Citations

Abstract We used a rigorous PRoBE (prospective-specimen collection, retrospective-blinded-evaluation) study design to compare the ability of biomarkers of systemic inflammation and biomarkers of gastrointestinal (GI) tissue damage to predict response to corticosteroid treatment, the incidence of clinically severe disease, 6-month nonrelapse mortality (NRM), and overall survival in patients with acute graft-versus-host disease (GVHD). We prospectively collected serum samples of newly diagnosed GVHD patients (n = 730) from 19 centers, divided them into training (n = 352) and validation (n = 378) cohorts, and measured TNFR1, TIM3, IL6, ST2, and REG3α via enzyme-linked immunosorbent assay. Performances of the 4 strongest algorithms from the training cohort (TNFR1 + TIM3, TNFR1 + ST2, TNFR1 + REG3α, and ST2 + REG3α) were evaluated in the validation cohort. The algorithm that included only biomarkers of systemic inflammation (TNFR1 + TIM3) had a significantly smaller area under the curve (AUC; 0.57) than the AUCs of algorithms that contained ≥1 GI damage biomarker (TNFR1 + ST2, 0.70; TNFR1 + REG3α, 0.73; ST2 + REG3α, 0.79; all P < .001). All 4 algorithms were able to predict short-term outcomes such as response to systemic corticosteroids and severe GVHD, but the inclusion of a GI damage biomarker was needed to predict long-term outcomes such as 6-month NRM and survival. The algorithm that included 2 GI damage biomarkers was the most accurate of the 4 algorithms for all endpoints.

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.

9008 Background: Amivantamab, a fully human bispecific antibody targeting epidermal growth factor receptor (EGFR) and MET, is approved for the treatment of non-small cell lung cancer (NSCLC) with EGFR exon 20 insertion after prior platinum-based chemotherapy. Given its bispecific nature, amivantamab is being explored in patients (pts) with primary MET exon 14 skipping mutation (METex14) in the MET-2 cohort of the CHRYSALIS study. Methods: CHRYSALIS (NCT02609776) is an ongoing phase 1 dose escalation/dose expansion study of amivantamab in pts with advanced NSCLC. Pts with primary METex14 whose disease progressed on or who declined current standard of care therapy were treated with amivantamab 1050 mg (pts <80 kg) or 1400 mg (pts ≥80 kg) weekly in cycle 1 and biweekly thereafter. Response was assessed by investigators using RECIST v1.1. Results: As of 2 Dec 2021, 43 pts with METex14 had received amivantamab. Median age was 70 y (range, 43-88), 58% were women, median prior lines of therapy was 2 (range, 0-10) [eg, crizotinib (n=13), capmatinib (n=11), tepotinib (n=5), anti-MET antibody (n=1)], and 23% had history of brain metastases at baseline. In 36 pts with ≥1 postbaseline disease assessment, median duration of follow-up was 5.8 months (range, 0.3-15.8); 6 pts had no prior treatment, 11 had no prior MET inhibitor, and 19 had a prior MET inhibitor. Overall response rate was 33% (50% [3/6] in treatment-naïve pts, 46% [5/11] in pts with no prior MET inhibitor, and 21% [4/19] in pts with prior MET inhibitor therapy). Clinical benefit rate was >54% regardless of prior treatment (Table). Median duration of response (DOR) was not reached (range, 2.1-12.2 months); 67% (8/13) had DOR ≥6 months. Ten of the 12 responders remain on treatment (6.0-14.4 months) with ongoing responses; 2 discontinued after 2 and 12 months, respectively. Safety profile was consistent with previously reported experience of amivantamab (Sabari 2021 JTO 16(3):S108-109). Treatment-related adverse events leading to dose reduction or discontinuation occurred in 3 pts, each. Conclusions: Amivantamab demonstrates anti-tumor activity in primary METex14 NSCLC including after prior MET inhibitor treatment. Enrollment is ongoing and updated data will be shown. Clinical trial information: NCT02609776. [Table: see text]

e24125 Background: Gynecologic, gastrointestinal (GI), and thoracic cancers account for significant morbidity and mortality in the U.S. Women with these types of cancers frequently experience psychological distress, among other poor outcomes. Previous research has indicated that mindfulness-based interventions, such as yoga, can be effective in decreasing distress in cancer patients. Notably, this research has primarily been conducted in a breast cancer population with limited research assessing the feasibility, acceptability, and/or efficacy of this type of intervention in other prevalent and impactful cancers among women. The purpose of the present study was to assess the Feasibility and Acceptability of a yoga intervention for women with gynecologic, GI, or thoracic cancers. Methods: A total of 124 women diagnosed with a gynecologic, GI, or thoracic cancer in the prior year were recruited via outpatient oncology clinics to participate in a 10-week, group-based manualized yoga intervention entitled “Stilling the Waters of Uncertainty” (Author: E. Kacel) that is nearing the end of accrual. Participants completed an Acceptability evaluation following each yoga session with ratings on a 5-point Likert scale from “not at all” to “extremely.” Feasibility of the study was operationalized as percentage of eligible participants who (a) enrolled, (b) attended sessions, and (c) completed post-intervention assessment. Acceptability was operationalized as the percentage of participants with average session ratings of “very” or “extremely” for intervention usefulness, enjoyableness, safety, clarity, relevance, and likelihood of continuing to practice skills. Criteria for operationalizing Feasibility and Acceptability for this study were defined a priori based on recommendations of Bowen and colleagues (2009). A minimum of 80% for each measure of feasibility and acceptability was set as the a priori threshold of success in each domain. Results: All measures of Feasibility were below the a priori benchmark of 80%: Of the 318 eligible patients approached for participation, (a) 124 patients (39.0%) enrolled; 49/124 (39.5%) attended at least 1 yoga session; 44/124 (35.4%) attended at least 8 sessions; and (c) 41/124 (33.1%) completed post-intervention assessment procedures. At least 80% of attendees rated the intervention as “very” or “extremely” useful, enjoyable, safe, and clear; 75.5% and 79.6% of attendees rated the intervention as “very” or “extremely” relevant and likely to be continued to be practiced. Conclusions: The results of this study indicate that a yoga intervention for women with prevalent non-breast cancer types did not meet a priori criteria for feasibility. However, participants who attended at least 1 session rated the intervention as generally acceptable. Future research is needed to improve study/intervention feasibility in this population. Clinical trial information: NCT03385577.

12129 Background: Depression, anxiety, and fear of cancer recurrence (FCR) constitute prevalent psychological concerns necessitating further attention in developing supportive care interventions for women with gynecologic, gastrointestinal, and thoracic cancers. Recent evidence indicates that such concerns may be especially severe among underserved women of color and women affected by low-socioeconomic status (SES). The purpose of the present study is to evaluate the magnitude of changes in depression, anxiety, and FCR associated with a mindfulness-based yoga intervention among a diverse sample of women with these cancers. A second aim is to identify how changes in these concerns may differ across sociodemographic groups. Methods: Women with gynecologic ( n=86), gastrointestinal ( n=17), or thoracic ( n=20) cancers were enrolled in a group-based 10-week yoga intervention utilizing mindfulness meditation, relaxation, and gentle yoga. Prior to and following intervention, participants were administered assessments, including the Beck Depression Inventory – Second Edition (BDI-II) to measure depression, the State-Trait Anxiety Inventory (STAI) to assess anxiety, and the Fear of Cancer Recurrence Inventory (FCRI) to evaluate aspects of FCR. Mixed-linear models evaluated change in outcomes from pre- to post-intervention, with conditional models assessing the effects of age, race/ethnicity, and SES on change. Analyses were conducted prior to trial completion due to approaching accrual period termination. Results: The sample demonstrated a mean age of 58.46 ( SD=10.82) and mean SES score of 3.98 ( SD=1.55) using a 1 to 7 composite scale. Twenty-six percent of participants were of racial and/or ethnic minority status ( n=32). Significant declines in total depressive symptoms, somatic depressive symptoms, state anxiety, and psychological distress due to FCR were observed across the sample. Higher SES was associated with significantly greater reductions in total depressive symptoms and affective depressive symptoms, specifically. Women of color experienced significantly greater declines in somatic symptoms compared to non-Hispanic White women. Conclusions: This mindfulness-based yoga intervention was associated with significant reductions in depressive symptoms, state anxiety, and psychological distress related to FCR among women with gynecologic, gastrointestinal, and thoracic cancers. Higher SES and underserved race/ethnicity status moderated some of these effects. Future research should explore the efficacy of this intervention among diverse women in a randomized clinical trial context. Clinical trial information: NCT03385577.