First-line Therapy For Patients Research Articles

Ablation Versus Antiarrhythmic Drugs as First-Line Therapy for Treatment-Naive Atrial Fibrillation: A Systematic Review and Meta-Analysis

Evidence on the relative safety and efficacy of atrial fibrillation catheter ablation and antiarrhythmic drugs (AADs) as the first-line therapy for patients with treatment-naive atrial fibrillation (AF) remains disputed. Digital databases were queried to identify relevant randomized controlled trials. The incidence of recurrent AF, major adverse cardiovascular events, and its components (all-cause death, nonfatal stroke, and bleeding) were compared using the DerSimonian and Laird method under the random-effects model to calculate pooled unadjusted risk ratio (RR) with 95% confidence intervals (CIs). A total of 6 randomized controlled trials consisting of 1,120 patients (574 ablation and 549 AADs) were included in the final analysis. Over a median follow-up of 1year, the risk of any AF recurrence (RR 0.54, 95% CI 0.39 to 0.75) was significantly lower in patients receiving ablation than in patients receiving AADs. However, there was similar risk of major adverse cardiovascular events (RR 2.65, 95% CI 0.61 to 11.46), trial-defined composite end point of adverse events (RR 0.71, 95% CI 0.28 to 1.80), stroke (RR 2.42, 95% CI 0.22 to 26.51), all-cause mortality (RR 1.98, 95% CI 0.28 to 13.90), and procedure/medication failure (RR 2.65, 95% CI 0.61 to 11.46) with both therapies. In conclusion, in patients presenting with treatment-naive AF, ablation as a first-line therapy lowers the risk of AF recurrence with no associated increase in major adverse events, stroke, and mortality compared with AADs.

Efficacy and Safety Outcomes in Patients with Cancer-Associated Thromboembolism Treated with Tinzaparin According to the Tumor Site: Meta-Analysis of Prospective Studies Involving 1413 Individual Patients' Data

Introduction DOAC (direct oral anticoagulant) and LMWH (Low Molecular Weight Heparin) are recommended by international guidelines as first line therapy in patients with CAT (Cancer Associated Thrombosis), but the risk of venous thromboembolic recurrence (rVTE) and the risk of major bleeding (MB) remains high. Several scores have attempted to predict these risks with disappointing results, probably because of heterogeneous treatments and small sample sizes representing various tumor sites. We conduct a meta-analysis on individual patient level data to report the rate of rVTE and MB by 6 months according to site of cancer from prospective studies involving CAT patients on tinzaparin. Methods The meta-analysis is based on individual patient data from prospective studies that included patients with CAT treated with tinzaparin who were followed for 6 months (PROSPERO registration CRD42019119907). Eligible studies must include controlled data and a central decision for study outcomes. Main outcomes were cumulative incidence of rVTE and MB at 6 months. Time-to-event outcomes were estimated using competing risk regression (Fine and Gray's method with death as competing risk). Cumulative incidences were presented with corresponding 95% confidence interval (95% CI). Time-to-event outcomes were estimated using competing risk regression (Fine and Gray's method with death as competing risk). Cumulative incidences were presented with corresponding 95% confidence interval (95% CI). Results Three prospective cohort studies (AXA - NCT02898051, 308 patients; PREDICARE - NCT03099031, 409 patients (1); TICAT - NCT01164046, 247 patients (2) and the Tinzaparin arm of the CATCH study (NCT01130025, 449 patients (3)) were included. A total of 1413 patients (median age 65.0 [IQR 56.0-73.5], 51.9% female) were included in the meta-analysis. Cancers were mostly solid tumors (91.7%); primary sites were gastrointestinal (27.0%), lung (18.0%), breast (11.8%), genitourinary (14.4%); ECOG performance status was ≥ 2 for 30.2%. At 6 months, 74 patients experienced a rVTE, for a cumulative incidence of 5.4% [95% CI: 4.3%; 6.7%], while 47 patients had a MB, for a cumulative incidence of 3.4% [95% CI: 2.6%; 4.6%]. Clinical outcomes according to the type of cancer are summarized in the Table. rVTE cumulative incidence varied from 0.6 to 8.5% and rVTE occurred more frequently in patients with genitourinary, lung and gynecological cancers, while MB cumulative incidence ranged from 2.1% to 4.2% across different cancer sites (Table). Overall mortality ranged from less than 18% (breast and hematological cancers) to 45.2% (lung cancer) within 6 months of the index VTE. Conclusion In CAT patients receiving tinzaparin for up to 6 months, rVTE and MB vary according to tumor site. The CAT entity is not sufficient to describe a situation at risk of recurrence or bleeding for patient management.

Adjuvant Sorafenib for Postoperative Patients with Hepatocellular Carcinoma and Macrovascular Invasion.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality in Taiwan. Some patients with HCC are diagnosed with macrovascular invasion (MVI), which is associated with a poorer prognosis. In Taiwan, sorafenib is the first-line therapy for patients with advanced HCC. However, the efficacy of adjuvant sorafenib therapy remains unclear for the subset of patients with HCC and MVI who are eligible for surgery. Therefore, we investigated the potential benefit of adjuvant sorafenib therapy for patients with HCC and MVI after surgery. Our study showed that the lack of improved PFS or OS of adjuvant sorafenib challenged the therapeutic benefit of postoperative sorafenib. Alcohol consumption and an α-fetoprotein level of ≥400 ng/mL were independent predictors of overall survival (OS); however, adjuvant sorafenib therapy was not a predictor of progression-free survival (PFS) or OS. In conclusion, our study indicated that adjuvant sorafenib therapy did not provide PFS or OS benefits in patients with HCC and MVI.

Efficacy and Safety of Orelabrutinib-Containing Regime (TORM) As First-Line Therapy in Primary Central Nervous System Lymphoma (PCNSL): A Retrospective Analysis

Introduction: Primary central nervous system lymphoma (PCNSL) is a rare, aggressive extranodal lymphoma with poor prognosis. Currently there is no standard therapeutic strategy for PCNSL, and high-dose methotrexate-based regimens remain the first option (Siegal et al. Acta Haematologica 2019). Recently, studies have shown that Bruton's tyrosine kinase (BTK) plays a crucial part in B cell receptor and Toll-like receptor signaling pathways, which are constitutively active in PCNSL (Shen et al. Front Oncol. 2022). BTK inhibitor has been proven effective in treating chronic lymphocytic leukemia and other B-cell lymphomas (Yoshitaka et al. Neuro-Oncology 2021). Orelabrutinib is a novel and highly selective BTK inhibitor with high cerebrospinal fluid (CSF) concentration, which has demonstrated efficacy and safety in PCNSL (Wu et al. Invest New Drugs. 2022). Thus, we conducted a retrospective study to evaluate the efficacy and safety of the orelabrutinib-containing regimens as first-line therapy for patients (pts) with PCNSL. Methods: This isa retrospective analysis of pts with PCNSL who received TORM regimens (temozolomide 150 mg/m 2 day 2-5; orelabrutinib 150 mg qd day 2-21; rituximab 375 mg/m 2 day 1; methotrexate 3.5 g/m 2 day 2; 3 weeks per cycle) as first-line induction therapy between June 2021 and April 2023. It was proposed to receive autologous stem cells transplantation (ASCT) as consolidation therapy or orelabrutinib monotherapy as maintenance after TORM therapy when deemed necessary. The primary endpoint was overall response rate (ORR) according to the International PCNSL Collaborative Group (IPCG) criteria. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. Results: Twelve pts (8 males) with PCNSL were included, with a median age of 63.5 years (range, 40-77). All pts had a histologically confirmed diffuse large B-cell lymphoma and a history of deep intracranial lesions. 8 pts (66.7%) had non-germinal center B-cell-like subtypes. 5 pts (41.7%) had an Eastern Cooperative Oncology Group performance status of ≥2, and 10 pts (83.3%) had International Extranodal Lymphoma Study Group scores ≥2. 4 pts (33.3%) underwent ASCT after induction therapy and 4 pts (33.3%) received orelabrutinib maintenance monotherapy. As of the cut-off date (July 1, 2023), the median follow-up was 11.7 (range, 1.9-23.0) months, and median treatment cycle was 6 cycles (range, 2-9). All 12 pts were evaluated for the treatment response. An interim evaluation after 3/4 cycles was available for 12 pts, showing complete remission (CR) rate of 83.3% (10/12), partial response (PR) rate of 16.7% (2/12), giving an ORR of 100.0% (12/12, Table 1). At data cutoff, of all 12 evaluable pts, the best ORR was 100.0% (12/12), with all pts achieved CR ( Table 1). The median time to response was 1.7 (range, 0.7-2.4) months. Of 12 responders, 9 had an ongoing response, 2 developed progressive disease, and 1 died of covid-19 infection ( Figure 1). Median PFS was 22.6 months, with a 95% CI of 10.4-not reached (NR). Based one OS event, median OS was 22.6 months (95% CI, NR-NR). The most common AEs were anemia. Reported AEs were generally manageable and resolved soon after supportive treatment. AEs associated with off-target activities such as atrial fibrillation, diarrhea, and major hemorrhage were not reported. Conclusions: TORM regimens demonstrated encouraging efficacy and well-tolerated safety profile among pts with PCNSL in this retrospective study. This orelabrutinib-containing regimens may provide a potential treatment strategy for pts with PCNSL.

Potent CD8+ T-Cell Proliferation and Effector Differentiation Following Subcutaneous (SC) Mosunetuzumab Administration in Patients with Untreated, High Tumor-Burden Follicular Lymphoma (FL)

Introduction: Bispecific antibodies (BsAb) have emerged as a potent therapeutic option for patients with B-cell non-Hodgkin lymphoma, including FL. These drugs leverage endogenous CD3+ T-cells to enable cytotoxic tumor cell killing. While their mode of action has been hypothesized in in vitro and animal models, the mechanisms by which these drugs promote both initial and long-term immune-dependent disease control remains unknown. We recently initiated a multicenter phase 2 trial of the CD20xCD3 BsAb mosunetuzumab (mosun) as first-line therapy for patients with high-burden FL (NCT05389293). As part of this study, we performed serial sampling of both blood and lymph node tissues in order to elucidate T-cell changes associated with response and outcome. Here we present the first analysis of peripheral blood immune profiling. Methods: Patients with untreated, high-burden stage 2-4 FL in need of treatment received SC mosun at the dose of 5 mg on D1 and 45 mg on D8 and D15 of C1, and 45 mg on D1 of each subsequent 21-day cycle. Peripheral blood samples were obtained on C1D1, C1D8, C1D15, C2D1, C3D1, C5D1, and end of treatment (EOT, 24w from C1D1). Peripheral blood mononuclear cells (PBMCs) and plasma were isolated and cryopreserved. Samples were later thawed in batches and processed as follows: CITE-Seq + single-cell TCR sequencing was performed on viable CD11b-/CD19-/CD56-/CD3+ T-cells using the 10x Genomics Single Cell Immune Profiling Platform. RNA was extracted from 1 x 10 6 viable PBMCs using TriZol, followed by phenol/chloroform-based extraction, followed by bulk TCR sequencing using an in-house platform developed by MSKCC's Integrated Genomics Operation. The remaining cells were stained with antibodies targeting CD45RA, CD8, CD45, CD45RO, CD38, CD27, CD28, CXCR3, LAG-3, CD3, CD4, HLA-DR, CXCR5, CCR6, CD56, CD11b, CD19, CD39, PD-1, OX40, Tim-3, CCR4, Granzyme B, T-bet, FoxP3, Ki-67, and CTLA-4 and analyzed using a Cytek Aurora Spectral Cytometer. Flow cytometry analysis was performed using OMIQ. Statistical analyses were performed using a paired t-test. Results: A total of 45 samples obtained from 8 patients were analyzed, including samples from C1D1 (8), C1D8 (6), C1D15 (3), C2D1 (7), C3D1 (8), C5D1 (6), and EOT (7). High dimensional clustering of spectral cytometry data using the FlowSOM algorithm revealed 9 clusters of CD8+ T-cells corresponding to known CD8+ T-cell subsets. Among these subsets, we observed two distinct temporal patterns of CD8+ T-cells within the blood. On C1D8 there was a profound drop in circulating effector CD8+ T-cells as well as terminally differentiated CD8+ Temra cells (Figure 1), with a corresponding enrichment of naïve CD8+ T-cells (Figure). We also observed significant proliferation of newly activated T-cells on C1D8, followed by expansion of CD8+ T-cells expressing several activation and exhaustion markers including PD-1, Tim-3, and CD39, peaking on C2D1 (Figure 2). CD4+ T-cell responses were more modest with a small early increase in CD28+OX40+PD-1+ CD4+ T-cells on C1D8 and a drop in circulating GzmB+OX40+ CD4+ T-cells on C1D15. Conclusion: SC mosun therapy for newly diagnosed FL was associated with a unique peripheral blood immune profile, with early mobilization of pre-differentiated CD8+ T-cell effector cells and subsequent activation and expansion of newly primed CD8+ T-cells. Further immune phenotyping, including scRNA-seq and TCR clonal dynamics in the peripheral blood over time, as well as TCR clonality of distinct CD8+ and CD4+ T-cell populations are currently being analyzed on these and additional samples, and will be presented in detail.

Soluble and Membrane P-Glycoprotein Expression in Lymphocytes from Diffuse Large B Cell Non-Hodgkin's Lymphoma Patients Treated with R-CHOP

Introduction Diffuse large B cell lymphoma (DLBC) accounts for 25% of all Non-Hodgkin's Lymphoma (NHL) in the United States. Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) has been the first-line therapy for patients with DLBC-NHL since the early 2000s. Nearly 40% relapse in the following 2-years after complete response and 15% are refractory to first-line therapy. Despite many efforts, other chemotherapy combinations have failed to improve the response rate of NHL patients. Mechanisms of resistance to cytotoxic drugs are vast and include augmented drug efflux mediated through ATP-dependent pumpsas P-glycoprotein (P-gp), which has been related to lesser efficacy. This is due to an over-expression of the glycoprotein with the consequent increase of the drug's efflux from the cytosol. Almost all components of the R-CHOP therapy are P-gp substratesand thereby are affected by P-gp activity. Objectives Analyze serum, plasmatic levels, and membrane expression of P-gp in lymphocytes from patients with DLBC-NHL. Methods A case-control study was conducted to measure serum and plasmatic levels of P-gp, and membrane P-gp expression at the end of treatment on DLBC-NHL patients at “Hospital Civil de Guadalajara Fray Antonio Alcalde,” diagnosed from April to September 2022. Inclusion criteria were age ≥ 18 years, without cancer history and without P-gp inductors or inhibitors. Exclusion criteria were pregnancy, hepatitis, autoimmune disease, Richter syndrome and infection 15 days before blood draw. Using whole blood samples, we identified T and NK cells expressing membrane P-gp by flow cytometry on Attune® NxT (Life Technologies) using the following antibodies and fluorochrome conjugates: CD3-APC/Cy7, CD4-AlexaFlour488, CD8-APC, CD56-BrilliantViolet, CD243-PE. Data was analyzed with FlowJo v10 software. Serum and plasmatic P-gp measurement were done using the Human Permeability Glycoprotein (P-gp) ELISA kit (MyBioSource). Statistical Analysis Proportion comparison between groups was made using Chi-Square or Fisher exact tests. A quantitative variable comparison was done using the U Mann-Witney test. Correlation analysis was made using the Spearman correlation coefficient. Statistical significance was calculated using the p<0.05 two-tailed test. All statistical analysis was made using the software R version 4.1.2 and ggpurb/ggplot2 package. Results Only 15 patients and 30 control individuals were included. Group characteristics and comparisons are summarized in table 1. Regarding the DLBC-NHL group, 27% patients were classified as Lugano I, II and IV stages respectively and 20% as Lugano III stage. Nearly 27% of the patients received radiotherapy as consolidation therapy. Also, 40% of patients showed lymphopenia with a median of 1.23 x10 3/μL (IQR 0.94 - 1.34). Serum and plasmatic P-gp concentrations were similar between groups (p>0.05). The CD8+, CD4+, and CD56+ lymphocyte percentage with membrane P-gp expression comparison between the DLBC-NHL group and the control group presented no significant differences (p>0.05). However, the P-gp median fluorescence index (MFI) in CD8+, CD4+, and CD56+ lymphocytes was higher in the control group than DLBC-NHL group (p<0.05), as displayed in figure 1. Discussion When analyzing only the DLBC-NHL group, we identified a negative correlation between serum P-gp concentration and its expression in NK cell membrane and a positive correlation with membrane expression in CD4+ and CD8+ lymphocytes. Kato et al. reported that P-gp can be secreted through exosomes in patients with drug resistance. Lettau et al. found that CD4+ and CD8+ T lymphocytes have higher exosome expulsion compared to NK cells. These could be related to our finding of negative correlation between serum P-gp and membrane P-gp expression in NK lymphocytes. Ghetie et al. found that Rituximab-an anti-CD20 monoclonal antibody-inhibits P-gp efflux function and therefore makes multi-drug-resistant cell cultures chemosensitive again. B-cells affected by rituximab may influence T-cell P-gp expression and this may be the reason why MFI was lower on DLBC-NHL group than control group. This study helps to expand the understanding of P-gp's role in DLBC-NHL patients as well as R-CHOP therapy effects on the expression of the P-gp in circulating T-cells.

726. Risk factor analysis for cefepime and piperacillin/tazobactam resistant organisms

Abstract Background Carbapenems (CAR) are first line therapy for patients with infections caused by multidrug resistant organisms. As the prevalence of antibiotic resistance is increasing, CAR use has become a common choice for empiric therapy. This increase in use is concerning as prior CAR exposure is a risk factor for CAR resistance. Identification of risk factors associated with resistance for other beta-lactam antibiotics could aid in the appropriate use of CAR therapy while minimizing overuse. The objective of this study was to identify risk factors for cefepime (FEP) and piperacillin/tazobactam (PTZ) resistance and which population required CAR as an empiric therapy. Methods This is a retrospective cohort conducted at HonorHealth John C Lincoln Medical Center, Phoenix AZ between January 2020 to July 2021. The case patients will be those who had an infection which is resistant to FEP or PTZ, while control patients have infection which is susceptible to FEP or PTZ. Recurrence of infection after receiving appropriate antimicrobial therapy considered as a separate case. Patients who do not have antimicrobial susceptibilities were excluded. Variables were compared between groups. Multivariate analysis using logistic regression was used to control for confounding variables. Results Overall, 230 patients met inclusion criteria and were evenly distributed between cohorts. The mean age of the population at baseline was 64 ± 17.4, 111 (48.3%) patients were in an ICU and 103 (44.8%) patients required mechanical ventilation. Clinical variables which were significant in univariate analysis were included in multivariate analyses. Multivariate analyses revealed prior resistance to FEP or PTZ in the past 12 months (OR 8.35, 95% CI [2.28-30.50], p=0.001), transferred from outside facility (OR 3.40, 95% CI [1.80-6.42], p< 0.001), prior ICU admission in the past 90 days (OR 4.40, 95% CI [1.72-11.27], p=0.002), and prior antibiotic use in the past 30 days (OR 2.60, 95% CI [1.33-5.09], p=0.005) were associated with increased risk of FEP- or PTZ-resistant infections. Conclusion Patients with prior resistance to FEP and PTZ within the last 12 months can benefit by initiating empiric therapy with CAR due to the increased risk for subsequent FEP- or PTZ-resistant organisms. Further investigation is warranted. Disclosures All Authors: No reported disclosures

Diagnosis and Therapy of Visceral Vein Thrombosis: An Update Based on the Revised AWMF S2k Guideline.

Splanchnic or visceral vein thromboses (VVTs) are atypical thrombotic entities and include thrombosis of the portal vein, hepatic veins (Budd-Chiari syndrome), mesenteric veins, and splenic vein. All VVTs have in common high 30-day mortality up to 20% and it seems to be difficult to diagnose VVT early because of their rarity and their wide spectrum of unspecific symptoms. VVTs are often associated with myeloproliferative neoplasia, thrombophilia, and liver cirrhosis. VVT is primarily diagnosed by sonography and/or computed tomography. In contrast to venous thromboembolism, D-dimer testing is neither established nor helpful. Anticoagulation is the first-line therapy in patients with stable circulation and no evidence of organ complications. Anticoagulation improves significantly recanalization rates and stops the progress of thrombosis. Low-molecular-weight heparin, vitamin K antagonists, as well as direct-acting oral anticoagulants are possible anticoagulants, but it is noteworthy to be aware that all recommendations supporting the off-label use of anticoagulants are based on poor evidence and consist predominantly of case series, observational studies, or studies with small case numbers. When choosing a suitable anticoagulation, the individual risk of bleeding and thrombosis must be weighted very carefully. In cases of bleeding, bowel infarction, or other complications, the optimal therapy should be determined on a case-by-case basis by an experienced multidisciplinary team involving a surgeon. Besides anticoagulation, there are therapeutic options including thrombectomy, balloon angioplasty, stenting, transjugular placement of an intrahepatic portosystemic shunt, liver transplantation, and ischemic bowel resection. This article gives an overview of current diagnostic and therapeutic strategies.

Design and Rationale for the Direct Oral Anticoagulant Apixaban in Left Ventricular Assist Devices (DOAC LVAD) Study

Implantable left ventricular assist devices (LVAD) therapy is used to improve quality of life, alleviate symptoms, and extend survival in patients with advanced heart failure (HF). LVAD patients require chronic anticoagulation to reduce the risk of thromboembolic complications and frequently experience bleeding events. Apixaban is a direct oral anticoagulant which has become first-line therapy for patients with non-valvular atrial fibrillation and venous thromboembolism; however, its safety in LVAD patients has not been well-characterized. The evaluation of the hemocompatibility of the Direct Oral Anti-Coagulant apixaban in Left Ventricular Assist Devices (DOAC LVAD) trial is a Phase 2, open label trial of LVAD patients randomized to either apixaban or warfarin therapy. Patients randomized to apixaban will be started on a dose of 5 mg twice daily, while those randomized to warfarin will be managed to an INR goal of 2.0-2.5. All patients will be treated with aspirin 81mg daily. We plan to randomize and follow up to 40 patients for 24 weeks to evaluate the primary outcome of freedom from death or hemocompatibility related adverse events (HRAEs) (stroke, device thrombosis, bleeding, aortic root thrombus, and arterial non-CNS thromboembolism). DOAC LVAD will establish the feasibility of apixaban anticoagulant therapy in LVAD patients.Clinicaltrials.gov: NCT04865978

Amiodarone is associated with increased mortality compared with other antiarrhythmic drugs in female patients with atrial fibrillation

Abstract Objective Antiarrhythmic drug (AAD) is the first-line therapy in patients with atrial fibrillation (AF) to maintain sinus rhythm. Amiodarone is one of the commonly used AAD that is known to lead to cardiac and extra-cardiac toxicities including pulmonary fibrosis and thyroid function abnormalities. However, the effect of amiodarone as compared with other-AADs (mainly Ic sodium channel blockers) on all-cause mortality is not fully evaluated. Methods This study used nationwide healthcare insurance system data. Patients with new-onset AF between 2013 and 2019 were enrolled. Use of AADs were confirmed if the patient were prescribed with AAD for more than six months during first year of AF diagnosis (medication possession ratio > 0.5). Clinical follow-up duration was three years from the moment AAD prescription after AF diagnosis. All-cause mortality was compared between amiodarone vs. other-AAD users. Results A total of 770,977 new-onset AF cases were detected. Among these people, 15,142 and 38,707 were identified as amiodarone and other-AAD users, respectively. Significant differences were observed in mean age and prevalence of heart failure, myocardial infarction, chronic kidney disease, diabetes mellitus, and dyslipidemia. After propensity score matching, 9,672 amiodarone users were compared with other-AAD users with same sample size and baseline characteristics were well matched. In multivariate adjusted analysis, amiodarone was associated with 2.5-fold increase in all-cause mortality (hazard ratio=2.520; 95% confidence interval=2.202 – 2.883; p< 0.001). Amiodarone did not show any significant interactions with age, thyroid disease, chronic kidney disease, heart failure, myocardial infarction, diabetes mellitus, dyslipidemia, and hypertension. However, the association between amiodarone and increased mortality was more pronounced in women compared with men (HR=3.124 vs. 2.231; p for interaction=0.022). Conclusion This study showed that all-cause mortality was significantly higher in amiodarone users than other-AAD users due to the toxicities, not by underlying diseases, which was more profound in female. This findings suggests that avoiding amiodarone as a first-line therapy should be considered in AF patients who have no compelling indications such as significant coronary artery disease or heart failure.All-cause mortality

Abstract 14478: Electrocardiographic Predictors of Response to Sacubitril/Valsartan Therapy in Heart Failure With Reduced Ejection Fraction: A Retrospective Cohort Study

Introduction: Sacubitril/valsartan (SV) therapy is currently recommended as first-line therapy in patients with heart failure and reduced ejection fraction (HFrEF) due to its significant clinical and prognostic benefit; however, not all patients respond to therapy and predictors of clinical response to SV remain under-studied. Hypothesis: Certain electrocardiographic (ECG) parameters may predict response to SV therapy in HFrEF patients. Methods: Retrospective analysis of a hospital heart failure registry was undertaken. Consecutive HFrEF patients (NHYA class II - III) on maximal-dose SV were studied. Response to SV was defined as ≥10% relative improvement in left ventricular ejection fraction (LVEF) at 3-months post-therapy. Pre-therapy ECGs were retrospectively analyzed for axes and standard wave and interval durations. Logistic regression was used to estimate odds ratios and 95% confidence intervals for associations between predictors and therapeutic response. For P-wave duration (PWD), the reference level was set to <100ms; for the remaining variables, reference levels were set as: (a) the normal range for ECG variables; (b) absence for bundle branch blocks; and (c) the other category for binary variables. Calibration and discriminative performance of the models were also assessed. Results: In the 102 patients studied, PWD 100 - 120ms, PWD >120ms, and QTc >460ms were independently associated with response to SV therapy: OR 18.00 (4.45 - 122.90), 5.00 (1.47 - 20.42), and 3.10 (1.18 - 9.22) respectively. A multivariate logistic regression model including these predictors, and adjusting for pre-therapy LVEF, was both highly selective (area under the ROC curve = .840) and well-calibrated (Hosmer-Lemeshow p = .973). Conclusions: Prolongation of both PWD and QTc interval on baseline ECG in HFrEF patients is predictive of therapeutic response to maximal-dose SV therapy and may indicate early cardiac remodeling that is highly amenable to reversal.

The efficacy and safety assessment of oncolytic virotherapies in the treatment of advanced melanoma: a systematic review and meta-analysis

BackgroundThe efficacy and safety of oncolytic virotherapies in the treatment of advanced melanoma still remains controversal. It is necessary to conduct quantitative evaluation on the basis of preclinical trial reports.MethodsPublicly available databases (PubMed, Embase, Medline, Web of Science and Cochrane Library.) and register (Clinicaltrials.gov) were searched to collect treatment outcomes of oncolytic virotherapies (including herpes simplex virus type 1 (HSV), coxsackievirus A21 (CVA21), adenovirus, poxvirus and reovirus) for advanced/unresectable melanoma. Comparisons of treatment response, adverse events (AEs) and survival analyses for different virotherapies were performed by R software based on the extracted data from eligible studies.ResultsFinally, thirty-four eligible studies were analysed and HSV virotherapy had the highest average complete response (CR, 24.8%) and HSV had a slightly higher average overall response rate (ORR) than CVA21 (43.8% vs 42.6%). In the pooled results of comparing talimogene laherparepve (T-VEC) with or without GM-CSF/ICIs (immune checkpoint inhibitors) to GM-CSF/ICIs monotherapy suggested virotherapy was more efficient in subgroups CR (RR = 1.80, 95% CI [1.30; 2.51], P < 0.01), ORR (RR = 1.17, 95% CI [1.02; 1.34], P < 0.05), and DCR (RR = 1.27, 95% CI [1.15; 1.40], P < 0.01). In patients treated with T-VEC+ICIs, 2-year overall survival (12.1 ± 6.9 months) and progression-free survival (9.9 ± 6.9) were significantly longer than those treated with T-VEC alone. Furthermore, we found that AEs occurred frequently in virotherapy but decreased in a large cohort of enrolled patients, some of which, such as abdominal distension/pain, injection site pain and pruritus, were found to be positively associated with disease progression in patients treated with T-VEC monotherapy.ConclusionGiven the relative safety and tolerability of oncolytic viruses, and the lack of reports of dose-limiting-dependent toxicities, more patients treated with T-VEC with or without ICIs should be added to future assessment analyses. There is still a long way to go before it can be used as a first-line therapy for patients with advanced or unresectable melanoma.

Subcutaneous (SC) Mosunetuzumab (mosun) As First-Line Therapy for Patients (pts) with High Tumor-Burden Follicular Lymphoma (FL): First Results of a Multicenter Phase 2 Study

Introduction: Cytotoxic chemotherapy plus anti-CD20 antibodies is the current standard of care for pts with newly diagnosed high-burden FL. While effective, this approach is burdened by toxicities, including infections and second cancers, and up to 20% of pts progress within 2 years and have poor outcomes. Intravenous (IV) mosun is a CD20xCD3 bispecific antibody recently approved for the treatment of pts with relapsed or refractory FL based on remarkable efficacy data, and its activity may be even greater in chemotherapy-naïve patients. Furthermore, SC mosun proved as effective as, and possibly better tolerated than, the IV formulation while increasing administration efficiency and convenience. Here, we present the first results of a phase 2 multicenter trial of SC mosun in patients with untreated high-burden FL. Methods: Key eligibility criteria included: Age ≥18 years, stage 2-4 FL in need of therapy per GELF criteria, being fit for chemoimmunotherapy, adequate bone marrow and organ function. SC mosun was administered at the dose of 5 mg on D1 and 45 mg on D8 and D15 of C1, and 45 mg on D1 of each subsequent 21-day cycle. Premedication consisted of dexamethasone, diphenhydramine, and acetaminophen before each mosun dose during C1 and on C2D1 if cytokine release syndrome (CRS) occurred in C1. Subjects with ≥3 CRS risk factors (stage 3-4, bulky disease, bone marrow (BM) involvement, elevated LDH) received dexamethasone 10 mg for 3 days with each mosun dose in C1 and C2. Prophylactic hospitalization was not required. Treatment lasted 8 cycles in pts who achieved complete response (CR), and up to 17 in those with partial response. Response was assessed per the Lugano 2014 and LYRIC 2016 criteria. BM evaluation was mandated in pts with baseline BM involvement who achieved radiographic CR. CRS and neurotoxicity were graded per the 2019 ASTCT criteria. Results: Between July 2022 and July 2023, 43 pts were enrolled. Median age was 55 years (range 26-77), 40% of pts had bulky disease (≥7 cm), 25% had grade 3A FL, and 27% had a FLIPI score ≥3. The median SUV max was 11.5 (range 3.7-41.1)(Table). At the cutoff date of 07/21/2023, 4 pts were in screening, 22 were on treatment, and 13 completed treatment. Four pts discontinued therapy early due to progressive disease (1), or adverse events (AE) (3, one related to study drug). Out of 230 patient-cycles administered, 9 (4%) were delayed due to AEs, by a median of 13 days (range 7-17). Among 39 safety-evaluable pts, the most common treatment-emergent AE were injection site reaction (72%, all G1), CRS (51%), fatigue (33%), dry skin (33%), skin rash (26%), ALT elevation (23%), and AST elevation (21%). G≥3 neutropenia occurred in 4 pts (10%), while infections occurred in 10 pts (26%), and were G1-2 in 8 cases and G3 in 2 cases. One pt died of cardiac arrhythmia in the setting of COVID19-associated pneumonia. CRS occurred most commonly after C1D1 and was G1 in 18 pts (90%) and G2 in 2 (10%). Median time to onset of the first CRS episode was 31h (2-91). Hospitalization and tocilizumab were only required in the two pts who experienced G2 CRS. Twenty-six pts were evaluable for response (1 had concurrent neoplasm at first response assessment, 1 had indeterminate response (IR)3 per LYRIC criteria, and 15 are yet to be evaluated). The best overall response rate was 96% and the CR rate was 81%. All 22 CR were seen at the first response assessment (Figure). Similar response rates were observed among higher-risk subgroups, including pts with high-risk FLIPI (figure), grade 3A FL (ORR 100%, CR 75%), bulky disease (ORR 100%, CR 82%), or SUVmax ≥13 (ORR 83%, CR 83%)). At a median follow-up for response-evaluable pts of 6.0 months, 2 pts have experienced progression, one with CD20-negative FL at the end of therapy, the other with DLBCL diagnosed 6 weeks after treatment initiation on a left axillary lymph node with baseline SUV 41 and not previously biopsied. Conclusion: SC mosun demonstrated a manageable safety profile and highly encouraging efficacy in pts with newly diagnosed high-burden FL, including those with higher-risk disease. Assessment of durability of responses will require additional follow-up. Enrollment continues and updated data will be presented.

3-Year Analysis of ZUMA-12: A Phase 2 Study of Axicabtagene Ciloleucel (Axi-Cel) As First-Line Therapy in Patients with High-Risk Large B-Cell Lymphoma (LBCL)

Background: Axi-cel is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for the treatment of relapsed/refractory (R/R) LBCL. ZUMA-12 (NCT03761056) is a Phase 2, multicenter, single-arm study of axi-cel as part of first-line treatment in patients with high-risk LBCL. In the primary efficacy analysis (n=37; median follow-up of 15.9 months), axi-cel demonstrated a high rate of investigator-assessed complete response (CR; 78%; 95% CI, 62-90) and an 89% objective response rate (ORR; 95% CI, 75-97). Axi-cel also had a manageable safety profile, with no new safety signals observed in the first-line setting (Neelapu et al. Nat Med. 2022). Here, we report updated efficacy and safety outcomes from ZUMA-12 in all patients treated with axi-cel after a median follow-up of ≥40 months. Methods: Eligible adults had high-risk LBCL, with MYC and BCL2 and/or BCL6 rearrangements (double- or triple-hit histology) per investigator or an International Prognostic Index (IPI) score ≥3, plus a positive interim PET per Lugano classification (Deauville score 4/5) after 2 cycles of an anti-CD20 monoclonal antibody and anthracycline-containing regimen. Patients underwent leukapheresis, followed by lymphodepleting chemotherapy (cyclophosphamide and fludarabine) on Days -5, -4, and -3, and a single axi-cel infusion of 2×10 6 CAR T cells/kg on Day 0. Per investigator discretion, non-chemotherapy bridging could be administered. The primary endpoint was investigator-assessed CR rate per Lugano classification (Cheson et al. J Clin Oncol. 2014). Secondary endpoints included ORR, duration of response (DOR), event-free survival (EFS), progression-free survival (PFS), overall survival (OS), safety, and levels of CAR T cells in blood and cytokines in serum. Results: As of May 3, 2023, 42 patients were enrolled and 40 were treated with axi-cel, with a median follow-up of 40.9 months (range, 29.5-50.2). In total, 37 patients were evaluable for response (centrally confirmed double- or triple-hit histology or IPI score ≥3). The CR rate was 86% (95% CI, 71-95), and 92% (95% CI, 78-98) of patients had an objective response. Patients with centrally confirmed double- or triple-hit histology (n=10) had a CR rate of 90%. Responses were ongoing in 73% of response-evaluable patients at data cutoff. Medians for DOR, EFS, PFS, and OS were not reached. The 36-month estimates for DOR, EFS (Figure 1), PFS, and OS (Figure 2) were 82%, 73%, 75%, and 81%, respectively. All treated patients (n=40) experienced adverse events (AEs) of any grade and 88% of patients had grade ≥3 AEs. Similar to the primary analysis, the most common any-grade AEs were pyrexia (100%), headache (70%), and neutrophil count decreased (55%). No new cases of cytokine release syndrome (CRS) or neurologic events of any grade occurred since the prior data cut and all cases of CRS and neurologic events reported were resolved by data cutoff. Prolonged cytopenias of any grade (present Day ≥30 post-infusion) occurred in 9 patients (n=7 neutrophil count decreased) and were resolved by data cutoff. There were 8 deaths due to progressive disease (n=5) and other causes not related to axi-cel (1 COVID-19, 1 esophageal adenocarcinoma, 1 septic shock on Days 350, 535, and 287 post axi-cel infusion, respectively). Two of the 8 deaths (1 progressive disease and 1 esophageal adenocarcinoma) occurred after the primary analysis. Among treated patients, post-infusion CAR T-cell expansion by peak and area under the curve was 36.9 cells/µL and 368.0 cells/µL×days, respectively, in those with ongoing responses at data cutoff (n=17), 45.1 cells/µL and 413.4 cells/µL×days in those who relapsed (n=6), and 34.7 cells/µL and 566.8 cells/µL×days in non-responders (n=3). Conclusion: In this updated analysis of ZUMA-12 with a median follow-up of ≥40 months, axi-cel demonstrated a high rate of durable responses and no new safety signals. Axi-cel may benefit patients exposed to fewer prior therapies and those with high-risk LBCL, a population with high unmet need and poor outcomes after standard first-line chemoimmunotherapy.

Flumatinib for Newly Diagnosed Chronic Phase Chronic Myeloid Leukemia: An Open-Label, Multi-Center Study

Background Tyrosine kinase inhibitors (TKIs) ushered in the era of targeted therapy for chronic myeloid leukemia(CML), which greatly improved the prognosis of patients with CML. Flumatinib is a second-generation tyrosine kinase inhibitor (TKI), which is currently approved for patients with Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) in China. And some current clinical trials revealed that flumatinib has been shown to be a more potent inhibitor of BCR::ABL than imatinib. Methods In this open label, single-arm, multicenter study, 127 patients with newly diagnosed chronic-phase chronic myeloid leukemia (CP-CML) treated with flumatinib were enrolled. The primary endpoint of this study was early molecular response (EMR) rates at 3 months. The secondary were the rates of complete cytogenic response (CCyR), major molecular response (MMR) at 3, 6, 12 months and treatment-related adverse events (AEs). The trial is registered with ClinicalTrials.gov NCT04591197. Results From October 2020 to December 2022, a total of 158 patients with CP-CML were assessed for eligibility, of whom 127 were followed up for more than 3 months. 79(62%) patients were men and 48 (38%) were women. The median age was 47 years (range, 19-82 years), The median time from diagnosis to treatment was 6 days (0-176 days) and the median follow-up was 9.7 months (range 3.1-26.6 months). Of evaluable 127 patients, EMR was achieved by 85% (95% confidence interval [CI], 77.6%-90.7%) of patients at 3 months. After the initiation of flumatinib treatment, the incidence of MMR at 3, 6, and 12 months was 24%, 59%, and 73%, respectively. Patients receiving flumatinib had higher rates of CCyR at 6 months and MMR 12 months than the data from DASISION (dasatinib) and ENESTnd (nilotinib) therapy (85% vs 73% vs 67% and 73% vs 46% vs 44%). Progression-free survival (PFS) rate at 1-year was 97.2%. Diarrhea (34%) were the most commonly reported adverse events. Most treatment-related adverse events were grade 1/2. None of the patients discontinued or died due to AEs. Conclusion Flumatinib as first-line therapy in patients with newly diagnosed CP-CML was not inferior to nilotinib and dasatinib and well tolerated.

70P Overall survival of eribulin, trastuzumab, and pertuzumab as first-line therapy for patients with HER2-positive metastatic breast cancer: A phase II, single-arm clinical trial

70P Overall survival of eribulin, trastuzumab, and pertuzumab as first-line therapy for patients with HER2-positive metastatic breast cancer: A phase II, single-arm clinical trial

Using real world practice patterns to identify clinical equipoise in cancer treatment: Advanced non-small cell lung cancer as an exemplar.

539 Background: Novel therapies have improved the survival for patients with advanced non-small cell lung cancer (NSCLC). Clinical scenarios with high treatment variation indicate a lack of consensus about the standard of care, and can identify instances there is less clinical equipoise, and comparative effectiveness research is urgently needed. We quantified the variation in the first-line therapy, stratified by patient’s biomarker and Eastern Cooperative Oncology Group (ECOG) performance score. Methods: Using Flatiron database, we categorized patients with advanced NSCLC diagnosed between 1/1/2016 and 6/30/2020 into groups by biomarker findings and performance status. Patients with unknown status of biomarkers or negative actionable gene alterations, or missing ECOG score were excluded. The degree of variation in first-line treatment regimens was measured using the Herfindahl-Hirschman Index (HHI), which calculates the sum of squared proportion of patients receiving different regimen categories. The HHI ranges from close to 0 to 10,000, with low values indicate heterogeneous treatment patterns whereas high values indicate more uniformity in treatment patterns. We used bootstrapping to calculate 95% confidence intervals (CIs) for the HHI scores. Results: Our cohort consisted of 12,708 patients. Among them, 327 were ALK-positive, 1,816 were EGFR-positive, and 10,565 were ALK/EGFR negative or unknown (including 3,616 patients who were PD-L1 &lt;1%, 3,139 PD-L1 1-49%, and 3,810 PD-L1 ≥50%, respectively). The HHI score for first-line therapy in our overall cohort was 2171 (95% CI: 2167, 2175). The HHI differed by biomarker status: 4403 for the EGFR+ group, 3809 for the ALK+ group, 3065 for the PD-L1 &lt;1% group, 2925 for the PD-L1 1-49% group, and 3370 for the PD- L1 ≥50% group. When we stratified patients by both biomarker and ECOG status, the HHI ranged from 2791 (95% CI: 2740, 2840) for patients with PD-L1 1-49% and ECOG 2-4 to 5364 (95% CI: 5161, 5649) for patients with EGFR+ and ECOG 2-4 (details in Table). Conclusions: Using HHI, we were able to quantify and compare variation in treatment patterns across clinically distinct subgroups of patients. Large variation in the first-line therapy for patients with PD-L1 1-49% suggests lack of strong consensus regarding the optimal treatment regimens for these patients.[Table: see text]

Cost-Effectiveness Analysis of Tislelizumab Plus Chemotherapy as First-Line Treatment for Advanced or Metastatic Esophageal Squamous Cell Carcinoma in China.

Tislelizumab plus chemotherapy improved overall survival compared to chemotherapy alone, while maintaining an acceptable level of safety. But it's still unclear which strategy is the most cost-effective. The objective of the study was to compare the cost-effectiveness of tislelizumab plus chemotherapy as first-line therapy for patients with advanced or metastatic esophageal squamous cell carcinoma (ESCC) versus chemotherapy alone. A partitioned survival model with three states was constructed based on the RATIONALE-306 trial. The model's time horizon was ten years, and its cycle was three weeks. Only direct medical costs were considered from the healthcare perspective in China. Calculations were performed on total costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs). One-way sensitivity and probabilistic sensitivity analysis (PSA) were performed to determine the uncertainty regarding model parameters. Tislelizumab plus chemotherapy provided 1.35 QALYs for $26,450.77, while chemotherapy alone provided 0.89 QALY for $16,687.15. Compared to chemotherapy alone, tislelizumab had an ICER of $21,062.09/QALY. At the threshold of three times the Chinese GDP per capita ($38,253/QALY), the PSA indicated that tislelizumab had a 96.4% likelihood of being designated cost-effective. At the threshold of 1.5 times the Chinese GDP per capita ($19,126.5/QALY), the PSA indicated that tislelizumab had a probability of 48.7% of being designated cost-effective. Tislelizumab plus chemotherapy as the first treatment for patients with advanced or metastatic ESCC may be a cost-effective option compared to chemotherapy alone at 3 times Chinese GDP per capita.

219P Clinical effectiveness of tislelizumab plus TKI as first-line therapy in patients with metastatic renal cell carcinoma (mRCC): A real-world study

219P Clinical effectiveness of tislelizumab plus TKI as first-line therapy in patients with metastatic renal cell carcinoma (mRCC): A real-world study

Comparison of Efficacy and Safety of Anti-Programmed Cell Death-1 Antibody Plus Lenvatinib and Chemotherapy as First-Line Therapy for Patients with Stage IV Gallbladder Cancer: A Real-World Study in a Chinese Population.

Background: The present study aimed to evaluate and compare the efficacy and safety of anti-programmed cell death protein 1 (anti-PD-1) antibody plus lenvatinib (tyrosine kinase inhibitor) therapy and chemotherapy as the first-line treatment to unresectable stage IV gallbladder cancer (GBC). Methods: We retrospectively analyzed the clinical data of patients with stage IV GBC who received chemotherapy or anti-PD-1 antibody combined with lenvatinib therapy at our hospital from March 2018 to October 2022. Patients with previous antitumor treatment were excluded. The overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and adverse events (AEs) were assessed. Results: A total of 64 patients were enrolled, of which 33 patients received chemotherapy (gemcitabine + cisplatin) in the chemotherapy group, and 31 patients received anti-PD-1antibody (camrelizumab) combined with lenvatinib therapy in the combined therapy group. The median OS was 12.00 months in the combined therapy group and 10.00 months in the chemotherapy group (hazard ratio (HR), 0.57; 95% CI: 0.32-1.03; p < 0.05). The median PFS was 9.00 months in the combined therapy group and 6.00 months in the chemotherapy group (HR, 0.46; 95% CI: 0.25-0.84; p < 0.01). The ORR was 54.84% and 39.39% in the combined therapy and chemotherapy groups, respectively, and the difference was not significant (p = 0.22). The DCR was 80.65% and 72.72% in the combined therapy and chemotherapy groups, respectively (p = 0.46). One patient successfully underwent radical surgery after 8 months of combined therapy and achieved a pathological complete response. Furthermore, no patients experienced AEs of hematologic toxic effects in the combined therapy group compared with the chemotherapy group, demonstrating the advantage of the combined therapy. Conclusions: Anti-PD-1 antibody combined with lenvatinib may be a potentially effective and tolerable first-line treatment for unresectable stage IV GBC.