Citations

1089 Background: T-DXd has become an important treatment option in mBC and other malignancies. Interstitial lung disease/pneumonitis (ILD) occurred in 10-14% of pts in the DESTINY-Breast trials (0-2% G5 ILD), and with potential lower incidence/severity in earlier line settings (Krop et al, ASCO 2023). We previously reported the Mayo Clinic Rochester, MN experience with T-DXd related ILD in mBC (Hoppenworth et al, ASCO 2024). Here, we expand the data to include patients treated at all locations of the Mayo Clinic Enterprise. Methods: We retrospectively identified pts with mBC who received ≥1 dose of T-DXd across the Mayo Clinic enterprise (Rochester, MN; Mayo Clinic Health System locations in MN/WI; Scottsdale, AZ; and Jacksonville, FL) between July 2022-December 2023. Demographic, mBC characteristics, and pulmonary clinical variables were abstracted from the clinical records. Data were summarized using descriptive statistics. Diagnosis of ILD was determined by treating clinicians, and severity was approximated to CTCAE V5 based on clinical documentation. Results: 252 pts with mBC received T-DXd during the study period. The majority were Caucasian (86%) and female (99%) with a median age of 63. 91 pts (36%) were current/formers smokers and 97 (39%) had prior pulmonary comorbidities. The majority had HER2 low (155, 62%) and HR positive (164, 65%) mBC. 35 (14%) developed any grade ILD [G1: 6 (17%), G2: 13 (37%), G3: 3 (8.6%), G4: 3 (8.6%), G5: 10 (29%)], with 15 (43%) presenting with ≥G3. 29 (83%) presented with at least 1 symptom (cough or SOB). Among those with previous pulmonary toxicity, 4 (33%) had previous pneumonitis in the ILD cohort. The median prior lines of all therapies (including endocrine therapy) were 5, with a median of 3 prior lines of chemotherapy in both the ILD (range 1-13) and non-ILD cohorts (range 1-13). Median onset to any grade ILD was 7 cycles. 20 pts (57%) received steroids for ILD. 14 (40%) had a bronchoscopy, all had a CT chest, 16 (46%) were hospitalized, 7 (20%) were intubated and 1 (3%) had a lung biopsy. Pts with G5 ILD had a median of 3 lines of chemo and a median of 8 cycles prior to onset of ILD, compared to 3 lines of chemo and a median of 7 cycles for those with G1-4 ILD. G5 pts were all Caucasian females, 5 were former smokers, 5 were non-smokers, 1 had a history of pneumonitis. T-DXd was rechallenged in 4 pts (G1-2 ILD) without ILD recurrence. Conclusions: In this retrospective case series,14% of pts treated with T-DXd experienced any grade ILD (4% G5) which is in alignment with the rate observed in the pivotal DESTINY-Breast trials, though with higher rates of G5 toxicity. Among those with ILD, increased lines of therapy were not associated with increased risk. Further research is needed to correlate risk.

Abstract Context Primary aldosteronism (PA) is a leading endocrine cause of secondary hypertension. Objective To support the development of the Endocrine Society Clinical Practice Guideline on managing PA. Data Source MEDLINE, Embase, Scopus, and others were searched on October 4, 2024. Study Selection Studies were selected by pairs of independent reviewers. Data Extraction Data were extracted and appraised by pairs of independent reviewers. Data Synthesis We included 95 studies (7 randomized trials and 88 observational studies). We did not identify trials that evaluated the outcomes of PA screening. One observational study suggested that screening was associated with higher rates of using PA-specific medical therapies and better blood pressure control. Patients managed with adrenal venous sampling (vs computed tomography alone) may have a better post-adrenalectomy biochemical cure rate, but with an increased risk of adrenal hemorrhage. Two small observational studies suggested that PA-specific medical or surgical therapy was likely associated with better blood pressure control than nonspecific therapy. Small randomized trials suggested that surgical therapy may be associated with better blood pressure control than medical therapy, with a lower number and dosage of antihypertensive medications. Compared to eplerenone, spironolactone may be associated with better control of hypokalemia and a lower number and dosage of antihypertensive agents. Unsuppressed plasma renin activity was associated with better control of hypokalemia, while suppression was associated with higher risk of mortality, atrial fibrillation, and stroke (very low certainty). Conclusion This systematic review addresses various aspects of managing PA and will support the development of the Endocrine Society guidelines.

ABSTRACT Evidence indicates that the integrity of in utero development influences late life healthy or unhealthy aging; however, specific links between them are unclear. Histone chaperone HIRA is thought to play a role in both life stages, and here, we explore this role using the murine pigmentary system by investigating and comparing the effects of its lineage‐specific knockout, either conditionally during embryogenesis or postnatally. Embryonic knockout of Hira in tyrosinase+ neural crest‐derived lineages, including melanoblasts, led to reduced melanoblast numbers during embryogenesis, with single‐cell RNA sequencing analysis indicating evidence of lineage‐specificity defects. This was supported in an in vitro model using melb‐a melanoblasts in which Hira knockdown affected lineage identity and melanoblast differentiation potential, with ATAC‐seq data indicating a role of HIRA in orchestrating chromatin accessibility. Interestingly, however, newborn Hira knockout mice had wild type numbers of differentiated melanocytes, albeit functionally defective, as demonstrated by very mild hypopigmentation of the first hair coat, increased melanocyte telomere‐associated DNA damage foci, and impaired response to proliferative challenge. Moreover, as they aged, mice with embryonic melanoblast Hira knockout displayed marked defects in melanocyte stem cell maintenance and premature hair graying. Importantly, this phenotype was not observed after postnatal inducible knockout, indicating an essential role for HIRA at embryonic stages that is transmitted to adulthood, rather than a direct postnatal requirement within the pigmentary system. This genetic model shows that HIRA function during early development lays a foundation for maintaining lineage identity and subsequent maintenance of adult tissue‐specific stem cells during aging.

Abstract Introduction:IgG4-related disease (IgG4-RD) is a systemic fibroinflammatory condition marked by lymphoplasmacytic infiltrates that tend to affect various organs, leading to diverse clinical manifestations. While commonly linked to conditions like pancreatitis and sialadenitis, it can also impact the lungs, causing pulmonary masses, consolidations, or pneumonia. Key histopathological features include IgG4-positive plasma cells and storiform fibrosis, although these may not always be present. Case Presentation: We present a case of an 82-year-old male with a past medical history significant for pulmonary cryptococcal infection and a previous COVID-19 infection, who presented to our pulmonology clinic with fatigue for two months followed by an upper respiratory infection that did not respond to several rounds of antibiotics. A chest CT scan revealed bilateral consolidative airspace opacities and lymphadenopathy. Subsequent bronchoscopy with transbronchial biopsy and bronchoalveolar lavage (BAL) suggested a possible cryptococcal infection; however, his symptoms did not improve after a course of fluconazole. A follow-up PET-CT scan showed increased metabolic activity in the bilateral pulmonary consolidations, thoracic adenopathy, a possible right supraclavicular lymph node, and bilateral inguinal lymph nodes. He underwent a repeat bronchoscopy with EBUS-guided biopsy of the FDG-avid lymphadenopathy, and pathology results indicated granulomatous inflammation. He was evaluated by ophthalmology for uveitis and signs of retinal detachment on brain MRI, as well as nephrology for a progressive decline in kidney function. A renal biopsy showed numerous plasma cells staining for IgG and IgG4, along with storiform interstitial nephritis, consistent with IgG4-related interstitial nephritis. His autoimmune evaluation revealed elevated levels of ANA, double-stranded DNA, RNP antibodies, and various IgG subclasses, including IgG1, IgG3, and IgG4. Considering the biopsy results and the reduced suspicion of an infectious process, he was initiated on immunosuppression treatment with prednisone and rituximab for the IgG4-related disease which resulted in significant improvement in both the patient's symptoms and kidney function. Discussion:In conclusion, this case emphasizes the diagnostic challenges of IgG4-related pulmonary disease, largely due to the nonspecific nature of the respiratory manifestations. In our case, the diagnosis remained unclear despite the patient undergoing both transbronchial and EBUS-guided lymph node biopsies. This highlights the importance of maintaining a high clinical suspicion for this underdiagnosed condition as early treatment can lead to notable recovery.

Abstract Introduction: The variety of pulmonary function tests (PFTs) offered in the pulmonary function lab (PFL) can confuse providers unfamiliar with the clinical role of the individual components of the PFT, potentially leading to repeat tests, diagnostic delays, patient burden, and reduced lab efficiency. We hypothesized that a symptom- and diagnosis-based ordering set will reduce the need for repeat testing visits. Methods: Baseline data (June 2022-June 2023) were first collected to establish PFL performance benchmarks and identify common reasons for incomplete or repeat PFL visits. We then implemented an electronic order set reflecting the clinical need of the PFT, based on symptoms, diagnoses, suspected diagnoses, or other common clinical indication in addition to a physician-supervised, results-driven protocol to allow de-escalation of testing when appropriate The pre-implementation data was compared to the post-implementation data (July 2023-June 2024), evaluating for its impact on PFL access, utilization of the specific PFT components (e.g. methacholine challenge test, MCT), and on diagnoses. Results: During the study period 52,292 PFTs were performed during the pre-implementation phase compared to 58,310 tests in the post-implementation phase. Following intervention, the need for a second PFL visit for the same clinical indication decreased from 26% to 13% (p<0.0001). The same day PFL capacity increased by 3-4 patients per day. 80% of primary care providers reported the new order design was more intuitive and easier to use. Among the specific components of the PFT, there was a significant increase in the number MCTs being performed, from 2.5% to 4%, (p<0.0001), with a change rate ranging between 26 – 81% / month. In a subset analysis of 57 consecutive patients having MCTs, the primary indications were evaluation for cough or wheezing (57.9%), initial asthma evaluation (22.8%), and specifically requested by the ordering provider (19.3%). MCT was not performed in 23% due to a low baseline lung function, difficulty with repeatable efforts, recent bronchodilator administration, or due to complicating comorbidities. Of the 39 tests completed, 89% were deemed appropriate, with 32% having positive results and 42% ultimately diagnosed with asthma. Conclusions: A symptom and/or diagnosis guided ordering set for pulmonary function testing appears to improve the efficiency of the PFL, while improving provider experience, PFL access, as well as on patient burden and diagnoses. Further research is needed to determine potential benefits for provider decision-making and patient outcomes.

Abstract Introduction Abemaciclib is a selective CDK4/6 inhibitor approved for metastatic breast cancer. We report the clinical course of Abemaciclib-induced pneumonitis, emphasizing the need for vigilant monitioring for interstitial lung disease (ILD) in patients receiving this therapy. Case description An 85-year-old woman with a history of HR-positive, HER2-negative breast cancer, Atrial fibrillation, and stage 3 chronic kidney disease presented with cough and weakness and a temperature of 100.1° F. She was hypoxic, requiring 4 liters of oxygen, she was in atrial fibrillation with a heart rate of 114, and blood pressure was 98/46. Laboratory testing showed an NT-Pro BNP: 5768, leukocytes: 2900 with 420 lymphocytes and an acutely elevated creatinine of 1.83 mg/dL (basline 1.3-1.4 mg/dL). Her CRP was 245 mg/L. Chest X-Ray revealed diffuse interstitial opacities. She was treated for pneumonia with cefepime and azithromycin, volume resuscitation and subsequent diuresis. However, her hypoxia continued to worsen. A chest CTA excluded pulmonary embolism but revealed progression of diffuse ground-glass and reticular opacities with a basilar apical gradient and enlarged mediastinal and hilar lymph nodes. An echocardiogram showed a mildly enlarged right ventricle and elevated right ventricular systolic pressure of 60. Subsequent infectious and autoimmune workups were inconclusive, bronchoscopy evaluation was deferred due worsening respiratory status. Given the concern for drug induced pneumonitis she was started on a steroid taper with 2 mgs/kg of IV Methylprednisolone. Over two weeks, her condition improved, and she was discharged without supplemental oxygen. Discussion Pneumonitis is a rare adverse effect of abemaciclib likely driven from CDK4/6 inhibitors. In a safety analysis of the MONARCH 2&3 trials, the incidence of pneumonitis was 2-5%, compared to 0.4-0.6% in the placebo arms. In these trials, two and one patients died of pneumonitis respectively. Our patient received abemaciclib for 2 years and 10 months, during which her follow up PET CT scan few months after treatment initiation demonstrated a new ground-glass and reticular opacities that continued to worsen on subsequent surveillance PET CT scans with significant progression noted on admission CT. In the absence of other contributing factors, our patient was diagnosed with Grade 3 lung toxicity, and abemaciclib was discontinued. The progression of her imaging before admission highlights the need for close monitoring for interstitial lung disease in patients receiving abemaciclib, to determine if dose reduction or treatment adjustment is warranted.

Purpose The time to complete oncology pharmacist tasks is needed to determine workload and productivity. The Hematology/Oncology Pharmacy Association (HOPA) and the Hematology/Oncology Practice and Research Network (PRN) of the American College of Clinical Pharmacy (ACCP) partnered with the aim of establishing consensus on the time required to complete oncology pharmacy tasks. Methods Fifteen patient care tasks and 9 non-patient care tasks, commonly completed by oncology pharmacists were each assigned an average amount of time to be completed. This list was then converted into 24 statements and the Delphi survey method was utilized with an expert panel to arrive at consensus between December 2023 and February 2024. Consensus was defined as at least 75% agreement. The complete manuscript was endorsed by HOPA and ACCP Hematology/Oncology PRN. Results Thirty-three pharmacist-experts agreed to participate in this survey with all participating in round 1, and 29 (87.9%) participating in round 2. In round 1, 9 tasks achieved consensus, with 7 of these being classified as patient care associated. Seven statements reaching 65% but less than 75% agreement were deemed to reach borderline consensus. Eight statements failed to achieve at least 65% agreement and were modified based on respondent feedback. In round 2, 15 statements were included with all achieving consensus. At the completion of round 2, all 24 statements reached consensus, and the survey was deemed complete. Conclusion This project produced the first comprehensive consensus statements for the average time for a US-based oncology pharmacist to complete common patient and non-patient care-related tasks.

Background/Objectives: This study aimed to establish the clinical utility of a therapeutic drug monitoring (TDM)-supported, model-informed precision dosing (MIPD) approach (precision-guided dosing [PGD]) by assessing the impact of pharmacokinetic (clearance [CL]) and clinical laboratory parameters on adalimumab (ADA) dosage adjustments during maintenance therapy for inflammatory bowel disease (IBD). Methods: In the EMPOWER study, blood was collected at any time post-ADA injection. Pharmacokinetic (PK) testing was conducted in an accredited lab. Inputs for the PGD test included ADA concentrations, antibodies to ADA, albumin levels, and the current dosing regimen. CL was calculated using nonlinear mixed-effect models. Results were reported to health care providers (HCPs) within 3 days. HCPs’ treatment decisions were recorded and classified as treatment reduction, continuation, intensification, or ADA discontinuation. The physician global assessment (PGA) of disease activity was collected. Relationships between drug concentrations, CL, disease activity, and physician decision-making were assessed using logistic regression. Results: A total of 213 cases were assessed by 21 HCPs. ADA treatment was intensified in 24% and discontinued in 13% of cases. An ADA concentration ≤ 10 μg/mL was associated with a 23.7-fold and 3.0-fold higher likelihood of therapy intensification and PGA > 0, respectively, compared to concentrations > 10 μg/mL. An ADA concentration < 5 μg/mL was associated with a 3.3-fold higher likelihood of treatment discontinuation. CL ≥ 0.318 L/day was associated with a 10.4-fold higher likelihood of therapy intensification. Higher CL (>0.8 L/day) was associated with a 3.5-fold and 4.2-fold higher likelihood of treatment discontinuation and PGA > 0, respectively. Conclusions: PGD enables earlier and precise optimization of ADA dosing by predicting trough levels at any time during the therapy cycle. Optimized dosing to achieve target ADA concentrations and low clearance is crucial to mitigate therapy discontinuation and active disease in IBD patients.

Abstract Objective Dravet syndrome (DS) is a developmental and epileptic encephalopathy. Diagnosis is clinical, but ~90% of patients have pathogenic variants in SCN1A . ATP6V0C has recently been proposed as a novel candidate gene for epilepsy, with or without developmental delay. Here we describe two adult patients with a clinical diagnosis of DS associated with ATP6V0C variants. Methods Patients with developmental and epileptic encephalopathies were evaluated by physicians who are experts in DS, and their clinical diagnosis was correlated with genetic findings. A subgroup of those patients with DS but without known genetic causes were evaluated through gene panels, whole exome sequencing, and chromosome microarray. Phenotype was determined by pediatric and adult chart reviews, interviews, and physical examinations. Results Of 753 patients with DS, two unrelated individuals with classic features of DS during childhood and adulthood were identified with heterozygous de novo missense variants in ATP6V0C (c.319G > C, p.(Gly107Arg) and c.284C > T, p.(Ala95Val), respectively). Both variants were absent in normal populations and computational prediction algorithms suggested deleterious effects on protein structure and/or function. No disease‐causing variants in other genes previously associated with DS were found. Significance Here we describe two adult patients with Dravet‐like syndrome and pathogenic/likely pathogenic variants in ATP6V0C . We propose that abnormal ATP6V0C function can, at the severe end of the clinical spectrum, be associated with Dravet‐like phenotype. This is relevant, as these patients would not qualify for disease‐modifying antisense nucleotide or gene therapies targeting SCN1A .