Citations

Introduction: While Coronavirus disease 2019 (COVID-19) primarily affects the respiratory system but can impact the cardiovascular system can triggering various complications. Hypothesis: To investigate the trend in age-adjusted mortality rates (AAMRs) in patients with atrial fibrillation(AF) among COVID-19-positive patients (CPP) by race and sex. Methods: Trends in AAMRs (per 100,000) from all-cause in patients with AF between April to December 2016-2020 were evaluated via the National Inpatient Sample and the US Census Bureau. The AAMRs among CPP with AF in 2020 was also evaluated between racial and sex cohorts. Results: A gradual rise in AAMR(all causes) in patients with AF was observed between 2016-2019, with a 49.4% overall rise between 2019(271 per 100,000) and 2020(405 per 100,000) ( Table 1a and Figure ). Around 250475 COVID-19-positive patients had AF, and 24.2% of cases did not survive their hospitalization (vs. 10.9% in those without AF, p<0.01, aOR 1.457, 95% CI 1.438-1.477). Among CPP males and females with AF that died, White females and males were the oldest, while Black males and females reported the highest mean Charlson Comorbidity Index (CCI) score ( Table 1b ).Furthermore, among the CPP with AF in 2020, Hispanics reported a higher AAMR (119.6 per 100,000) than Whites(111.1 per 100,000) and Blacks(101.9 per 100,000). AAMRs in males were higher in Hispanic males (144.8 per 100,000), followed by White males (129.7 per 100,000), and Black males (110 per 100,000). However, the AAMRs in females were highest in Black females (91.3 per 100,000), followed by White females (88.3 per 100,000) and Hispanic females (87.0 per 100,000). ( Table 1c ) Conclusions: AAMRs in patients with AF are on the rise and a sharp growth was seen during the first year of the pandemic. AAMRs among CPP patients with AF were highest among Black females and Hispanic males, while White males and females were oldest and Black males and females reported the highest CCI scores.

Background:Richter transformation (RT) occurs in up to 10% of patients with chronic lymphocytic leukemia (CLL), typically presents as an aggressive diffuse large B-cell lymphoma (DLBCL) and is associated with poor survival. RT has no approved standard therapy; and clinical trial enrollment is the preferred first line of therapy. Pirtobrutinib, a highly selective, non-covalent (reversible) BTKi, that inhibits both wildtype and C481-mutant BTK with equal low nM potency, has favorable oral pharmacology that enables continuous BTK inhibition throughout the dosing interval. Pirtobrutinib demonstrated durable overall response rates (ORR) and was well tolerated in patients (pts) with poor-prognosis B-cell malignancies regardless of prior therapy. Here we provide updated safety and efficacy of pirtobrutinib in RT pts from the phase 1/2 BRUIN trial (NCT03740529). Methods: Pts with previously treated, histologically confirmed RT were eligible in the global, multicenter, phase 1/2 BRUIN study. Pts with untreated RT became eligible after Amendment 10. All but one patient received the recommended phase 2 dose of 200 mg daily. Key endpoints included investigator-assessed ORR, DoR per Lugano 2014 criteria, OS, and safety. A data cut of 05 May 2023 was utilized. To assess clonal relationship, IGH rearrangement studies were done on tissue biopsies with RT involvement, and baseline blood or bone marrow (BM) samples with CLL involvement. Results: Among all pts with RT (N=82) the median age was 67 (range, 26-95) and the median total number of lines of prior systemic therapy was 4 (range, 0-13). Pts with prior treatment had a median of 2 CLL-directed therapies and 2 RT-directed therapies. Eight pts did not have a previous line of RT-directed therapy, and 1 patient received neither RT- nor CLL-directed therapy. Common prior RT- and CLL-directed therapies (RT, CLL) included: chemotherapy (76%, 52%), cBTKi (34%, 62%), anti-CD20 antibody (78%, 66%), BCL2i (38%, 49%), stem cell transplant (SCT; 6%, 7%), and CAR-T (11%, 4%). Of 29 pts with bone marrow screening, 41.4% had CLL alone present in BM, 13.8% had DLBCL present and 24.1% had both CLL and DLBCL present. For 39 pts with available PET data, the median SUVmax was 19.1 (range, 2.6-41.2). For all 82 pts, the ORR was 50.0% (95% CI, 38.7-61.3) including complete (13.4%, n=11) and partial (36.6%, n=30) responses. For 61 pts who received prior cBTKi therapy, the ORR was 45.9% (95% CI 33.1-59.2). Among 28 pts with an RT-directed cBTKi and 51 pts with prior CLL-directed cBTKi, the ORR was 42.9% (95% CI, 24.5-62.8) and 43.1% (95% CI, 29.3-57.8), respectively. In 50 pts who discontinued prior cBTKi due to disease progression, the ORR was 42.0% (95% CI, 28.2-56.8). At median follow-up time of 9.7 months, the median DoR for all 82 RT pts was 7.4 months (95% CI, 3.1-19.1) and the estimated rate at 12 months was 45.9% (95% CI, 28.3-61.8). The median time on treatment for the 41pts who responded to treatment was 8.3 months. Eight pts stopped pirtobrutinib to pursue curative-intent allogeneic SCT and DoR was censored at the last preceding disease assessment. At a median survival follow-up of 18.3 months, the median OS for the entire RT cohort was 12.5 months (95% CI, 6.9-20.5). At 18 months, the OS rate was 44.3% (95% CI, 32.5-55.4). Frequent treatment-emergent adverse events (TEAE) in the RT cohort (n=82) were neutropenia/decreased neutrophil count (29.3%, n=24), fatigue (24.4%, n=20) and diarrhea, dyspnea, thrombocytopenia, and pyrexia (18.3% each, n=15). Common grade ≥3 TEAEs were neutropenia/decreased neutrophil count (23.2%, n=19), thrombocytopenia (11.0%, n=9), plus anemia and sepsis (9.8% each, n=8). Any grade hypertension (3.7%, n=3) or atrial fibrillation (1.2%, n=1) were infrequent. Three pts (3.7%) had treatment-related AEs leading to dose reductions, but no pt had a treatment-related AE leading to pirtobrutinib discontinuation. Analyses of clonality will be presented. Conclusions: Continued follow-up from BRUIN demonstrates encouraging response and OS in pts with RT. Pirtobrutinib remains well-tolerated with low rates of discontinuation and manageable safety profile. While RT remains a challenging diagnosis, pirtobrutinib represents a potential treatment option that warrants further investigation.

Background Screening for monoclonal gammopathy (MG) is often performed in the evaluation of anemia. While certain MGs may be associated with anemia, these are rare conditions. Monoclonal gammopathy of undetermined significance (MGUS; prevalence of 8% among age &gt;50 years) is common, but rarely causes anemia in isolation. Therefore, abnormal results from MG screening may be unrelated to patient symptoms and result in both financial and psychological harm. Limited data exist to guide clinicians regarding the utility of MG testing for anemia. Aims This study aims to describe both the clinical utility of MG screening during the evaluation of anemia and the most common etiologies for anemia in patients whose workup included MG screening. Methods We reviewed medical records of patients who received MG screening to evaluate anemia at Mayo Clinic in 2021. Patients with a previously diagnosed MG were excluded. MG testing included serum protein electrophoresis and free light chain assessments. The following data were extracted: hemoglobin, hematocrit, mean corpuscular volume (MCV), calcium, creatinine, eGFR, and the final hematologic diagnosis related to the monoclonal protein. Clinician documentation was evaluated to determine the attributed etiology of anemia. Results Among the 271 patients with anemia who were screened for MG, 33 (12.2%) were found to have a newly diagnosed MG. Only 2 patients screened for MG were ultimately found to have anemia caused by MG. These included a case of multiple myeloma and one patient with cold agglutinin disease and secondary hemolysis. In all patients screened, their anemia was ultimately thought to be due to iron deficiency (31.7%), B12 deficiency (3.0%), anemia of chronic disease (ACD)/inflammatory anemia (14.4%), chronic kidney disease (CKD) (3.7%), hemolysis (1.5%), hypogonadism (1.9%), idiopathic (21.0%), multifactorial: iron deficiency + ACD/inflammatory (3.0%), multifactorial: nutritional; iron deficiency + B12 deficiency (3.0%), multifactorial: ACD + CKD (5.2%), multifactorial: iron deficiency + CKD (1.8%), multifactorial: not otherwise specified (NOS) (6.6%), medications (0.4%), and other (2.6%). Both patients with newly diagnosed MG associated anemia presented with peripheral neuropathy as their primary symptom. Among these 2 patients diagnosed with dysproteinemia associated anemia, only one (0.4%) was placed on therapy for their MG. Summary/Conclusions In the evaluation of anemia, routine MG screening has low clinical utility. Less than 1 in 100 patients were found to have anemia attributable to MG. Furthermore, only 0.4 in 100 patients received MG-directed therapy. Most patients screened with SPEP for undifferentiated anemia were found to have anemia attributable to common causes including iron/nutritional deficiency, inflammatory processes, and CKD. Most patients with undifferentiated anemia would benefit from an anemia evaluation that focuses on the most common causes up front. Given the cost to healthcare and potential psychological harm to the patient of incidental MG diagnosis, further study is warranted to guide clinicians and limit the ordering of MG testing to individuals who are most likely to derive benefit.

Abstract Immunomodulatory drugs (IMiD) are a backbone therapy for multiple myeloma (MM). Despite their efficacy, most patients develop resistance, and the mechanisms are not fully defined. Here, we show that IMiD responses are directed by IMiD-dependent degradation of IKZF1 and IKZF3 that bind to enhancers necessary to sustain the expression of MYC and other myeloma oncogenes. IMiD treatment universally depleted chromatin-bound IKZF1, but eviction of P300 and BRD4 coactivators only occurred in IMiD-sensitive cells. IKZF1-bound enhancers overlapped other transcription factor binding motifs, including ETV4. Chromatin immunoprecipitation sequencing showed that ETV4 bound to the same enhancers as IKZF1, and ETV4 CRISPR/Cas9-mediated ablation resulted in sensitization of IMiD-resistant MM. ETV4 expression is associated with IMiD resistance in cell lines, poor prognosis in patients, and is upregulated at relapse. These data indicate that ETV4 alleviates IKZF1 and IKZF3 dependency in MM by maintaining oncogenic enhancer activity and identify transcriptional plasticity as a previously unrecognized mechanism of IMiD resistance. Significance: We show that IKZF1-bound enhancers are critical for IMiD efficacy and that the factor ETV4 can bind the same enhancers and substitute for IKZF1 and mediate IMiD resistance by maintaining MYC and other oncogenes. These data implicate transcription factor redundancy as a previously unrecognized mode of IMiD resistance in MM. See related article by Welsh, Barwick, et al., p. 34. See related commentary by Yun and Cleveland, p. 5. This article is featured in Selected Articles from This Issue, p. 4

518 Background: Oncology has entered the digital era, accompanied by changes in patient interactions and expectations involving telemedicine. While much emphasis is appropriately placed on digital interactions with patients, little is known about modern non-digital interactions with patients in oncology practices. Methods: We analyzed Medical Oncology Pager (MOP) data from 7/1/18 – 4/14/23, during which patients had access to the electronic health record and messaging capabilities. The MOP for Mayo Clinic (Rochester) is covered by the medical oncology fellows, including after hours (6PM – 7AM). It covers consults and direct patient calls after hours and during weekends, in addition to critical results back up and inpatient oncology matters at all times. We also analyzed Medical Oncology Call Center (MOCC) data since 6/1/22, which takes inbound patient calls during working hours (7AM – 6PM) and is staffed by appointment office employees. Results: The MOP received a total of 17,679 pages during the analyzed period for a mean of 10.1 pages per day. Of these, 6,319 pages occurred after hours. The most after-hours pages were received on Fridays (n=1,091) and the least on Sundays (n=701); of those years with fully available data, 2022 had the highest volume (n=1,405) (Table 1). When comparing the MOP activity pre-pandemic (7/1/18 – 3/10/20) and intra-pandemic (3/11/20 – 4/14/23), the mean number of after-hours pages per day was relatively stable with 3.47 pre-pandemic and 3.69 intra-pandemic. Since 6/1/22, the MOCC has averaged 6,464 inbound calls per month during working hours, each of which had an average talk time of approximately five minutes. The majority of inbound calls occur on Monday mornings between 9 – 11AM, with over 6,500 recorded throughout the previous year. Conclusions: Telemedicine is multi-faceted, comprised of both digital and non-digital patient interactions. We show that many oncology patients utilize telephone communication with the healthcare system despite increased availability of digital capabilities. These data have implications for addressing the digital divide for those with limited digital access, serving older patient populations unfamiliar with digital technologies, healthcare navigation, trainee responsibilities, and resource allocation. Further work and standardization in non-digital telemedicine is necessary as it remains a pillar of modern healthcare delivery and oncology practices.[Table: see text]