Real-world Patient Population Research Articles

Abstract 18672: Impact of Enhanced Artificial Intelligence on Clinic Burden From False Alerts of Insertable Cardiac Monitors

Background: AccuRhythm AI is a suite of cloud-based classification algorithms that filter and suppress false pause alerts and atrial fibrillation (AF) episodes transmitted by insertable cardiac monitors (ICMs). An enhancement to the AF algorithm (AI v2) reduces false AF alerts by 50% relative to the original AI (AI v1) but the impact of this improvement on clinic experience is unknown. Aim: Determine the projected annual impact of AI v2 on Pause and AF alerts in a real-world patient population. Methods: Real-world data were obtained from de-identified LINQ II ICM patients with ≥3 months of follow-up. Previously published performance of each AI algorithm broken out by patient reason for monitor were projected onto the data. Results were extrapolated to the average 200-ICM clinic. The study endpoints were true alert retention, false alert suppression, and clinic review burden reduction. Results: The dataset consisted of 16,301 ICMs with mean follow-up of 7 months. Reasons for monitor were Known AF (25%), Suspected AF / Cryptogenic Stroke (40%), Syncope (23%), and Other (12%). The mean number of alerts per patient-year was 17.9 AF and 4.3 Pause. Projection of AI v2 resulted in minimal loss (0.9%) of true AF and Pause alerts, annually, with no loss in Pause and 1.0% in AF. AI v2 reduced annualized false AF and Pause alerts by 91% (97.4% false Pause and 88.1% false AF reduction) relative to the ICM and 35% relative to AI v1. This translates to 401 and 22 annual review hours saved for a 200-ICM clinic, respectively. Conclusion: The AF enhancement provides a meaningful reduction to the average ICM clinic’s review burden by eliminating most false Pause and AF alerts while maintaining nearly all true alerts.

Abstract 14276: Using Artificial Intelligence and Natural Language Processing on Electronic Health Records of Heart Failure Patients to Examine the Impact of Estimated Glomerular Filtration Rate Trend on Mortality

Introduction and Hypothesis: Heart failure (HF) often leads to an imbalance between heart and kidney function, with a poor prognosis in HF patients linked to dynamic changes in renal function as well as chronic kidney disease (CKD). This study aimed to determine the incidence of reduced renal function upon HF diagnosis and to explore the potential for dynamic changes in kidney function to predict short- and long-term outcomes in a real-world cohort of HF patients. Methods: Clinical data of patients with a diagnosis of HF (index event) were gathered retrospectively using natural language processing. Patients were classified as having CKD based on their eGFR (<60 mL/min/1.73m2) and a history of CKD and/or dialysis. eGFR trajectories were analyzed using linear mixed effects models. Cox proportional hazard models were used to analyze the relationship between baseline variables and mortality. Joint modeling was employed to assess the relationship between the eGFR trend and mortality. Results: There were 1986 patients in the study population, with a mean (SD) age of 74.8 ± 11.7 years and 58% of males. At the index event, 58% (n = 1156) had CKD, and 17% (n = 339) had HF with preserved ejection fraction (HFpEF). Median follow-up was 3.16 years. After 2 years, 10% (n = 198) of the patients had passed away. The proportion of CKD at index was considerably lower in the 2-year survivors group (55% vs 76%, p < 0.001) in this group. The calculated mean annual eGFR reduction was 4.2 mL/min/1.73m 2 . Age, CVA, diastolic blood pressure, hemoglobin, HDL, potassium, and NT-proBNP levels in blood serum were found to be the primary predictors of mortality in multivariate Cox PH model. Joint modeling revealed that a current eGFR value that was 10 mL/min/1.73m 2 lower between patients corresponded with a higher mortality hazard of 1.22 ± 0.05 (p < 0.001). In addition, a drop in eGFR of 10 mL/min/1.73m 2 over the previous year showed an the elevated mortality hazard of 1.97 ± 0.16 (p < 0.001). Conclusions: We show that the prevalence of CKD is significant in a real-world population of HF patients, and CKD is a standalone predictor of mortality. Current eGFR value and the eGFR slope from the previous year have a potential to be used for individual mortality hazard assessment in the clinical follow-up of HF patients.

Multicenter, Real-World Study in Patients with R/R Large B-Cell Lymphoma (LBCL) Who Received Lisocabtagene Maraleucel (liso-cel) in the United States (US)

Background: Liso-cel is an autologous, CD19-directed, 4-1BB CAR T cell product administered at equal target doses of CD8 + and CD4 + CAR + T cells that has demonstrated efficacy and favorable safety based on clinical studies. Liso-cel is approved in the US for the treatment of adults with R/R LBCL after 1 or more lines of systemic therapy, but data describing outcomes in patients treated with liso-cel in the real-world setting are limited. We report real-world clinical effectiveness and safety of commercial liso-cel in patients with R/R LBCL based on a postmarketing study using data collected at the Center for International Blood and Marrow Transplant Research (CIBMTR). Methods: This is a noninterventional, observational, multicenter study of US patients who were followed in the CIBMTR Cellular Therapy Registry between February 2021 and November 2022 after infusion with commercial liso-cel (conforming product only) for the treatment of R/R LBCL. Patients who received nonconforming product are being followed in a separate postmarketing study. The primary objective was to evaluate the real-world clinical effectiveness and safety outcomes of patients with R/R LBCL receiving liso-cel, including ORR, CR, duration of response (DOR), progression-free survival (PFS), overall survival (OS), and risk of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Results were analyzed and reported descriptively. Results: At data cutoff (May 4, 2023), 323 patients who received commercial liso-cel across > 50 treatment sites were included in the analysis. The median vein-to-vein time (from leukapheresis to liso-cel infusion) was 36 days (IQR, 34‒42), which is consistent with clinical studies of liso-cel. The median age was 70 years (range, 24‒91). Patients included those with high-risk disease (Table). Most patients had DLBCL not otherwise specified (NOS; 81%), 27% had disease transformed from indolent lymphoma, 12% had high-grade B-cell lymphoma (HGBCL), 37% had International Prognostic Index (IPI) ≥ 3, 6% had active CNS involvement, and 15% had prior transplant. The median number of prior lines of systemic therapy was 3 (range, 0‒11), with 25% of patients having received ≥ 4 lines. The median time from diagnosis to liso-cel infusion was 1.4 years (range, 0.2‒29.7). At a median follow-up of 7.4 months, ORR was 79%, with a 65% CR rate. Median time to response was 1.2 months (IQR, 1.0‒3.1). The median DOR has not been reached; DOR rate at 6 months was 73% (95% CI, 66%‒79%). The median PFS and median OS had not been reached at the time of data cutoff. Estimated 6-month PFS and OS rates were 64% and 82%, respectively. Most events of CRS and ICANS were of low grade, with no CRS and ICANS reported in 48% and 70% of patients, respectively. Overall, 52% of patients had CRS and 3% had grade ≥ 3 events. There was a high concordance on CRS grading per Lee 2014 and American Society for Transplantation and Cellular Therapy criteria. The most common treatments for CRS were tocilizumab (20%) and corticosteroids/tocilizumab (12%). ICANS was seen in 30% of patients, with grade ≥ 3 events in 11%. ICANS was mostly treated with corticosteroids (12%) and corticosteroids/antiepileptics (5%). Based on the attributed cause of death, grade 5 CRS or ICANS were observed in 3 and 3 patients, respectively, and all but 2 patients had concomitant causes of death, including disease progression (n = 3) and hemophagocytic lymphohistiocytosis (n = 2). Prolonged cytopenia (grade 4 thrombocytopenia and/or neutropenia persistent at 30 days postinfusion) occurred in 10% of patients. Conclusions: This is the first large, multicenter, real-world study of patients with R/R LBCL who received commercial liso-cel in the US. Baseline characteristics of patients treated in the real-world setting were consistent with or worse than the liso-cel registrational study experience, including the percentage of patients who had received ≥ 4 lines of prior systemic therapy (25% vs 26% in TRANSCEND). One-time infusion of liso-cel demonstrated deep and durable responses in patients with R/R LBCL across a broad age range, including those with high-risk features characteristic of poor prognosis. The incidence of severe (grade ≥ 3) CRS and ICANS was low. These results further support liso-cel as a therapeutic option with a favorable benefit/risk profile for a broad, real-world population of patients with R/R LBCL.

Real World Outcomes with Idecabtagene Vicleucel (Ide-Cel) CAR-T Cell Therapy for Relapsed/Refractory Multiple Myeloma

Introduction: Idecabtagene vicleucel (ide-cel) was the first FDA approved BCMA targeted CAR-T cell therapy for the treatment of relapsed/refractory multiple myeloma (RRMM). However, clinical trials are highly selective with stringent eligibility criteria. The objective of this study was to evaluate the safety and efficacy of standard of care ide-cel. Methods: Patients treated with ide-cel were reported to the CIBMTR registry for long-term follow up of safety and efficacy outcomes. The current analysis includes the first 603 adult patients who received infusion with commercial ide-cel for the treatment of RRMM, with at least one follow-up form reported. Patients treated on investigational clinical trials or who received non-conforming products were excluded. Multivariate analysis was done using Cox regression. Results: Median follow-up of the 603 patients is 6.6 months, with updated follow up to be presented at the meeting. As shown in Table 1a median age of patients was 65 years, 26% (n=157) were ≥70 years old and 59% (n=354) were male. Black and Hispanic patients comprised 13% (n=77) and 7% (n=42) of the cohort, respectively; 23% (n=137) had Karnofsky performance status <80%, 75% (n=451) had ≥ 1 significant comorbidity and 13% (n=77) had platelets <50,000/µL. Patients for whom data on prior lines of therapy (LoT) were documented (n=470), the median prior LoT was 7 (4-21), 36% (n=217) had penta-refractory disease and 5% (n=28) had received prior-BCMA directed CAR T cell therapy. Data on the use of other BCMA targeting agents are being gathered. 17% (56/331 with PET-CT data) of patients had extramedullary disease (EMD) and 1.5% (n=9) had plasma cell leukemia. High risk cytogenetics [del17p, t(4;14), t(14;16) and/or t(14;20)] were present in 23% (n=141/523) and 45% (n=269/523) when including abnormalities of 1q (ab1q). 36% (n=101/283) of patients had ISS II and 16% (n=46/283) had ISS stage III disease. Lymphodepletion regimen was fludarabine + cyclophosphamide in 95% (n=574) of patients. All patients received ide-cel dose of 300-460 million CAR-T cells, with dose of > 400 million in 56% of patients. Cytokine release syndrome (CRS) was seen in 81% (n=490) of patients (grade ≥3: 3%), with median time to onset being 2 days. Neurotoxicity was seen in 27% (n=164) of patients (grade ≥3: 4%), with median time to onset being 2 days. Prolonged neutropenia (defined as non-recovery of ANC ≥ 500/uL by day 30) and thrombocytopenia (non-recovery of platelets ≥ 20,000/uL by day 30) was seen in 13% (n=81) and 25% (n=148) of patients, respectively. Hemophagocytic Lymphohistiocytosis-like syndrome was seen in 1% (n=6) and tumor lysis syndrome in 1.5% (n=9) of patients. Clinically significant infections were seen in 42% (n=252) of patients (bacterial: 22%, viral: 23%, fungal: 2%). Second malignancies were seen in 4.5% (n=27) of patients, including AML/MDS in 5 patients. Table 1b shows multivariate analysis for CRS and neurotoxicity. Risk factors associated with higher likelihood of grade >2 CRS were age ≥ 70, female sex and baseline platelets < 50,000/uL. Similarly, higher risk of neurotoxicity was seen with older age, high-risk cytogenetics, lower performance status and platelets < 50,000/uL. Overall response rate was 71% (n=421), ≥ very good partial response rate was 53% (n=319) and ≥ complete response (CR) rate was 27% (n=162). On multivariate analysis for response, presence of EMD, CAR-T cell dose ≤ 400 million, penta-refractory disease and lower performance status were associated with lower likelihood of CR. Estimated progression free survival (PFS) at 6 months was 62% (95% CI: 58-66%) and overall survival (OS) at 6 months was 82% (95% CI, 79-85%). At last follow-up, 26% of patients have died, majority due to disease progression (70%, n=108); causes of death in the remaining 47 patients were infection (n=15), CRS (n=1), neurotoxicity (n=2), tumor lysis (n=1), organ failure (n=7), second cancer (n=5), intracranial hemorrhage (n=3) and other (n=13). Conclusion: This is the largest real-world study of ide-cel CAR-T cell therapy in patients with RRMM. We observed a favorable safety and efficacy profile in this real-world population, despite a very heavily pre-treated population and large proportion of patients having co-morbidities that would have made them ineligible for the KarMMa clinical trial. These results further support ide-cel as a therapeutic option for a broad, real-world population of patients with RRMM.

Meter: A Multi-Country, Real-World Chart Review Study to Explore Treatment Patterns, Effectiveness and Healthcare Resource Utilization for Patients with Myelofibrosis

Background : Myelofibrosis (MF) is a rare myeloproliferative disorder associated with significant morbidity and mortality. The hallmarks of MF pathobiology include aberrant myeloproliferation, cytokine-induced inflammation, bone marrow reticulin fibrosis, extramedullary hematopoiesis, cytopenias, and constitutional symptoms. Hydroxyurea was the most commonly used drug in patients with MF prior to the approval of ruxolitinib (RUX), a first-in-class Janus kinase 1/2 inhibitor (JAKi) that is widely approved for symptomatic patients with MF. In addition to RUX, the JAKis fedratinib and, more recently, pacritinib have also been approved by the US Food and Drug Administration. Real-world treatment patterns and impact of currently available JAKis on patients with MF are not well understood. Several novel agents are in advanced development and will further reshape the treatment landscape of MF. A better understanding of current treatment patterns will assist in positioning novel treatments within the MF therapeutic landscape. Methods : The METER study (NCT05444972) is an ongoing multicountry noninterventional retrospective chart review assessing treatment patterns, effectiveness, and healthcare resource utilization (HCRU) in patients diagnosed with MF. Data from patients aged ≥18 years with primary or secondary MF treated on or after the local first date of RUX approval until December 31 , 2021 were assessed. Patients who received treatment for MF in a clinical trial were excluded. The primary objective is to describe real-world MF treatment patterns, including patient characteristics, time from MF diagnosis to first-line (1L) therapy, choice, duration and reason for change/discontinuation of initial and subsequent treatments for MF, and treatment procedures. Secondary objectives include assessments of days hospitalized as part of HCRU. Results : As of June 1, 2023, 928 patient charts were included, met eligibility criteria, and had initial treatment information available. Most patients were male (54%) and White (65%), and the median (range) age for patients ≤89 years of age was 66 (58-73) years; the most common geographic locations were Europe (53%), Latin America (23%), and North America (13%). Of patients, 66% (614/928) had primary MF, and 10% (97/928) were transfusion-dependent. Of patients tested for high molecular risk mutations, 50% (81/162) were positive. Of patients with available bone marrow fibrosis data, 82% (554/680) had grade ≥2 bone marrow fibrosis at diagnosis. The average interval from MF diagnosis to start of initial treatment (index date) was approximately 8.5 months. RUX was the most commonly used 1L therapy (47%; 437/928) followed by hydroxyurea (41%; 380/928). RUX was also the most common therapy used in second-line (2L), third-line, fourth-line, and fifth-line treatment for 62% (217/353), 63% (107/171), 66% (56/85), and 59% (24/41) of patients, respectively. Mean (SD) time from index date to procedural intervention was 556 (519) days; the most common procedure was stem cell transplant (n = 71) followed by splenectomy (n = 20). Of the 927 patients who received 1L therapy, 98% remained on 1L therapy through Week 24, and 66% did not initiate 2L therapy until Week 156. Median (95% CI) duration of 1L therapy was 48 (45-52) months (Figure). Median (95% CI) survival from the start of 1L therapy was 79 (71-NR) months. The estimated survival rate (95% CI) was 76% (73-79) at Week 156. Median (95% CI) overall survival was 120 (93-147) months. Median (Q1-Q3) total number of days hospitalized after the index date was 2 (0-19), and median (Q1, Q3) total number of days in the intensive care unit after the index date was 0 (0, 0). Analyses will be updated for presentation. Conclusions : In patients with MF, RUX was the most commonly used agent in all lines of therapy. The greatest reduction in duration of MF treatment occurred from 1L to 2L. Most patients remained on 1L therapy through Week 24 and did not initiate 2L therapy until Week 156. Median survival time from start of 1L therapy to death was 79 months (approximately 6 years). There was a high degree of advanced bone marrow fibrosis as well as transfusion dependence among this real-world patient population. Together, these results highlight the importance of optimizing 1L therapy.

Carfilzomib, Lenalidomide and Dexamethasone (KRd) As Induction Therapy in High-Risk Newly Diagnosed Multiple Myeloma

Background: Carfilzomib, lenalidomide and dexamethasone (KRd) has been shown to be an effective induction regimen for newly diagnosed myeloma (NDMM), particularly in myeloma with high-risk (HR) features in the FORTE trial (Mina et al, Lancet Onc 2023). Here, we present a retrospective analysis in patients with HR NDMM in a real-world population from two high-volume centers, highlighting efficacy and survival outcomes in high-risk subgroups to gain a better understanding of the utility of this regimen in clinical practice. Methods: We conducted a retrospective study of patients with HR NDMM treated with KRd at Memorial Sloan Kettering (MSK) and Winship Cancer Institute from 1/1/2015 to 9/30/22. Cutoff date for analysis was 12/31/2022. HR was defined as the presence of high-risk cytogenetic abnormalities (HRCA) including +1q, del(1p), t(4;14), t(14;16), t(14;20), and/or del(17p), circulating plasma cells (cPC) ≥5%, extramedullary disease (EMD), and/or complex cytogenetics by conventional cytogenetics. Patients who received ≤1 prior cycle of a different MM regimen were included. Responses and progression were evaluated per International Myeloma Working Group Uniform Response Criteria. Discrete patient characteristics were summarized by frequency (percentage) and continuous characteristics were summarized by median (Interquartile Range, IQR). Progression-free survival (PFS) and overall survival (OS) were evaluated by Kaplan-Meier method. Association between time to event outcomes and patient's characteristics were determined by log-rank test. Univariate Cox proportional hazard model was used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs). Results: We identified 179 consecutive NDMM patients with HR features treated with KRd at MSK (N=106) and Winship Cancer Institute (N=73). Baseline patient characteristics are listed in Table 1. The median age was 62 (IQR, 55-68) and 28% of patients were Black. There were 45 (25%), 76 (42%), 47 (26%), and 11 (6%) patients with 0, 1, 2, 3+ HRCA, respectively. A median of 5 (IQR 4-6) cycles were administered. At data cutoff, 70% of patients received upfront autologous stem cell transplant (ASCT). Best overall response rate (ORR) by the end of KRd induction was 94% for 178 response-evaluable patients, including 39% with ≥complete response (CR) and 78% with ≥very good partial response (VGPR). After a median follow-up of 41.9 (95% CI 39-45.6) months, the median PFS (mPFS) was 78.2 months (95% CI 52.5-not reached [NR]), and 2-year estimated PFS was 79% (73%-85%). Median OS (mOS) was not reached, and 2-year OS was 92% (95%CI 89%-97%). For HR subgroups based on the number of HRCA present, mPFS was 78.2 (95% CI 40.1-NR), 65.2 (43.4-NR), 55.9 (44.9-NR), and 17.5 (8.78-NR) months for patients with 0, 1, 2, 3+ HRCA, respectively, with 2-year PFS of 83% (95% CI, 73%-95%), 82% (74%-92%), 78% (67%-91%), and 46% (24%-87%), respectively (P=0.35). Median OS was NR for patients with 0, 1, and 2 HRCA and was 58.2 months (95% CI 38.8-NR) for patients with 3+ HRCA with 2-year OS of 93% (95% CI, 86%-100%), 96% (91%-100%), 89% (81%-99%), and 81% (60%-100%), respectively (P=0.13). In univariable analysis, lack of t(14;16) (HR 0.32, 95%CI 0.11-0.95; P=0.03), White race (HR 0.38, 95%CI 0.17-0.84; P=0.02), presence of ≤2 HRCA (HR 0.31, 95%CI 0.11-0.92; P=0.04) were associated with longer OS in this cohort of HR-NDMM patients treated with KRd induction. Multivariable analysis for clinical variables, including specific HRCA, number of HRCA present, age, gender, race, R-ISS stage, presence of EMD, presence of cPCs, cardiac history, and upfront ASCT did not demonstrate any single variable was a significant predictor of progression or death. Conclusion: For this real-world patient population, KRd induction was associated with high response rates and promising outcomes with best ORR of 94% and mPFS of 6.5 years for patients with high-risk newly diagnosed multiple myeloma consistent with FORTE trial data. PFS did not significantly differ among HR patients with 0, 1, 2, 3+ HRCA although mPFS for patients with 3+ HRCA was only 17.5 months. Data with maintenance therapy and longer follow-up outcomes will be presented at the meeting.

Real-World Outcomes of Brexucabtagene Autoleucel (brexu-cel) for Relapsed or Refractory (R/R) Adult B-Cell Acute Lymphoblastic Leukemia (B-cell ALL): Evidence from the CIBMTR Registry

Background Brexu-cel is a CD19 CAR T therapy first approved by the FDA in 2021 for adult patients (pts) with R/R B-cell ALL. In the pivotal phase II ZUMA-3 single arm trial, brexu-cel achieved a high rate (71%) of complete remission or complete remission with incomplete hematological recovery (CR/CRi) with a manageable safety profile. Here, we report outcomes of brexu-cel in a broad real-world patient population. Methods A total of 197 pts with B-cell ALL were infused with brexu-cel and prospectively enrolled between July 2021 and May 2023 in the CIBMTR registry across 67 centers in the US. In this analysis, we included 138 pts with at least one scheduled follow-up at Day 100 and evaluable safety and effectiveness outcomes. Descriptive statistics, Kaplan-Meier estimator and cumulative incidence functions were used to summarize outcomes. Results Median age was 43 years (range, 19.4-79.4; 19% were age ≥60 years) and 52% were males. Pts had a diverse ethnic background: 50% non-Hispanic White, 28% Hispanic, 11% non-Hispanic Black and 7% non-Hispanic Asian. More than half (55%) of pts had poor cytogenic risk score at diagnosis. Prior to lymphodepletion (LD), the majority of pts had: ECOG performance status of 0 or 1 (80%); at least one clinically significant comorbidity (79%); and Ph-negative disease (64%). Furthermore, 44% had evidence of ≤5% bone marrow blasts; of these (n=49), 65% were MRD negative. Extramedullary disease and CNS involvement was observed in 22% and 10% of pts prior to LD, respectively. As such, based on adapted criteria available in the registry data, 91% of pts in this cohort would have been ineligible for ZUMA-3. Pts received a median of 4 prior lines of therapy (range 1-13); 46% had prior inotuzumab and 58% had prior blinatumomab. One third (35%) had prior allogeneic (allo) stem cell transplant (SCT). Moreover, 41% of pts received bridging therapy prior to LD. Median time from leukapheresis to brexu-cel infusion was 32 days (inter-quartile range [IQR] 27-42)) and median follow-up time was 5.9 months (95% CI: 5.1-6.1) (Table 1). Overall CR/CRi rate by Day 100 post infusion was 76%; 70% were still in remission at 6 months post initial response (95% CI: 55-80). For those who were not in response before LD, 63% of them converted into a CR/CRi. Relapse free survival at 6 months was 53% (95% CI: 42-62). The overall survival rate at 6 months was 78% (95% CI: 69-84); primary causes of death were primary disease (n=13/32, 41%) and infection (n=7/32, 22%). About one third (31%) of responders received a subsequent allo SCT. High response rates were observed in all pts regardless of age, prior exposure to blinatumomab, allo SCT, or presence of extramedullary disease prior to LD. Grade ≥3 cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS, ASTCT consensus) occurred in 9% and 24% of pts, respectively (Table 2). Treatment for CRS and/or ICANS consisted mainly of tocilizumab (67%) and corticosteroids (51%). Most of these adverse events were resolved within 3 weeks of infusion (CRS, 94%; ICANS, 80%). Prolonged cytopenia and neutropenia 30 days post infusion was experienced by 42% and 33% of pts, respectively. Conclusion In this largest-to-date real-world evidence study of brexu-cel in adult pts with B-cell ALL, response and safety outcomes were consistent with findings from ZUMA-3, even with 91% of patients not meeting ZUMA-3 eligibility criteria. Updated data with longer follow-up will be reported at the time of presentation. *First and second authors are equal contributors

Characteristics of Real-World Patients with High-Risk BRAFV600E/K-Mutated Melanoma Receiving Adjuvant Treatment with Dabrafenib Plus Trametinib After Surgical Resection, Through the Italian Managed Access Program.

Real-world data from patients with BRAFV600-mutated, resected, stage III melanoma treated with dabrafenib plus trametinib as adjuvant targeted therapy are limited, and it is important to gain an understanding of the characteristics of this patient population, as well as of the patient journey. Here we aimed to describe the characteristics, dosage reductions and discontinuations in patients with BRAFV600E/K-mutated melanoma receiving adjuvant dabrafenib plus trametinib after surgical resection through an Italian managed access program (MAP). Eligible patients had completely resected cutaneous melanoma with confirmed BRAF V600E or V600K mutation, or initially resectable lymph node recurrence after a diagnosis of stage I or II melanoma. The starting dose of dabrafenib and trametinib was 150 mg twice daily and 2 mg once daily, respectively. A total of 557 patients received dabrafenib plus trametinib through the MAP (stage III resected disease at inclusion, 554). Median age was 54.0 years, and 40.2% of patients were female. The proportion of all treated patients who required a dose reduction was low (10.8%) as was the proportion of patients who discontinued treatment (13.5%). The main reason for treatment discontinuation was adverse events (36.0%). New treatments, including BRAF-targeted therapies and immunotherapy, have transformed the natural history of melanoma. This is the largest study to date describing patients treated with dabrafenib plus trametinib in routine clinical practice in Italy between 2018 and 2019. Results highlight the characteristics of the patients treated and their journey, as well as the tolerable safety profile of dabrafenib plus trametinib in a real-world patient population.

Applicability and performance of heart failure prognostic scores in dilated cardiomyopathy: the real-world experience of an Italian referral center for cardiomyopathies

BackgroundThe performance of heart failure (HF) risk models is validated in the general population with HF but in specific aetiological settings, and specifically in dilated cardiomyopathy (DCM), has scarcely been explored. We tested eight of the main prognostic scores used in HF in a large real-world population of patients with DCM. MethodsWe included 784 consecutive DCM patients enrolled, both inpatients and outpatients, enrolled between January 2000 and December 2017. The risk of 1 and/or 3-year all-cause mortality/heart transplantation/durable left ventricular assist device (LVAD) implantation (D/HTx/LVAD) was estimated in our cohort according to the following risk scores SHFM, 3-CHF, CHARM, MAGGIC, GISSI-HF, MECKI, Barcelona Bio-HF, Krakow score and their accuracy calculated through the receiver operator characteristic (ROC) curve analysis. ResultsDuring a median follow-up of 5.8 years (Interquartile Range 3.2–7.6 years), 191 patients (20%) died or underwent HTx/LVAD (158 deaths, 30 heart transplantations, and 3 LVAD implantations). The high missing rate allowed to calculated only four prognostic models (MAGGIC, CHARM, 3-CHF and SHFM). All the scores overestimated the rate of D/HTx/LVAD. The prognostic accuracy was suboptimal for MAGGIC (AUC 0.754) and CHARM (AUC 0.720) scores and only modest for 3-CHF (AUC 0.677) and SHFM (AUC 0.667). ConclusionsMain prognostic scores for the risk stratification of HF are only partially applicable to real-world patients with DCM. MAGGIC and CHARM scores showed the best accuracy, despite the overestimation of risk. Our findings corroborate the need of specific risk scores for the prognostic stratification of DCM. Clinical perspective:What is new?The present study is the largest analysis in literature which investigate how the main existing heart failure prognostic risk scores performed in a real-world of dilated cardiomyopathy population, both in- and outpatients.What are the clinical implications?DCM is a stand-alone model of heart failure, where the performance of multiple heart failure prognostic scores for the risk stratification is quite limited. The need for contemporary, dedicated prognostic scores in this disease is increasingly evident.

Insights of Clinical Significance From 109 695 Solid Tumor Tissue-Based Comprehensive Genomic Profiles.

FoundationOneCDx is approved in the US and Japan as a companion diagnostic test to identify patients with cancer who may benefit from treatment with 30 drug therapies in the US and 23 in Japan. Tumor profiling with FoundationOneCDx also detects genomic findings with evidence of clinical significance that may inform clinical care decisions beyond companion diagnostic claims. This observational study reports the breadth and impact of clinical decision insights from FoundationOneCDx solid tumor profiles. Consecutive test result reports for patients with solid tumor diagnoses (n = 109 695) were retrospectively analyzed for clinically significant predictive, prognostic, and diagnostic genomic alterations and signatures, determined in accordance with professional guidelines. Interventional clinical trials with targeted therapies or immune checkpoint inhibitors were matched to tumor profiles based on evidence that the genomic finding may be an actionable, investigational, or hypothetical target in the patient's tumor type. In 14 predefined cancer types (80.7% of analyzed solid tumors), predictive, prognostic, and diagnostic markers were reported in 47.6%, 13.2%, and 4.5% of samples, respectively, accounting for a total of 51.2% of tumor profiles. Pan-cancer predictive markers of tumor mutational burden (TMB) of 10 or more mutations per megabase, high microsatellite instability (MSI), or NTRK1/2/3 fusions were observed in 15.6%, 2.0%, and 0.1% of solid tumors, respectively. Most solid tumor profiles (89.2%) had genomic results that could theoretically inform decisions on the selection of immunotherapy and targeted therapy clinical trials. For this real-world population of patients with FoundationOneCDx solid tumor profiles in the routine course of clinical care, clinically significant findings were reported for approximately half of patients with genomic results.

Impact of androgen receptor alterations on cell-free DNA genomic profiling on survival outcomes in metastatic castration-resistant prostate cancer.

Androgen receptor (AR) gene alterations, as detected by circulating tumor cell-free DNA (cfDNA) genomic profiling, have been shown to emerge after a variable duration of androgen signaling inhibition. AR alterations were associated with inferior outcomes on treatment with androgen receptor pathway inhibitors (ARPI) in the first line metastatic castration-resistant prostate cancer (mCRPC) setting in a phase 2 trial. Here in, we assessed the impact of these AR alterations on survival outcomes in a real-world patient population of mCRPC experiencing disease progression on an ARPI. In this IRB-approved retrospective study, consecutively seen patients with a confirmed diagnosis of mCRPC, with disease progression on a treatment with ARPIs in the first line mCRPC setting, with no prior exposure to an ARPI in the castration sensitive setting, and with available cfDNA profiling from a CLIA certified laboratory were included. Patients were categorized based on AR status: wild-type (ARwt ) or alteration-positive (AR+ ). The objective was to correlate overall survival (OS) after disease progression on the first-line ARPI with the presence or absence of AR alterations. Kaplan-Meier and Cox Regression Tests were used as implemented in R-Studio (v.4.2). A total of 137 mCRPC patients were eligible: 69 with ARwt versus 68 with AR+ . The median OS posttreatment with the first ARPI was significantly higher for ARwt than AR+ patients (30.1 vs. 15.2 mos; p < 0.001). Of 108 patients who received a subsequent line of therapy, 63 received an alternate ARPI (AR+ 39 vs. 24 ARwt ), while 20 received a taxane-based therapy (11 AR+ vs. 9 ARwt ). Among patients receiving an alternate ARPI, AR+ had numerically shorter OS (16.8 vs. 30.4 mos, p = 0.1). Among patients receiving taxane-based regimens, the OS was not significantly different between AR+ and ARwt (14.5 vs. 10.1 mos, p = 0.18). In this real-world study, mCRPC patients with AR alterations on cfDNA had inferior OS after disease progression on the first ARPI, compared to those who did not, and may impact outcomes on a subsequent ARPI but not on subsequent taxane-based therapy received. By providing survival estimates for patients with or without AR alterations, our data may aid in patient counseling, prognostication, treatment decision, and for designing future clinical trials in this setting.

REducing INFectiOns thRough Cardiac device Envelope: insight from real world data. The REINFORCE project.

Infections resulting from cardiac implantable electronic device (CIED) implantation are severely impacting on patients' and on health care systems. The use of TYRXTM absorbable antibiotic-eluting envelope has proven to decrease major CIED infections within 12 months of CIED surgery. The aim is to evaluate the impact of the envelope use on infection-related clinical events in a real-world contemporary patient population. Data on patients undergoing CIED surgery were collected prospectively by participating centers of the One Hospital ClinicalService project. Patients were divided into two groups according to whether TYRXTM absorbable antibiotic-eluting envelope was used or not. Out of 1819 patients, 872 (47.9%) were implanted with an absorbable antibiotic-eluting envelope and included in the Envelope group and 947 (52.1%) patients who did not receive an envelope were included in the Control group. Compared to control, patients in the Envelope group had higher thrombo-embolic or hemorrhagic risk, higher BMI, lower LVEF and more comorbidities. During a mean follow-up of 1.4 years, the incidence of infection-related events was significantly higher in the control compared to the Envelope group (2.4% vs. 0.8%, P = 0.007). The five-year cumulative incidence of infection-related events was 8.1% in the control and 2.1% in the Envelope group (HR: 0.34, 95%CI: 0.14-0.80, P = 0.010). In our analysis, the use of an absorbable antibiotic-eluting envelope in the general CIED population was associated with a lower risk of systemic and pocket infection.

Safety and Clinical Outcomes of Insulin Degludec in Korean Patients with Diabetes in Real-World Practices: A Prospective, Observational Study.

To investigate the safety and effectiveness of insulin degludec (IDeg) in a real-world population of Korean patients with diabetes requiring insulin therapy. This was a multicenter, prospective, single-arm, open-label, non-interventional study. Patients aged ≥ 12months and treated with previous glucose-lowering medications were eligible to switch to IDeg. The primary endpoint was the incidence of adverse events (AEs), and the secondary endpoints were changes in glycated hemoglobin (HbA1c), fasting plasma glucose (FPG), postprandial glucose (PPG), and target HbA1c < 7.0%. In total, 3225 and 2450 patients were included in the safety analysis set (SAS) and effectiveness analysis set (EAS), respectively. The mean baseline HbA1c and duration of diabetes were 9.4% and 13.0years, respectively. Adverse events were reported in 740 patients (22.9%); the majority were mild and resolved. Significant improvements were observed in HbA1c, FPG, and PPG at week 26 (all p < 0.0001). The target of HbA1c < 7% was achieved in 22.2% of patients at week 26. In real-world clinical practice, 26weeks of IDeg treatment resulted in significant reductions in glycemic parameters with a low incidence of AEs in Korean patients with diabetes. No new safety signals were observed. This trial is registered under ClinicalTrials.gov (NCT02779413) and the universal trial number is [U1111-1176-2287].

High interindividual variability in LDL-cholesterol reductions after inclisiran administration in a real-world multicenter setting in Germany

Background and aimsLow-density lipoprotein cholesterol (LDL-C) is the main therapeutic target in the treatment of hypercholesterolemia. Small interfering RNA (siRNA) inclisiran is a new drug, which targets PCSK9 mRNA in the liver, reducing concentrations of circulating LDL-C. In randomized trials, inclisiran demonstrated a substantial reduction in LDL-C. The German Inclisiran Network (GIN) aims to evaluate LDL-C reductions in a real-world cohort of patients treated with inclisiran in Germany.MethodsPatients who received inclisiran in 14 lipid clinics in Germany for elevated LDL-C levels between February 2021 and July 2022 were included in this analysis. We described baseline characteristics, individual LDL-C changes (%) and side effects in 153 patients 3 months (n = 153) and 9 months (n = 79) after inclisiran administration.ResultsSince all patients were referred to specialized lipid clinics, only one-third were on statin therapy due to statin intolerance. The median LDL-C reduction was 35.5% at 3 months and 26.5% at 9 months. In patients previously treated with PCSK9 antibody (PCSK9-mAb), LDL-C reductions were less effective than in PCSK9-mAb-naïve patients (23.6% vs. 41.1% at 3 months). Concomitant statin treatment was associated with more effective LDL-C lowering. There was a high interindividual variability in LDL-C changes from baseline. Altogether, inclisiran was well-tolerated, and side effects were rare (5.9%).ConclusionIn this real-world patient population referred to German lipid clinics for elevated LDL-C levels, inclisiran demonstrated a high interindividual variability in LDL-C reductions. Further research is warranted to elucidate reasons for the interindividual variability in drug efficacy.Graphical abstract

Outcomes in patients with BRAFV600-mutated melanoma and brain metastases at baseline treated with dabrafenib plus trametinib.

Brain metastases (BM) and lactate dehydrogenase (LDH) levels above the upper limit of normal (ULN) are associated with poor prognosis in patients with melanoma. Although treatment with the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib have demonstrated long-term clinical benefit in patients with melanoma, data on their efficacy in patients with BM are limited. DESCRIBE Italy is an observational, retrospective, real-world study evaluating dabrafenib plus trametinib in 499 patients with BRAFV600-mutant stage III unresectable or stage IV melanoma from various sites across Italy. Here, we analyzed the clinical outcomes for the subgroup of patients receiving first-line treatment and presenting with BM at diagnosis and assessed the impact of predictive factors such as LDH levels and the presence of other metastases on median progression-free survival (mPFS). Overall, 325 evaluable patients were on first-line therapy and are the focus of this analysis; of these, 76 patients (23.4%) had BM at baseline. mPFS was lower for patients with BM at baseline compared with overall patients (8.7 months vs 9.3 months, respectively). Patients with BM at diagnosis and LDH >ULN had a considerably shorter mPFS compared with patients with LDH ⩽ULN (5.3 months vs 9.9 months, respectively). mPFS was noticeably longer for patients with cerebral metastases only compared with patients with cerebral and other metastases (15.0 months vs 8.7 months, respectively). Dabrafenib plus trametinib showed effectiveness in a real-world population of patients with advanced BRAFV600-mutated melanoma and BM at baseline, supporting its use in this population with poor outcomes.

Plasma Cell-free RNA PD-L1 and Survival with Immune Checkpoint Inhibitor Therapy in Metastatic Non-Small Cell Lung Cancer

Background: Tissue programmed death-ligand 1 (PD-L1) protein expression is predictive of immune checkpoint inhibitor (ICI) benefit. However, tissue testing can be fraught with tissue acquisition and heterogeneity limitations. Plasma testing can overcome these limitations. However, the overall survival predictive benefit of plasma PD-L1 assays have not been well characterized. Methods: Patients with stage IV non-small cell lung cancer (NSCLC) and plasma cell free RNA PD-L1 by polymerase chain reaction (PCR) expression were identified and assessed for overall survival. Sixteen patients treated with front-line ICI-based regimens were assessed and represented a real-world patient population with over half with a performance status of 2 or greater. Ten contemporaneous patients at the same institution treated with chemotherapy alone were also identified and assessed. With a median follow-up of 33 months, median overall survival was 13 months with a 30% 3-year OS for the ICI treated patients compared to a median OS of 3 months and a 10% 3- year OS for those treated with chemotherapy alone. Comparative log-rank test p-value = 0.014 and a hazard ratio 0.376 (95%-CI 0.134-1.057). Conclusions: A plasma cell free RNA PD-L1 by PCR assay was associated with a statistically significant survival benefit from ICI-based treatment compared to chemotherapy in the first line treatment of a real-world patient population of advanced NSCLC.

Trends in outcomes associated with the use of Auryon atherectomy system in a real-world setting

BackgroundWhile endovascular approaches are considered first line treatment for stenosis or occlusion of the lower limb arteries, major dissections and embolic events remain procedural risks. Newer technologies are needed which limit these complications while achieving desired clinical outcomes. MethodsThe Auryon atherectomy system (AngioDynamics) consists of a 355-nm wavelength solid-state Nd:YAG short pulse laser combined with dedicated optical catheters. This single-center, retrospective chart review assessed the safety and efficacy of this device in patients with PAD treated at our center between March and December 2020. ResultsA total of 55 patients were included. Mean age was 73.7 ± 9.3 years with 63.6 % of patients being males. Lesions were above the knee only for 16.4 % of patients, below the knee only for 3.6 %, and both above and below the knee for 80.0 % of patients. One patient had in-stent restenosis. Chronic total occlusions and critical limb ischemia were present for 43.6 % of patients respectively. Procedural success, defined as <30 % residual stenosis without any complications, was achieved in 85.5 % of patients. Stenosis/re-occlusion occurred in 25.5 % of patients at a mean of 168.9 ± 73.4 days with resultant target lesion revascularization (TLR) at 218.3 ± 92.4 days. Four patients underwent minor amputations. No patients experienced procedure-related complications. One patient died unrelated to the procedure. ConclusionThe Auryon laser system was shown to be safe and effective in this real-world patient population with no procedural adverse events or deaths and improvements in patient outcomes.

Usefulness of contrast echocardiography for detection of left ventricular thrombus in a real-world population with acute anterior myocardial infarction

Abstract Funding Acknowledgements Type of funding sources: None. Background/Introduction The treatment of ST-elevation myocardial infarction (STEMI) has considerably changed in recent years, with early, mainly transcatheter reperfusion therapy improving survival. However, left ventricular thrombus (LVT) is still reported as a relatively common complication especially in anterior STEMI. Two-dimensional transthoracic echocardiography (TTE) is the most commonly used diagnostic modality in this setting due to its wide availability and low cost but can lead to misdiagnoses. The use of ultrasound contrast agents has dramatically improved the visualization of cardiac chambers and thus detection of LVT. Purpose The purpose of this study was to assess the value of contrast echocardiography (CE) for the detection of apical LVT in a real-world population of patients with acute anterior myocardial infarction (MI) in the modern era. Methods The population of this prospective study consisted of consecutive patients presenting within a year with acute anterior MI in a tertiary hospital with capability of primary percutaneous coronary intervention (PCI). Patients with confirmed COVID-19 infection and/or current use of anticoagulant medication were excluded from the study. All patients underwent TTE without and with contrast within 7 days post-MI by an experienced cardiologist. CE was considered the reference standard. Results A total of 102 patients (mean age 61±13 years, 19% female) with anterior STEMI were prospectively recruited in our study. Ninety-eight patients underwent primary PCI, 3 patients underwent rescue PCI after unsuccessful thrombolysis, 1 patient underwent surgical revascularization. Two patients did not receive contrast agent (1 due to known hypersensitivity to contrast agent and 1 due to cardiogenic shock). Mean ejection fraction (EF) was 46% ± 10% in total population and was significantly lower in patients with LVT (42% ± 7% vs 47% ± 10%, p = 0.025). The incidence of confirmed LVT by CE was 28% (28/100) within 7 days post-MI. In total, 8 out of 28 LVT cases (28.5%) would have been missed using TTE without contrast within 7 days post-MI (sensitivity 71%, specificity 100%, positive predictive value 100% and negative predictive value 90%). Example of missed LVT on TTE without and with contrast (left and right panel respectively) is shown in Figure 1. Conclusions LVT is not uncommon after anterior STEMI in the modern era of primary PCI. LVT would have been missed in a significant proportion of patients with anterior STEMI if CE was not used, depriving these patients from the option of early anticoagulation treatment.

Real-world effectiveness of third-line cabazitaxel in patients with metastatic castration-resistant prostate cancer: CARD-like analysis of data from a post-marketing surveillance in Japan

BackgroundThe CARD trial was conducted in patients with metastatic castration-resistant prostate cancer (mCRPC) who had received docetaxel and experienced disease progression within 1 year on an androgen receptor-axis-targeted therapy (ARAT). Subsequent treatment with cabazitaxel had improved clinical outcomes compared with an alternative ARAT. This study aims to confirm the effectiveness of cabazitaxel in real-world patients in Japan and compare their characteristics with those of patients from the CARD trial.MethodsThis was a post-hoc analysis of a nationwide post-marketing surveillance registering all patients who were prescribed cabazitaxel in Japan between September 2014 and June 2015. Included patients had received docetaxel and ≤ 1 year of an ARAT (abiraterone or enzalutamide) prior to receiving cabazitaxel or an alternative ARAT, as their third-line therapy. The primary effectiveness endpoint was the time to treatment failure (TTF) of the third-line therapy. Patients were matched (1:1) from the cabazitaxel and second ARAT arms based on propensity score (PS).ResultsOf the 535 patients analysed, 247 received cabazitaxel and 288 the alternative ARAT as their third-line therapy, of which, 91.3% (n = 263/288) received abiraterone and 8.7% (n = 25/288) received enzalutamide as their second third-line ARAT. Patients in the cabazitaxel and second ARAT arms had TNM classification of M1 or MX in 73.3% and 68.1%, Gleason score of 8–10 in 78.5% and 79.2% and mean (standard deviation) serum PSA levels of 483 (1370) and 594 (1241) ng/mL, respectively. Initial cabazitaxel dose was ≤ 20 mg/m2 in 61.9% (n = 153/247) of the patients in the cabazitaxel arm. The median TTF (95% confidence interval [CI]) of the third-line therapy was 109 (94–128) days for cabazitaxel and 58 (57–66) days for the second ARAT, with a hazard ratio (95% CI) of 0.339 (0.279–0.413) favouring cabazitaxel. Similar results were obtained after PS-matching, with a hazard ratio (95% CI) of 0.323 (95% CI 0.258–0.402) favouring cabazitaxel.ConclusionsConsistent with the CARD trial, cabazitaxel demonstrated superior effectiveness over a second alternative ARAT in a real-world patient population in Japan, despite the population having more advanced disease status and a lower dose of cabazitaxel being more frequently administered, than in the CARD trial.

Knowing Is Not Doing: A Qualitative Study of Parental Views on Family Beverage Choice.

Sugary drink consumption is associated with adverse health outcomes in children, highlighting the need for scalable family interventions that address barriers to water consumption. To inform development of a scalable, health-care-system-based intervention targeting family beverage choice, a formative qualitative study was conducted using semi-structured interviews with parents whose children were identified as over-consuming sugar-sweetened beverages (SSB) and/or fruit juice (FJ). The first goal of these interviews was to understand, in a diverse real-world patient population, what parents viewed as the primary drivers of their family's beverage choices, and explore how these drivers might need to be addressed in order to make changes to beverage consumption. A second goal was to explore parental preferences for planned intervention components. An exploratory goal of the interviews was to examine whether knowledge, attitudes, and beliefs around family beverage choice differed across racial and ethnic groups in this sample. Semi-structured phone interviews were conducted and interviews audio-recorded and transcribed. 39 parents/caregivers of children ages 1-8 who over-consumed sugary drinks as determined by screenings at pediatric visits. Parents were interviewed about family beverage choices and preferences to inform development of a multi-component intervention. Thematic analysis was performed, including comparison of themes across racial/ethnic groups. Parents expressed that sugary drinks were unhealthy and water was a better alternative. Most were familiar with the health consequences of excess sugar consumption. They identified many reasons why sugary drinks are chosen over water despite this knowledge. One common reason was concern about tap water safety. Few differences were noted across racial and ethnic groups in our sample. Parents were enthusiastic about a technology-based intervention to be delivered through their child's doctor's office. Knowledge is not enough to change behavior. Beverage interventions need to be easy to access, make water more appealing, and elevate beverage choice above the "white noise" of everyday life. Delivering an intervention in a clinical setting could provide an extra level of care, while technology would reduce the amount of live contact and decrease the burden for clinicians and parents.