Cumulative Incidence Of Death Research Articles

Reassessing blood product irradiation in haploidentical transplantation: a single-center perspective

ABSTRACT Objectives: The main objective was to investigate the incidence of transfusion-associated graft-versus-host disease (TA-GVHD) in patients who underwent haploidentical hematopoietic cell transplants (HCT) and received non-irradiated leukoreduced blood components. The secondary objective was to describe our leukodepletion results in blood products obtained by the filters employed at our center. Study Design and Methods: Clinical records from 2018 to 2023 were retrospectively analyzed, along with a prospective evaluation of residual leukocytes in blood components from June to November 2023 in order to confirm effectivity of our leukodepletion method. Results: 150 patients were included, no cases of TA-GVHD were reported after using non-irradiated blood products. The incidence of grade 3–4 acute and moderate-severe chronic GVHD was 12.7% (n = 19) and 2.7% (n = 4), respectively. The cumulative incidence of death was 39.3% (n = 52) with a 3.7-year overall survival (CI 95%, 3.3- 4.1 years). Leukodepletion analysis showed a reduction of 99.93% in platelet concentrates and 99.98% in packed red blood cells. Discussion: TA-GVHD in HCT remains a concern traditionally mitigated using blood product irradiation. Recent evidence obtained in favor of leukoreduction techniques question this need, especially in resource-limited settings. Conclusion: These findings support leukoreduction as a primary TA-GVHD preventive measure,along with the advantage in cost reduction.

Heart rate and prognosis of heart failure with reduced ejection fraction in women and men in sinus rhythm

Abstract Background Resting heart rate (HR) is a well-established therapeutic target for treating heart failure (HF). Beta-blockers are the primary drugs to reduce HR. Elevated HR is associated with higher mortality in heart failure with reduced ejection fraction (HFrEF). However, the influence of HR on mortality and predictors of death in women with HFrEF in sinus rhythm is not well understood. Purpose to analyse mortality for HR ≤60>bpm and ≤70>bpm in women and men. Methods From February 2017 to January 2022, we analysed the influence of resting HR (≤60> and ≤70>bpm) on mortality and predictors of death in women and men with HFrEF in sinus rhythm. Baseline data included clinical characteristics and echocardiographic findings. The HR used in the analysis was obtained at the closest outpatient visit to the death event. We used the adjustment for multiple comparisons for the log-rank test of Kaplan-Meier (K-M) and Cox proportional hazards methods to analyse mortality rates and search for death predictors for women and men. Results We analysed 2,984 patients, with a mean age of 61 ± 13.8 years, 1,922 (64.4%) men. Age, body mass index, myocardial infarction, diabetes, chronic kidney disease, stroke, carvedilol dosage, hospitalization, and initial left ventricular ejection fraction (LVEF) were similar in both genders. Over the follow-up period of 3.7±1.6 years, we observed an increase in LVEF in men (29.5%±6.7% vs. 36.7%±12.9%; p<0.001) and women (29.9%±6.4 vs. 38.0%±13.4%; p<0.001), and HR reduced in men (73.1±13.0 to 72.1±11.8 bpm; p=0.007) and women (72.8±12.7 to 71.8±11.3 bpm; p=0.026). Death incidence was higher in men (43.7% vs. 36.7%; p<0.001). The cumulative incidence of death was higher in men with HR>60bpm (K-M: log-rank p<0.001) and >70bpm (K-M: log-rank p=0.011) compared to women. Cox regression for death, adjusted for covariates with p<0.25, showed age (HR=1.01;95%CL:1.008-1.017; p<0.001), men (HR=0.80;95%CL:0.71-0.90; p<0.001), LVEF (HR=0.986;95%CL:0.98-0.99; p=0.001), and HR (HR=1.005;95%CL:1.00-1.01; p=0.025) as independent death variables. For men, the independent variables were age (HR=1.01;95%CL:1.01-1.02; p=0.002), LVEF (HR=0.98;95%CL:0.97-0.99; p=0.001), and HR (HR=1.008;95%CL:1.00-1.01; p=0.008), and for women, only the age (HR=1.02;95%CL:1.01-1.02; p<0.001). Conclusion Increased HR was an independent variable of death in men but not in women. Future studies are needed to determine the best reference HR for a chronotropic drug intervention to reduce mortality in women with HFrEF in sinus rhythm.

Clinical outcome based on functional complete revascularization in patients with three-vessel coronary artery disease: The FAME 3 Trial

Abstract Background Anatomic complete revascularization after angiography-guided percutaneous coronary intervention (PCI) is associated with improved clinical outcomes. The impact of functional complete revascularization (PCI of all fractional flow reserve (FFR) positive lesions) in patients with 3-vessel coronary artery disease (3VD) amenable to PCI or coronary artery bypass grafting (CABG) is unknown. Purpose To investigate the clinical impact of functional complete revascularization after FFR-guided PCI in the FAME 3 trial Methods The FAME 3 trial is a multicenter, international, randomized study comparing FFR-guided PCI with CABG in patients with angiographic 3VD. This pre-specified sub-study evaluated the impact of functional complete revascularization after PCI on the primary endpoint of death, myocardial infarction (MI), or stroke at 3 years. The degree of functional complete revascularization was quantified by calculating the residual functional SYNTAX score (rFSS), defined as the residual anatomic SYNTAX score based on post-PCI angiography minus any FFR-negative deferred lesions. Results Of the 757 patients treated with FFR-guided PCI, the rFSS could be calculated by the core laboratory in 81% (n=601). Among the angiographically significant lesions, PCI was deferred based on FFR in 17% (51 % of patients had deferral of at least one lesion). The patients were divided into two groups according to acceptable functional complete revascularization: rFSS 0-8 (63%) and functional incomplete revascularization: rFSS>8 (37%). The cumulative incidence of death, MI, or stroke at 3 years was significantly lower in patients with rFSS 0-8 (9% vs. 17%, Hazard ratio[HR]:0.5, 95% confidence interval[CI]:0.3-0.8, p=0.006) compared with rFSS>8. In comparison with the CABG arm, the patients with rFSS 0-8 had similar outcome (HR:0.97, 95%CI:0.6-1.5, p=0.87), while in those with rFSS >8 outcome was worse (HR:1.9, 95%CI: 1.3-2.8, p=0.002) (Figure). There was no difference in death, MI or stroke in CABG patients with or without anatomic complete revascularization. In a multivariate-adjusted model, rFSS>8 showed a significant association with death, MI or stroke at three years (adjusted HR: 1.83, 95% CI: 1.09-3.09, p=0.02). Conclusions Acceptable functional complete revascularization with FFR-guided PCI in patients with 3VD is an independent predictor of death, MI or stroke at three years and can be achieved in 63% of patients resulting in similar outcomes compared with CABG.

PD-L1 protein expression in breast cancer

AimsThe immune checkpoint marker, Programmed cell death-ligand 1 (PD-L1), is expressed by both cancer epithelial cells and tumour-infiltrating immune cells (TICs) thus constituting a potential target for immunotherapy. This is...

Prospective evaluation of cystatin C in the assessment of kidney dysfunction and survival in liver transplant candidates.

Kidney dysfunction is associated with decreased survival in liver transplant (LT) candidates, yet serum creatinine (sCr) is a poor surrogate for glomerular filtration rate (GFR) in this population. Serum cystatin C (CysC) may provide a more accurate assessment of kidney function and predict outcomes. We performed a multicenter prospective cohort study of consecutive candidates for LT. CysC was obtained at LT evaluation (n = 244), and a subset underwent simultaneous I 125 -iothalamate clearance for measured GFR (mGFR) assessment (n = 137). Patients were followed to assess the need for pre-LT renal replacement therapy, simultaneous liver and kidney transplant, and survival. Estimated GFR (eGFR) based on MDRD-4, GRAIL, Royal Free Hospital Cirrhosis GFR, and the CKD-EPI equations was assessed for bias, precision, and accuracy in reference to mGFR. Receiver operator characteristic (AUROC) and competing risk survival analyses were performed. CysC more accurately discriminated mGFR than sCr at thresholds of ≤60 and ≤30mL/min/1.73m 2 with AUROC 0.92 ( p = 0.005) and 0.96 ( p =0.01), respectively. All eGFR equations overestimated GFR, especially among females ( p < 0.05). The GRAIL equation demonstrated the least bias, while CKD-EPI-cystatin C was associated with the greatest precision and lowest frequency of GFR overestimation. Among 165 recipients of LT, CysC discriminated pre-LT renal replacement therapy and the need for simultaneous liver and kidney transplant with AUROC of 0.70 and 0.85, respectively. Cumulative incidence of death, accounting for LT as a competing event, increased with CysC ( p = 0.002) but was not observed with sCr overall or among subgroups ( p = NS). CysC more accurately predicts thresholds of mGFR than sCr in candidates for LT. Elevated CysC discriminates pre-LT renal replacement therapy and simultaneous liver and kidney transplant and is strongly associated with survival in contrast with sCr. CysC is a promising tool to improve prognostication among candidates for LT.

Survival Following Diagnosis of HIV-Associated Kaposi Sarcoma Among Adults in East Africa in the "Treat-All" Era.

Despite widespread access to antiretroviral therapy (ART) in the "Treat All" era, HIV-associated Kaposi sarcoma (KS) remains among the most common malignancies in sub-Saharan Africa. Survival after KS diagnosis has historically been poor in Africa, but knowledge whether survival has changed at the population level in the contemporary era has been limited by lack of community-representative surveillance and monitoring systems. We identified all adult persons living with HIV (PLWH) with a new diagnosis of KS made between 2016 and 2019 during outpatient or inpatient care at prototypical primary care-providing medical facilities in Kenya and Uganda using rapid case ascertainment. Participants were subsequently followed for vital status, including community tracking for those who became lost to follow-up. Among 411 participants with newly diagnosed KS, 71% were men, median age was 34 (IQR: 30 to 41) years, and 91% had ACTG T1 tumor extent. Over a median follow-up of 7.8 (IQR: 2.4 to 17.9) months, cumulative incidence of death (95% CI) at months 6, 12 and 18 were 34% (30% to 39%), 41% (36% to 46%) and 45% (40% to 51%), respectively. Having the highest number of anatomic sites (11 to 16) harboring KS lesions (hazard ratio 2.2 (95% CI: 1.3-3.8) compared to 1 to 3 sites) and presence of oral KS lesions (hazard ratio 2.2 (95% CI: 1.4-3.3)) were independently associated with higher mortality. Lower hemoglobin and CD4 count as well as higher plasma HIV RNA were also associated with higher mortality. Among PLWH with newly diagnosed KS in East Africa in the "Treat All" era, survival was poor and related to mucocutaneous extent of KS. The findings emphasize the need for better control of KS in Africa, including novel approaches for earlier detection, better linkage to oncologic care, and more potent therapy.

Risk of prostate cancer death in men diagnosed with prostate cancer at cystoprostat-ectomy. A nationwide population-based study.

One out of three men who undergo cystoprostatectomy for bladder cancer is diagnosed with incidental prostate cancer (PCa) at histopathological examination. Many of these men are PSA tested as part of their follow-up, but it is unclear if this is needed. The aim of this study was to assess the risk of PCa death in these men and the need of PSA-testing during follow-up. Between 2002 and 2020, 1,554 men were diagnosed with PCa after cystoprostatectomy performed for non-metastatic bladder cancer and registered in the National Prostate Cancer Register (NPCR) of Sweden. We assessed their risk of death from PCa, bladder cancer and other causes up to 15 years after diagnosis by use of data in The Cause of Death Register. The use of androgen deprivation therapy (ADT) as a proxy for PCa progression was assessed by fillings in The Prescribed Drug Register. Fifteen years after diagnosis, cumulative incidence of death from PCa was 2.6% (95% CI 2.3%-2.9%), from bladder cancer 32% (95% CI: 30%-34%) and from other causes 40% (95% CI: 36%-44%). Only 35% of men with PCa recorded as primary cause of death in The Cause of Death Register had started ADT before date of death, indicating sticky-diagnosis bias with inflated risk of PCa death. For a large majority of men diagnosed with incidental PCa at cystoprostatectomy performed for bladder cancer, the risk of PCa death is very small so there is no rationale for PSA testing during follow-up.

Abstract P253: Lifetime Risk of Dementia by Midlife Vascular Risk Factor Burden: The Atherosclerosis Risk in Communities (ARIC) Study

Introduction: Vascular risk factors play an important role in the development of dementia and death over the lifecourse. However, no absolute lifetime risk of dementia by individual and composite number of vascular risk factors have been reported. Methods: We conducted a prospective cohort analysis of data from the Atherosclerosis Risk in Communities (ARIC) Study. We examined the associations of vascular risk factors with incident dementia. Risk factors were measured at visit 2 (1990-1992) and included hypertension (SBP140mmHg, DBP90mmHg or medication use), diabetes status (self-reported physician diagnosis, medication use or HbA1C6.5%) and smoking status. Incident dementia was ascertained via active surveillance involving cognitive function assessments, informant reports, hospitalization codes and death records. We performed survival analysis using age as time scale and accounted for death without dementia as a competing event. We used age 60 as the origin and age on December 31 st , 2019, as the administrative censoring endpoint. Results: Among 13,161 participants, 45%, 40%, and 15% had 0, 1 and 2+ risk factors. There was a dose-dependent association between number of risk factors and the cumulative incidence of dementia (Figure A) and death (Figure C) . In competing risk models ( Figure B ), the cumulative incidence of dementia (95% CI) in persons with 0, 1 and 2+ risk factors by age 80 was 7.5% (6.6-8.5%), 10.3% (9.2-11.5%) and 13.7% (11.5-15.7%). By age 90, due to higher risk of mortality among those with vascular risk factors, the dementia risk (95% CI) for 0, 1 and 2+ risk factors were 34.8 (32.3-37.3%), 31.2% (29.0-33.2%) and 26.7% (23.9-29.6%). Conclusion: Preventing vascular risk factors in midlife may substantially reduce the age-specific risk of dementia. However, since fewer risk factors also lead to longer survival to oldest ages where dementia risk is very high, reducing lifetime risk of dementia beyond age 90 years will require additional preventative strategies. Figure: Cumulative incidence of dementia using Kaplan Meier estimator (A), using cumulative incidence function with competing risk of death (B), and cumulative incidence of death (C), according to the number of vascular risk factors in mid-life.

Mitral valve replacement in children: balancing durability and risk with mechanical and bioprosthetic valves.

To investigate if there is still a place for bioprosthetic mitral valve replacement in children by comparing the prosthetic durability and transplant-free survival after bioprosthetic and mechanical mitral valve replacement. We reviewed all mitral valve replacements in children between 1981 and 2020. Bioprosthetic mitral valve replacement cases were individually matched to mechanical mitral valve replacement cases. The incidence rate of a 2nd replacement was calculated using the cumulative incidence function that considered death or transplantation as a competing risk. The median age at implantation was 3.6 years (interquartile range 0.8-7.9) for the bioprosthetic valve cohort (n = 28) and 3 years (interquartile range 1.3-7.8) for the mechanical valve cohort (n = 28). Seven years after bioprosthetic mitral valve replacement, the cumulative incidence of death or transplantation was 17.9% [95% confidence interval (CI) 6.3-34.1] and the cumulative incidence of a 2nd replacement was 63.6% (95% CI 39.9-80.1). Seven years after mechanical mitral valve replacement, the cumulative incidence of death or transplantation was 28.6% (95% CI 13.3-46) and the cumulative incidence of a 2nd replacement was 10.7% (95% CI 2.6-25.5). Fifteen years after mechanical mitral valve replacement, the cumulative incidence of death or transplantation was 33.6% (95% CI 16.2-52.1) and the cumulative incidence of a 2nd replacement was 41.1% (95% CI 18.4-62.7). The cumulative incidence curves for bioprosthetic and mechanical mitral valve replacement were statistically different for a 2nd valve replacement (P < 0.001) but not for death or transplantation (P = 0.33). There is no difference in transplant-free survival after bioprosthetic and mechanical mitral valve replacement in children. The lifespan of bioprosthetic mitral valves remains limited in children because of structural valve failure due to calcification. After 15 years, 40% of mechanical valves were replaced, primarily because of patient-prosthesis mismatch related to somatic growth.

Efficacy and safety of a novel antiviral herbal preparation in ICU-admitted patients with COVID-19: A phase III double-blinded controlled trial.

Despite an increasing number of studies, there is as yet no definite treatment developed for the coronavirus disease 2019 (COVID-19). In this clinical trial, we examined the efficacy of a novel herbal antiviral preparation in critically ill COVID-19 patients. A total number of 120 ICU-admitted patients with a diagnosis of COVID-19 pneumonia were recruited to the trial. Participants were equally randomized to receive either the novel antiviral preparation sublingually, for up to two consecutive weeks or till discharge, or placebo. Clinical and laboratory parameters as well as survival rates were compared between the two groups. The cumulative incidence of death throughout the study period was 8.33% in the intervention group and 60% in the placebo group (risk ratio: 0.14; 95% confidence interval [CI], 0.05 to 0.32; p<0.001). On day 7, several parameters including white blood cells (WBCs) count, C-reactive protein, and SpO2 were improved for the treatment group compared with the placebo group (p-values of 0.05, 0.01, and <0.001, respectively). This preparation might be suggested as a potentially promising COVID-19 treatment.

Waitlist Outcomes in Candidates With Rare Causes of Heart Failure After Implementation of the 2018 French Heart Allocation Scheme.

In 2018, an algorithm-based allocation system for heart transplantation (HT) was implemented in France. Its effect on access to HT of patients with rare causes of heart failure (HF) has not been assessed. In this national study, including adults listed for HT between 2018 and 2020, we analyzed waitlist and posttransplant outcomes of candidates with rare causes of HF (restrictive cardiomyopathy [RCM], hypertrophic cardiomyopathy, and congenital heart disease). The primary end point was death on the waitlist or delisting for clinical deterioration. Secondary end points included access to HT and posttransplant mortality. The cumulative incidence of waitlist mortality estimated with competing risk analysis and incidence of transplantation were compared between diagnosis groups. The association of HF cause with outcomes was determined by Fine-Gray or Cox models. Overall, 1604 candidates were listed for HT. At 1 year postlisting, 175 patients met the primary end point and 1040 underwent HT. Candidates listed for rare causes of HF significantly differed in baseline characteristics and had more frequent score exceptions compared with other cardiomyopathies (31.3%, 32.0%, 36.4%, and 16.7% for patients with hypertrophic cardiomyopathy, RCM, congenital heart disease, and other cardiomyopathies). The cumulative incidence of death on the waitlist and probability of HT were similar between diagnosis groups (P=0.17 and 0.40, respectively). The adjusted risk of death or delisting for clinical deterioration did not significantly differ between candidates with rare and common causes of HF (subdistribution hazard ratio (HR): hypertrophic cardiomyopathy, 0.51 [95% CI, 0.19-1.38]; P=0.18; RCM, 1.04 [95% CI, 0.42-2.58]; P=0.94; congenital heart disease, 1.82 [95% CI, 0.78-4.26]; P=0.17). Similarly, the access to HT did not significantly differ between causes of HF (hypertrophic cardiomyopathy: HR, 1.18 [95% CI, 0.92-1.51]; P=0.19; RCM: HR, 1.19 [95% CI, 0.90-1.58]; P=0.23; congenital heart disease: HR, 0.76 [95% CI, 0.53-1.09]; P=0.14). RCM was an independent risk factor for 1-year posttransplant mortality (HR, 2.12 [95% CI, 1.06-4.24]; P=0.03). Our study shows equitable waitlist outcomes among HT candidates whatever the indication for transplantation with the new French allocation scheme.

Robotic Versus Thoracoscopic Sub-lobar Resection for Octogenarians with Clinical Stage IA Non-small Cell Lung Cancer: A Propensity Score-Matched Real-World Study.

Minimally invasive sub-lobectomy is sufficient in treating small early-stage non-small cell lung cancer (NSCLC). However, comparison of the feasibility and oncologic efficacy between robot-assisted thoracoscopic surgery (RATS) and video-assisted thoracoscopic surgery (VATS) in performing sub-lobectomy for early-stage NSCLC patients age 80 years or older is scarce. Octogenarians with clinical stage IA NSCLC (tumor size, ≤2 cm) undergoing minimally invasive wedge resection or segmentectomy at Shanghai Chest Hospital from 2011 to 2020 were retrospectively reviewed from a prospectively maintained database. Propensity score-matching (PSM) with a RATS versus VATS ratio of 1:4 was performed. Perioperative and long-term outcomes were analyzed. The study identified 594 patients (48 RATS and 546 VATS patients), and PSM resulted in 45 cases in the RATS group and 180 cases in the VATS group. The RATS patients experienced less intraoperative bleeding (60 mL [interquartilerange(IQR), 50-100 mL] vs. 80 mL [IQR, 50-100 mL]; P = 0.027) and a shorter postoperative hospital stay (4 days [IQR, 3-5 days] vs. 5 days [IQR, 4-6 days]; P = 0.041) than the VATS patients. The two surgical approaches were comparable concerning other perioperative outcomes and postoperative complications (20.00% vs. 26.11%; P = 0.396). Additionally, during a median follow-up period of 66 months, RATS and VATS achieved comparable 5-year overall survival (90.48% vs. 87.93%; P = 0.891), recurrence-free survival (83.37% vs. 83.18%; P = 0.782), and cumulative incidence of death. Further subgroup comparison also demonstrated comparable long-term outcomes between the two approaches. Finally, multivariate Cox analysis indicated that the surgical approach was not independently correlated with long-term outcomes. The RATS approach shortened the postoperative hospital stay, reduced intraoperative bleeding by a statistically notable but clinically insignificant amount, and achieved long-term outcomes comparable with VATS in performing sub-lobectomy for octogenarians with early-stage small NSCLC.

Clinical outcomes of ST elevation myocardial infarction patients without standard modifiable risk factors

BackgroundStandard modifiable cardiovascular risk factors (SMuRFs; hypertension, diabetes mellitus, dyslipidemia, and smoking) are widely recognized as risk factors for coronary artery disease. However, the associations between absence of SMuRFs and long-term clinical outcomes in ST-segment elevation myocardial infarction (STEMI) patients are unclear. MethodsConsecutive STEMI patients who underwent primary percutaneous coronary intervention (PCI) between 1999 and 2015 were retrospectively analyzed. The primary endpoint was up to 5-year all-cause mortality. Clinical characteristics and outcomes were compared between patients with at least one of the SMuRFs and those without any SMuRFs. ResultsOf 1963 STEMI patients, 126 (6.4 %) did not have any SMuRFs. Patients without SMuRFs were significantly older, had lower body mass index, and were more likely to be female. During a median follow-up period of 4.9 years, the cumulative incidence of death was significantly higher in patients without SMuRFs than in those with SMuRFs (log-rank p < 0.0001). Landmark analysis showed that patients without SMuRFs had higher mortality within 30 days of STEMI onset (log-rank p = 0.0045) and >30 days after STEMI onset (log-rank p = 0.0004). Multivariable Cox hazards analysis showed that absence of SMuRFs was associated with a higher risk of mortality (hazard ratio, 1.59; 95 % confidence interval, 1.14–2.21; p = 0.006). ConclusionsOf STEMI patients undergoing primary PCI, patients without any SMuRFs had higher mortality than those with at least one of the SMuRFs. Patients without any SMuRFs have a poor prognosis and require more attention.

A comparison between patients with various etiologies of cirrhosis and examination of cardiac risk factors limiting survival to liver transplantation.

Objectives of this retrospective cohort study were to assess differences in patient survival between etiologies of cirrhosis while on the waitlist for liver transplantation (LT), and to identify cardiac risk factors that predict survival failure while on the waitlist for LT. This single-center retrospective cohort design included adult patients who were listed for LT at a tertiary academic hospital with a high-volume liver transplant center. Of the 653 patients listed for LT during the study period, 507 (77.6%) survived to transplant and 146 (22.4%) died or clinically deteriorated prior to transplant. Cumulative incidence of death or clinical deterioration did not differ statistically between patient groups (log rank p=.11). In multivariate analysis, compared to patients with NAFLD, there were no significant differences between patients with alcoholic cirrhosis (HR .95, 95%, CI, .62-1.45), cryptogenic cirrhosis (HR 1.31, 95%, CI, .77-2.23), or hepatitis C cirrhosis (HR 1.12, 95%, CI, .66-1.90). However, higher MELD scores (HR=1.52, 95% CI, 1.12-1.19), severe coronary artery disease (HR=2.09 95% CI, 1.23-3.55), and tricuspid regurgitation (HR=2.62, 95% CI, 1.31-5.26) were independently associated with increased risk for survival failure to LT. The presence of severe coronary artery disease and tricuspid regurgitation at the time of listing for transplant are associated with survival failure while on the LT waitlist across etiologies of liver disease. Diagnostic assessment of coronary and valvular disease should be considered in all patients undergoing evaluation for LT, such as cardiac catheterization and/or stress echocardiogram.

Validation of the Prognostic Risk Signatures for Older Patients with Acute Myeloid Leukemia Treated with Hypomethylating Agents and Venetoclax

Introduction: Hypomethylating agents (HMA) with Venetoclax (Ven) is the standard of care for patients with acute myeloid leukemia (AML) ≥ 75 yrs of age or not candidates to intensive treatment. Döhner, et al. (ASH 2022) demonstrated that the European LeukemiaNet (ELN) risk classifications do not accurately predict prognosis in HMA-Ven treated patients. A prognostic risk signature classification (PRSc) was proposed, stratifying patients by RAS, FLT3 and TP53 mutations alone. We report a validation of this PRSc in a large cohort of patients treated with HMA-Ven. Methods: This unicentric analysis included patients older than 60 years old with newly diagnosed treated with HMA-Ven in different treatment protocols. Responses were assessed with the ELN-2022 criteria. The PRSc allocated patients with [ K/N]- RAS or FLT3-ITD mutations in the intermediate benefit group, patients with TP53 in the lower benefit group, whereas patients with AML lacking these mutations were allocated in the higher benefit group. Cumulative incidence (CI) was calculated for pts achieving remission with death and relapse as competing events. Results: A total of 179 patients were included, diagnosed between 11/2014 and 12/2021. Median age was 74 yrs old (range, 61-89) and 58% were male. 31% of patients had diploid cytogenetics and 35% had complex karyotype. According to the ELN 2022 risk category, 30 (17%), 15 (8%) and 114 (64%) patients were allocated in the favorable, intermediate and adverse risk group, respectively. According to the PRSc, 75 (42%), 31 (17%) and 54 (30%) were allocated in the higher, intermediate and lower benefit group, respectively. In the PRSc intermediate benefit group, 21 patients had NRAS mutations, 9 patients had KRAS mutation and 7 patients had FLT3-ITD. Patients received treatment with decitabine 10 days with Ven (n=89, 50%), decitabine 5 days with Ven (n=69, 38%), oral decitabine 5 days with Ven (n=14, 8%) and Azacitidine 7 days with Ven (n=7, 4%). The overall response rate (ORR) was 70% (126/179), including 96 pts (54%) achieving complete remission (CR) rate and 30 (17%) having CR with incomplete hematologic recovery (CRi). The ORR for patients allocated in the ELN 2022 favorable, intermediate and adverse risk was 90% (27/30), 93% (14/15) and 63% (72/114). According to the PRSc, the ORR was 87% (65/75), 55% (17/31) and 59% (32/54) for patients of the higher, intermediate and lower benefit group, respectively. The median number of cycles to best response was 1 (1-8), and 22 patients (12%) underwent allogeneic stem cell transplantation. After a median follow-up of 35 months, the median overall survival (OS) was 11 months. According to the ELN 2022 classification, the mOS was 44, 13 and 8 months (p&amp;lt;0.001, C-index=0.6). When applying the PRSc, the median OS was 30, 12 and 5 months for higher, intermediate and lower benefit group (p&amp;lt;0.001, C-index=0.66). Median event-free survival (EFS) was 8 months, being 30, 8, and 5 months for ELN 2022 favorable, intermediate and adverse group, respectively (p&amp;lt;0.001, C-index=0.62). When applying the PRSc, the median EFS was 18, 8 and 4 months for higher, intermediate and lower benefit group, respectively (p&amp;lt;0.001, C-index=0.65). The 2-yr CI of relapse and death was 47% and 22%, respectively. By the ELN 2022 subgroups, the 2-yr CI of relapse was 29%, 43% and 55% for favorable, intermediate and adverse groups, respectively (p=0.1). The 2-yr CI of death was 12%, 21% and 25% for favorable, intermediate and adverse groups, respectively (p=0.4). By the PRSc, the 2-yr CI of relapse was 26%, 70% and 60% for higher, intermediate and lower benefit group, respectively (p=0.004). The 2-yr CI of death was 20%, 6% and 33% for higher, intermediate and lower benefit group, respectively (p=0.1). Conclusion: The PRSc classification can stratify 3 different groups of patients with distinct outcomes. In the present study the 3 categories defined by the PRSc have very similar survival than the median OS previously reported (27, 12 and 5 months for higher, intermediate and lower benefit group), with a better performance according to the C-index. Signaling mutations ( RAS or FLT3-ITD) as well as TP53 mutations represent a challenge with HMA-Ven, in which novel treatments or combinations are warranted to improve outcomes.

Implementation of Continuous Pegasparaginase Dosing without an Asparaginase-Free Interval Reduces Hypersensitivity in Children with Newly Diagnosed Acute Lymphoblastic Leukemia: Results of the DCOG ALL11 Pegasparaginase Randomization

Background: Asparaginase is key in the treatment of pediatric acute lymphoblastic leukemia (ALL). Hypersensitivity is one of its major side effects and hamper its use. Most hypersensitivity reactions occur after an asparaginase-free interval, as neutralizing anti-drug antibodies increase during these intervals. Thus we hypothesized that a continuous PEGasparaginase dosing schedule (without an asparaginase-free interval) would result in less hypersensitivity to PEGasparaginase compared to the standard non-continuous PEGasparaginase dosing schedule. Methods: Medium risk (MR) patients (aged 1-18 yrs) with ALL enrolled in the DCOG ALL11 protocol, were randomized to receive 14 individualized PEGasparaginase doses after an asparaginase-free interval of 3 months or to continue PEGasparaginase treatment following the first 3 doses in induction (EudraCT:2012-000067-25; Dutch Trial Register NL3227). Hypersensitivity included allergies, allergic-like reactions, and silent inactivations, where inactivating hypersensitivity reactions comprised the sum of allergies and silent inactivations. Secondary endpoints included other asparaginase-related adverse event (AEs) (CTCAE &amp;gt;grade 3), such as febrile neutropenia, infection, a thromboembolic event, pancreatitis, and avascular necrosis, as well as antibody levels and treatment outcome. Cumulative incidence of relapse (CIR), cumulative incidence of death (CID) in CR1 and disease-free survival (DFS) were compared between both treatment arms. Results: 312 MR patients were randomized to receive PEGasparaginase in a continuous (n=155) and non-continuous (n=157) dosing schedule. Hypersensitivity reactions occurred in 4 out of 155 (2.6%) patients in the continuous treatment arm versus 17 out of 157 (10.8%) patients in the non-continuous treatment arm (P&amp;lt;0.01), of which 2 (1.3%) versus 13 (8.3%) were inactivating reactions (Figure 1; P&amp;lt;0.01). Patients in de continuous treatment arm were significantly less likely to get an inactivating hypersensitivity reaction (odds ratio: 0.15 (0.032-0.653), P=0.012). Antibody levels were significantly lower in the continuous arm compared to the non-continuous arm (P&amp;lt;0.01). Without the asparaginase-free interval, the antibody levels slightly increased by 1.1-fold between dose 3 and 4 whereas antibody levels in the non-continuous arm increased by 2.5-fold during the asparaginase-free interval. We did not find any significant differences in the total number of asparaginase-associated AEs between the treatment arms (Figure 1). However, the generalized Poisson model analysis revealed that the occurrence of specific AEs, such as a thromboembolic event and pancreatitis, was influenced by both treatment phase and arm. These correlations can be attributed to the timing of asparaginase administrations, since at start of randomization asparaginase treatment was interrupted in the non-continuous arm but uninterrupted in the continuous arm. Consequently, thromboembolic events and pancreatitis occurred more frequently at the beginning of randomization in the continuous arm compared to the non-continuous arm (Table 1). This pattern reversed when the non-continuous arm resumed asparaginase treatment after the asparaginase-free period, while the continuous arm concluded their treatment. The occurrence of infections was not associated with treatment phase and treatment arm. The median duration of treatment phases was comparable between the two arms, with the exception of a longer duration of protocol M in the continuous versus non-continuous arm (median 10.3 versus 9.4 weeks respectively instead of the planned 9 weeks; P&amp;lt;0.01) Estimated median follow-up time was 57.2 months (95%-CI 51.9-61.3). The 5-yr CIR, CID in CR1 and DFS were 5.6% (SE 2.1%), 1.9% (SE 1.1%) and 91.9% (SE 2.4%) for continuous treatment vs 4.0% (SE 1.8%), 0.6% (SE 0.6%) and 95.3% (SE 1.9%) for non-continuous treatment (P=0.710; P=0.308; P=0.289), respectively. Conclusion: A continuous dosing schedule of PEGasparaginase resulted in a 7 times lower incidence of inactivating hypersensitivity reactions and lower anti-drug antibody levels compared with a non-continuous dosing schedule with an asparaginase-free interval. The continuous schedule of asparaginase treatment did not increase toxicity but changed the timing of toxicities and did not affect the efficacy of the therapy.

Outcome of Infants Treated on Total Therapy for Infants with Acute Lymphoblastic Leukemia I: Results from a Non-Randomized Multi-Center Study

Infants with KMT2A rearranged (KMT2Ar) acute lymphoblastic leukemia (ALL) have a poor prognosis with an event-free-survival (EFS) of 33.6-36.9% on recent Children's Oncology Group and Interfant trials. In preclinical studies, we identified bortezomib and vorinostat as novel active agents in primary KMT2Ar infant ALL specimens that have not been included in infant regimens to date. Total therapy for infants with acute lymphoblastic leukemia I (TINI) evaluated this novel combination in a multi-institutional pilot trial for infants with de novo ALL. In this study, bortezomib and vorinostat were incorporated into an ALL chemotherapy backbone containing dexamethasone, mitoxantrone, and pegasparaginase during induction and reinduction chemotherapy cycles. A run-in dose escalation evaluated 3 dose levels of vorinostat which was then followed by a dose expansion phase. The primary endpoint of the study was tolerability; secondary endpoints included minimal residual disease (MRD), 3-year EFS and overall survival (OS). Fifty patients enrolled between 2017-2021. Median follow up was 3.4 years (range 1.6-6.8 years). The six patients in the dose escalation phase had no dose-limiting toxicities. Forty-four patients received vorinostat at the third dose level (DL3) of 180 mg/m 2/dose. 68% of patients treated at DL3 had CNS involvement at diagnosis. 68% of DL3 patients carried a KMT2Ar. The most frequent KMT2A partner genes were AFF1 (40%), MLLT1 (20%), and MLLT3 (13%). The most frequent grade 3-4 non-hematologic adverse events during induction include neutropenic fever (45%), hypertension (43%), infection (40%), anorexia (32%), diarrhea (18%) and perineal skin ulceration (16%). There were 3 episodes of sepsis and 1 induction death due to parainfluenza pneumonia. Fewer events and no deaths or proven sepsis occurred during reinduction, with only grade 3 hypertriglyceridemia exceeding 10% of patients affected (18%). 79% of all patients and 69% of KMT2Ar patients became MRD negative by flow cytometry on day 22 of induction following our investigational block. Following induction intensification with cyclophosphamide, cytarabine, and mercaptopurine, 77% and 66% of all patients and KMT2Ar patients respectively were MRD negative at the time of count recovery. Eight of the forty-four patients, all KMT2Ar, underwent stem cell transplant in first remission due to persistent MRD positivity at the end of consolidation. The 3-year EFS and OS probabilities (SE) of all forty-four DL3 patients were 56.5% (8.0) and 70.5% (7.3), respectively. The 3-year cumulative incidence of relapse (CIR) with death considered a competing event was 29.3% (6.9) and the cumulative incidence of death (CID) as a first event was 8.9% (4.5). Patients lacking a KMT2Ar had superior outcomes with 85.7% (9.4) EFS and 92.9% (6.9) OS. The EFS and OS of KMT2Ar patients were 44.8% (9.5) and 62% (9.1) respectively. CIR and CID for KMT2Ar patients was 43.5% (9.6) and 7.2% (5) respectively. KMT2Ar patients ≥90 days at diagnosis had superior outcomes compared to their younger counterparts with 59.1% (10.5) EFS and 77.3% (8.9) OS. End of induction MRD was predictive of an event in this subgroup, with 85.6% (9.4) EFS for MRD negative patients and 14.3% (13.2) EFS for MRD positive patients. In contrast, KMT2Ar patients &amp;lt; 90 days of age at diagnosis had poor outcomes irrespective of MRD with 12.5% (11.7) EFS and 25% (15.3) OS. Notably KMT2Ar patients &amp;lt; 90 days who were MRD negative at the end of induction had a median time to relapse of 600 days (range 282-969 days), a late time point for this malignancy that typically relapses within a year from initial diagnosis. This suggests the regimen effectively reduced tumor burden leading to an extended duration of remission but failed to sufficiently eradicate disease to prevent relapse. We conclude that the incorporation of bortezomib and vorinostat for treatment of infants with ALL was well tolerated. MRD responses in KMT2Ar patients were robust. Although the study was not powered to evaluate outcomes, EFS and OS in KMT2Ar patients suggest a clinical signal worth pursuing given the low proportion of patients transplanted in first remission. The successor study, TINI 2 (NCT05848687), will build upon the bortezomib/vorinostat backbone by incorporating 2 cycles of blinatumomab and the menin inhibitor ziftomenib in combination with chemotherapy during reinduction.

Impact of Antibacterial Prophylaxis on Morbidity-Mortality of Patients with Myeloid Neoplasms Treated with Non-Intensive Venetoclax Combinations

Background and aims: The addition of Venetoclax (VEN) to the treatment of myeloid neoplasms, particularly newly diagnosed and relapse/refractory (R/R) Acute Myeloid Leukemia (AML), has shown improved responses compared to hypomethylating agents (HMA) in unfit patients. Nevertheless, side effects derived from deep cytopenias (infections) could potentially be a caved of such strategy. The use of antibacterial prophylaxis in this setting is controversial and its employment heterogeneous across centers, making difficult to draw conclusions from real-world studies. In this study we aimed to ascertain whether the use of antibacterial prophylaxis has an impact on the incidence of bacterial infections, hospitalization rates, infection severity, and mortality due to the infection. Finally, we also aimed to identify potential risk factors for bacterial infections. Methods: Retrospective data collection of patients with de novo, R/R or secondary AML, High Risk Myelodisplastic Syndrome and accelerated phases of Myeloproliferative Neoplasms treated with HMA or low dose cytarabine + VEN between January 2018 and May 2023 in 10 Spanish centers. Baseline characteristics and infectious episodes [presented as Microbiologically Documented Bacterial Infections (MDBI) or Clinically Documented infections without Isolation (CDI)], or febrile neutropenia without isolation or focus (FN) were recorded. Confirmed or suspected infections of parasites/fungi/viruses were excluded in this study. For each event, antibacterial prophylaxis, days of hospitalization, severity, disease status and dead due to infectious events/FN were collected. Results: In total, 165 patients have been included (clinical characteristics summarized in Table 1). VEN was initially used as 28 days/cycle and it had to be adjusted in 78 (48.75%) patients, mainly due to cytopenias and infections. The univariate analysis showed that infectious events and FN occurred more frequently in patients with high ELN risk than in those with Intermediate/favorable (OR; 2.71, 95% CI; 1.03-7.11, p = 0.041). In our cohort, 175 infections (MDBI/CDI) or FN occurred in 113 patients (68.5%) with an incidence of 26.1/100 cycles. These episodes correspond to 70 (40%) cases of MBI, 59 cases of CDI (33.7%) and 46 (26.3%) cases FN, with a median of 1 episode per patient (range 1-5). Most events occurred in the first (85; 48.9%) and second cycle (43; 24.7%) with a median of cycles at the moment of the event of 2 (p25-p75: 1-3) and a median time from VEN start to episode of 44 days (p25-p75: 18-105) because infections/FN usually led to delays on subsequent cycles. Considering the total number of events in patients with at least first disease evaluation available at the time of infection, only 48 (31%) had cytologic response (&amp;lt;5% blasts). Table 1 shows type of episode/isolation/focus. Antibacterial prophylaxis was used in 48 patients (29.5%), primarily with quinolones (levofloxacin 74%, ciprofloxacin 23%) according to physician decision. Incidence of infections (MDBI/CDI) or FN was lower in patients with antibacterial prophylaxis (OR; 0.37, 95% CI; 0.18-0.74, p = 0.05). Additionally, the median number of infections was lower in prophylaxis group (0.77 vs 1.18; p= 0.004). However, no differences were observed between both groups regarding hospitalization incidence or infection severity (defined as need of vasoactive drugs, high-flow oxygen therapy or deaths caused by the infectious episode). Microbiological isolations were significantly higher in non-prophylaxis group with infections (45.6% vs 23.7%, p 0.015). Incidence of multidrug-resistant organisms was 10.2% among all patients, with no differences between groups neither in Clostridioides difficile incidence (3.6%). In the competitive risk survival analysis, cumulative incidence of death from MBI/CDI or FN cause showed no differences between patients receiving or not antibacterial prophylaxis ( p= 0.98) (Figure 1). Conclusions: Our data suggest that avoiding antibacterial prophylaxis in non-intensive VEN-based treatments may result in a higher incidence of FN and infectious events, but it does not lead to impaired outcomes in terms of severity and/or mortality related to infections. Having a greater availability of microbiological isolations could enable more targeted antibiotic therapy, avoiding drug resistance. Additional data from the prophylaxis cohort will be included in the presentation.

Long-term prognostic significance modified body mass index in patients with decompensated acute heart failure: Insight from the OPAR study

Abstract Background/Introduction Malnutrition is a well-known poor prognostic factor in patients with acute decompensated heart failure (ADHF). Although conventional body mass index (cBMI) and serum albumin level are commonly used as indicators of malnutrition, these values are affected by fluid balance. The recently proposed modified BMI (mBMI, serum albumin [g/l] × cBMI [kg/m2] ) may be a better prognostic marker, but its usefulness in patients with ADHF remains unclear. Purpose This study aimed to investigate the prognostic significance of mBMI in patients hospitalized for ADHF. Methods The OPAR study is a single-center registry enrolling 605 consecutive patients who were admitted for ADHF with survival discharge between October 2011 and October 2017. The present study population was consisted of 573 patients admitted for ADHF who had a value of cBMI and serum albumin at discharge. The eligible patients divided into the following four groups according to the mBMI quartiles: lowest quartile (Q1, mBMI &amp;lt;600, n = 144), second quartile (Q2, 600≤ mBMI &amp;lt;715, n = 144), third quartile (Q3, 715≤ mBMI &amp;lt;842, n = 142), and highest quartile (Q4, mBMI ≥842, n = 143). The primary outcome measure was all-cause death, and the second outcome measures were cardiac death, non-cardiac death, and heart failure rehospitalizations. Cumulative incidences of death and heart failure rehospitalizations were estimated by the Kaplan-Meier and Gray’s method, respectively. Cox proportional hazards regression models were used to identify patients at risk of all-cause death to calculate the multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). The predictive power of mBMI for all-cause mortality was assessed using receiver operator characteristic curve analysis. Results During a median follow-up period of 4.68 years (interquartile range, 2.16–6.72 years), the cumulative 5-year incidences of all-cause death substantially increased in the lower mBMI quartiles (Q1: 60.7% [95% CI, 52.5%–68.9%], Q2: 53.9% [95% CI, 45.7%–62.5%], Q3: 38.8% [31.1%–47.7%], and Q4: 21.3%[15.3%–29.2%], log-rank P &amp;lt;0.001). After adjustment for the potential confounders, the excess risk of Q1 relative to Q4 for all-cause death tended to be higher (adjusted HR, 1.44 [95% CI, 0.94–2.20], P = 0.09). The predictive power of mBMI was modest with a C-statistic of 0.65 (95%CI, 0.61–0.70). The cumulative 5-year incidence of cardiac death and non-cardiac death also increased in the lower mBMI quartiles (Q1: 29.1% and 44.5%, Q2: 18.9% and 43.1%, Q3: 21.3% and 22.3%, and Q4: 7.2% and 15.2%, respectively, log-rank P &amp;lt;0.001 for both). The cumulative 5-year incidences of heart failure rehospitalizations did not significantly differ across the mBMI quartiles (P = 0.35). Conclusions The mBMI at discharge is a simple and potentially helpful marker for the prediction of long-term mortality in patients hospitalized for ADHF.Primary outcomeSecondary outcome

Mortality and predictors of death in women and men with congestive heart failure due to ischemic and nonischemic cardiomyopathy

Abstract Background Heart failure (HF) is one of the leading causes of death from cardiovascular disease. Studies have shown that women have better survival than men, despite the higher number of hospitalizations among women. However, little is known about differences in mortality and predictors of death in women and men with heart failure due to ischemic (iCMP) and nonischemic (niCMP) cardiomyopathy. Purpose To analyze the mortality and predictors of death in women and men with iCMP and niCMP cardiomyopathy. Methods From February 2017 to September 2020, we analyzed mortality and predictors of death in women and men with CHF by iCMP and niCMP. Baseline data included clinical features and echocardiographic findings. Statistical analyses were performed using the Kaplan-Meier (K-M) method and Cox proportional hazards methods to analyze mortality rates in women and men. We used the Score Chi-Square of Cox regression to search for death predictors for women and men. Results We studied 7,487 patients, mean age of 64.3 ± 14.2 years, 4,417 (59%) males. Women with iCMP and niCMP had, respectively, higher mean age (p&amp;lt;0.0001), higher mean left ventricular ejection fraction (LVEF) (p&amp;lt;0.001), and smaller left ventricular diastolic diameter (LVDD) (p&amp;lt; 0.001). The mean dose of carvedilol was similar in both genders for iCMP and niCMP. Over a 3-year follow-up period, 420 (15.7%) men and 325 (14.7%) women with niCMP died (p=NS), and in iCMP, 519 (29.8%) men and 211 men died. (24.5%) women (p=0.004). Higher mortality was observed in women with iCMP compared to men with iCMP (p&amp;lt;0.0001). The cumulative incidence of death was higher in men (K-M: log-rank p&amp;lt;0.0001) with iCMP, but similar for niCMP (Figure). Cox regression for death adjusted for age, sex, previous myocardial infarction (MI), diabetes, previous stroke, chronic kidney disease (CKD), atrial fibrillation (AF), HF phenotype (systolic, diastolic, or mildly reduced ejection fraction), and LVEF showed that CKD, AF, diabetes, stroke, LVEF, and age, in descending order of Score Chi-Square, were the main predictors of death for niCMP and CKD, stroke, diabetes, AF, LVEF, age, and MI for iCMP. Conclusions Women had a better prognosis than men in iCMP, but similar mortality in niCMP. Gender was not an independent variable of death. Secondary prevention of cardiovascular events from the main predictors of death can significantly reduce the death rate in women and men with CHF by iCMP and niCMP.