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e19010 Background: Mutated DEAD-box helicase 41 (m DDX41), and mutated GATA2 are germline mutations associated with familial predisposition syndromes. In this study, we compare the clinical characteristics and survival outcomes (OS) of m DDX41 and m GATA2 MN patients (pts). Methods: We retrospectively screened pts who had next-generation sequencing (NGS) (OncoHeme panel) performed at Mayo Clinic. 4,524 consecutive pts (2018-2021) were screened for DDX41 mutations and 3,872 for GATA2 mutations (2015-2020) and included 36 MN pts with m DDX41 genetic alterations, and 55 m GATA2 MN pts. m GATA2 cases were included at NGS date while m DDX41 were included at diagnosis date. Germline workup was not done in all cases. JMP 16.2.0 Software was used for statistical analysis. Results: Patient characteristics: The most common diagnosis was MDS (N = 22, 61% in m DDX41 N = 17, 31% in m GATA2 group; p = .0044). MDS/MPN overlap was seen in m GATA2 group only; (29% vs. 0%; p = .0004). Majority of pts were males with median age of 68 and 67 years for m DDX41 and m GATA2 pts; respectively (p = .7). m DDX41 pts had higher hemoglobin, platelets, and MCV (< .0001, 0.005, < .0001; respectively) and significantly lower white blood cells (WBC) count compared to m GATA2 pts (< .0001). All m DDX41-AML pts were (ELN) intermediate-risk, and 64% of m DDX41 MDS were intermediate risk (IPSS-R). In contrast, of m GATA2 pts 62% of AML were adverse risk and 44% of MDS very high risk. Majority of m DDX41 pts had normal karyotype (N = 32; 91% vs. N = 19, 37%; p < .0001), had isolated mutations (N = 23; 64%) and the most common co-mutations were DNMT3A (38%), ASXL1 (30%), JAK2 (23%). The majority of m GATA2 pts were co-mutated (96%) with a different co-mutation pattern ASXL1 (60%), SRSF2 (34%), RUNX1 (19%). Germline data: One m GATA2 pts had proven germline mutation, and 10/11 (91%) m DDX41 pts were confirmed Survival and progression in MDS/AML: After median follow-up of 30 months in MDS/AML, 7 (21%) m DDX41 and 23 (77%) m GATA2 pts died with superior OS in m DDX41 compared to m GATA2 pts with median OS of (136.7 vs. 6.8 months, p < .0001). Seven (31%) of 22 m DDX41 and 6 (35%) m GATA2 MDS pts progressed into AML with a median time to progression of (11.2 vs. 5.2 months, p = .045). The leukemia free survival (LFS) for m DDX41 MDS pts was significantly longer than LFS of m GATA2 MDS pts (24.4 vs. 6 months, p < .0001). Conclusions: We compare the outcomes of two unique mutations associated with germline predisposition. We found m DDX41 pts had fewer cytogenetic aberrations, no MDS/MPN overlap, and lower WBC count. Majority of m DDX41 MDS/AML pts were intermediate risk category, compared to predominance of adverse risk disease in m GATA2 pts, translating into better OS and LFS. This study is limited by the small size, lack of germline workup in all cases, and retrospective nature. However, it supports the favorable prognosis and indolent course of m DDX41 pts recently described.

TPS7080 Background: Myelodysplastic syndrome/myeloproliferative neoplasms (MDS/MPN) are classified as a distinct category under the World Health Organization (WHO) classification of myeloid neoplasms. MDS/MPN with RS and thrombocytosis (MDS/MPN-RS-T) and MDS/MPN, unclassifiable with > 15% bone marrow ring sideroblasts (MDS/MPN-U-RS) have similar clinical and pathological characteristics with symptomatic or transfusion-dependent anemia as the predominant morbidity. Luspatercept has been approved in myelodysplastic syndromes with ring sideroblasts (MDS-RS) and MDS/MPN overlap syndromes, based on the phase 3 MEDALIST clinical trial which primarily included MDS-RS patients with an objective erythroid response rate of approximately 40 per cent. In this trial, some MDS-RS patients also experienced an increase in neutrophil and platelet counts. This raises a safety concern for MDS/MPN patients with elevated platelet or WBC counts such as MDS/MPN-RS-T and MDS/MPN-U-RS. Previous studies have shown clinical and biological differences between MDS-RS and MDS/MPN-RS-T, with the latter group at a significantly elevated risk for thrombotic events. Additionally, several MDS/MPN-RS-T patients are on hydroxyurea which may blunt the erythroid response of luspatercept. Therefore, it is imperative to establish the safety and efficacy of luspatercept in this patient group. Methods: This is an investigator-initiated, prospective, phase II study of luspatercept in MDS/MPN overlap neoplasms with ring sideroblasts and thrombocytosis or unclassifiable with ring sideroblasts with 2 arms; hydroxyurea-independent (cohort A) and hydroxyurea-dependent (cohort B). Hydroxyurea and/or aspirin use is allowed as per investigator discretion. The primary goal is to study the efficacy and safety of luspatercept in MDS/MPN-RS-T or MDS/MPN-U-RS with symptomatic anemia. The primary endpoint is to assess erythroid response rate as per the 2015 International Working Group MDS/MPN response criteria. Secondary endpoints include response duration, time to acute myeloid leukemia (AML) transformation, thrombosis rate, AML-free and overall survival. Inclusion criteria include newly diagnosed or relapsed/refractory adult patients with WHO-defined diagnosis of MDS/MPN-RS-T or MDS/MPN-U-RS with symptomatic or transfusion-dependent anemia and unlikely to respond (EPO level > 200 IU/L) or intolerant to erythropoiesis stimulating agent (ESA) therapy. Prior therapy with lenalidomide, hypomethylating agents or immunosuppressive therapy is allowed. The overall plan is to enroll 54 patients across the three Mayo Clinic sites, Minnesota, Arizona and Florida. Enrollment to the trial began in January 2022 with 1 patient enrolled at the time of abstract submission. Clinical trial information: NCT05005182.

TPS7070 Background: Outcomes of adults with relapsed/refractory T-cell acute lymphoblastic leukemia (T-ALL) and acute myeloid leukemia (AML) have remained poor. CD38 is a transmembrane glycoprotein with several important functions including its role in immune escape of tumor cells [Chillemi A et al. Front Immunol 2017, Furano A et al. J Immunol 1990]. Several studies have demonstrated that CD38 is expressed in T-ALL and AML and is targetable with CD38 blocking agents [Naik J et al. Haematologica 2019, Bride KL et al. Blood 2018, Tembhare et al. J Immunother Cancer 2020]. XmAb18968 is a novel CD38-CD3 bi-specific T-cell engager with Fc domain modified to minimize Fcγ receptor binding and non-selective T-cell activation resulting in reduced cytokine release without compromising target cell killing. We hypothesize that targeting CD38 in relapsed/refractory T-ALL and AML would be safe and feasible using XmAb18968. Methods: This is an investigator-sponsored multi-institutional phase I study evaluating the safety and tolerability of XmAb18968. Patients aged 18 years or above with relapsed/refractory T-ALL or AML (including measurable residual disease relapse), CD38 expression ≥ 20% by flow cytometry, and adequate organ function will be eligible. Major exclusion criteria are hematopoietic cell transplantation within 6 months of enrollment, active acute graft-versus-host disease, and acute promyelocytic leukemia. The primary objective is to determine the recommended phase 2 dose (RP2D) and toxicity profile of XmAb18968. The secondary objectives include determination of response rates, duration of response, survival and pharmacokinetics. Exploratory objectives include correlation of responses with genomic profile, characterizing changes in serum cytokines and phenotypic expression of activated T-cells and leukemic cells, correlation of the phenotypic expression with changes in the transcriptome at the single-cell level, proteomics evaluation of cytokine secretion at the single-cell level and correlation of response with N-glycan profiling, quantitative site-occupancy and direct glycopeptide analysis. The study will follow 3+3 design. Dose escalation will proceed in two separate groups: Group A for subjects with T-ALL and Group B for subjects with AML. Patients will be entered sequentially to each dose level [0.8mg cohort, 1mg cohort, 1.3mg cohort, 1.5mg cohort). The observation period for dose-escalation will be 28-days. RP2D will be defined as the highest dose level at which none of the 3 treated subjects, or no more than 1 of the 6 treated subjects’ experiences a dose limiting toxicity. A minimum of 24 and a maximum of 60 patients will be enrolled. The study is being conducted at 6 sites in United States and is currently open for enrollment. Clinical trial information: NCT05038644.

e18790 Background: Patients with SARS-CoV-2 with a diagnosis of cancer have increased risk of severe COVID-19 outcomes compared to patients without cancer. However, little is known regarding outcomes of patients with COVID-19 and cancer in the setting of human immunodeficiency virus (HIV). Given the unique risks of this population, we sought to understand COVID-19 outcomes using registry data. Methods: This is a descriptive research study utilizing the CCC19 registry, an international multi-institutional registry with healthcare provider-reported cases of patients with cancer and COVID-19. Between March 2020-December 2021, 116 persons with HIV (PWH) and 10,642 persons without HIV (PWOH) with laboratory-confirmed SARS-CoV-2 infection were identified as eligible for the analysis. Results: Median follow-up time for both groups was 90 days, with interquartile range (IQR) 30-180 days. Most PWH were actively receiving antiretroviral therapy (ART) at the time of COVID-19 diagnosis, with 71% (n = 82) having named drug information available; bictegravir/emtricitabine/tenofovir was the most common ART (n = 25). PWH were of younger age (median 57.5 yrs [IQR 46.5-63.25] vs 65 yrs [IQR 55-74]), male (81% vs 47%), and either non-Hispanic Black or Hispanic (71% vs 34%) compared to PWOH. 12% of PWH (n = 14) were current smokers compared to 6% of PWOH (n = 638), and more than half in each group were never smokers (51% of PWH and 53% of PWOH). The following comorbidities were identified in PWH vs PWOH: cardiovascular (16% vs 20%), pulmonary (16% vs 20%), renal (15% vs 14%), and diabetes mellitus (18% vs 27%). A higher proportion of PWH had hematologic malignancy compared to PWOH (33% vs 19%). More PWH had active cancer which was progressing at the time of SARS-CoV-2 infection compared to PWOH (24% vs 14%). 44% of PWH (n = 51) had received active systemic anticancer therapy within the 3 months preceding SARS-CoV-2 infection (including cytotoxic, targeted, endocrine therapies, and immunotherapy) compared to 51% of PWOH (n = 5,420). PWH had an increased rate of hospitalization (58% vs 55%) compared to PWOH. Although a lower proportion of PWH required supplemental oxygen during hospitalization compared to PWOH (34% vs 38%) and ICU admission rates were identical between the two groups (16% vs 16%), PWH had an increased rate of mechanical ventilation (14% vs 10%) and death (24% vs 18%) compared to PWOH. Conclusions: This is the first known study describing outcomes of patients with cancer and COVID-19 in the PWH population from a large multinational dataset. PWH have characteristics associated with adverse outcomes in prior analyses (male sex, non-Hispanic Black or Hispanic, hematologic malignancy, progressing cancer) but are notably younger and have fewer comorbidities. HIV infection may portend increased risk of severe COVID-19 and death; however, additional analyses, including multivariable regression, are warranted.

OBJECTIVES: We designed this study to test whether clazakizumab, a direct interleukin-6 inhibitor, benefits patients hospitalized with severe or critical COVID-19 disease accompanied by hyperinflammation. DESIGN: Multicenter, randomized, double-blinded, placebo-controlled, seamless phase II/III trial. SETTING: Five U.S. medical centers. PATIENTS: Adults inpatients with severe COVID-19 disease and hyperinflammation. INTERVENTIONS: Eighty-one patients enrolled in phase II, randomized 1:1:1 to low-dose (12.5 mg) or high-dose (25 mg) clazakizumab or placebo. Ninety-seven patients enrolled in phase III, randomized 1:1 to high-dose clazakizumab or placebo. MEASUREMENTS AND MAIN RESULTS: The primary outcome was 28-day ventilator-free survival. Secondary outcomes included overall survival, frequency and duration of intubation, and frequency and duration of ICU admission. Per Data Safety and Monitoring Board recommendations, additional secondary outcomes describing clinical status and status changes, as measured by an ordinal scale, were added. Bayesian cumulative proportional odds, logistic, and Poisson regression models were used. The low-dose arm was dropped when the phase II study suggested superiority of the high-dose arm. We report on 152 patients, 74 randomized to placebo and 78 to high-dose clazakizumab. Patients receiving clazakizumab had greater odds of 28-day ventilator-free survival (odds ratio [OR] = 3.84; p [OR > 1] 99.9%), as well as overall survival at 28 and 60 days (OR = 1.75; p [OR > 1] 86.5% and OR = 2.53; p [OR > 1] 97.7%). Clazakizumab was associated with lower odds of intubation (OR = 0.2; p [OR] < 1; 99.9%) and ICU admission (OR = 0.26; p [OR < 1] 99.6%); shorter durations of ventilation and ICU stay (risk ratio [RR] < 0.75; p [RR < 1] > 99% for both); and greater odds of improved clinical status at 14, 28, and 60 days (OR = 2.32, p [OR > 1] 98.1%; OR = 3.36, p [OR > 1] 99.6%; and OR = 3.52, p [OR > 1] 99.8%, respectively). CONCLUSIONS: Clazakizumab significantly improved 28-day ventilator-free survival, 28- and 60-day overall survival, as well as clinical outcomes in hospitalized patients with COVID-19 and hyperinflammation.

AbstractIdentifying biomarkers associated with disease progression and drug resistance are important for personalized care. We investigated the expression of 121 curated genes, related to immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs) responsiveness. We analyzed 28 human multiple myeloma (MM) cell lines with known drug sensitivities and 130 primary MM patient samples collected at different disease stages, including newly diagnosed (ND), on therapy (OT), and relapsed and refractory (RR, collected within 12 months before the patients’ death) timepoints. Our findings led to the identification of a subset of genes linked to clinical drug resistance, poor survival, and disease progression following combination treatment containing IMIDs and/or PIs. Finally, we built a seven‐gene model (MM‐IMiD and PI sensitivity‐7 genes [IP‐7]) using digital gene expression profiling data that significantly separates ND patients from IMiD‐ and PI‐refractory RR patients. Using this model, we retrospectively analyzed RNA sequcencing (RNAseq) data from the Mulltiple Myeloma Research Foundation (MMRF) CoMMpass (n = 578) and Mayo Clinic MM patient registry (n = 487) to divide patients into probabilities of responder and nonresponder, which subsequently correlated with overall survival, disease stage, and number of prior treatments. Our findings suggest that this model may be useful in predicting acquired resistance to treatments containing IMiDs and/or PIs.

The purpose of our evaluation is to provide an example of how public health schools can use service-learning courses to teach students about health equity. By ensuring that the future workforce has a comprehensive understanding of regions such as the U.S./Mexico border, students will be better equipped to provide public health services. Specifically, our objectives were to (1) understand how student perceptions of the border evolve during the 1-week Border Health Service-Learning Institute (BHSLI) course and (2) understand how the service-learning experience impacted students’ proposed personal and professional goals. Using BHSLI student journals collected over 9 years, we conducted a qualitative investigation to evaluate students’ experiences of the service-learning course. Our findings suggest that BHSLI offered opportunities for advancing dialogue about health equity. Because BHSLI is immersive, it showed students a reality that they would not normally encounter. In reflecting on these new experiences, students were not only encouraged to question systems and policies but also made accountable to act upon the insights they gained. We found that BHSLI was a space for critical consciousness building, for shifting paradigms. Students learned how to intervene in real time to make change around public health issues. Service learning could be a practice-based solution to help public health students learn about health equity, especially in historically marginalized regions such as the U.S./Mexico border.

AbstractDecline of olfactory function is frequently observed in aging and is an early symptom of neurodegenerative diseases. As the olfactory bulb (OB) is one of the first regions involved by pathology and may represent an early disease stage, we specifically aimed to evaluate the contribution of OB pathology to olfactory decline in cognitively normal aged individuals without parkinsonism or dementia. This clinicopathological study correlates OB tau, amyloid β (Aβ) and α‐synuclein (αSyn) pathology densities and whole brain pathology load to olfactory identification function as measured with the University of Pennsylvania Smell Identification Test (UPSIT) and clinical data measured proximate to death in a large autopsy study including 138 cases considered non‐demented controls during life. Tau pathology was frequently observed in the OB (95% of cases), while both Aβ (27% of cases) and αSyn (20% of cases) OB pathologies were less commonly observed. A weak correlation was only observed between OB tau and olfactory performance, but when controlled for age, neither OB tau, Aβ or αSyn significantly predict olfactory performance. Moreover, whole brain tau and αSyn pathology loads predicted olfactory performance; however, only αSyn pathology loads survived age correction. In conclusion, OB tau pathology is frequently observed in normally aging individuals and increases with age but does not appear to independently contribute to age‐related olfactory impairment suggesting that further involvement of the brain seems necessary to contribute to age‐related olfactory decline.

Background: A composite metric for the quality of glycemia from continuous glucose monitor (CGM) tracings could be useful for assisting with basic clinical interpretation of CGM data. Methods: We assembled a data set of 14-day CGM tracings from 225 insulin-treated adults with diabetes. Using a balanced incomplete block design, 330 clinicians who were highly experienced with CGM analysis and interpretation ranked the CGM tracings from best to worst quality of glycemia. We used principal component analysis and multiple regressions to develop a model to predict the clinician ranking based on seven standard metrics in an Ambulatory Glucose Profile: very low–glucose and low-glucose hypoglycemia; very high–glucose and high-glucose hyperglycemia; time in range; mean glucose; and coefficient of variation. Results: The analysis showed that clinician rankings depend on two components, one related to hypoglycemia that gives more weight to very low-glucose than to low-glucose and the other related to hyperglycemia that likewise gives greater weight to very high-glucose than to high-glucose. These two components should be calculated and displayed separately, but they can also be combined into a single Glycemia Risk Index (GRI) that corresponds closely to the clinician rankings of the overall quality of glycemia (r = 0.95). The GRI can be displayed graphically on a GRI Grid with the hypoglycemia component on the horizontal axis and the hyperglycemia component on the vertical axis. Diagonal lines divide the graph into five zones (quintiles) corresponding to the best (0th to 20th percentile) to worst (81st to 100th percentile) overall quality of glycemia. The GRI Grid enables users to track sequential changes within an individual over time and compare groups of individuals. Conclusion: The GRI is a single-number summary of the quality of glycemia. Its hypoglycemia and hyperglycemia components provide actionable scores and a graphical display (the GRI Grid) that can be used by clinicians and researchers to determine the glycemic effects of prescribed and investigational treatments.