Specific Subgroups Of Patients Research Articles

Cost-effectiveness of utidelone and capecitabine versus monotherapy in anthracycline- and taxane-refractory metastatic breast cancer.

This study aimed to assess the cost-effectiveness of combining utidelone with capecitabine, compared to capecitabine monotherapy, for the treatment of anthracycline- and taxane-refractory metastatic breast cancer within the Chinese healthcare system. A partitioned survival model was formulated based on patient characteristics from the NCT02253459 trial. Efficacy, safety, and health economics data were sourced from the trial and real-world clinical practices. We derived estimates for costs, quality-adjusted life years (QALYs), and the incremental cost-effectiveness ratio (ICER) for the two treatment strategies. Sensitivity and subgroup analyses were conducted to rigorously evaluate uncertainties' impact. Over a 5-year span, the combination therapy manifested substantially higher costs than capecitabine monotherapy, with a differential of US$ 26,370.63. This combined approach conferred an additional 0.49 QALYs, resulting in an ICER of US$ 53,874.17/QALY. Utilizing the established willingness-to-pay threshold, the combination might not consistently be deemed cost-effective when juxtaposed against monotherapy. However, at an ICER of US$ 53,874.4/QALY, the probability of the combination being cost-effective increased to 48.97%. Subgroup analysis revealed that the combination was more cost-effective than capecitabine alone in specific patient groups, including those <60 years, patients with more than two chemotherapy rounds, patients lacking certain metastases, patients having limited metastatic sites, patients with an Eastern Cooperative Oncology Group status of 0, and patients with particular hormone receptor profiles. Although the combination of utidelone and capecitabine may not be an economically viable universal choice for anthracycline- and taxane-refractory metastatic breast cancer, it could be more cost-effective in specific patient subgroups than capecitabine monotherapy.

Feasibility of deep learning to predict tinnitus patient outcomes

Advances in machine and deep learning techniques provide a novel approach in understanding complex patterns within large datasets, leading to an implementation of personalized medicine approaches to support clinical decision making. Results from recent clinical trials (TENT-A1 and TENT-A2 studies; clinicaltrials.gov: NCT02669069 and NCT03530306) support that a novel bimodal neuromodulation approach could be a breakthrough treatment for patients with tinnitus, which adversely affects 10–15 % of the population. Given the heterogeneity of symptoms, it is important to identify whether treatment has an optimal effect on specific subgroups of tinnitus patients. The current study is a first look at the feasibility of using deep learning modelling on patient reported data to predict treatment outcomes in individuals with tinnitus, and highlights what features are most beneficial for clinical decision making.

Current perspectives in the management of sepsis and septic shock.

Within patients with sepsis, there exists significant heterogeneity, and while all patients should receive conventional therapy, there are subgroups of patients who may benefit from specific therapies, often referred to as rescue therapies. Therefore, the identification of these specific patient subgroups is crucial and lays the groundwork for the application of precision medicine based on the development of targeted interventions. Over the years, efforts have been made to categorize sepsis into different subtypes based on clinical characteristics, biomarkers, or underlying mechanisms. For example, sepsis can be stratified into different phenotypes based on the predominant dysregulated host response. These phenotypes can range from hyperinflammatory states to immunosuppressive states and even mixed phenotypes. Each phenotype may require different therapeutic approaches to improve patient outcomes. Rescue strategies for septic shock may encompass various interventions, such as immunomodulatory therapies, extracorporeal support (e.g., ECMO), or therapies targeted at specific molecular or cellular pathways involved in the pathophysiology of sepsis. In recent years, there has been growing interest in precision medicine approaches to sepsis and phenotype identification. Precision medicine aims to tailor treatments to each individual patient based on their unique characteristics and disease mechanisms.

First-Line Treatment for Advanced Hepatocellular Carcinoma: A Three-Armed Real-World Comparison.

There are several existing systemic 1st- line therapies for advanced hepatocellular carcinoma (HCC), including atezolizumab/bevacizumab (Atez/Bev), sorafenib and lenvatinib. This study aims to compare the effectiveness of these three 1st-line systemic treatments in a real-world setting for HCC, focusing on specific patient subgroups analysis. A total of 177 patients with advanced HCC treated with Atez/Bev (n = 38), lenvatinib (n = 21) or sorafenib (n = 118) as 1st line systemic therapy were retrospectively analyzed and compared. Primary endpoints included objective response rate (ORR), progression-free survival (PFS) and 15-month overall survival (15-mo OS). Subgroups regarding liver function, etiology, previous therapy and toxicity were analyzed. Atez/Bev demonstrated significantly longer median 15-month OS with 15.03 months compared to sorafenib with 9.43 months (p = 0.04) and lenvatinib with 8.93 months (p = 0.05). Similarly, it had highest ORR of 31.6% and longest median PFS with 7.97 months, independent of etiology. However, significantly superiority was observed only compared to sorafenib (ORR: 4.2% (p < 0.001); PFS: 4.57 months (p = 0.03)), but not comparing to lenvatinib (ORR: 28.6% (p = 0.87); PFS: 3.77 months (p = 0.10)). Atez/Bev also resulted in the longest PFS in patients with Child-Pugh A and ALBI 1 score and interestingly in those previously treated with SIRT. Contrary, sorafenib was non inferior in patients with impaired liver function. Atez/Bev achieved longest median PFS and 15-mo OS independent of etiology and particularly in patients with stable liver function or prior SIRT treatment. Regarding therapy response lenvatinib was non-inferior to Atez/Bev. Finally, sorafenib seemed to perform best for patients with deteriorated liver function.

Characterization and Subgrouping of Type 2 Diabetes

Among patients with type 2 diabetes, there exists considerable clinical heterogeneity, with variable mechanisms leading to disease onset. These differences may impact treatment responses and the course of the disease. Subgrouping diabetes aims to foster precision diagnostics to allow precision treatment. It is designed to better understand the diversity/heterogeneity within type 2 diabetes and to provide tailored therapies for specific subgroups of patients. There are two subgrouping approaches. The first is a “simple” method of categorizing patients based on specific clinical factors, which is practical but has not consistently improved clinical outcomes. The “complex” approach utilizes machine learning and considers various clinical and/or genomic data, demonstrating reproducible subgroups and associations with clinical outcomes. Nonetheless, whether these efforts translate into significantly superior outcomes compared to current standard treatments remains to be conclusively established and should be addressed in further research.

Impact of Prophylactic Antibiotics in Ischemic Stroke Patients on Reduction of Hospital Stay.

Background: Ischemic stroke is a leading cause of morbidity and mortality, with post-stroke infections significantly impacting patient outcomes. The use of prophylactic antibiotics to prevent these infections and reduce hospital stay durations has been a subject of debate in the medical community. Objective: This study aims to evaluate the impact of prophylactic antibiotic administration on the length of hospital stays in ischemic stroke patients. Methods: Conducted at the Combined Military Hospital, Peshawar, this randomized control trial involved 115 patients, divided into two groups. Group 1 (55 patients) received prophylactic ceftriaxone, while Group 2 (60 patients) did not receive antibiotics. Inclusion criteria were a Glasgow Coma Scale (GCS) score 13 and above, with no pre-existing conditions necessitating antibiotics or complications from the stroke. The primary outcome was the duration of hospital stay. Results: Group 1 had an average hospital stay of 6.65 days (SD: 2.06 days), while Group 2 had an average of 6.81 days (SD: 1.98 days). The P value of 0.677 indicated no statistically significant difference in hospital stay durations between the groups. Both groups had similar age and GCS score distributions. Conclusion: The administration of prophylactic antibiotics to ischemic stroke patients did not significantly reduce hospital stay durations. Given the risks associated with antibiotic resistance and side effects, a patient-specific approach to prophylactic antibiotic use is recommended. Future research should focus on identifying specific patient subgroups that may benefit from prophylactic antibiotics and optimal timing for their administration.

Agomelatine efficacy in treatment resistant obsessive-compulsive disorder: A randomized controlled trial.

Obsessive-compulsive disorder (OCD) is a prevalent and burdensome mental health condition, often resistant to conventional treatments. Agomelatine (Valdoxan), a compound acting on serotonin and melatonin systems, has shown promise in treating those with treatment-resistant OCD based on anecdotal reports and case studies. A randomized, double-blind controlled trial was conducted with 60 patients diagnosed with treatment-resistant OCD. Participants were randomized into an intervention group (receiving agomelatine 50 mg/day) and a control group (receiving placebo). OCD symptoms were assessed using the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) over a 12-week period. There were no significant differences in age, gender, or baseline Y-BOCS scores between intervention and control groups. Agomelatine did not demonstrate a significant improvement in OCD symptoms compared to placebo. Adverse events were comparable between groups, and liver enzyme levels remained within the normal range. This study, while not confirming superior efficacy compared to placebo, underscores the need for continued investigation into agomelatine's potential for treating specific subgroups of OCD patients, underscoring the need for more comprehensive and well-controlled trials in the future.

First clinical and oncological experiences with triplet therapy for high-volume metastatic hormone-sensitive prostate cancer

Treatment with androgen deprivation therapy (ADT) plus extended hormone therapy (ARTA) is the standard of care for metastatic hormone-sensitive prostate cancer (mHSPC). Recent data of triplet combination therapies of ADT + ARTA (abiraterone/darolutamide) + docetaxel chemotherapy showed asurvival advantage for specific mHSPC patient subgroups. What treatment response is observed in real-world mHSPC setting using triplet combination therapy and what are the expected side effects? All patients receiving triplet combination therapy of ADT + ARTA (abiraterone/darolutamide) + docetaxel were included in the current study. Atotal of 14patients with amedian age of 62years and 10/14 abiraterone or 4/14 darolutamide therapy could be included. The median PSA before initiation of therapy was 77 ng/ml (IQR 44-150). Overall, 86% of patients had aPSA response > 90% and the median PSA nadir was 0.3 ng/ml. Severe adverse events (gradeIII) during triplet therapy occurred in two patients (35,7%) with respectively febrile neutropenia 7.1% (1/14) and diarrhea with infection 7.1%. Other low grade adverse events (gradeI/II) consisted of polyneuropathy (1/14), mucositis (1/14), xerostomia (1/14), weight loss (1/14) and fatigue (3/14) were detected. Chemotherapy was interrupted in one patient due to adverse events. After amedian follow-up of ten months (IQR: 7-17), two patients (14.2%) showed progression to castration resistance. Triplet therapy shows avery good PSA response in clinical practice. Adverse events during therapy are mainly triggered by classical chemotherapy-known side effects.

Status epilepticus in BRAF-related cardio-facio-cutaneous syndrome: Focus on neuroimaging clues to physiopathology.

Cardio-facio-cutaneous syndrome (CFC) is a genetic disorder due to variants affecting genes coding key proteins of the Ras/MAPK signaling pathway. Among the different features of CFC, neurological involvement, including cerebral malformations and epilepsy, represents a common and clinically relevant aspect. Status epilepticus (SE) is a recurrent feature, especially in a specific subgroup of CFC patients with developmental and epileptic encephalopathy (DEE) and history of severe pharmacoresistant epilepsy. Here we dissect the features of SE in CFC patients with a particular focus on longitudinal magnetic resonance imaging (MRI) findings to identify clinical-radiological patterns and discuss the underlying physiopathology. We retrospectively analyzed clinical, electroencephalogram (EEG), and MRI data collected in a single center from a cohort of 23 patients with CFC carrying pathogenic BRAF variants who experienced SE during a 5-year period. Seven episodes of SE were documented in 5 CFC patients who underwent EEG and MRI at baseline. MRI was performed during SE/within 72 hours from SE termination in 5/7 events. Acute/early post-ictal MRI findings showed heterogenous abnormalities: restricted diffusion in 2/7, focal area of pcASL perfusion change in 2/7, focal cortical T2/FLAIR hyperintensity in 2/7. Follow-up images were available for 4/7 SE. No acute changes were detected in 2/7 (MRI performed 4 days after SE termination). Acute focal neuroimaging changes concomitant with ictal EEG focus were present in 5/7 episodes, though with different findings. The heterogeneous patterns suggest different contributing factors, possibly including the presence of focal cortical malformations and autoinflammation. When cytotoxic edema is revealed by MRI, it can be followed by permanent structural damage, as already observed in other genetic conditions. A better understanding of the physiopathology will provide access to targeted treatments allowing to prevent long-term adverse neurological outcome. Cardio-facio-cutaneous syndrome is a genetic disorder that often causes prolonged seizures known as status epilepticus. This study has a focus on electroclinical and neuroimaging patterns in patients with cardio-facio-cutaneous syndrome. During these status epilepticus episodes, we found different abnormal brain imaging patterns in patients, indicating various causes like brain malformations and inflammation. Understanding these patterns could help doctors find specific treatments, protecting cardio-facio-cutaneous syndrome patients from long-term brain damage.

The Role of t(11;14) in Tailoring Treatment Decisions in Multiple Myeloma.

Multiple myeloma (MM) represents a hematological neoplasia with an uncontrolled proliferation of malignant plasma cells and complex cytogenetic abnormalities. t(11;14) has emerged as a crucial genetic aberration and is one of the most common primary translocations in MM. Patients harboring t(11;14) represent a distinctive subgroup with a clinical profile that differs from t(11;14)-negative MM risk categories. One of the key features linked with t(11;14) is the BCL2 dependency, indicating vulnerability to BCL2 inhibition. BCL2 inhibitors, such as venetoclax, demonstrated impressive efficacy alone or in combination with other anti-myeloma drugs in patients with RRMM accompanied by t(11;14) and BCL2 overexpression. Therefore, t(11;14) plays a key role in both risk stratification and informed decision making towards a tailored therapy. In this review, we highlight the biology of t(11;14) in MM cells, summarize the current evolving role of t(11;14) in the era of novel agents and novel targeted therapies, illuminate current efficacy and safety data of BCL2-based treatment options and explore the future prospects of individualized precision medicine for this special subgroup of patients with MM.

New insights into the role of VKORC1 polymorphisms for optimal warfarin dose selection in Caribbean Hispanic patients through an external validation of a population PK/PD model

Warfarin, an oral anticoagulant, has been used for decades to prevent thromboembolic events. The complex interplay between CYP2C9 and VKORC1 genotypes on warfarin PK and PD properties is not fully understood in special sub-groups of patients. This study aimed to externally validate a population pharmacokinetic/pharmacodynamic (PK/PD) model for the effect of warfarin on international normalized ratio (INR) and to evaluate optimal dosing strategies based on the selected covariates in Caribbean Hispanic patients. INR, and CYP2C9 and VKORC1 genotypes from 138 patients were used to develop a population PK/PD model in NONMEM. The structural definition of a previously published PD model for INR was implemented. A numerical evaluation of the parameter-covariate relationship was performed. Simulations were conducted to determine optimal dosing strategies for each genotype combinations, focusing on achieving therapeutic INR levels. Findings revealed elevated IC50 for G/G, G/A, and A/A VKORC1 haplotypes (11.76, 10.49, and 9.22 mg/L, respectively), in this population compared to previous reports. The model-guided dosing analysis recommended daily warfarin doses of 3–5 mg for most genotypes to maintain desired INR levels, although subjects with combination of CYP2C9 and VKORC1 genotypes * 2/* 2-, * 2/* 3- and * 2/* 5-A/A would require only 1 mg daily. This research underscores the potential of population PK/PD modeling to inform personalized warfarin dosing in populations typically underrepresented in clinical studies, potentially leading to improved treatment outcomes and patient safety. By integrating genetic factors and clinical data, this approach could pave the way for more effective and tailored anticoagulation therapy in diverse patient groups.

The frail patient undergoing cardiac surgery: lessons learned and future perspectives.

Frailty is a geriatric condition characterized by the reduction of the individual's homeostatic reserves. It determines an increased vulnerability to endogenous and exogenous stressors and can lead to poor outcomes. It is an emerging concept in perioperative medicine, since an increasing number of patients undergoing surgical interventions are older and the traditional models of care seem to be inadequate to satisfy these patients' emerging clinical needs. Nowadays, the progressive technical and clinical improvements allow to offer cardiac operations to an older, sicker and frail population. For these reasons, a multidisciplinary team involving cardiac surgeons, clinical cardiologists, anesthesiologists, and geriatricians, is often needed to assess, select and provide tailored care to these high-risk frail patients to optimize clinical outcomes. There is unanimous agreement that frailty assessment may capture the individual's biological decline and the heterogeneity in risk profile for poor health-related outcomes among people of the same age. However, since commonly used preoperative scores for cardiac surgery fail to capture frailty, a specific preoperative assessment with dedicated tools is warranted to correctly recognize, measure and quantify frailty in these patients. On the contrary, pre-operative and post-operative interventions can reduce the risk of complications and support patient recovery promoting surgical resilience. Minimally invasive cardiac procedures aim to reduce surgical trauma and may be associated with better clinical outcome in this specific sub-group of high-risk patients. Among postoperative adverse events, the occurrence of delirium represents a risk factor for several unfavorable outcomes including mortality and subsequent cognitive decline. Its presence should be carefully recognized, triggering an adequate, evidence based, treatment. There is evidence, from several cross-section and longitudinal studies, that frailty and delirium may frequently overlap, with frailty serving both as a predisposing factor and as an outcome of delirium and delirium being a marker of a latent condition of frailty. In conclusion, frail patients are at increased risk to experience poor outcome after cardiac surgery. A multidisciplinary approach aimed to recognize more vulnerable individuals, optimize pre-operative conditions, reduce surgical invasivity and improve post-operative recovery is required to obtain optimal long-term outcome.

Cross-cultural assessment of the influence of the COVID-19 pandemic on the perceived mental health and medical experiences of persons with inherited bleeding disorders and their parents/guardians

ABSTRACT Background Objectives were to 1) assess COVID-19-associated medical and psychological challenges facing persons with inherited bleeding disorders (PIBD) and their parents/guardians (PG) in Germany, the US, and the UK; 2) describe similarities and differences among these countries; 3) identify needs and opportunities for intervention by patient advocacy organizations (PAGs). Research Design & Methods A cross-sectional, international survey was conducted in three countries using validated psychometric instruments and investigator-developed items. Results Five hundred and four surveys were included. Significant differences between countries were found including experiences with medical care, specific thoughts, and concerns about COVID-19, anxiety, and other mental health measures, as well as resources used to cope with stress. Age, education, income, race, IBD diagnosis, PIBD vs. BD group, and gender had moderating effects on resources used. Communication with friends/relatives and use of PAG and HTCs as resources for information/coping decreased in all countries during the pandemic. Conclusions There were similarities and differences between respondents across the country in the perceived impact of the pandemic, mental health scores, and strategies used to cope with stress. Recommendations: strategies to increase PAG access for PIBD and their PG during pandemics and natural disasters, ongoing assessment and adaptation to provide supportive resources to specific patient subgroups.

Abstract A125: Clinical evaluation of a functional combinatorial precision medicine platform to predict combination immunotherapy responses in hematological malignancies

Abstract Purpose: Proliferation of immune checkpoint inhibitors and lineage-specific antigen-based therapy have made identifying the most appropriate immunotherapy for specific patients or subgroups of patients increasingly difficult. Furthermore, combination of these therapeutic antibodies with other targeted agents or chemotherapy is often required to achieve durable response. To address the large search space of possible combinations of these immunotherapies with available targeted and cytotoxic drug partners, we applied a hybrid experimental-analytical platform, Flow Cytometry Immunophenotyping–Quadratic Phenotypic Optimization Platform (FCI-QPOP), on primary patient samples from acute myeloid leukemia (AML) and multiple myeloma (MM) cases to predict patient and subtype-specific combination immunotherapy responses. Successful development of this functional combinatorial precision medicine platform could help guide combination therapy treatment while also providing a tool for improving combination therapy design for emerging immunotherapies. Experimental Detail: Single drug dosage response analysis of a set of immunotherapies, targeted small molecules and cytotoxic agents were performed from initial patient samples and used to inform subsequent dosing levels for 8-drug, 3-level FCI-QPOP. In FCI-QPOP, primary AML or MM patient samples composed of both cancer cells and normal cells were treated with an array of test combinations and analyzed by flow cytometry to provide a quantitative phenotypic output for each test combination. This OACD dataset was then analyzed by QPOP to rank all possible drug combinations towards a predicted treatment outcome. Concordance analysis was then performed comparing patient sample results with parallel treatment initiated at time of sample collection. Results: Drug-dose response analysis by flow cytometry could accurately identify samples-specific response, including IC50 determination, to both therapeutic antibodies and small molecule drugs. Following this, 8-drug, 3-level FCI-QPOP was successfully performed on 14 of 17 primary patient samples. Concordance analysis could be performed on 9 cases, with 5 cases still pending clinical follow-up. Concordance to both antibody therapies as well as small molecule treatments were analyzed following FCI-QPOP. FCI-QPOP had a sensitivity of 80% and specificity of 75% and a total predictive value (TPV) of 77.78%. Additionally, FCI-QPOP provided potentially effective combination rankings for a diverse range of therapeutic antibodies, including gemtuzumab-based combination therapies. Conclusion: The results show the potential for FCI-QPOP to predict clinical response to immunotherapy-based treatments. Furthermore, FCI-QPOP can improve drug development pipelines through patient samples-based design of effective immunotherapy-based combinations that may benefit larger populations of patients or specific subgroups of patients. Citation Format: Noor Rashidha Bte Meera Sahib, Masturah Rashid, Sanjay de Mel, Wei Ying Jen, Melissa Ooi, Edward K Chow. Clinical evaluation of a functional combinatorial precision medicine platform to predict combination immunotherapy responses in hematological malignancies [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A125.

How to Handle Elevated Triglycerides: Life after PROMINENT.

Hypertriglyceridaemia (HTG) is a common condition characterised by elevated levels of plasma triglycerides (TG), which are transported in the blood mainly by TG-rich lipoproteins (TRL). Elevated TG levels (150-400 mg/dL) are associated with increased cardiovascular risk. Severe HTG (>880 mg/dL) is associated with a risk of acute pancreatitis only. Randomised clinical trials investigating the clinical benefit of TG-lowering drugs in patients with elevated TG levels have provided conflicting results. Elevated TG levels are only one marker of altered lipid/lipoprotein metabolism and indeed reflect altered concentrations of one or more classes or subfractions of TRL, which in turn may have a different association with CV risk. Fibrates, the drugs most commonly used to treat HTG, provide cardiovascular benefits to only a specific subgroup of patients. The lack of clinical benefit from pemafibrate has emphasised the concept that lowering TG levels is not sufficient to reduce the CV risk unless it is accompanied by a reduction in the number of circulating atherogenic lipoproteins, which can be assessed by determining apolipoprotein B levels. Treatment with omega-3 fatty acids was also ineffective in reducing CV risk, with the exception of icosapent ethyl, which, however, appears to have beneficial effects beyond lipids. New drugs are currently being developed that aim to lower TG levels by targeting apolipoprotein C-III or angiopoietin-like-3, both of which are involved in the metabolism of TGs. TG reduction can be achieved by various drugs, but most of them are ineffective in reducing CV risk. The results of outcome studies on new TG-lowering drugs will clarify whether lowering apoB levels is critical to achieve clinical benefit.

Abstract C099: Establishment and characterization of an NUP98-KDM5A-driven AML XPDX model

Abstract Background: Acute myeloid leukemia (AML) with NUP98 fusions is associated with poor prognosis in adults and especially children. Pediatric AML is a rare and heterogeneous disease characterized by a high prevalence of gene fusions as driver mutations, including the NUP98-KDM5A fusion found in a particular subgroup of patients with complex karyotypes. To better understand this subtype of AML, we established and characterized a XPDX model designated ST1653 representing NUP98-KDM5A-driven disease from a previously treated AML patient. We performed DNA and RNA-based sequencing of the model. Further we evaluated in vivo sensitivity towards cytarabine and inhibitors targeting the JAK and CDK6 pathways, which have been shown to be important in NUP98-KDM5A-driven AML. Methods: ST1653 was established from a bone marrow aspirate collected from a 63-year-old Caucasian male who had AML recurrence following high dose cytarabine. The sample was injected subcutaneously into a triple-deficient mouse and the P0 model passaged after seventy days into CB-17 SCID and athymic nude mice and further developed until stable. WES and RNAseq were then performed. For in vivo studies, ST1653 was evaluated against cytarabine and the JAK inhibitors ruxolitinib, baricitinib and tofacitinib and the CDK4/6 inhibitors palbociclib, abemaciclib and ribociclib. Endpoints in all studies included tumor volume and time from treatment initiation with %T/C values and tumor regression reported at study completion; a T/C of ≤ 20% versus control was considered sensitive. Tumor regression (%T/C&amp;lt;0%) versus Day 0 tumor volume was also reported. Results: Growth of the ST1653 AML XPDX model was similar in CB-17 SCID or athymic nude mice with a median time to endpoint of forty-five days, although the take rate in the SCID strain was superior. Sequencing identified the presence of the NUP98-KDM5A fusion and chimeric protein expression was confirmed. In vivo, ST1653 was insensitive to cytarabine and the JAK inhibitors but demonstrated limited sensitivity to CDK4/6i treatment. Conclusion: We have established and characterized a XPDX model of NUP98-KDM5A-driven AML including sequencing and in vivo evaluation. This model is an important tool for developing novel therapies to this high-risk leukemia subtype. Citation Format: Armando Diaz III, Alyssa Simonson, Johnnie Flores, Joseph Holahan, Kyriakos P Papadopoulos, Jim Lund, Drew Rasco, Amita Patnaik, Michael J Wick. Establishment and characterization of an NUP98-KDM5A-driven AML XPDX model [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C099.

Neutrophil-to-albumin ratio: a promising tool for CAD assessment in non-ST elevation AMI.

In the context of coronary artery disease (CAD) pathogenesis, inflammation has emerged as a critical player. This study investigates the potential of the Neutrophil-to-Albumin Ratio (NAR) as a novel biomarker for assessing CAD severity and extension in patients suffering from acute myocardial infarction (AMI) without ST-segment elevation. We conducted a comprehensive analysis of consecutive patient records (n = 211) from a single center, focusing on individuals diagnosed with non-ST elevation AMI. To gauge CAD severity, we employed Syntax Scores (SS) and examined their correlation with NAR, C-reactive protein-albumin ratio (CRPALB), and the systemic immune inflammation index (SII). Statistical analyses were conducted to establish associations and predictive capabilities. Our analysis revealed a significant correlation between NAR and Syntax Scores (r: .416, p<0.01). Notably, patients with intermediate-high SS exhibited significantly elevated NAR values compared to those in the low SS group [20.86+5.38 vs. 16.41+6.30 (p<0.001)]. Furthermore, NAR outperformed CRPALB, SII, and Neutrophil Percent-to-Albumin Ratio (NPAR) in discriminating CAD severity, as demonstrated by the Receiver Operating Characteristic (ROC) curve analysis (NAR AUC: 0.736; CRPALB AUC: 0.673; SII AUC: 0.660; NPAR AUC: 0.717). This study underscores the potential of NAR as a robust predictor of CAD severity and extension in non-ST elevation AMI patients. While previous markers, such as CRPALB and SII, are advantageous, NAR's superior predictive capabilities are a valuable addition to the clinician's toolkit, offering enhanced risk assessment for this specific patient subgroup.

Upfront Autologous Stem Cell Transplant at First Complete Remission in Patients with Advanced-Stage Extra-Nodal NK/T Cell Lymphoma: A Multicenter Retrospective Study

Objective: Treatment outcome of patients with advanced-stage extranodal NK/T cell lymphoma (NKTCL) remains unsatisfactory. The role of consolidation therapy with autologous stem cell transplantation (ASCT) at first complete remission (CR1) in these patients is controversial. This study aimed to investigate the effect of upfront ASCT on the prognosis of patients with advanced-stage NKTCL achieving CR1 to frontline therapy. Methods:This is a multicenter retrospective study. Data were collected from patients diagnosed with NKTCL between 2006 and 2021 in the China Lymphoma Collaborative Group (CLCG) database. The inclusion criteria were as follows: pathologically confirmed diagnosis of NKTCL, age≤65 years at diagnosis, stage III or IV disease, and achievement of CR1 at the completion of frontline induction therapy. Clinical characteristics, treatment including the use of ASCT, and follow-up information were reviewed. The primary endpoints were progression-free survival (PFS) and overall survival (OS). Results: A total of 99 patients from 14 medical centers in China were included in this study. The median age was 38 years (range: 6-64 years). Sixteen patients (16%) had an ECOG-PS≥2 at diagnosis, and 26 patients (26%) presented with primary extra-nasal disease. The baseline Prognostic Index for NK-cell lymphoma (PINK) was≥2 in 63 patients (64%). Regarding first-line treatment, 85 patients (86%) received non-anthracycline-based chemotherapy, and the remaining patients received anthracyline-based chemotherapy. At the time of CR1, 32 patients (32%) received upfront ASCT consolidation and 67 patients did not. Baseline clinical characteristics were comparable between the ASCT group and non-ASCT group. With a median follow-up time of 33 months, median PFS was not reached in the ASCT group versus 46 months in the non-ASCT group (3-year PFS: 76.6% versus 54.9%, P=0.012). OS was not significantly different between the ASCT group and the non-ASCT group (3-year OS: 85.2% versus 69.4%, P=0.098). In multivariate analyses, upfront ASCT was independently associated with better PFS (HR=0.40, 95%CI 0.17-0.94, P=0.037) after adjusting for baseline PINK score and types of first-line chemotherapy (anthracyline-based versus non-anthracyline-based). Only non-anthracyline-based first-line chemotherapy (HR=0.32, 95%CI 0.11-0.88, P=0.028) was associated with better OS in multivariate analysis. Conclusions: In this multicenter real-world study, upfront ASCT improves PFS of patients with advanced stage NKTCL achieving CR1 to front-line chemotherapy, but the effect of upfront ASCT on OS in the era of non-anthracycline-based chemotherapy remains uncertain. The specific subgroups of patients most likely to gain a survival benefit from upfront ASCT need to be further investigated.

Pre-Graft Immune Status Predicts Survivals and Relapse in Adults Receiving Matched Peripheral Blood Stem Cell Allotransplants for Myeloid Malignancies

Background The impact on outcomes of pre-graft immune status has not been explored so far in recipients of allogeneic stem cell transplant (allo-SCT). Patients and Methods This was a retrospective and monocentric study including all consecutive adults who underwent a peripheral blood stem cell (PB) allo-SCT for a hematological malignancy between May 2017 and December 2021 in our Hematology Department. Immune status was routinely evaluated before transplant in each patient. Absolute lymphocyte (ALC) and monocyte counts were obtained from complete blood counts, while absolute counts of lymphocyte subsets (CD3+, CD4+ and CD8+ T cells, B and NK cells) were assessed by multiparameter flow cytometry, and gamma globulin levels by standard serum electrophoresis. We evaluated the impact of these parameters, considered as continuous variables, on overall survival (OS), progression-free survival (PFS), graft-versus-host disease (GVHD)-free, progression-free survival (GRFS), non-relapse mortality (NRM), and relapse incidence (RI), according to the type of the disease (myeloid vs. lymphoid) and the type of the donor (matched vs. haploidentical). Results This study included 264 patients with a median age of 59 years old (range 20-73, Table). A majority had a myeloid malignancy (75%, n=196) and received a graft from a matched donor (64%, n=170, sibling n=46; matched unrelated n=124) and a reduced-intensity conditioning regimen (80%, n= 211). Almost all (96%) patients with a matched donor received anti-thymoglobulin as GVHD prophylaxis while it was the case for 79% of those receiving a graft from a haploidentical donor. With a median follow-up of 32 months estimated by reversed Kaplan Meier analysis, 3-year (y) OS, PFS, and GRFS were respectively 53%, 46% and 31%, while 3-y NRM and RI were 28% and 25%, for the whole cohort. Pre-graft immune status was evaluated at a median of 20 days before transplant, showing significant higher median T and B cell counts and gamma globulin level in patients with myeloid malignancy, reflecting probably the less immunosuppressive intensity of chemotherapies received before transplant ( Table). Considering myeloid malignancies, OS and NRM were not impacted by the pre-graft immune status. In multivariate analysis, adjusting for disease type, status, donor type (sibling versus [vs] unrelated), and conditioning (RIC vs MAC vs sequential), a higher ALC was associated with significant lower PFS (hazard ratio [HR] 1.39, 95%CI: 1.11-1.74, p=0.004) and GRFS (HR: 1.30, 1.07-1.59, p=0.009), and a significant higher risk of relapse (HR 1.85, 1.32-2.59, p=&amp;lt;0.001), but this was true only in case of a matched transplant. Interestingly, T-cell subsets were associated with relapse (CD3: HR 1.94, p&amp;lt;0.001; CD4: HR 2.34, p=0.004; CD8: HR 2.34, p&amp;lt;0.001), but not B-cells (HR 2.23, p=0.56), gamma-globulin levels (HR 0.98, p=0.68), nor NK-cells (HR 2.72, p=0.17). T cell subsets, B cells, NK cells, gamma-globulin and monocytes were not associated with PFS and GRFS. Also, to highlight the adverse effect of an elevated ALC, and using a ROC curve, a threshold of 1.23 Giga/L was retained as the best cut-off to predict relapse. This was then applied to create a visual comparison of PFS, GRFS and RI ( Figure), revealing an early increased RI in patients with ALC &amp;gt; 1.23 Giga/L (3-month relapse rate: 13% vs 2.3%, p=0.03). Finally, the pre-graft immune status did not impact the outcomes of patients receiving a PB haplotransplant for a myeloid malignancy. This was true also for those who received a PB matched or again a haploidentical transplant for a lymphoid disease. Conclusions This retrospective analysis suggests that higher ALC at transplant predicts lower PFS and GRFS due to higher RI in adults receiving a PB matched transplant for a myeloid malignancy. Patients with a myeloid malignancy had also a better immune status at transplant which may reflect less immunosuppressive treatments received before transplant. Paradoxically, this better immune status may interfere with allogeneic T lymphocytes by reducing the graft-versus-leukemia effect. Thus, increasing immunosuppression (via the conditioning or drugs used for GVHD prophylaxis) may improve outcome in some specific sub-groups of patients with higher autologous T lymphocytes at transplant.

Improved Survival with Venetoclax in Patients with Acute Myeloid Leukemia: A Retrospective Single-Center Cohort Study

Background: Venetoclax in combination with azacitidine or low-dose cytarabine has become standard treatment for newly diagnosed elderly or unfit patients with acute myeloid leukemia (AML). Since approval of venetoclax in 2020 in Japan, venetoclax combination therapy have been also used for relapsed or refractory patients although its role in relapsed or refractory disease is not well defined. The survival impact of chemotherapy with venetoclax combination therapy compared with that without venetoclax combination therapy on AML patients in a real-life setting is scarcely reported. Objective: The aim of this retrospective study was to evaluate chemotherapy with or without venetoclax combination therapy in patients with newly diagnosed AML in our institution. Patients and Methods: This study included 234 non-M3 newly diagnosed AML patients who were treated with or without venetoclax combination therapy between February 2008 and July 2023 in our hospital. We evaluated overall survival and composite complete remission (complete remission or complete remission with incomplete hematologic recovery). Overall survival was compared with the use of a cox proportional-hazards regression model adjusted for age (1-year increase) and cytogenetic risk (favorable or intermediate vs. adverse). Composite complete remission was compared between the treatment groups with the use of a logistic regression model adjusted for the same prognostic factors. Subgroup analyses of overall survival was performed according to variables based on disease characteristics at baseline to assess whether the beneficial effect of venetoclax combination therapy varied among specific patient subgroups. Results: We identified 41 patients who were treated with venetoclax as first-line or later treatment and 193 patients who were treated without venetoclax. In the venetoclax group, 26 (63.4%) received venetoclax combination therapy as first-line and 15 (36.6%) as second- or later-line treatement. Twenty (48.8%) were treated with venetoclax combined with azacitidine, 12 (29.3%) with low-dose cytarabine and 9 (22.0%) with both in their course of treatment. Patients in the venetoclax group was older than those in the non-venetoclax group (median age, 76 years vs. 67 years, respectively; P&amp;lt;0.001). FLT3, NPM1, TP53 and IDH1/2 mutational status was comparable between groups. The percentage of patients classified as poor cytogenetic risk category according to the NCCN guidelines for AML, 2021 was higher in the venetoclax group than that in the non-venetoclax group (51.2% vs. 28.0%, respectively; P=0.005). The percentage of patients who umderwent allogeneic hematopoietic stem cell transplantation was lower in the venetoclax group than that in the non-venetoclax group (2.4% vs. 16.6%, respectively; P=0.014). Composite complete remission was achieved in 46.3% (95% CI, 30.7 to 62.6) of the patients in the venetoclax group and 54.4% (95% CI, 47.1 to 61.6) of the patients in the non-venetoclax group (P=0.199). In a Cox model adjusting for age and cytogenetic risk, the 1-year overall survival rate was 79.4% (95% confidence interval [CI], 66.5 to 87.8) in the venetoclax group, as compared with 68.0% (95% CI, 59.6 to 75.0) in the non-venetoclax group (adjusted hazard ratio, 0.64; 95% CI, 0.41 to 1.00; P=0.049). Subgroup analysis of overall survival showed a greater survival benefit in the venetoclax group than in the non-venetoclax group in patients who were 70 years of age or older (P=0.003 for interaction) and in patients with de novo AML (P=0.022 for interaction) after adjustment for age and cytogenetic risk. Conclusions: These real-world data suggested that incorporation of venetoclax combination therapy into existing therapies improved survival in patients with AML. The survival benefit of venetoclax combination therapy was greater in elderly patient and in de novo AML patients than secondary AML patients. Interpretation of the results must be careful because the sample size in the venetoclax group was small. To confirm our findings, further investigation in a larger patient population is required.