rates in adult patients (pts) with relapsed and refractory B-cell non-Hodgkin’s lymphoma (NHL), 20-30% of pts still have primary refractory disease, and 30-40% of pts relapse, often within 6 months of therapy. Given that durable clinical response can be achieved without CAR T cell persistence, we hypothesized that durable remission is correlated with the expansion of tumor-reactive T-cell receptor (TCR) clones following CAR T-cell infusion. To assess this, we examined the TCR repertoire of adult pts with B-NHL who received CD19 CAR T-cell (axi-cel) therapy to identify correlates of clinical response. Methods: Single-cell (sc) RNA sequencing (seq) and scTCR-seq were performed on peripheral blood mononuclear cells from B-NHL pts before lymphodepletion chemotherapy (pre), at peak CAR-T expansion (peak), and one month following CAR-T (M1). scRNAseq and scTCR-seq data were processed using CellRanger v7.0.1, which were then analyzed using Immunarch (v0.9.0) for TCR clonality and sample diversity. Diversity was assessed using the Gini coefficient to indicate clone size inequality (0 = maximum diversity). TCR diversity and phenotype of expanded and emerged TCR clones post CAR-T were compared across clinical response categories: CR (complete remission for at least 6 months), PD1 (primary refractory), and PD2 (relapsed after partial or complete response). Results: We analyzed 107,035 T cells from 77 serial samples of 32 pts (16 CR, 4 PD1, 12 PD2) and 5 healthy controls. Compared to pts with PD1 and PD2, pts with CR had a larger Gini coefficient for TCR clones at M1 relative to Pre and Peak. The Gini coefficient was the largest for tumor recirculating CD8 T effector memory (Tem) and activated CD8 peripheral memory (Tpm) cells at M1 for pts with CR. Examining the repertoire of emerged and expanded TCR clones at Peak and M1 from Pre, pts with PD2, compared to pts with CR, had a higher percentage of activated CD8 T peripheral memory (Tpm) and T regulatory cells (Treg) among the emerged clones and activated CD8 Tpm among the expanded clones. Patients with PD1, relative to patients with CR, had more proliferating and non-activated CD8 Tpm among the expanded and emerged clones. Conclusion: NHL pts with CR after CAR-T had more robust clonal expansion of T cells, particularly tumor recirculating CD8 Tem and activated CD8 Tpm, compared to pts with relapsed or refractory disease. In contrast, pts with relapsed or refractory disease had an expansion of TCR clones with a larger proportion of CD8 Tpm and Tregs. Endogenous tumor-reactive TCR expansion may help predict favorable clinical response following CAR T-cell therapy. Citation Format: Aiman J. Faruqi, Panwen Wang, Radhika Bansal, Andre De Menezes Silva Corraes, Henan Zhang, Zuoyi Shao, Kevin Regan, Eider Moreno Cortes, Arushi Khurana, Nora Bennani, Yucai Wang, Paul Hampel, Jonas Paludo, Patrick Johnston, Hemant Murthy, Madiha Iqbal, Stephen Ansell, Javier Munoz, Allison Rosenthal, Mohamed Kharfan Dabaja, Januario E. Castro, Saad Kenderian, Haidong Dong, Ying Li, Yi Lin. T-cell receptor repertoire changes associated with clinical response in patients with B-cell non-Hodgkin’s lymphoma receiving CD19 CAR-T therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 53.

Abstract The Voyage Study is a large-scale, prospective cohort study of long-term health outcomes among participants with a valid multi-target stool DNA (mt-sDNA) test order. Recently, the Voyage Study achieved its enrollment target of 150,000 participants. The intent of this descriptive analysis is to provide baseline geographic and socio-demographic characteristics of Voyage Study participants to set the stage for future comparisons to the broader mt-sDNA user population. Participants were randomly selected from all persons in the U.S. or Puerto Rico who had a valid order for mt-sDNA screening during the enrollment period (10/18/2019 - 10/17/2023). Enrolled participants completed a baseline questionnaire that collected socio-demographic and health information. Participant characteristics and baseline survey answers were compared between regions using chi-square tests where appropriate. Regional geographic data was aggregated for the broader mt-sDNA user population during the enrollment period, though no formal comparisons were made between the broader population and the Voyage population at this time. Analyses were limited to 139,369 participants with available baseline questionnaire data. Voyage participants were more likely to reside in the Midwest, Northeast, or Southeast (29.9%, 22.5%, 22.6% respectively) and less likely to reside in the Southwest and West (11.6%, 13.4%). During the enrollment period, differential participation was also observed in the mt-sDNA user population, with the Midwest, Northeast, and Southeast having the greatest proportion (25.4%, 22.2%, 26.7%) and the Southwest and West having the lowest proportion of mt-sDNA users (13.8%, 11.9%). In the Voyage cohort, Midwest participants reported the lowest education attainment as characterized by years of school completed (14.1% high school or below, 59.2% college or greater), while participants in the West reported the highest education attainment (7.9% high school or below, 67.3% college or greater). The West also had the highest percentage of participants reporting an income of $100,000 or greater (51.6%), with the Southeast being the lowest (42.2%), as compared to the other regions. We report here early results of geographic and socio-demographic characteristics from a new research resource that will enable future analyses of health outcomes and behaviors in a population of mt-sDNA users. We observed that the greatest percentage of Voyage participants resided in the Midwest, Northeast, or Southeast, and that there was differential socio-demographic participant characteristics based on region. Future analyses will compare long-term healthcare outcomes and differences in colorectal cancer incidence and mortality between the broader mt-sDNA user population and the Voyage cohort. Citation Format: Allison M. Berry, Jessica A. Grimm, Christine R. Kirt, Emily J. Kirsch, Rachel E. Dixon, Winnie Z. Fan, Kandace A. Bohn, Jennifer St. Sauver, Kathleen J. Yost, Lila J. Finney Rutten, Janet E. Olson. U.S. Geographic and socio-demographic characteristics of Voyage Study participants [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3453.

Abstract Introduction: Chimeric antigen receptor T-cell (CAR-T) therapy is an established treatment modality for the management of refractory and/or relapsed non-Hodgkin lymphoma (NHL). Despite restrictions on granulocyte colony-stimulating factor (G-CSF) use in registration clinical trials due to potential worsening of cytokine release syndrome (CRS), G-CSF is often prescribed for neutrophil recovery post-CAR-T in clinical practice. We conducted a retrospective study to assess the association between G-CSF use and the safety and efficacy of CAR-T. Methods: Following Institutional Review Board approval, we retrospectively analyzed NHL patients receiving commercial CD19-targeted CAR-T across Mayo Clinic sites (Arizona, Florida, and Minnesota) between October 2017 and May 2023. Demographics, labs, and post CAR-T events were collected. Electronic medical records were reviewed for G-CSF exposure within Day 1 - 100 post-CAR T. Differences by G-CSF status were examined using a Chi-square test and Kruskal Wallis tests. Hazard ratios (HR) and 95% confidence intervals (CI) for overall survival (OS) were calculated using Cox model. Results: Among 270 CAR-T patients; 106 received G-CSF within 30 days and 164 did not. Median age was 56.9 with G-CSF and 58.3 without G-CSF. Most were male (75.2% G-CSF, 62.6% no G-CSF). Diffuse large B cell lymphoma was the predominant NHL subtype (67.0% G-CSF, 65.2% no G-CSF). G-CSF within 30 days was not associated with reduced incidence of neutropenic fever (11.7% G-CSF vs 9.9% no G-CSF, p = 0.6593) or documented infection (22.1% vs 18.3%, p = 0.4439). G-CSF correlated with decreased profound neutropenia duration (ANC < 100 μL, 0 vs 2 days, p < 0.0001) and incidence within 30 days ( 31.7% vs 60.4%, p < 0.0001) as well as incidence of protracted profound neutropenia (> 7 days, 3.8% vs 22.8%, p < 0.0001). G-CSF was associated with a higher incidence of cytopenias between days 30 -100: severe neutropenia (ANC < 500/uL, 28.8% vs 15.2%, p = 0.0075), severe anemia (Hb < 8 g/dL, 21% vs 9.7%, p = 0.0114), and severe thrombocytopenia (Plt < 50 g/L, 35.2% vs 20.9%, p = 0.0099). Logistic regression analysis showed that none of the examined covariates, including prior autologous stem cell transplant, ECOG PS score, and receipt of bridging therapy, were associated with severe neutropenia likelihood. G-CSF was associated with a higher CRS incidence (89.6% vs 79.9%, p = 0.0343), but grade 3 CRS or higher (4.7% vs 3.7%, p = 0.6675) was no different. No difference in complete response rates (66% vs 61.1%, p = 0.4707) or 2-year OS (p = 0.523) was observed between the 2 groups. Conclusion: G-CSF within 30 days was associated with reduced duration and incidence of profound neutropenia without a significant impact on incidence of neutropenic fever or documented infections. There was a signal of association between G-CSF and increased incidence of low-grade CRS and delayed cytopenias (day 30-100) that warrants confirmation in larger studies. Citation Format: Lay She Ng, Claire I. Yee, Radhika Bansal, Mohamed A. Kharfan-Dabaja, Grzegorz S. Nowakowski, Allison C. Rosenthal, Javier Munoz, Januario Castro, Wern Lynn Ng, Hemant S. Murthy, Yi Lin, Matthew R. Buras, Madiha Iqbal, Yucai Wang, Talal Hilal. Impact of G-CSF on safety and efficacy of CAR T-cell therapy in non-Hodgkin lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6327.

AbstractBackgroundIsotretinoin treatment for acne can reduce adverse psychiatric outcomes in adults, but there has been little investigation of the incidence of psychiatric outcomes in treated adolescents.MethodsThis retrospective cohort study using the Rochester Epidemiology Project identified 606 patients aged 12–18 prescribed isotretinoin over a 10‐year period between January 1, 2008 and December 31, 2017. Medical records were reviewed to identify psychiatric diagnoses before and during isotretinoin therapy, as well as psychiatric symptoms not captured by formal diagnoses and changes to isotretinoin dosing because of psychiatric diagnoses or symptoms.ResultsOne hundred seventy‐seven (29.2%) had a psychiatric diagnosis prior to isotretinoin initiation, but 98 (16.2%) had a new psychiatric diagnosis or psychiatric symptom while taking isotretinoin. Patients with a psychiatric history were no more likely than those without to receive a new psychiatric diagnosis during treatment (4.5% vs. 3.7%; p = .650), but did experience more psychiatric symptoms, primarily low mood and mood swings (23.7% vs. 7.7%; p < .001). Only 25.5% of the 98 with a new psychiatric diagnosis or psychiatric symptom had a subsequent dose change. A dose change was more likely if patients received a new psychiatric diagnosis (41.7% vs. 20.3%; p = .037) or patients did not have a psychosocial explanation for psychiatric symptoms (34.4% vs. 10.8%; p = .009).ConclusionsA substantial proportion of adolescent patients prescribed isotretinoin had a prior psychiatric diagnosis. This predicts more psychiatric symptoms during isotretinoin treatment. Adolescents with a psychiatric history who have worsening symptoms and those with new‐onset psychiatric symptoms would benefit from close monitoring while taking isotretinoin.

Background Although VCAM‐1 (vascular cell adhesion molecule‐1) and ICAM‐1 (intercellular adhesion molecule‐1) have been associated with incident heart failure with preserved ejection fraction (HFpEF) and atrial fibrillation (AF), the associations of VCAM‐1 and ICAM‐1 with sensitive measures of cardiac structure/function are unclear. The objective of this study is to evaluate associations between VCAM‐1, ICAM‐1, and measures of cardiac structure and function as potential pathways through which cellular adhesion molecules promote HFpEF and AF risk. Methods and Results In MESA (Multi‐Ethnic Study of Atherosclerosis), we evaluated the associations of circulating VCAM‐1 and ICAM‐1 at examination 2 (2002–2004) with measures of cardiac structure/function on cardiac magnetic resonance imaging at examination 5 (2010–2011) after multivariable adjustment. Mediation analysis of left atrial (LA) strain on the association between VCAM‐1 or ICAM‐1 and AF or HFpEF was also performed. Overall, 2304 individuals (63±10 years; 47% men) with VCAM‐1 or ICAM‐1, cardiac magnetic resonance imaging, and covariate data were included in analysis. Higher VCAM‐1 and ICAM‐1 were associated with lower LA peak longitudinal strain and worse global circumferential left ventricular strain but were not associated with left ventricular myocardial scar or interstitial fibrosis. Lower LA peak longitudinal strain mediated 8% (95% CI, 2–30) of the relationship between VCAM‐1 and HFpEF and 9% (95% CI, 2–21) of the relationship between VCAM‐1 and AF. Conclusions Higher VCAM‐1 and ICAM‐1 were associated with lower LA function and left ventricular systolic function but were not associated with myocardial scar or interstitial fibrosis. VCAM‐1 and ICAM‐1 may promote HFpEF and AF risk through impaired LA reservoir function.

ImportanceRedirection of care refers to withdrawal, withholding, or limiting escalation of treatment. Whether maternal social determinants of health are associated with redirection of care discussions merits understanding.ObjectiveTo examine associations between maternal social determinants of health and redirection of care discussions for infants born extremely preterm.Design, Setting, and ParticipantsThis is a retrospective analysis of a prospective cohort of infants born at less than 29 weeks’ gestation between April 2011 and December 2020 at 19 National Institute of Child Health and Human Development Neonatal Research Network centers in the US. Follow-up occurred between January 2013 and October 2023. Included infants received active treatment at birth and had mothers who identified as Black or White. Race was limited to Black and White based on service disparities between these groups and limited sample size for other races. Maternal social determinant of health exposures were education level (high school nongraduate or graduate), insurance type (public/none or private), race (Black or White), and ethnicity (Hispanic or non-Hispanic).Main Outcomes and MeasuresThe primary outcome was documented discussion about redirection of infant care. Secondary outcomes included subsequent redirection of care occurrence and, for those born at less than 27 weeks’ gestation, death and neurodevelopmental impairment at 22 to 26 months’ corrected age.ResultsOf the 15 629 infants (mean [SD] gestational age, 26 [2] weeks; 7961 [51%] male) from 13 643 mothers, 2324 (15%) had documented redirection of care discussions. In unadjusted comparisons, there was no significant difference in the percentage of infants with redirection of care discussions by race (Black, 1004/6793 [15%]; White, 1320/8836 [15%]) or ethnicity (Hispanic, 291/2105 [14%]; non-Hispanic, 2020/13 408 [15%]). However, after controlling for maternal and neonatal factors, infants whose mothers identified as Black or as Hispanic were less likely to have documented redirection of care discussions than infants whose mothers identified as White (Black vs White adjusted odds ratio [aOR], 0.84; 95% CI, 0.75-0.96) or as non-Hispanic (Hispanic vs non-Hispanic aOR, 0.72; 95% CI, 0.60-0.87). Redirection of care discussion occurrence did not differ by maternal education level or insurance type.Conclusions and RelevanceFor infants born extremely preterm, redirection of care discussions occurred less often for Black and Hispanic infants than for White and non-Hispanic infants. It is important to explore the possible reasons underlying these differences.

Abstract Defining prognostic variables in T-lymphoblastic lymphoma (T-LL) remains a challenge. AALL1231 was a Children’s Oncology Group phase 3 clinical trial for newly diagnosed patients with T acute lymphoblastic leukemia or T-LL, randomizing children and young adults to a modified augmented Berlin-Frankfurt-Münster backbone to receive standard therapy (arm A) or with addition of bortezomib (arm B). Optional bone marrow samples to assess minimal residual disease (MRD) at the end of induction (EOI) were collected in T-LL analyzed to assess the correlation of MRD at the EOI to event-free survival (EFS). Eighty-six (41%) of the 209 patients with T-LL accrued to this trial submitted samples for MRD assessment. Patients with MRD &lt;0.1% (n = 75) at EOI had a superior 4-year EFS vs those with MRD ≥0.1% (n = 11) (89.0% ± 4.4% vs 63.6% ± 17.2%; P = .025). Overall survival did not significantly differ between the 2 groups. Cox regression for EFS using arm A as a reference demonstrated that MRD EOI ≥0.1% was associated with a greater risk of inferior outcome (hazard ratio, 3.73; 95% confidence interval, 1.12-12.40; P = .032), which was independent of treatment arm assignment. Consideration to incorporate MRD at EOI into future trials will help establish its value in defining risk groups. CT# NCT02112916.

Abstract Patients treated with antineoplastic therapy often develop thrombocytopenia requiring platelet transfusion, which has potential to exacerbate pulmonary injury. This study tested the hypothesis that amotosalen-UVA pathogen–reduced platelet components (PRPCs) do not potentiate pulmonary dysfunction compared with conventional platelet components (CPCs). A prospective, multicenter, open-label, sequential cohort study evaluated the incidence of treatment-emergent assisted mechanical ventilation initiated for pulmonary dysfunction (TEAMV-PD). The first cohort received CPC. After the CPC cohort, each site enrolled a second cohort transfused with PRPC. Other outcomes included clinically significant pulmonary adverse events (CSPAE) and the incidence of treatment-emergent acute respiratory distress syndrome (TEARDS) diagnosed by blinded expert adjudication. The incidence of TEAMV-PD in all patients (1068 PRPC and 1223 CPC) was less for PRPC (1.7 %) than CPC (3.1%) with a treatment difference of –1.5% (95% confidence interval [CI], –2.7 to –0.2). In patients requiring ≥2 PCs, the incidence of TEAMV-PD was reduced for PRPC recipients compared with CPC recipients (treatment difference, –2.4%; 95% CI, –4.2 to –0.6). CSPAE increased with increasing PC exposure but were not significantly different between the cohorts. For patients receiving ≥2 platelet transfusions, TEARDS occurred in 1.3% PRPC and 2.6% CPC recipients (P = .086). Bayesian analysis demonstrated PRPC may be superior in reducing TEAMV-PD and TEARDS for platelet transfusion recipients compared with CPC recipients, with 99.2% and 88.8% probability, respectively. In this study, PRPC compared with CPC demonstrated high probability of reduced severe pulmonary injury requiring assisted mechanical ventilation in patients with hematology disorders dependent on platelet transfusion. This trial was registered at www.ClinicalTrials.gov as #NCT02549222.

Acute pancreatitis (AP), defined as acute inflammation of the pancreas, is one of the most common diseases of the gastrointestinal tract leading to hospital admission in the United States. It is important for clinicians to appreciate that AP is heterogenous, progressing differently among patients and is often unpredictable. While most patients experience symptoms lasting a few days, almost one-fifth of patients will go on to experience complications, including pancreatic necrosis and/or organ failure, at times requiring prolonged hospitalization, intensive care, and radiologic, surgical, and/or endoscopic intervention. Early management is essential to identify and treat patients with AP to prevent complications. Patients with biliary pancreatitis typically will require surgery to prevent recurrent disease and may need early endoscopic retrograde cholangiopancreatography if the disease is complicated by cholangitis. Nutrition plays an important role in treating patients with AP. The safety of early refeeding and importance in preventing complications from AP are addressed. This guideline will provide an evidence-based practical approach to the management of patients with AP.