Citations

Abstract We surveyed the performance of ponatinib, as salvage therapy, in a real-world setting of chronic phase chronic myeloid leukemia (CML-CP). Among 55 consecutive patients (median age 49 years) with relapsed/refractory CML-CP, 35 (64%) had failed ≥ 3 tyrosine kinase inhibitors (TKIs), 35 (64%) were pre-treated with nilotinib, and 14 (28%) harbored ABL1T315I. At start of ponatinib (median dose 30 mg/day), 40 patients were already in complete hematologic (CHR), 4 in complete cytogenetic (CCyR), 3 in major molecular (MMR) remission, while 8 had not achieved CHR (NR). Ponatinib improved the depth of response in 13 (33%), 3 (75%), 2 (66%), and 4 (50%) patients with CHR, CCyR, MMR, and NR, respectively (p = 0.02). At a median follow-up of 42 months, 13 (23%) deaths, 5 (9%) blast transformations, and 25 (45%) allogeneic transplants were recorded. Five/10-year post-ponatinib survival was 77%/58% with no significant difference when patients were stratified by allogeneic transplant (p = 0.94), ponatinib-induced deeper response (p = 0.28), or a post-ponatinib ≥ CCyR vs CHR remission state (p = 0.25). ABL1T315I was detrimental to survival (p = 0.04) but did not appear to affect response. Prior exposure to nilotinib was associated with higher risk of arterial occlusive events (AOEs; 11% vs 0%; age-adjusted p = 0.04). Ponatinib starting/maintenance dose (45 vs 15 mg/day) did not influence either treatment response or AOEs. Our observations support the use of a lower starting/maintenance dose for ponatinib in relapsed/refractory CML-CP but a survival advantage for deeper responses was not apparent and treatment might not overcome the detrimental impact of ABL1T315I on survival. The association between prior exposure to nilotinib and a higher risk of post-ponatinib AOEs requires further validation.

AbstractObjectiveTo examine the experience of interracial anxiety among health professionals and how it may affect the quality of their interactions with patients from racially marginalized populations. We explored the influence of prior interracial exposure—specifically through childhood neighborhoods, college student bodies, and friend groups—on interracial anxiety among medical students and residents. We also examined whether levels of interracial anxiety change from medical school through residency.Data SourceWeb‐based longitudinal survey data from the Medical Student Cognitive Habits and Growth Evaluation Study.Study DesignWe used a retrospective longitudinal design with four observations for each trainee. The study population consisted of non‐Black US medical trainees surveyed in their 1st and 4th years of medical school and 2nd and 3rd years of residency. Mixed effects longitudinal models were used to assess predictors of interracial anxiety and assess changes in interracial anxiety scores over time.Principal FindingsIn total, 3155 non‐Black medical trainees were followed for 7 years. Seventy‐eight percent grew up in predominantly White neighborhoods. Living in predominantly White neighborhoods and having less racially diverse friends were associated with higher levels of interracial anxiety among medical trainees. Trainees' interracial anxiety scores did not substantially change over time; interracial anxiety was highest in the 1st year of medical school, lowest in the 4th year, and increased slightly during residency.ConclusionsNeighborhood and friend group composition had independent effects on interracial anxiety, indicating that premedical racial socialization may affect medical trainees' preparedness to interact effectively with diverse patient populations. Additionally, the lack of substantial change in interracial anxiety throughout medical training suggests the importance of providing curricular tools and structure (e.g., instituting interracial cooperative learning activities) to foster the development of healthy interracial relationships.

Abstract BACKGROUND: Multiple Myeloma (MM) is an incurable disease with no known germline high penetrant risk gene. The higher risk of MM among affected relatives suggests a genetic contribution to the etiology. To date, 24 common risk variants with low effect sizes were identified using genome-wide association studies, which account for 17% of heritability. However, a systematic analysis of the known rare alleles in cancer predisposition genes has not been undertaken so far in MM. We collaborated with six other academic centers across the United States to identify and select cases for analysis of germline predisposition of MM. METHODS: We performed whole exome, next-generation sequencing of 2,387 familial or early onset germline MM cases from the myeloma sequencing consortium (MMSEQ). We called 1.5 million variants and performed standard quality control of the data. We also obtained exome data on 1,285 cases from UK Biobank (UKBB) and 344,513 non-cancer controls (total=3,672 cases). We analyzed the ultra-rare, coding variants in 90 clinically relevant or putative candidates for cancer predisposition. We then used the automated variant curator PathoMAN to annotate and assert pathogenicity of each variant. We contrasted our results with assertions of pathogenicity from ClinVar and tested for gene association with MM. RESULTS: Overall, we observed several pathogenic or likely pathogenic variants, both singleton and recurrent founder mutations. In the MMSEQ, 8.7% of MM cases harbored a pathogenic variant in these known/putative cancer predisposition genes. Predominant group of pathogenic variants were observed within CHEK2 (19%), TP53 (8%), and ATM (5%). A case-control analysis revealed strong association with TP53 and weakly with ATM. In the familial/early onset MMSEQ cases, TP53 mutations were enriched 68 times more than in the UKBB controls. Our preliminary results suggest that known genes of cancer susceptibility such as TP53 and ATM may also play a role in myeloma risk. CONCLUSION: In a large study of multi-center MM cases, we identified a significant proportion of individuals who are carriers of known (solid) cancer predisposition genes. This study suggests that these known cancer predisposition genes may be relevant in a subset of MM cases. Citation Format: Michael T. Conry, Nicola Camp, Celine Vachon, Michelle Hildebrandt, Elizabeth E. Brown, Steven M. Lipkin, Judy Garber, Susan L. Slager, Samantha Stokes, Aaron D. Norman, Aalin Izhar, Sita Dandiker, Kylee Maclachlan, Kenneth Offit, Saad Usmani, Vijai Joseph. Pathogenic germline mutations and risk of multiple myeloma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5229.

Abstract Introduction: Cytokines are protein factors that regulate diverse cellular processes. The malignant progression of immunoglobulin M monoclonal gammopathy of undetermined significance (IgM-MGUS) to Waldenstrom macroglobulinemia (WM) is in part cytokine mediated, and we have previously shown IL-6 mediates IgM secretion in WM via the JAK/STAT pathway. Cytokine signaling can be epigenetically modulated by micro-RNAs (miRs). We aimed to identify the role of miRs in the regulation of inflammatory cytokine pathways between these diseases. Methods: Bone marrow samples of patients with IgM-MGUS (n=7) and WM (n=25) were prospectively collected and sorted for CD19+ and/or CD138+ malignant cells. Total RNA extraction and sequencing were performed, miR and mRNA profiling was conducted, and differential expression was calculated between WM and IgM-MGUS using a log2 fold change (FC)>0.5 and ←0.5, false discovery rate<0.05. Experimental differentially expressed miR-mRNA pairing was performed, and pairs were filtered for correlated expression (i.e., upregulated miR/downregulated mRNA, and vice-versa). Filtered pairs were analyzed using the Ingenuity Pathway Analysis to identify pathways between WM and IgM-MGUS with absolute activation Z-score ≥1. Results: We identified 34 differentially expressed miRs experimentally targeting 1132 mRNAs. Pathway analysis showed overall miR-based inactivation of inflammatory cytokine signaling pathways in WM compared to IgM-MGUS, especially of the interleukin (IL) family: IL-2, IL-6, IL-8, IL-9, IL-15, and IL-17. Underlying multiple pathways was upregulation of miRs-146a, 150, 194, all targets of Signal Transducer and Activator of Transcription 1 (STAT1), observed to be downregulated. Of relevance, miR-146a has been previously shown to be an inhibitor of inflammatory cytokines, including IL-6. Next, we observed upregulation of miR-142 which targets phosphoinositide-3-kinase regulatory subunit 6 (PIK3R6), observed to be downregulated. Both the STAT and PIK3 families are important cytokine signal transducers, and we have previously shown the PI3k-AKT-IkB-p65 pathway induces expression of IL-6 via a GLI2-mediated mechanism. We additionally observed granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling to be inactivated in WM. Here, miR-19b and miR-30e were upregulated, both target CSF 2 receptor subunit beta (CSF2RB), found to be downregulated. CSF2RB is the common receptor subunit of GM-CSF, IL-3, and IL-5. Conclusion: Our study identifies multiple cytokines pathways involved in inflammation and the tumor microenvironment to be potentially inactivated by differentially expressed miRs in WM compared to IgM-MGUS. Downregulation of these pathways and targeting of the STAT and PIK3 family indicates a possible miR-based negative feedback loop to down-modulate inflammatory cytokine signaling in WM. Citation Format: Karan Chohan, Jonas Paludo, Surendra Dasari, Jithma P. Abeykoon, Prashant Kapoor, Esteban Braggio, Michelle K. Manske, Aneel Paulus, Craig B. Reeder, Sikander Ailawadhi, Asher A. Chanan-Khan, Robert A. Kyle, Morie A. Gertz, Anne J. Novak, Stephen M. Ansell. Micro-RNA induced inactivation of inflammatory cytokine signaling pathways in Waldenstrom macroglobulinemia compared to IgM-MGUS. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3811.

IMPORTANCE: Initial Society of Critical Care Medicine Discovery Viral Infection and Respiratory illness Universal Study (VIRUS) Registry analysis suggested that improvements in critical care processes offered the greatest modifiable opportunity to improve critically ill COVID-19 patient outcomes. OBJECTIVES: The Structured Team-based Optimal Patient-Centered Care for Virus COVID-19 ICU Collaborative was created to identify and speed implementation of best evidence based COVID-19 practices. DESIGN, SETTING, AND PARTICIPANTS: This 6-month project included volunteer interprofessional teams from VIRUS Registry sites, who received online training on the Checklist for Early Recognition and Treatment of Acute Illness and iNjury approach, a structured and systematic method for delivering evidence based critical care. Collaborators participated in weekly 1-hour videoconference sessions on high impact topics, monthly quality improvement (QI) coaching sessions, and received extensive additional resources for asynchronous learning. MAIN OUTCOMES AND MEASURES: Outcomes included learner engagement, satisfaction, and number of QI projects initiated by participating teams. RESULTS: Eleven of 13 initial sites participated in the Collaborative from March 2, 2021, to September 29, 2021. A total of 67 learners participated in the Collaborative, including 23 nurses, 22 physicians, 10 pharmacists, nine respiratory therapists, and three nonclinicians. Site attendance among the 11 sites in the 25 videoconference sessions ranged between 82% and 100%, with three sites providing at least one team member for 100% of sessions. The majority reported that topics matched their scope of practice (69%) and would highly recommend the program to colleagues (77%). A total of nine QI projects were initiated across three clinical domains and focused on improving adherence to established critical care practice bundles, reducing nosocomial complications, and strengthening patient- and family-centered care in the ICU. Major factors impacting successful Collaborative engagement included an engaged interprofessional team; an established culture of engagement; opportunities to benchmark performance and accelerate institutional innovation, networking, and acclaim; and ready access to data that could be leveraged for QI purposes. CONCLUSIONS AND RELEVANCE: Use of a virtual platform to establish a learning collaborative to accelerate the identification, dissemination, and implementation of critical care best practices for COVID-19 is feasible. Our experience offers important lessons for future collaborative efforts focused on improving ICU processes of care.

Since fibroids are known to be hormonally receptive tumors, it is biologically plausible that fibroids decrease in size after menopause. Patients may opt for more conservative therapy or expectant management if fibroid growth could be predicted[1](#ref-0001). Studies assessing fibroid growth in premenopausal patients have shown that individual tumors in a single uterus grow at different rates and can grow consistently or in short bursts 2 . These variations and the unknown effect of natural menopause make patient counseling difficult. Studies that include only symptomatic menopausal patients or those undergoing treatment can result in selection bias towards fibroids that are increasing in size 3,4 . The objective of our study was to estimate fibroid growth course before and after menopause among women not specifically seeking fibroid treatment. Our hypothesis was that fibroid growth would decline after menopause.

TPS5634 Background: The prognosis for women with recurrent or persistent EC after progressing on first-line chemotherapy is poor, with a median overall survival (OS) of 12 months, highlighting the need for more efficacious therapies for this population. Immune checkpoint inhibitors either as monotherapy or when combined with kinase inhibitors have recently demonstrated encouraging response rates in pts with microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) and MS-stable (MSS)/MMR-proficient (MMRp) EC, respectively. Atezo is a humanized monoclonal anti-programmed cell death ligand 1 (PD-L1) inhibitor that has demonstrated monotherapy antitumor activity with an acceptable safety profile in relapsed recurrent EC. Atezo has shown compelling clinical efficacy for pts with certain solid tumors (e.g., urothelial, NSCLC, triple negative breast cancer) as monotherapy and as part of combinatorial therapy. The AFT-50 EndoMAP trial is a platform trial designed to evaluate the efficacy and safety of Atezo in combination with biomarker-defined targeted agents in pts with recurrent or persistent EC. Recognizing pts may have either progressed through or received a checkpoint inhibitor in a prior line of therapy, a non atezo cohort will also be open to enrollment. Methods: This is a phase IB/II non-randomized, multicenter, multicohort, biomarker-driven platform study consisting of two cohorts: A (atezo containing) and B (non atezo). Eligible pts have recurrent or persistent EC and have received no more than 2 prior lines of therapy. FoundationOne CDx (F1CDx) NGS assay will be used for genomic tumor profiling. In cohort A, pts may be eligible for one of the following doublets: Atezo+ipatasertib (PIK3CA/PTEN/AKT1-altered cancers), Atezo+talazoparib (tumors with genomic loss of heterozygosity (LOH) ≥16%), Atezo+Trastuzumab emtansine (ERBB2/HER2 mutated and/or amplified tumors), Atezo+Tiragolumab (MSI-H and/or TMB>10 mut/MB), and Atezo+bevacizumab (biomarker unmatched). Pts will receive Atezo in addition to the targeted agent (at the study approved dosing schedule) until progression, unacceptable toxicity, pt or physician decision to withdraw from the study, death, or study termination. Pts in cohort B, will be eligible for inavolisib (PIK3CA/PTEN/AKT1-altered cancers) + letrozole. Each cohort will enroll ~20 pts; however, the exact size of the cohort may be adjusted. The primary endpoint for Cohort A is confirmed overall response rate (ORR) for each cohort, and for Cohort B is progression free survival at 6 months. Secondary endpoints include disease control rate, duration of response, OS, safety and tolerability, 6-month PFS (cohort A). As a platform study, additional arms may be added, as supported by evolving understanding of EC and molecular targets. EndoMAP is actively enrolling at 17 sites in the US with a target of 25 sites nationwide. Clinical trial information: NCT04486352 .

e15626 Background: Studies have shown the effectiveness of immune checkpoint inhibition (ICI) in patients with tumors demonstrating microsatellite instability (MSI-H) and an associated defect in DNA mismatch repair (dMMR). In particular, KEYNOTE-177 demonstrated significant survival benefit for patients with unresectable or metastatic colorectal cancer with MSI-H or dMMR. Recently published case reports and series have demonstrated similar outcomes for patients with locally advanced and resectable rectal cancer. We report on the experience of patients with locally advanced, resectable rectal adenocarcinoma treated across the Mayo Clinic Health System. Methods: We conducted a retrospective analysis of patients treated at Mayo Clinic since 2015 A search of the Mayo Clinic database was done to include parameters for confirmed rectal adenocarcinoma, dMMR in pathology reports. Patients receiving ICI treatment including pembrolizumab, nivolumab/ipilimumab and durvalumab in any combination with chemotherapy and/or radiation were included. Patients with metastatic disease at the time of surgical intervention or ICI were excluded. Clinical data was assimilated. Results: Twenty-one patients met criteria for inclusion in our analysis. Fifteen patients had de novo disease. Six patients had local recurrence and had been treated previously with chemotherapy, radiation (RT) and surgery. None of the patients included had prior ICI therapy. Fifteen patients had Lynch syndrome. The median age of diagnosis was 41.5 years. Seven patients underwent surgical intervention. of the seven patients received surgery upfront followed by immunotherapy. The remaining six had neoadjuvant immunotherapy alone or in combination with chemotherapy and/or radiation. Prior to surgery, all patients demonstrated radiographic partial response (rPR). 67% of these demonstrated a pathologic complete response (pCR) while 33% had residual disease. The patient who received surgery upfront and adjuvant ICI continues to have radiographic stable disease after 1 year of treatment. For patients who did not have surgery, 50% had radiographic “complete or near complete” response (rCR), 43% had rPR and 7% had radiographic stable disease. Ten patients received RT and ICI with 70% demonstrating rCR and 30% rPR. Overall, the objective response rate was 90 Response to treatment was observed upwards of 75 months. Only 1 person in the study had progression of disease that occurred after 14 months of therapy. Conclusions: Similar to KEYNOTE-177, patients with locally advanced MSI-H/dMMR rectal cancer have significant and durable response to immunotherapy alone or in combination with chemotherapy, radiation and surgery. Further large prospective trials are needed to validate these findings and determine a standardized approach.