Prior Drug Research Articles

Characterization of ventricular tachycardia ablation in end-stage heart failure patients with left ventricular assist device (CHANNELED-Registry)

Abstract Background Left-ventricular-assist-devices (LVAD) are an established therapy for patients with end-stage heart failure. These patients are at high risk for ventricular tachycardia (VT) and ICD-shocks due to the arrhythmogenic substrate of the underlying cardiomyopathy itself and as the LVAD cannula might be arrhythmogenic, too. Purpose Data on catheter ablation of VT in LVAD patients are scarce and current evidence predominantly consists of case reports and small single-center series. This multicenter registry seeks to systematically assess the mechanism and origin of VA in LVAD patients and to evaluate procedural parameters and outcome of VT ablation in this special subset of patients. Methods Retrospective data of LVAD patients referred for VT ablation at 11 tertiary care centers between January 2017 and August 2023 were included in this multicenter registry. VT mechanisms, procedural data, clinical follow-up, and outcome were assessed. Results We report 49 patients (88% male, age 61±8 years) undergoing 51 ablation procedures included in this ongoing registry. The underlying cardiomyopathy was ischemic in 25/49 patients (51%) and nonischemic in 24/49 patients (49%) with a mean left ventricular ejection fraction of 21%±6% before LVAD implantation. Most catheter ablations were conducted after prior antiarrhythmic drug (AAD) treatment (15/51 on amiodarone, 13/51 on prior intensification of amiodarone treatment, 18/51 on prior combination of two or more AADs). A total of 75 VTs were targeted (39/51 transseptal, 3/51 retrograde aortic, 9/51 combined approaches) and 13/49 patients required VT ablation less than 1 month after LVAD implantation. Of the targeted VTs the majority (69%) were cardiomyopathy related and only 31% of the targeted VTs were related to the LVAD cannula. In 5/51 procedures access site complications and in 1/51 procedures a pericardial effusion occurred; one patient showed a post procedural oxygen desaturation; despite immediate intubation the patient deceased from hypoxic brain injury. No LVAD related complications were observed. A follow-up was available for 35/49 patients. During a median follow-up of 277 days (IQR 78-625 days), 5/35 patients were transplanted and 13/35 died. Patients died after a median time of 124 days (IQR 34-952 days) primarily from heart failure, sepsis, or intracranial bleeding. Of the remaining 17/35 patients, 7/17 patients were arrhythmia-free at a median follow-up of 212 days (IQR 78-639 days). Conclusion Although often chosen as last resort, catheter ablation of VT in LVAD patients is feasible and can be performed safely in this critically ill subset of heart failure patients in experienced centers. Intrinsic myocardial scar seems to be the dominant substrate in these patients but LVAD cannulae contribute to a significant number of VTs. In the presence of severely reduced LV function the VT recurrence remains high despite maximal therapy and prognosis of these patients is limited.

The Efficacy and Safety of Sodium-Glucose Co-transporter2 (SGLT2) Inhibitors in Real-World Clinical Practice: Potential Cautionary Use in Elderly Patients with Type2 Diabetes (T2D).

Sodium-glucose co-transporter2 (SGLT2) inhibitors have shown safe and therapeutic efficacy in randomized controlled trials (RCT) to reduce adverse cardiorenal events in high-risk patients with type2 diabetes (T2D). In this study, we investigated the efficacy and safety of SGLT2 intervention in patients with T2D in a real-world clinical practice to confirm the validity of the RCT results. As a retrospective study, we evaluated medical records from 596 patients with T2D treated with SGLT2 inhibitors (dapagliflozin or empagliflozin) in addition to their prior drug regimen to improve glucose control between 2015 and 2019 in the Endocrinology Department at Chungbuk National University Hospital. No control arm was evaluated to compare the effects of adding SGLT inhibitors to the pre-existing regimen. The primary objective was the measurement of glycated hemoglobin (HbA1c) from each individual patient over a 36-month period at 6-month intervals. The secondary parameters were the measurement of fasting plasma glucose (FPG) and body weight (Bwt) changes, as well as the monitoring of adverse events (AEs) and determining the reasons for drug discontinuation. HbA1c levels were reduced at each of the time points throughout the 36-month period and were significantly reduced by 12.5% (P < 0.01) from time0 (8.8 ± 1.3%) to 36months (7.7 ± 1.0%). FPG levels [from basal (180 ± 60mg/dL) to 36months (138 ± 38mg/dL)] and Bwt [from basal (74 ± 15kg) to 36months (72 ± 15kg)] were also significantly reduced (P < 0.01) for both measurements in the SGLT2 inhibitor add-on group. Similar to HbA1c profile, the FPG and Bwt were measured at a consistently lower level at 6months until the end of the study. The most common AEs were hypoglycemia (n = 57), genitourinary infection (GUI) (n = 31), and polyuria (n = 28). In the elderly population (≥ 75years old), AEs (31%) were generally more prevalent (P < 0.001) than those (21%) in the adult (< 75years old) patients. Over the study period, 211 (35%) patients either dropped or completely discontinued the use of the SGLT2 inhibitor, and the elderly patients tended to have a higher discontinuation rate (52%; P = 0.005) than the adults (33%). In this study, we demonstrated that SGLT2 inhibitors are an effective and durable hypoglycemic agent to control blood glucose levels with reduced maintenance of Bwt, but their use in the elderly (≥ 75years old) patients with T2D may warrant some additional caution due to increased probability of AEs and discontinuation of drug use.

DReAmocracy: A Method to Capitalise on Prior Drug Discovery Efforts to Highlight Candidate Drugs for Repurposing.

In the area of drug research, several computational drug repurposing studies have highlighted candidate repurposed drugs, as well as clinical trial studies that have tested/are testing drugs in different phases. To the best of our knowledge, the aggregation of the proposed lists of drugs by previous studies has not been extensively exploited towards generating a dynamic reference matrix with enhanced resolution. To fill this knowledge gap, we performed weight-modulated majority voting of the modes of action, initial indications and targeted pathways of the drugs in a well-known repository, namely the Drug Repurposing Hub. Our method, DReAmocracy, exploits this pile of information and creates frequency tables and, finally, a disease suitability score for each drug from the selected library. As a testbed, we applied this method to a group of neurodegenerative diseases (Alzheimer's, Parkinson's, Huntington's disease and Multiple Sclerosis). A super-reference table with drug suitability scores has been created for all four neurodegenerative diseases and can be queried for any drug candidate against them. Top-scored drugs for Alzheimer's Disease include agomelatine, mirtazapine and vortioxetine; for Parkinson's Disease, they include apomorphine, pramipexole and lisuride; for Huntington's, they include chlorpromazine, fluphenazine and perphenazine; and for Multiple Sclerosis, they include zonisamide, disopyramide and priralfimide. Overall, DReAmocracy is a methodology that focuses on leveraging the existing drug-related experimental and/or computational knowledge rather than a predictive model for drug repurposing, offering a quantified aggregation of existing drug discovery results to (1) reveal trends in selected tracks of drug discovery research with increased resolution that includes modes of action, targeted pathways and initial indications for the investigated drugs and (2) score new candidate drugs for repurposing against a selected disease.

Risk of adverse events in patients with bullous pemphigoid treated with oral corticosteroids in the United States

AbstractBackgroundThe potential association of long‐term oral corticosteroid (OCS) use with adverse events (AEs) in patients with bullous pemphigoid (BP) is not well characterized in a real‐world setting.ObjectiveTo evaluate the effect of OCS use and treatment duration on the incident AEs in patients with BP.MethodsThis retrospective cohort study used medical and pharmacy claims and patient enrollment data from IQVIA PharMetrics® Plus from 2006−2021. Eligible patients had a diagnosis of BP between 1 January 2006 and 30 June 2020 (≥2 claims for BP ≥ 30 days apart). Patients in the OCS cohort also had a claim for OCS use, ≥7.5 mg daily dose of prednisone or equivalent, and no claims for a nonoral systemic corticosteroid (CS) at any time during the study period. A control cohort of patients with BP not using OCS was also selected. Relative risk ratios were estimated between the incidence of AEs in OCS users with different exposure durations (short‐term, &lt;30 days; medium‐term, 30−90 days; long‐term, &gt;90 days) and nonusers by Poisson regression, after adjusting for age, sex, prior drug use, and baseline Charlson Comorbidity Index score within the follow‐up period.ResultsAt the 1‐year follow‐up, long‐term OCS users had a higher incidence of infections, cataract, osteoporosis, heart failure, depression or anxiety, and diabetes compared with OCS nonusers (p &lt; 0.05). Furthermore, compared with nonusers, long‐term users had increased 1‐year risks (risk ratio; 95% confidence interval) for heart failure (2.27; 1.50−3.44), diabetes (2.05; 1.30−3.24), osteoporosis (1.72; 1.23−2.41), and infection (1.50; 1.13−1.99). Long‐term OCS users also had increased 1‐year risks for heart failure (2.00; 1.21−3.28) and osteoporosis (1.70; 1.16−2.50) compared with short‐term OCS users.ConclusionLong‐term OCS use (≥7.5 mg) in patients with BP was associated with an increased risk of AEs. Study findings demonstrate a need for steroid‐sparing options with an improved safety profile.

Reduced fetal cerebral blood flow predicts perinatal mortality in a mouse model of prenatal alcohol and cannabinoid exposure

BackgroundChildren exposed prenatally to alcohol or cannabinoids individually can exhibit growth deficits and increased risk for adverse birth outcomes. However, these drugs are often co-consumed and their combined effects on early brain development are virtually unknown. The blood vessels of the fetal brain emerge and mature during the neurogenic period to support nutritional needs of the rapidly growing brain, and teratogenic exposure during this gestational window may therefore impair fetal cerebrovascular development.Study DesignTo determine whether prenatal polysubstance exposure confers additional risk for impaired fetal-directed blood flow, we performed high resolution in vivo ultrasound imaging in C57Bl/6J pregnant mice. After pregnancy confirmation, dams were randomly assigned to one of four groups: drug-free control, alcohol-exposed, cannabinoid-exposed or alcohol-and-cannabinoid-exposed. Drug exposure occurred daily between Gestational Days 12–15, equivalent to the transition between the first and second trimesters in humans. Dams first received an intraperitoneal injection of either cannabinoid agonist CP-55,940 (750 µg/kg) or volume-equivalent vehicle. Then, dams were placed in vapor chambers for 30 min of inhalation of either ethanol or room air. Dams underwent ultrasound imaging on three days of pregnancy: Gestational Day 11 (pre-exposure), Gestational Day 13.5 (peri-exposure) and Gestational Day 16 (post-exposure).ResultsAll drug exposures decreased fetal cranial blood flow 24-hours after the final exposure episode, though combined alcohol and cannabinoid co-exposure reduced internal carotid artery blood flow relative to all other exposures. Umbilical artery metrics were not affected by drug exposure, indicating a specific vulnerability of fetal cranial circulation. Cannabinoid exposure significantly reduced cerebroplacental ratios, mirroring prior findings in cannabis-exposed human fetuses. Post-exposure cerebroplacental ratios significantly predicted subsequent perinatal mortality (p = 0.019, area under the curve, 0.772; sensitivity, 81%; specificity, 85.70%) and retroactively diagnosed prior drug exposure (p = 0.005; AUC, 0.861; sensitivity, 86.40%; specificity, 66.7%).ConclusionsFetal cerebrovasculature is significantly impaired by exposure to alcohol or cannabinoids, and co-exposure confers additional risk for adverse birth outcomes. Considering the rising potency and global availability of cannabis products, there is an imperative for research to explore translational models of prenatal drug exposure, including polysubstance models, to inform appropriate strategies for treatment and care in pregnancies affected by drug exposure.

Acute Myopic Shift after a Single Dose of Acetazolamide: A Case Report and Review of the Literature.

We report the case of a 32-year-old male who presented with an acute myopic shift as a result of uveal effusion following a single administration of 250 mg acetazolamide. The drug was discontinued and following cycloplegia and topical steroid therapy, we observed progressive deepening of the anterior chamber, reopening of the iridocorneal angle, and complete resolution of the myopic shift after 5 days. A literature review since 1956 identified 23 cases, including ours, which developed a myopic shift after a median time of 24 h (3 - 24) following a median dose of 500 mg (125 - 1000) acetazolamide, with about a third complicated by angle closure ocular hypertension. This presumed idiosyncratic reaction can occur without prior drug exposure and independent of the phakic status. Treatment options include systematic drug withdrawal associated with cycloplegia, anti-glaucomatous agents, and/or corticosteroids. Full recovery is achieved within about 5 days (2 - 14). Given the widespread use of acetazolamide, awareness of this idiosyncratic reaction is crucial to avoid complications of acute angle-closure glaucoma.

Abstract 3541: Systematic assessment of the mechanism of action landscape of glue compounds

Abstract We have recently completed a large-scale project to elucidate the Mechanism of Action (MoA) of clinically relevant compounds in over twenty tumor specific contexts. Many novel, translationally relevant findings have arisen from this work, including (a) the identification of context-specific inhibitors of many proteins considered to be poor pharmacologic targets—including transcription (co-)factors and undruggable signaling proteins; (b) graph theory-based elucidation of drug polypharmacology; and (c) identification of MoA overlap between previously unrelated drugs. However, a limitation of the study is it relies on the existing repertoire of small-molecular inhibitors that is heavily biased towards specific target classes. Compounds that inhibit master regulators (MR) of tumor state are missing or under-represented. In this new project, we explore an extra molecular space of “molecular glues”, as they might be more effective modulators of MRs. Similar to our prior oncology drug study, we will leverage the automated PLATE-Seq technology and the VIPER algorithm to characterize compound MoA in a proteome-wide fashion. Specifically, we will first generate genome-wide RNA-Seq profiles of patient-matched cell lines using a panel of ~150 glue compounds, including a subset of them named PROteolysis TArgeting Chimeras (PROTACs) that were designed to degrade therapeutic targets by recruiting them to E3 ligases. We will analyze the PLATE-seq perturbational profiles with a set of complementary algorithms including the VIPER, which, akin to a multiplexed, tissue-specific gene reporter assay, can accurately measure the differential activity of over 6,000 regulatory/signaling proteins, by assessing the enrichment of their transcriptional targets in differentially expressed genes. Current effort of this project is focused on six PDA cell lines including three MAPK-pathway dependent (M+) and three MAPK-pathway independent (M-) contexts, each one representing the gastrointestinal lineage state (GLS), morphogenic state (MOS), and acinar to ductal metaplasia-like state (ALS). Using this data, we explore similarity-based connections between PLATE-seq perturbational profiles and the Connectivity Map (CMAP) that contains transcriptional consequences of chemical and genetic perturbations. We will also compare PLATE-seq perturbational profiles to tissue-specific differential expression signatures that distinguish cell lines sensitive to compounds in the Cancer Therapeutics Response Portal (CTRP) and Broad Repurposing Hub, each of which houses results from exposing hundreds of compounds exposed to dozens to hundreds of cell lines. Taken together, the data and analyses will help understand MoAs and polypharmacologies/off-targets of molecular glues, which also serve to enable interpretation and prioritization of new candidate MoA for molecular glues by comparing them to compounds with known targets and MoAs. Citation Format: Lucas ZhongMing Hu, Charles Karan, Andrea Califano. Systematic assessment of the mechanism of action landscape of glue compounds [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3541.

Treatment-relevant factors among adults receiving court-mandated substance use treatment: The role of emotion dysregulation.

Despite often being mandated to substance use treatment after release, many people on probation do not complete treatment. Several historical factors have been identified as relevant to substance use treatment in this population (i.e., past substance use, treatment history, and criminal history); however, less is known about the psychological characteristics, such as emotion dysregulation, that influence treatment-relevant factors among people in the criminal justice system. The present study used cross-sectional data to examine whether emotion dysregulation was associated with past-year substance use severity, engagement in prior drug and alcohol use treatments (yes/no, number of prior treatments), and previous criminal charges (total number of charges, number of charge types) in a sample of adults on probation who were receiving court-mandated substance use treatment (N = 163). We also examined whether these relationships varied across sex. Results showed that overall emotion dysregulation was more strongly linked to substance use severity and criminal charges for females than males. Emotion dysregulation dimensions of difficulties engaging in goal-directed behaviors and controlling impulsive behaviors when distressed were associated with more severe past-year substance use, more prior drug treatments, and a greater number of lifetime criminal charges and charge types. Emotion dysregulation plays a role in substance use treatment-relevant factors among people on probation. Sex-specific clinical implications of targeting emotion dysregulation in the context of mandated treatment in order to prevent treatment failures are discussed. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

White Paper: American Gastroenterological Association Position Statement: The Future of IBD Care in the United States–Removing Barriers and Embracing Opportunities

Despite incredible growth in systems of care and rapidly expanding therapeutic options for people with inflammatory bowel disease, there are significant barriers that prevent patients from benefiting from these advances. These barriers include restrictions in the form of prior authorization, step therapy, and prescription drug coverage. Furthermore, inadequate use of multidisciplinary care and IBD specialists limits patients access to high quality care, particularly for medically vulnerable populations. However, there are opportunities to improve access to high quality, patient centered care. This position statement outlines the policy and advocacy goals that the AGA will prioritize for collaborative efforts with patients, providers, and payors.

P1036 Persistence of biologics and advanced small molecules in 4th, 5th and 6th line of therapy for inflammatory bowel disease: a cross-sectional retrospective study

Abstract Background The choice of treatment for inflammatory bowel disease (IBD) with multiple prior drug failures, also known as difficult-to-treat (D2T) IBD, is an increasing challenge. We assessed the persistence of biologics and advanced small molecules, a surrogate for their efficacy, in patients with Crohn's disease (CD) and ulcerative colitis (UC) overall and in 4th, 5th and 6th lines of advanced treatment. Methods We retrospectively searched the electronic medical records of patients with IBD followed at the San Raffaele Hospital (Milan, Italy) up to 1 October 2023. Patients enrolled in clinical trials that changed disease management or receiving experimental drugs were excluded. Drug persistence was defined as the time from initiation to discontinuation of each treatment. Welch's ANOVA and Games-Howell's method for multiple comparisons were used. Results A total of 679 patients with moderate to severe IBD were included. 350 had CD, 326 UC, and 3 IBD-U. The mean disease duration was 11 years and 452 (66%) had received 5-aminosalicylates or antimetabolites as first maintenance treatment. Escalation to and changes between advanced treatments over time is summarised in Figure 1A. A greater use of anti-TNF agents was observed in the first lines of treatment whereas newer medications were proportionally more prescribed in refractory patients. In the overall analysis, regardless of the line of treatment, there was no difference in drug persistence between agents at 12 months (p=0.62), with approximately half of the patients having discontinued the drug. Figure 1B In subsequent lines of treatment, drug persistence decreased significantly in patients with CD (p=0.002). The trend was particularly pronounced from line 2, with a mean duration of 31 months, to line 7, with a mean duration of 11 months. In UC, the reduction was less evident and borderline non-significant (p=0.05), although it suggests a decrease in drug efficacy as the disease progresses. Figure 2 A, B In patients with D2T IBD, drug persistence in 4th, 5th and 6th line advanced treatment was similar for all agents (all p&amp;gt;0.05), indicating no clear advantage of one drug over the others. Figure 2 C, D, E Conclusion In CD, and possibly in UC, the persistence of patients on any advanced drug decreases with subsequent lines of treatment. None of the advanced agents showed a longer persistence time when used as a 4th, 5th or 6th line of treatment.

Predictors of Suicidal Ideation and Continued Substance Use Problems Among Patients Receiving Methadone Maintenance Treatment Who Have Co-Occurring Cocaine Use Disorder

Background Persons with polysubstance use problems are at high suicide risk, which may complicate substance use treatment. The purpose of this study was to a) examine cross-sectional and longitudinal risk factors for suicidality among persons in methadone maintenance treatment who present with co-occurring cocaine use disorder and b) evaluate whether suicidality impacts substance use outcomes independently and differentially depending on treatment type (i.e. standard methadone care [SC] vs. contingency management plus standard care [CM + SC]). Methods Data come from five randomized controlled trials of CM conducted within methadone clinics (N = 562). Participants were categorized (mutually exclusive) as no history of suicidality (56.4%, n=317), past suicidal ideation (SI; 11%, n=62), recent SI (3.6%, n=20), or lifetime suicide attempt (29%, n=163). Results Suicidality groups differed by sex and baseline employment, income, trauma history, and psychosocial functioning. Suicide attempt history was positively associated with years of polysubstance use, prior drug treatments, and unintentional overdose history. Baseline psychological problem severity and emotional abuse history were associated with SI likelihood 12 weeks later. Past SI was associated with longer durations of abstinence than no suicidality. Unexpectedly, those with recent SI reported lower drug use severity at 12 week if they received SC compared to CM + SC. Effects were small to medium. Conclusions Despite greater polysubstance use history, patients with suicide attempts did not show worse substance use outcomes than persons without suicidality. Patients with past SI fared better than those without suicidality on abstinence over 12 wk. Methadone clinics could be key points of entrance and continued services for suicide prevention.

Prior drug allergies are associated with worse outcome in patients with idiosyncratic drug-induced liver injury: A machine learning approach for risk stratification

The impact of prior drug allergies (PDA) on the clinical features and outcomes of patients who develop idiosyncratic drug-induced liver injury (DILI) is largely unknown. We aimed to assess the clinical presentation and outcomes of DILI patients based on the presence or absence of PDA and explore the association between culprit drugs responsible for DILI and allergy. We analysed a well-vetted cohort of DILI cases enrolled from the Spanish DILI Registry. Bootstrap-enhanced least absolute shrinkage operator procedure was used in variable selection, and a multivariable logistic model was fitted to predict poor outcomes in DILI. Of 912 cases with a first episode of DILI, 61 (6.7%) had documented PDA. Patients with PDA were older (p = 0.009), had higher aspartate aminotransferase (AST) levels (p = 0.047), lower platelet count (p = 0.011) and higher liver-related mortality than those without a history of drug allergies (11% vs. 1.6%, p < 0.001). Penicillin was the most common drug associated with PDA in DILI patients (32%). A model including PDA, nR-based type of liver injury, female sex, AST, total bilirubin, and platelet count showed an excellent performance in predicting poor outcome in patients from the Spanish DILI Registry (area under the ROC curve [AUC] 0.887; 95% confidence interval [CI] 0.794 – 0.981) and the LATINDILI Network (AUC 0.932; 95% CI 0.884 – 0.981). Patients with suspected DILI should be screened for PDA as they would require a close monitoring for early detection of worsening clinical course.

Do crashed drivers need more drug testing? A retrospective analysis of blood samples from hospitalised post-crash drivers in New Zealand

Driving under the influence of alcohol and other drugs is a prominent safety concern in New Zealand and across the world. While alcohol testing is routinely performed for drivers involved in hospitalisation crashes, testing for other drugs is often not undertaken. The present study refers to 530 traffic crashes that occurred from October 2019 to January 2020 on New Zealand roads. The blood samples from 550 drivers who were injured in a crash and were admitted to a hospital (66% of all drivers involved in these crashes), previously tested for drugs and/or alcohol, were retested for a wider range of drugs.Alcohol above the applicable limit was found to be present in 38% of hospitalised drivers, while other drugs of interest were found in 47% of hospitalised drivers.Binary logistic regression was used to predict the presence of drugs of interest for a crashed driver using previous offence data. A driver having at least one prior drink and drug driving offence is 61% more likely to be positive for a drug of interest when involved in a crash. Similarly, a driver having at least one prior non-traffic drug offence is 4.7 times more likely to be positive for at least a drug of interest when involved in a crash.While the presence of a drug or drugs cannot be presumed to have played a role in the occurrence of the crash, this study has provided a unique and comprehensive picture of the presence of various drugs present in New Zealand drivers’ blood.It is recommended to consider standardising drug testing on all blood specimens taken in relation to a serious injury or fatal crash. This procedure is not only of interest for information purposes but may importantly inform appropriate charging decisions.

Nonsteroidal anti-inflammatory drug “allergy” labeling is associated with increased postpartum opioid utilization

Current guidelines recommend a stepwise approach to postpartum pain management, beginning with acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs), with opioids added only if needed. Report of a prior NSAID-induced adverse drug reaction (ADR) may preclude use of first-line analgesics, despite evidence that many patients with this allergy label may safely tolerate NSAIDs. We assessed the association between reported NSAID ADRs and postpartum opioid utilization. We performed a retrospective cohort study of birthing people who delivered within an integrated health system (January 1, 2017, to December 31, 2020). Study outcomes were postpartum inpatient opioid administrations and opioid prescriptions at discharge. Statistical analysis was performed on a propensity score-matched sample, which was generated with the goal of matching to the covariate distributions from individuals with NSAID ADRs. Of 38,927 eligible participants, there were 883 (2.3%) with an NSAID ADR. Among individuals with reported NSAID ADRs, 49.5% received inpatient opioids in the postpartum period, compared to 34.5% of those with no NSAID ADRs (difference= 15.0%, 95% confidence interval 11.4-18.6%). For patients who received postpartum inpatient opioids, those with NSAID ADRs received a higher total cumulative dose between delivery and hospital discharge (median 30.0 vs 22.5 morphine milligram equivalents [MME] for vaginal deliveries; median 104.4 vs 75.0 MME for cesarean deliveries). The overall proportion of patients receiving an opioid prescription at the time of hospital discharge was higher for patients with NSAID ADRs compared to patients with no NSAID ADRs (39.3% vs 27.2%; difference= 12.1%, 95% confidence interval 8.6-15.6%). Patients with reported NSAID ADRs had higher postpartum inpatient opioid utilization and more frequently received opioid prescriptions at hospital discharge compared tothose without NSAID ADRs, regardless of mode of delivery.

French Early Nationwide Idecabtagene Vicleucel (Ide-Cel) Chimeric Antigen Receptor (CAR) T-Cell Therapy Experience in Patients with Relapsed/Refractory Multiple Myeloma (FENIX): Update of the IFM Study from the Descar-T Registry

Introduction Prognosis of patients with relapsed/refractory multiple myeloma (RRMM) is poor, particularly in triple-class refractory patients (refractory to a proteasome inhibitor, an immunomodulatory drug and an anti-CD38 monoclonal antibody). Idecabtagene vicleucel (Ide-Cel) is the first chimeric antigen receptor (CAR) T-cell therapy targeting the B-cell maturation antigen (BCMA) approved by both the European Medicines Agency and the US FDA and the only one available in France through the Early Access Program for treatment (≥ 3 lines) of RRMM. Here we present an update of characteristics and outcome of patients enrolled in this program. Methods We conducted a multicenter, retrospective, observational study that included all consecutive patients with RRMM registered in the DESCAR-T database of patients treated with CAR T therapy, who underwent apheresis up to November 2022 to be treated by commercial Ide-Cel in France. The main objective was to analyze efficacy in terms of response rates, progression free survival (PFS) and overall survival (OS). Secondary objectives included evaluation of safety in terms of cytokine release syndrome (CRS), neurotoxicity, cytopenia, infections and management of relapse including subsequent anti myeloma therapies (sAMT). Results From June 2021 to November 2022, 207 patients were registered in DESCAR-T and underwent leukapheresis to be treated with Ide-cel, 164 (79%) were infused; 43 were not infused: 13 due to rapidly progressive disease or death and 5 due to manufacturing failure. Fifty seven (28%) patients did not meet KarMMa inclusion criteria: cytopenia (n=23), kidney failure (n=13), performance score (PS) &amp;gt;1 (n=15), prior anti BCMA drug conjugate antibody (n=8), prior allograft (n=5). Median age of the 164 patients was 60.5 years (range 34-82), 59% were male, median number of prior treatment lines was 4 (range 2-12) including prior autologous stem cell transplantation in 147 (90%); 130 (80%) were triple-refractory, 47 (29%) were penta-refractory. At diagnosis, 12 (16%) patients had R-ISS stage III disease (89 missing). High tumor burden (&amp;gt; 30% BMPCs) was present in 71 patients (54%) (33 missing). High risk cytogenetic abnormalities defined by del(17p) or t(4;14) were present in 63 patients (58%) (56 missing) and 15 (23%) had extramedullary disease (EMD) (98 missing). One hundred and forty-two (87%) received bridging therapy of which 39 (27%) responded: 25 had partial response (PR); 8 very good partial response (VGPR); 6 complete response (CR). Median time from apheresis to infusion was 62 days. Median follow-up after infusion was 6.2 months. In the first 3 months, overall response rate was 82% (n=134), best achieved response was CR, VGPR and PR in 60 (38%), 36 (23%) and 38 (24%) respectively. Median PFS was 11.6 months (95% CI (7.1; NA)). The 12-month OS was 73% (95% CI (64; 84)). In the first 6 months post-infusion, MRD was analyzed for 45 patients and reached negativity rate in 77%. In univariate analysis, only EMD had a significant impact on PFS: median PFS was 6.3 months (95% CI (3; NA)) for patients with EMD (p = 0.003; HR 3.5, 95% CI (1.55; 7.9)). CRS occurred in 146 (89%) patients, with only 3 cases (2%) of grade ≥ 3. Neurotoxicity occurred in 19 (12%) patients (5 with grade ≥ 3). Ninety-eight (60%) patients received tocilizumab, and 37 (23%) received steroids. Persistent grade ≥ 3 thrombocytopenia, anemia and neutropenia at M1 were observed in 55 (34%), 20 (12%) and 90 (55%) patients, respectively. Forty (24%) patients presented infections grade ≥ 3 in the first six months after infusion. Fifty-two patients progressed during follow-up. 34/52 patients (65%) received a sAMT. Median time from relapse to first administration of sAMT was 0.6 months. Eighteen received bispecific antibodies including 12 anti-BCMA and 6 anti-GPRC5D. Among these 34 patients, a total of 13 (38%) died. Overall, at data cut-off, 26 patients had died, including 9 after disease progression, 4 of acute toxicity and 2 of sepsis. Conclusion This updated study confirms safety and efficacy of Ide-cel in patients with RRMM in real world settings. Response rates and safety were comparable to those reported in the registration trial (Munshi et al., 2021) and American real world study (Hansen et al., 2023). Importantly, patients with EMD had a significant lower PFS. Prognosis data at relapse following ide-cel require a longer follow up and will be presented at ASH.

Unraveling the Link: Cannabis Use Disorder and Pulmonary Embolism-Related Hospital Outcomes in Female Breast Cancer Survivors

Background: The use of cannabis in cancer patients has gained significant attention due to its analgesic properties, which help alleviate cancer-related pain. Studies have also shown the interference of cannabis with the coagulation system. We aimed to study the impact of cannabis use disorder (CUD) and Pulmonary embolism (PE) on outcomes in female breast cancer survivors, considering reports suggesting significant overlap between recreational and medicinal use. Our objective was to compare outcomes in CUD+ (with cannabis use disorder) and CUD- (without cannabis use disorder) cohorts to gain critical insights into this group and understand the impact of CUD on PE-related hospitalization and outcomes. Methods: National Inpatient Sample (NIS) data from 2020 was utilized in order to analyze inpatient cohorts of PE hospitalizations. The International Classification of Diseases 10 (ICD 10) codes for pulmonary embolism, cannabis use disorder, and female breast cancer were utilized to classify cohorts. All cases of female breast cancer and pulmonary embolism with an age &amp;gt;18 years were included in the final analysis. The primary outcome was the impact of CUD on PE-related hospitalizations in female breast cancer survivors. We also compared demographic correlations and comorbidities affecting outcomes between cohorts. Results: This study included a total of 508065 admissions among breast cancer survivors, with a median age of 74 years for the entire cohort. The prevalence of PE admissions was lower in CUD+ cohort compared to CUD- cohort (1.3% vs. 2.1%). The CUD+ cohort was relatively younger (median 66 vs 74 years, p&amp;lt;0.001). Overall, admission rates were higher among white patients (77%) and this trend was statistically significantly higher in the 76-100 th percentile household income group (p&amp;lt;0.002) compared to CUD+(50%) and CUD-(26.5%). Most admissions were non-elective (95.4%), with no statistical significance between CUD- and CUD+ patients (p=0.16). The majority of readmissions occurred in urban teaching hospitals (75.5%), with no significant difference observed between CUD- and CUD+ patients (p=0.111). Regionally, the South had a higher admission rate (37.2%) compared to other regions and this difference was statistically significant (p&amp;lt;0.001) between CUD- and CUD+ patients. Among the coexisting comorbidities, hypertension showed a significant difference between CUD- (70%) and CUD+(37.5%) patients (p&amp;lt;0.001). Alcohol use disorder (p&amp;lt;0.001) and cancer (p&amp;lt;0.001) had significant associations with CUD+, along with prior myocardial infarction (p=0.005) and drug use (p&amp;lt;0.001) were significantly associated with CUD+.Furthermore, there was difference in routine patient disposition between between CUD-(45.3%) and CUD+(37.5%),(p=0.033) and length of stay (4 VS 2 days), (p=0.033) and cost of stay (47033 vs 27668 $), (p=0.017). The multivariable logistic regression analysis showed that the odds of PE-related hospitalization in CUD+ vs CUD- cohorts among female breast cancer survivors were not statistically significant, with an OR of 0.79 (CI: 0.38-1.62, p=0.512). Subgroup analysis by age demonstrated no statistically significant differences in odds for PE-related hospitalization between CUD+ and CUD- cohorts. For the age group of 18-44 years, the OR was 1.37 (CI: 0.18-10.60, p=0.762). In the 45-64 years age group, the OR was 0.48 (CI: 0.15-1.53, p=0.215), and for those aged ≥65 years, the OR was 1.32 (CI: 0.48-3.67, p=0.590). Furthermore, the analysis by race indicated that the odds of PE-related hospitalization did not reach statistical significance in both white and black female breast cancer survivors with CUD. For white patients, the OR was 0.64 (CI: 0.23-1.73, p=0.375), while for black patients, the OR was 1.15 (CI: 0.38-3.46, p=0.804). Conclusion: Among female breast cancer survivors, the presence of CUD did not show a statistically significant impact on the odds of PE-related hospitalization. Subgroup analysis by age and race also revealed no significant differences in the odds of PE-related hospitalization between CUD+ and CUD- cohorts. These findings underscore the importance of considering CUD when managing pulmonary embolism in breast cancer survivor females and emphasize the need for further research to understand the complex interplay between these factors.

Comparison of the Efficacy in Clinical Trials Versus Effectiveness in the Real-World of Treatments for Multiple Myeloma: A Population-Based Cohort Study

Introduction: Improvements in outcomes of patients with multiple myeloma (MM) depend on the use of regimens approved based on results from large phase III randomized controlled trials (RCTs) demonstrating their efficacy. However, many real-world (RW) patients would not have met the stringent RCTs inclusion criteria. Therefore, the effectiveness of these drugs in the RW setting is unknown. Understanding this efficacy-effectiveness gap is important to contextualize the expected outcomes in the current RW setting. Therefore, we conducted a retrospective population-based study to compare the efficacy versus effectiveness of registration RCTs with RW patients using standard of care (SoC) MM regimens for the primary outcomes of 1) progression free survival [PFS]; 2) overall survival [OS] and 3) serious adverse events (AEs). Methods: RW data was obtained from the Institute for Clinical Evaluative Sciences, an administrative database capturing all health records in the publicly funded health care system in Ontario, Canada. Adult patients treated between Jan 2007 to Dec 2020 with SoC regimens were included. Only regimens with corresponding registrational phase III RCTs which led to the public reimbursement in Ontario were included (lenalidomide/dex [Rd] and bortezomib/Rd [VRd] for newly diagnosed transplant ineligible patients, and relapsed MM (RRMM) regimens included carfilzomib/Rd [KRd], carfilzomib/dex [Kd], daratumumab/Rd [DRd], daratumumab/bortezomib/dex [DVd], pomalidomide/dex [Pd]). In the RW cohort, PFS was defined as the time from initiation of index regimen to death, initiation of subsequent MM treatment, or last follow-up, and patients remaining on the index regimen as last follow up were censored. Kaplan-Meier curves from pivotal phase 3 RCTs were manually digitized to provide individual patient-level estimates of PFS and OS. Meta-analyses were performed to compare the gap of PFS and OS outcomes of RW versus RCT patients, and effect estimates were summarized using hazard ratios (HR). The frequency of serious AE data was abstracted from published RCTs. Given that serious AEs in RCTs would have resulted in hospitalization, hospital admission during treatment with the index regimen was used as a surrogate for serious AEs in the RW cohort. Differences in RW and RCT safety outcomes were reported descriptively. Results &amp; Discussion: A total of 3951 RW MM patients, treated with 7 standard of care MM regimens, were included. Baseline characteristics of patients in the RW and RCT cohorts are shown in table 1. Overall, patients in the RW cohort were older than in the RCTs. For relapsed regimens, there was a longer time between MM diagnosis and start of the regimen in the real-world versus RCT. With regards to the efficacy-effectiveness gap, MM patients treated in routine practise in the RW had a worse PFS despite overestimated of RW PFS compared to highly selected RCT patients for 6 of the 7 MM regimens evaluated, with a pooled HR of 1.44 (95% CI 1.34-1.54) in the meta-analysis (Figure 1A). Similarly, RW patients had a worse OS compared to RCT patients treated with 6 of the 7 regimens, with a pooled HR of 1.75 (95% ci 1.63-1.88) in the meta-analysis (Figure 1B). RRMM patients in the RW had higher rates of prior lenalidomide exposure compared to RCT patients. The only regimen which showed a trend towards performing better in the RW as compared to RCTs was Pd. The reason for this is likely multifactorial but perhaps patients included in the MM-003 RCT may have had more refractory MM (given the higher prior immunomodulatory drug exposure and longer time from diagnosis to treatment among Pd RCT patient) compared to RW patients in this study. With regards to safety, the percentage of patients with inpatient hospitalization during treatment in the real-world cohort and reported serious AEs in RCT were comparable (VRD 57% vs not reported [NR]; Rd 64% vs NR; Kd 57% vs 59%; KRd 53% vs 60%; DVd 36% vs NR; DRd 46% vs 49%; Pd 59% vs 61%). Conclusion: This is one the largest population-level studies highlighting the significant efficacy-effectiveness gap between registrational RCTs and RW usage of these regimens, with RW patients experiencing 44% worse PFS and 75% worse OS compared to RCT patients. Our data emphasize the importance of ongoing evaluation of RW data to contextualize effectiveness and toxicity of selected regimens in the clinic, and better inform both clinicians and patients for shared treatment decision making.

Teclistamab Induces Favorable Responses in Patients with Relapsed and Refractory Multiple Myeloma after Prior BCMA-Directed Therapy

Introduction: Teclistamab (TEC) received regulatory approval for the treatment of patients with Relapsed/Refractory Multiple Myeloma (RRMM) after ≥ 3 prior lines of therapy based on the results of the pivotal MajesTEC-1 trial in which such patients achieved an overall response rate (ORR) of 63%, ≥ complete response (CR) of 39%, and median progression free survival (PFS) of 11.3 months (Moreau et al. N Engl J Med 2022). Patients who had received a prior B-cell maturation antigen-targeted therapy (BCMA-TT) were excluded from MajesTEC-1 trial. Data on the efficacy of TEC in patients who have received and relapsed after prior BCMA targeted therapy is lacking. Several studies have shown reduced efficacy of both FDA approved BCMA targeted chimeric antigen receptor T cell therapies (CAR-T) for myeloma, idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel), when administered after BCMA targeted bi-specific antibodies. There is a paucity of data on the efficacy of TEC when administered in patients who progress after ide-cel or cilta-cel. We evaluated the real-world outcomes of patients treated with standard of care (SOC) TEC after having previously received a BCMA-TT. Methods We performed a retrospective chart review to find patients treated at our center that were &amp;gt; 30 days from first dose of commercial TEC, received at least one prior BCMA-targeted therapy, and were consented to an IRB approved registry protocol. Cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity syndrome (ICANS) were graded per ASTCT consensus criteria, while responses were graded based on the International Myeloma Working Group (IMWG) response criteria. Results: A total of 22 patients who had received prior BCMA-TT and TEC were evaluable for response, safety, and survival analyses. Median age was 66 years (range 48-81), 59% were male, and 13% had an ECOG PS ≥2. Beside prior BCMA-TT, other exclusion to MajesTEC-1 would have been cytopenias (27%), performance status ≥2 (9%), creatinine clearance &amp;lt;40 mL/min (5%), and plasma cell leukemia (5%). Eleven pts (50%) had high risk cytogenetics (defined as del17, t(4;14), t(14;16)), and 13 pts (59%) had gain 1q. Patients were heavily pretreated with a median of 8 (5-13) prior lines of therapy, 45% had R-ISS III, 14% had extramedullary disease (EMD), 27% had a high marrow burden (≥60% PCs in the marrow) and 11 (50%) were penta-class refractory. Sixty-eight percent (n=15) had received prior Chimeric Antigen Receptor T-cell Therapy (CAR-T), 9% (n=2) prior Antibody Drug Conjugate (ADC), and 23% (n= 5) both CAR-T and ADC, all BCMA-TT. Median time from prior BCMA-TT to TEC was 12.3 (1.3-33.5) months. With a median follow up of 4.16 (1.07-7.27) months, the best overall and ≥ CR response rates were 63% and 36% (N=8), respectively. Of those who had achieved a ≥ CR, 3 were MRD negative by clonoSEQ® (10 −6). Thirteen (57%) pts received TEC as the next line of therapy from prior BCMA-TT. Thirteen of 14 pts tested for BCMA expression were positive by IHC, with 9 expressors responding to TEC; the non-expressor responded to TEC. Toxicity was comparable to that seen in MajesTEC-1. Cytokine release syndrome (CRS) of any grade occurred in 16 (73%) pts. All events occurred during step-up and cycle 1 doses. All events of CRS were grade 1 (n=13; 59%) and 2 (n=3; 14%). The median time to onset of CRS was 3 (1-12) days after the most recent dose, and the median duration was 3 (1-9) days. Tocilizumab was administered to 4 (18%) pts. Only 1 patient had ICANS, grade 3 and requiring steroids. Infections were seen in 12 (55%) pts, including viral (10), bacterial (1), and fungal (1). 6 (50%) infections were deemed severe and required hospitalization. Prior to TEC, 13 (59%) pts had hypogammaglobulinemia (IgG&amp;lt; 400). After TEC, 6 pts developed new hypogammaglobulinemia. 11 (50%) pts had treatment delays, mainly due to CRS and infections. Four pts died due to progression of disease. Conclusions: This single center study in patients with heavily pretreated and prior BCMA-TT demonstrated favorable ORR (63%) and CR (36%) rates, comparable to pts in the MajesTEC-1 trial, without prior BCMA-TT exposure. No new safety signals were identified. Results on progression free survival (PFS) and overall survival (OS) will be reported with continued follow up and will be presented in the meeting.

High Responses Rates with Single Agent Belantamab Mafodotin in Relapsed Systemic AL Amyloidosis

Introduction: Systemic AL amyloidosis, a rare incurable plasma cell disorder, has no approved treatments at relapse. Belantamab mafodotin is an antibody-drug conjugate which targets BCMA antigen approved for relapsed refractory myeloma. We report our results using belantamab mafodotin monotherapy for the treatment of patients with relapsed refractory AL amyloidosis including those traditionally excluded from clinical trials (eGFR&amp;lt;30 ml/min/1.73m 2 and cardiac Mayo stage IIIb disease). Methods: All patients treated with belantamab mafodotin monotherapy at standard dose (2.5 mg/kg) or dose reduction between April 2021 - July 2023. Standardised assessments including measurement of cardiac biomarkers, clonal parameters and imaging were performed and disease assessment was reported as per International Society of Amyloidosis consensus criteria. Results: Twenty-seven patients were included. The median age at was 65 years (range 41-76) and eight (30%) patients were aged &amp;gt;70 years. Eighteen (67%) had λ AL-type and nine (33%) κ AL-type. A median of two organs were involved at baseline (range 1-4) with renal and cardiac involvement in 20 (74%) and 15 (56%) respectively (3 each for Mayo stage IIIa and stage IIIb). The median time from AL amyloidosis diagnosis to first administration of belantamab mafodotin was 69 (range 5-174) months (~6 years) with a median of 3 prior lines of treatment (range 2-6). Prior drug class exposure included proteasome inhibitors (100%), immunomodulatory drugs (81%) and anti-CD38 antibody (81%) therapy. Ten patients (37%) had undergone prior melphalan-conditioned autologous stem cell transplantation. At the time of first belantamab mafodotin dose, the median involved free light chain concentration was 118mg/l (range 31-1778), eGFR was 40 ml/min (range 7 - 120) and a third (9/27) with an eGFR &amp;lt;30 ml/min/1.73m 2. NT-proBNP was 845 ng/l (range 99-70,000). At data cut-off, a median of 5 (range 1-11) doses of belantamab mafodotin were delivered. Of those with evaluable disease, best haematological overall response rate (partial response or better) was 80% (20/25) at a median time to best haematological response of 2 months (95% CI 1-4, range 1-17). Complete response (CR) or very good partial response (VGPR) was achieved in 64% (16/25). Two patients have only had 1 cycle and too early to perform response assessment. Reasons for treatment discontinuation (n=12) were: inadequate response/progression (n=7), keratopathy (n=1), grade 3 thrombocytopenia (n=1), physician choice (n=3: discontinued due to treatment for unrelated metastatic squamous cell carcinoma but remains in CR; facilitation of renal transplant; prior to BCMA-directed CAR-T in VGPR). At a median follow-up of 13 months follow-up (95% CI 4-18, range 1-27) from belantamab mafodotin initiation, 15 patients (56%) remain on therapy. Two patients died (1 due to progressive disease, 1 unrelated) and seven patients progressed and had subsequent line of therapy at a median time of 6 months (95% CI 2-4) in those that had a next line of therapy. Median treatment-free survival or death was 27 months (10-NR), and 1-year treatment-free survival/death was 69% (95% CI 41-86). Median overall survival (OS) is not reached. 1-year OS is 88% (95% CI 59-97). Bilateral microcystic corneal keratopathy, the most frequent adverse event, was seen in 19 (70%) patients (5%; 1/19 grade 4).Ocular adverse events improved in all patients after treatment delay. Only one patient required treatment cessation due to ocular toxicity (despite achieving PR after one dose). Thrombocytopenia was reported in 3 (11%) (grade 3: 1; grade 2: 1). Only two patients remained on the standard dose of 2.5mg/kg for &amp;gt;3 cycles. Nine patients had eGFR &amp;lt;30ml/min and 6/9 started at a dose of 1.25mg/kg with no unexpected side effects (1 patient had grade 3 keratopathy). One patient post-renal transplantation (on tacrolimus and mycophenolate) had no significant toxicity and achieved a CR after cycle 3. No treatment-related deaths, cardiac or renal toxicities observed in our cohort. Conclusion: Belantamab mafadotin has high efficacy and good tolerability in multiply relapsed AL amyloidosis including efficacy in patients otherwise excluded from clinical trials. Treatment-emergent adverse events (especially keratopathy) do not preclude delivery of drug with appropriate dose reductions.

Building Quality Improvement Initiatives through Anti-Cancer Stewardship in the Veterans Health Administration (VHA): CML Pilot

The Department of Veterans Affairs (VA) Pharmacy Benefits Management (PBM) Services created a national stewardship with focus on anti-cancer therapeutics within a disease-specific cohort . Directing stewardship initiatives to a cohort of Veterans with a common malignancy is a novel approach. A multidisciplinary team with National PBM and VISNs (Veterans Integrated Service Network) promotes standardization of practice with accountability to monitor outcomes as a continual quality improvement process. A toolkit was built to support stewardship activities and includes: near-real-time process to identify a national disease-specific Veteran cohortdisease validation processcentralized MUE data collectioneducational resourcessite for communication and training materials Tyrosine Kinase Inhibitors (TKIs) account for the second highest utilization among outpatient oral anti-cancer therapies in VHA . Imatinib has demonstrated persistent efficacy and is the preferred TKI on the VA National Formulary. Utilizing our toolkit, we developed two MUEs for our national CML cohort to determine why Veterans were not prescribed imatinib as 1L therapy and reasons for switching from first to second line therapy. Methods Business rules identified VISN CML cohorts by using data sources and diagnostic coding from the VA Electronic Health Record (EHR): primary care and hematology/oncology visits (ICD-10), inpatient stays (ICD-10), and problem lists (ICD-10; SNOMED CT). Retrospective chart review of two subsets: Veterans who received a drug other than imatinib as their initial VA prescriptionVeterans who received at least two unique drugs to treat CML Data abstracted for MUE #1: Disposition of TKI prescriptionIf new initiation, documented reason(s) for drug selectionIf continuation, prior drug therapy history Data abstracted for MUE #2: Documented reason(s) for switch to 2LIf adverse drug reaction (ADR) included as a reason, is it documented in the EHR? Analysis combined responses with prescription data from the EHR. Results Of the 18 VISNs, 9 participated in MUE data collection. 365 patients were identified as not having received imatinib 1L and 360 were identified as having received at least two unique drugs to treat CML. These counts are each approximately 30% of the total CML patient cohort. In the total cohort, ~50% of patients received imatinib 1L and have not switched to 2L. Responses for 1L TKI therapy (N=365) 199 (55%) continued therapy originally started outside VA with 67% of these patients (n=133) without documentation of prior imatinib therapy166 (45%) were newly initiating CML therapy with top documented reasons for drug selection: Intermediate or high risk (e.g., SOKAL risk scoring): 77 (46%)46 (28%)18 (11%)Dasatinib was the most prescribed 1L therapy in this cohort (64%; 235), followed by nilotinib (23%; 85), which had a higher prevalence when therapy was continuation (30%).53 patients (15%) had subsequent imatinib therapyResponses for switch from 1L to 2L therapy (N=360) Top documented reasons for switch from 1L to 2L therapy 215 (60%)81 (23%)Resistance / inadequate response: 69 (19%)Only 37 (17%) who experienced an ADR had it documented in the EHRThe most common 2L drug was dasatinib (55%;198). The median number of days between 1L and 2L initiation was 275 (range: 7 - 2, 573)136 patients (38%) received third line therapy or beyond Conclusions A formalized oncology stewardship with focus on disease-specific initiatives within a national healthcare system is feasible. Responses from our 1L MUE indicate that despite geography, imatinib remains the preferred TKI and accounts for the highest utilization. Most veterans not receiving imatinib as 1L therapy, received dasatinib or nilotinib. Continuation of therapy due to transition of care to VA was the primary reason for 1L therapy with a non-preferred TKI. Other reasons included: FDA indication and SOKAL risk scoring. In our pilot 1L to 2L MUE, ADRs were the most common reason for CML patients to be switched to 2L (45%) followed by resistance/inadequate response and disease progression . Most ADRs were not documented in the EHR. Further interventions in TKI prescribing may be instituted in select sites . Following initiatives for CML, Anti-Cancer Stewardship will be expanded to other oncologic diseases.