Very-high Risk Research Articles

Assessment of the urban waterlogging resilience and identification of its driving factors: A case study of Wuhan City, China

With rapid urbanization and extreme rainstorm events associated with climate change, urban waterlogging has become one of the most frequent and severe disasters globally. In this study, a multi-dimensional and multi-process index system based on the Pressure-State-Response (PSR) framework was developed to measure the level of urban waterlogging resilience (UWR). The spatial distribution of UWR on a block scale was explored based on the entropy weight method with the natural breakpoint method (EWM-NBM) in the central district of Wuhan City, China. In addition, the effects of the runoff control facilities and early warning measures on UWR were also quantified. Further, the Geodetector was used to investigate the main driving factors of UWR and their interactions. Results showed that the constructed index system for UWR based on the PSR framework performed reasonably, and the EWM-NBM was validated to be effective in the integrated assessment. In terms of the validation results, 82.72 % of the recorded waterlogging points belonged to high and very-high risk levels. The spatial heterogeneity of UWR was significant in the study area where the higher-level UWR mainly appears in the areas near the undeveloped suburban and water bodies (lakes and rivers), and the lower-level UWR was concentrated in central urban areas with more impervious surfaces. There was a clear increasing trend in UWR after the implementation of runoff control facilities and early warning measures, but its spatial distribution remained almost invariant. Among all the indexes, the impervious surface percentage had the strongest (69.58 %) explanatory ability for the UWR, and mean annual precipitation (15.51 %), GDP (14.03 %), and population density (11.98 %) also demanded attention. Most driving factors of UWR showed nonlinear interactions. This research could provide a benchmark for urban planning to enhance UWR to mitigate the waterlogging within the main urban area.

Missing the mark -- new methods needed to detect and address high-risk pesticide residues in the global food supply

The primary metric used by regulators to track whether pesticide residues in food pose worrisome risks is the percent of samples tested in a given year that contain residues above applicable tolerances in the US and Maximum Residue Limits (MRLs) in most other countries. The Dietary Risk Index (DRI) system is used to determine the degree to which current policies governing allowed pesticide residue levels in food are keeping high-risk residues out of the global food supply. Residue data generated by the US Pesticide Data Program (PDP) and UK-Food Standards Agency (FSA) are utilized. Over the last 10 years 2449 samples of food have contained violative residues over applicable tolerances or MRLs. Of these, about 60% posed low or very-low dietary risks relative to acceptable dietary intake levels set by regulators. Conversely, only about 4% of high- and very-high risk samples tested by the US-PDP contained residues above the applicable tolerance. Accordingly, current US and UK policies are failing to flag most high-risk samples and are triggering more intense scrutiny and/or adverse regulatory actions in the case of many samples posing low or very-low risks. Recommendations are offered to enhance the ability to track and incrementally reduce pesticide dietary risks.

S-11-2: AORTIC PULSE WAVE VELOCITY AND CARDIOVASCULAR RISK

Aortic pulse wave velocity (PWV), which can be non-invasively approached by measuring carotid-femoral (cf) PWV, but also to a certain degree by measuring brachial-ankle (ba) PWV, is currently thought to be the gold standard assessment of aortic / large artery stiffness, an important physical property of the arterial system. The assessment of cfPWV/baPWV can be recommended at several stages in the cardiovascular continuum: + Primordial and primary prevention: cfPWV/baPWV increase the risk of incident hypertension and diabetes mellitus (thus, cardiovascular (CV) risk) in apparently healthy adolescents and young and middle aged adults. + Patients with arterial hypertension: Increased PWV is associated with masked hypertension and is the most prevalent measure of hypertension-mediated organ damage (which is, in turn, an important marker of increased CV risk in patients with hypertension) + Patients with diabetes mellitus: PWV is associated with CV and renal complications in patients with type 1 and type 2 diabetes (and, thus, with very high CV risk in these patients). + Young and middle-aged patients up to their 60ies with intermediate CV risk: Increased cfPWV/baPWV can reclassify CV risk in many of these patients, which was confirmed in a metaanalysis including individual participant data of 17.635 patients of 16 observational studies. Associations stratified by sex, diabetes and hypertension were similar, but decreased with age. Adding cfPWV to the traditional CV risk estimation method resulted in net reclassification indices of 25%, 10%, 13% and 11% for 10-year CV mortality, CHD events, CVD events, and stroke events, respectively. In a large meta-analysis including individual participant data of 14.673 Japanese participants (mean age 59–66 years) from 8 cohort studies without a history of CV disease, similar findings were reported for baPWV. Addition of baPWV to a model incorporating the Framingham risk score (FRS) significantly improved the category-free net reclassification (0.247). Finally, improvement in PWV over a few years is associated with improved prognosis. Although no randomised study so far has proven a reduction of CV events, based on a PWV driven strategy (as compared to a strategy based on traditional CV risk factors), prevention of the normal age-related increase in PWV has been shown recently in the SPARTE study. Furthermore, it is reasonable to treat high and very-high risk patients, detected by measurement of PWV, according to the respective risk category in current prevention guidelines.

1075 USE OF LIPID-LOWERING COMBINATION THERAPIES IN SANTORINI STUDY: EVIDENCE FROM ITALIAN COHORT

Abstract The SANTORINI registry is an observational study that aims to evaluate the management of patients with high and very high cardiovascular (CV) risk in clinical practice, collecting data at enrolment and after 12 months. Italy participated in this study with 1531 patients at very high risk and 446 at high risk. The scope of the present analysis was to investigate low-density lipoprotein cholesterol (LDL-C) goal attainment in patients who do not qualify for PCSK9 inhibitors (PCSK9i) (according to Italian reimbursement regulations) in Italian cohort, with focus on patients in secondary prevention. The current indications for PCKS9i charged to the National Health System in Italy in secondary prevention, are for patients aged ≤ 80 years with LDL-c levels ≥ 70 mg/dl in at least three detections despite therapy for at least 6 months with high intensity statin at the highest tolerated dose and ezetimibe or after a single LDL-C detection for recent myocardial infarction or multiple cardiovascular events or with demonstrated intolerance to statins and/or ezetimibe. At enrolment, a total of 509 (33.2%) of 1531 patients at very-high risk had an LDL-C level of less than 70 mg/dl. Of them, about half do not reach the LDL-C target. In particular, 34.4% takes statin monotherapy, and 50.3% of them do not reach the target. Even patients taking high-intensity statins as monotherapy reach the target in only 47.9% of cases, leaving more than half of patients with LDL-C levels between 55 and 70 mg/dl. Regarding combination therapy, statin and ezetimibe, patients taking this combination account for 26.9%, of these those taking the combination of moderate-intensity statin and ezetimibe reach the target in 56.7% of cases while those taking high-intensity statins and ezetimibe reach the target in 51.4% of cases. Our findings show that there is a proportion of patients with LDL-C below 70 mg/dl who do not qualify for PCSK9i who are not at target for LDL-C levels despite maximal therapy with statins and ezetimibe.

Undertreatment and Underachievement of LDL-C Target among Individuals with High and Very High Cardiovascular Risk in the Malaysian Community.

Dyslipidaemia is a major cause of morbidity and mortality. The aims of this study are to determine the prevalence of dyslipidaemia subtypes, the proportions of lipid-lowering therapy (LLT) use, and the achievement of low-density lipoprotein cholesterol (LDL-C) treatment targets for high-risk (HR) and very high-risk (VHR) Malaysians. This cross-sectional study involves 5279 participants across 11 states in Malaysia. The data were obtained through a standardised questionnaire, anthropometric measurements, venous glucose and lipid profile. The participants with existing cardiovascular disease (CVD) or diabetes with at least one of the other major risk factors (smoking, hypertension or dyslipidaemia) were grouped into the VHR category. Other participants were risk-categorised using the Framingham General CVD Risk Score (FRS-CVD). The prevalence of elevated LDL-C, LLT use and LDL-C target were set according to respective risk categories. Pearson's chi-squared test was used to test the difference in the proportions. The mean ± standard deviation (SD) age was 41.1 ± 14.8 years, and 62.2% (3283/5279) of the group were females. Within the participant group, 51.5% were found to have elevated total cholesterol, 28.8% had low HDL-C, and 33.8% had high triglyceride. As for elevated LDL-C, 9.8% were in VHR, 8.6% in HR, 5.8% in MR and 34.9% in LR categories. Among the VHR group, 75.8% were not on LLT, and only 15.9% achieved the LDL-C target. As for the HR category, 87.7% were not on LLT, and only 16.1% achieved the LDL-C target. Dyslipidaemia is highly prevalent among Malaysians. The majority of VHR and HR participants were not on LLT and did not achieve LDL-C treatment targets. Proactive programs are warranted to combat dyslipidaemia-associated CVD events in these groups.

Implantable cardiac monitor after ischemic stroke – a case report in the context of current guidelines

Long-term cardiac rhythm monitoring using implantable cardiac monitors in patients with ischemic stroke has been described both in cardiac and neurological clinical practice guidelines. We present a case study describing the clinical decision-making process that led to the diagnosis of atrial fibrillation in a very-high risk patient and the initiation of a proper treatment.

HSD14 Lacking Observance of the Guidelines on Dyslipidaemias as Possible Reason for Low LDL-C Goal Attainment in Patients at High and Very High Cardiovascular Risk

Several studies have clearly demonstrated the causative role of increased plasma concentrations of LDL-C in the process of atherosclerotic plaque formation. These findings have been reflected in the updated guidelines for the management of dyslipidaemias, proposing new stringent LDL-C goals and treatment algorithm. Although the evidence is quickly translated into the guidelines, there still exists a large gap between recommendations and real clinical practice. The objective of the study was to investigate the adherence of Czech cardiologists to the dyslipidaemias guidelines, especially in the management of patients with high- and very-high cardiovascular risk.

External Validation of the Skin and UV Neoplasia Transplant Risk Assessment Calculator (SUNTRAC) in a Large European Solid Organ Transplant Recipient Cohort

The Skin and UV Neoplasia Transplant Risk Assessment Calculator (SUNTRAC) tool has been developed in the US to facilitate the identification of solid organ transplant recipients (SOTRs) at a higher risk of developing skin cancer. However, it has not yet been validated in populations other than the one used for its creation. To provide an external validation of the SUNTRAC tool in different SOTR populations. This retrospective external validation prognostic study used data from a prospectively collected cohort of European SOTRs from transplant centers at teaching hospitals in the Netherlands (1995-2016) and Spain (2011-2021). Participants were screened and followed up at dermatology departments. Data were analyzed from September to October 2021. The discrimination ability of the SUNTRAC tool was assessed via a competing risk survival analysis, cumulative incidence plots, and Wolbers concordance index. Calibration of the SUNTRAC tool was assessed through comparison of projected skin cancer incidences. Skin cancer diagnoses included squamous cell carcinoma, basal cell carcinoma, melanoma, and Merkel cell carcinoma. A total of 3421 SOTRs (median age at transplant, 53 [quartile 1: 42; quartile 3: 62] years; 2132 [62.3%] men) were assessed, including 72 Asian patients (2.1%), 137 Black patients (4.0%), 275 Latinx patients (8.0%), 109 Middle Eastern and North African patients (3.2%), and 2828 White patients (82.7%). With a total of 23 213 years of follow-up time, 603 patients developed skin cancer. The SUNTRAC tool classified patients into 4 groups with significantly different risks of developing skin cancer during follow-up. Overall, the relative rate for developing skin cancer estimated using subdistribution hazard ratios (SHRs) and using the low-risk group as the reference group, increased according to the proposed risk group (medium-risk group: SHR, 6.8 [95% CI, 3.8-12.1]; P < .001; high-risk group: SHR, 15.9 [95% CI, 8.9-28.4]; P < .001; very-high-risk group: SHR, 54.8 [95% CI, 29.1-102.9]; P < .001), with a concordance index of 0.72. Actual skin cancer incidences were similar to those predicted by the SUNTRAC tool (5-year skin cancer cumulative incidence for medium-risk group: predicted, 6.2%; observed, 7.0%). The findings of this external validation prognostic study support the use of the SUNTRAC tool in European populations for stratifying SOTRs based on their skin cancer risk and also detecting patients at a high risk of developing skin cancer. This can be helpful in prioritizing and providing better screening and surveillance for these patients.

Correlation of Minimal Residual Disease (MRD) at the End of Induction (EOI) and Event Free Survival (EFS) in T-Cell Lymphoblastic Lymphoma (T-LL), a Report from the Children's Oncology Group (COG) Trial AALL1231

Background: Defining prognostic variables that correlate to EFS in T-LL remains a clinical challenge. Traditional variables such as stage or radiologic response to therapy have failed to correlate with EFS in recent trials. AALL1231 was a COG phase 3 clinical trial for newly diagnosed with T Acute Lymphoblastic leukemia (T-ALL) or T-LL patients that randomized children and young adults (age 1-30 years) to a modified augmented BFM (aBFM) backbone with no bortezomib (Arm A) or with bortezomib (Arm B) during induction and delayed intensification (DI) (1.3mg/m2 x 4 doses per block). T-LL patients were stratified as standard (SR), intermediate (IR), or very high risk (VHR), based upon minimal detectable disease (MDD) in the bone marrow at diagnosis, prior steroid pre-treatment and radiographic response at the end of induction. Bone marrow (BM) samples to assess MRD by flow cytometry at the EOI were an optional submission for T-LL participants and those collected were analyzed to assess its correlation to EFS. Results: AALL1231 accrued 209 T-LL patients from 2014 until closure in 2017. At the end of induction, 43.6% were in radiologic remission, 55.4% had a partial response and 1% had stable disease or no response. There were 86 (41%) patients for whom EOI samples for MRD assessment were submitted. Patients with MRD <0.1% (n=75) at EOI had a superior EFS versus those with MRD >0.1% (n= 11), (89.0 + 4.4% verses 63.6 + 17.2%, p= 0.025). Overall survival did not significantly differ between the two groups (88.9 + 4.4% versus 72.7 + 15.5% p= 0.15). As previously reported, Arm B demonstrated a superior outcome for both EFS and OS for the entire cohort. Within risk groups, IR and SR patients had similar EFS outcomes (Arm A 73.9 + 7.5% versus 80.4 + 6.7, Arm B 87.2 + 5.8 % versus 90.5 + 4.8%) with only two patients the VHR, both in Arm B. Cox regression for EFS using Arm A as a reference demonstrated that MRD EOI ≥0.1% was associated with a greater risk of inferior outcome (Hazard Ratio, HR = 3.73 (1.12-12.40, p = 0.032), (Table 1) which was independent of treatment arm assignment. OS failed to reach statistical significance for patients MRD EOI ≥0.1%, HR = 2.714 (0.72-10.44, p=0.14). Furthermore, Cox regression failed to demonstrate a superior EFS with decreasing MDD at diagnosis (>5% versus 1-5%, versus <1%), HR=2.67 (0.336-21.145, p=0.141, HR= 0.830 (0.255-2.699, HR= 0.57 (0.289-1.073, p= 0.080)(Table 2). Conclusions: In this pediatric T-LL trial, BM EOI MRD by flow cytometry was associated with improved EFS in in both arms (+/- bortezomib) in both univariate and multivariate analyses. In contrast, race, age, gender, risk group, MDD, stage and radiologic response to therapy were not prognostic. Consideration to incorporate MRD at EOI into the design of future trials will establish its value in defining risk groups for subsequent therapeutic trials. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Outcomes of Myelofibrosis Patients in the Era of Using JAK2 Inhibitor with Allogeneic-HSCT at the University of Southern California

Introduction: In myelofibrosis (MF) patients, the standard of care curative option is with allogeneic-hematopoietic stem cell transplantation (allo-HSCT) but no clear standard of care pre- and post-allo-HSCT management exists. Questions then arise such as whether use of JAK inhibitors pre- or post-transplant lead to better outcomes. In addition, further elucidation of patient characteristics/risks/response are needed due to scarcity of data post-transplant. In this study, we aim to provide further data concerning this field. Methods: This retrospective chart review included patients aged 18 years with MF diagnosed in 2012-2020 and received allo-HSCT at our institution. Primary objectives include over-all survival (OS) and progression-free-survival (PFS) since transplant, stratified by risk, peri-transplant JAK2 inhibitor use and conditioning + associated graft versus host disease prophylaxis (GVHD ppx) use. Secondary objectives include patient/treatment/transplant characteristics, response, survival and GVHD rates. Two-sided p value ≤ 0.05 was significant. RESULTS: 21 screened MF patients received allo-HSCT at our institution, median age 61.1 years (85.7% non-Hispanic and 14.3% Hispanic). 71.4% had primary MF. 9.5% had unfavorable/high risk karyotype/cytogenetics with 38.1% at high risk per Dynamic International Prognostic Scoring System (DIPSS) Plus, and 38.1% high risk, 28.6% very high-risk per Mutation-Enhanced International Prognostic Score System (MIPSS) 70+ v2.0. 52.4% had JAK2 V617F mutation, 28.6% triple negative (lacked JAK2/MPL/CALR mutations) with 23.8% as having any positivity in either ASXL1, EZH2, SRSF2, IDH1/2 and U2AF1 mutations. Pre-transplant, 100% had pancytopenia requiring transfusions. 9.5% had CR/PR, 42.9% had PD and 47.6% had SD. Of note, 57.9% had any peri-transplant JAK2 inhibitor use (defined as use within 3 months pre- and post-transplant) with or without other MF related-treatments. 33.3% underwent MSD, 38.1% MUD and 28.6% underwent HAPLO allo-HSCT. 80% had reduced intensity conditioning (RIC) with an equal distribution of fludarabine-based regimens. In terms of GVHD ppx, 55% received tacrolimus+ methotrexate and 35% had post-transplant cyclophosphamide (PTCY). 30% underwent HAPLO + PTCY. In terms of outcomes and adverse events, pancytopenia improved from 90.5% at d+30 to 57.1% at d+365. Transfusion dependency decreased from 60% from d+90 to 26.7% by d+365. None had leukemic transformation. Clinical improvement rates increased from 33.3% d+30 to 78.6% by d+365. CR/PR rate increased from 5% at d+90 to 28.6% at d+365. 14.3% had relapsed/PD, 37.5% had primary graft failure with 33.3% any deaths post allo-HSCT. 42.9% had any acute GVHD pre-d+100, 42.1% had any chronic GVHD post d+100. Of note, 100% of our population were alive at d+100, and 78.9% alive by d+365. Since transplant, 3y OS was 62.6%, 3y EFS at 59.2% with corresponding worsening of OS/EFS with higher DIPSS (p=0.19-0.33) and a 3y OS (40%) (p=0.29) and EFS (40%) (p=0.41) in patients with very-high risk per MIPSS 70+ v2.0. With peri-transplant JAK2 inhibitor use, 3y OS was 56.8% vs 75% without; 3y EFS was 51.1% vs 75% without (p=0.33-0.51) (Fig.1). For patients who underwent HAPLO+PTCY GVHD ppx, OS and EFS reached at 16 months while patients who underwent non-HAPLO+ any GVHD ppx did not reach their median OS yet and achieved an EFS median of 57 months. 2y OS and EFS was at 50% for those who underwent HAPLO+PTCY vs a 67.1% OS and a 61.9% EFS for those who had non-HAPLO+ any GVHD ppx (p=0.51-0.72) (Fig.2). CONCLUSIONS: Given that most of our patients had high/very high-risk scores, we achieved a good rate of clinical improvement with less transfusion dependency. A good survival rate was also achieved (100% survival at d+100 and 78.9% at 1y). Our 3y OS of 62.6% and 3y EFS of 59.2% is also appreciable even with the rates of GVHD. Our data also further supports that having a higher risk score per DIPSS/MIPSS leads to poorer survival. Interestingly, there may be no difference in OS/EFS with peri-transplant JAK2 inhibitor use. Also, those who underwent HAPLO+PTCY had their median OS/EFS reached first (16 months) with a possible lower survival trend compared to those who underwent MSD/MUD + any GVHD ppx combination treatment. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Subjects with Chronic Myeloid Leukemia Identified As Intermediate- or High-Risk Subjects Using the Imatinib Therapy Failure (IMTF) Model Benefit from Initial Therapy with a Second-Generation Tyrosine Kinase Inhibitor

Objective Validate the imatinib therapy failure (IMTF) model in 3,752 subjects with chronic phase chronic myeloid leukemia (CML) receiving initial imatinib therapy, and further test prediction accuracy in 1,353 persons receiving initial a second-generation tyrosine kinase inhibitor (2G-TKI). Compare the cumulative incidences of therapy failure in each IMTF risk cohort between initial imatinib and a 2G-TKI therapy. Methods Data from 1,356 consecutive subjects with chronic phase CML receiving initial imatinib therapy at one centre (Beijing, China) were interrogated as an internal dataset and compared with results in 2,396 similar subjects from 65 other centers in China, an external dataset to validate the IMTF model (https://www.nature.com/articles/s41375-022-01527-y.) The IMTF model divided subjects into the very low-, low-, intermediate-, high- and very high-risk cohorts. Data from 1,353 subjects receiving initial 2G-TKI therapy were also interrogated using the IMTF model to extensionally test predictive performance. Propensity score matching (PSM) was used to adjust the differences in baseline co-variates between subjects receiving initial imatinib or a 2G-TKI. Results In the imatinib internal validation dataset, 467 (34%), 263 (19%), 302 (22%), 219 (16%) and 105 (9%) subjects were classified as the very low-, low-, intermediate-, high- and very high-risk cohorts. 5-year cumulative incidences of therapy-failure were 7% (95% Confidence Interval [CI] 4, 9%), 19% (15, 23%), 33% (29, 37%), 52% (46, 58%) and 78% (67, 89%; p < 0.001; Figure 1A). Hazard ratios (HRs) (very low-risk cohort as reference) were 2.6 (1.7, 4.0; p < 0.001), 4.3 (2.9, 6.3; p < 0.001), 6.4 (4.3, 9.5; p < 0.001) and 11.3 (7.5, 17.2; p < 0.001; p for trend < 0.001; Figure 1B). In the imatinib external validation dataset, 575 (24%), 589 (24%), 696 (29%), 420 (18%) and 116 (5%) were classified as the very low-, low-, intermediate-, high- and very high-risk cohorts. 5-year cumulative incidences of therapy-failure were 9% (7, 11%), 21% (16, 26%), 36% (25, 47%), 41% (33, 50%) and 58% (46, 70%; p < 0.001; Figure 2A). HRs (very low-risk cohort as reference) were 2.0 (1.5, 2.8; p < 0.001), 4.0 (3.0, 5.3; p < 0.001), 4.9 (3.6, 6.6; p < 0.001) and 6.9 (4.8, 9.9; p < 0.001; p for trend < 0.001; Figure 2B). In the internal 2G-TKI dataset, 74 (24%), 55 (18%), 67 (21%), 69 (22%) and 44 (15%) subjects were classified as the very low-, low-, intermediate-, high- and very high-risk cohorts. 5-year cumulative incidences of therapy-failure were 10% (4, 15%), 15% (3, 27%), 19% (5, 33%), 36% (13, 59%) and 63% (44, 82%) (p < 0.001; Figure 3A). There were no significant differences in therapy failure among the cohorts except those in the high- and very-high risk. In the external 2G-TKI dataset, 287 (27%), 227 (22%), 284 (27%), 179 (17%) and 67 (7%) subjects were classified very low-, low-, intermediate-, high- or very high-risk cohorts. 5-year cumulative incidences of therapy-failure were 3% (0, 6%), 10% (4, 16%), 18% (6, 31%), 24% (12, 36%) and 52% (25, 79%; < 0.001; Figure 3B). In PSM analyses, subjects in the intermediate- and high-risk cohorts in the 2G-TKI internal dataset receiving initial 2G-TKI therapy had significantly lower cumulative incidences of therapy-failure compared with those receiving initial imatinib therapy (p = 0.038 and 0.018) whereas therapy-failure was similar in the very low-, low- and the very high-risk cohorts (p = 0.42 - 0.47, Figure4A-4E). Similar results were obtained in the 2G-TKI external dataset (Figure4F-4J). Conclusions The IMTF model accurately predicts therapy failure in persons receiving initial imatinib therapy and in those receiving initial 2G-TKI therapy. Subjects identified as intermediate- and high-risk using the using the IMTF model might benefit from initial 2G-TKI therapy whereas those in lower risk cohorts might not. If further validated by randomized controlled trial (in process), our data on preferred initial therapy should help physicians optimize TKI-therapy strategy in persons with chronic phase CML. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

ATG-Ptcy-CSA for Gvhd Prevention in Peripheral Blood Haploidentical Hematopoietic Cell Transplantation for Adults with Hematological Malignancies

INTRODUCTION The introduction of post-transplant cyclophosphamide (PTCY) for GVHD prevention can be considered a milestone in haploidentical hematopoietic cell transplantation (haplo-HCT). And secondary to its efficacy, the use of haplo-HCT with peripheral blood stem cell (PBSC) grafts has significantly increased in last decade. However the optimal immunosuppressive agents to combine with PTCY using peripheral blood stem cell (PBSC) sources is still a matter of debate, as in a retrospective analysis conducted by CIBMTR using PBSC grafts and PTCY-based GVHD prophylaxis in the haplo-HCT setting, was associated with higher rates of acute and chronic GVHD than with using bone marrow stem cell grafts. PTCY-based prophylaxis is considered a standard of care when haploidentical donors are selected. PTCY combined with anti-thymocyte globulin and cyclosporine (PTCY-ATG-CsA) became our institutional GVHD prophylaxis for peripheral blood (PB) haplo-HCT in 2015. The present analysis aims to share updated information about our experience using ATG-PTCY-CsA for GVHD prevention in PB haplo-HCT. METHODS Between October 2015 to December 2021, 157 consecutive adults underwent haplo-HCT at our institution and were included in the study. The GVHD prophylaxis was composed of rabbit-ATG (Thymoglobulin; Genzyme-Sanofi, Lyon, France), PTCy (50 mg/kg/day on days +3 to +4), and CsA (started on day +5 and titrated to therapeutic levels ranging between 200 and 400 ng/ml). One hundred twenty (76.4%) adults received a total dose of 4.5mg/kg of ATG (0.5 mg/kg on day -3, 2 mg/kg on day -2 and 2 mg/kg on day-1), and 37 (23.5%) received 2 mg/kg (0.5 mg/kg on day -2 and 1.5 mg/kg on day -1). T-cell replete PBSC grafts were infused on day 0 in all cases. Data was collected retrospectively and updated in March 2022. To perform regression analyses, post-transplant follow-up was censored at 2 years. RESULTS Of the 157 patients, the median age was 57 years (range: 43-66), and 67 (44%) were 60 years or older. Sixty-four (44%) patients were females. Acute myeloid leukemia was the most prevalent baseline diagnosis (n=79, 50.3%), and 38 (24.2%) patients received myeloablative conditioning (MAC) regimens. Forty-six (30%) adults had a KPS ≤80%, 46 (30%) had an HCT-CI score >3, and 34 (23.4%) had a high or very-high disease risk index (DRI). Fresh products were infused in 90 (57.32%) cases. A total of 152 patients achieved engraftment. The median time for neutrophil and platelet engraftment were 17 (IQR 19-15) and 22 days (IQR: 12-28). The cumulative incidence function (CIF) of bloodstream infection at day +28 was 51.6%. The day +180 CIF of CMV and EBV reactivations were 62.5% and 65.4%, respectively, and 5 (3.2%) patients had post-transplant lymphoproliferative disorder. The CIFs of grade II-IV and grade III-IV acute GVHD estimated at day +100 were 26.3% and 9.5%, and the CIF of moderate/severe cGVHD at 1 year was 19.9%. As reported in Table 1, the use of MAC regimens (HR 2.70), the administration of 2 mg/kg of ATG (HR 4.42, P=0.003) and the selection of donors older than 40 years (HR 3.35, P=0.011) increased the risk for grade III-IV aGVHD. The infusion of frozen products was not found to be predictor for GVHD. Nevertheless, a non-significant trend to lower grade II-IV aGVHD was documented in patients receiving frozen PBSC grafts (HR 0.54, P=0.060). The median follow-up in survivors was 32 months. Overall, 73 (46.5%) patients died, and 28 (17.3%) relapsed. The leading causes of death were infection and relapse. The median of days to discontinuation of the immunosuppression in survivors was 83 days (IQR: 69-119). As shown in Figure 1, the estimated 2-year OS, RFS, NRM, CIR, and GRFS were respectively: 49.4%, 44.6%, 36.6%, 18.8%, and 35.7%. The multivariate regression analysis reported n Table 1 showed that older patients and those with high and very-high DRI were at higher risk for worse OS and higher NRM. CONCLUSION Dual T-cell depletion using PTCy and ATG (total dose of 4.5mg/kg) combined with CsA is a safe drug combination for PB haplo-HCT. The use of this prophylaxis provided an effective GVHD prevention with acceptable relapse rates. Moreover, the selection of younger donors, and the use of a total dose of 4.5mg/kg of ATG increased the effectiveness of GVHD prevention. Further research is needed to decrease rates of NRM for patients undergoing haplo-HCT using this prophylaxis. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Differences in Clinical Course and Management of Sars-CoV2 Infection in Patients with Chronic Lymphocytic Leukemia between the Sequential Pandemic Phases: An Eric Study

BACKGROUND. Infection by SARS-CoV2 remains a worldwide health burden. Previous studies by the ERIC (European Research Initiative on CLL) showed that patients with chronic lymphocytic leukemia (CLL) have a very-high risk of severe Coronavirus disease 19 (COVID19). In particular, age, CLL-directed treatment, and cardiac failure were identified as significant risk factors of overall survival (OS). Since the beginning of 2020 different treatment strategies have been used to fight COVID19 and different SARS-CoV2 variants alternated during the pandemic, however very few studies analyzed their impact on patients with CLL. AIMS. The aims of this study were to investigate different manifestations, treatments and outcome of COVID19 in patients with CLL/SLL (small lymphocytic lymphoma), and MBL (monoclonal B-cell lymphocytosis). METHODS. This is a retrospective international multicenter ERIC study from Jan 2020 till May 2022. CLL diagnosis, COVID-19 management, review of medical history, and assessment of patient status were performed by local investigators following international guidelines. Ninety institutions participated in the study. Statistical analyses were conducted using R software. During the pandemic we identified 4 phases: 1st Jan 2020 - Jun 2020, 2nd Jul 2020 - Feb 2021, 3rd Mar 2021 - Dec 2021 and 4th Jan 2022 - May 2022. RESULTS. We gathered data from 1540 patients (93.8% CLL, 4.1% SLL and 2.1% MBL), 65% males, the median age at COVID19 was 69 years, median CIRS score was 4 (IQR 2-7), 49.6% were treated in the last 12 months before COVID19, 38.8% was on treatment at COVID19 onset (BTK inhibitor-based 51.1%, BCL2 inhibitor-based 20.7%, chemo/chemoimmunotherapy 21.5%, 6.7% others). Overall, 34.4% of patients was managed at home, 49.9% needed hospitalization and 15.7% was admitted to the intensive care unit (ICU). After a median follow-up of 2.7 months, the infection was resolved in 1124/1540 (73%) cases, while 23% died and 3.6% were still under medical observation. Distribution of patients among time is shown in Fig. 1A. Three hundred and four (19.8%) patients were infected during the 1st, 737 (48%) during the 2nd, 137 (8.9%) during the 3rd and 357 (23.3%) during the last 4th phase. Comparing the features of patients infected in different phases, age at COVID19 and distribution of biological markers were similar, but more patients in the latter phases suffered from arrhythmias (8.2% vs 10.5% vs 16.1% vs 14.2%, p=0.01), chronic renal disease (3.9% vs 5.9% vs 8.9% and 11.1%, p=0.003) and other malignancies (0.3% vs 1.8% vs 2.2% vs 3.6%, p=0.04). Vaccinated patients (0% vs 0.4% vs 45.7% vs 89.1%, p<0.001) and those treated for CLL in the last 12 months (44.1% vs 44.1% vs 55.7% vs 66.1%, p<0.001) were also more common in the last phases. COVID19 signs and symptoms differed between early and late phases, with less fever (p<0.001) and dyspnea (p=0.028) but more fatigue (p<0.001), cough (p<0.001), headache (p<0.001), anosmia/ageusia (p<0.001) and myalgia/arthralgia (p<0.001) in the later phases. COVID19 management also changed over time, with less patients receiving a SARS-CoV2 therapy (87.6% vs 74.7% vs 78.1% vs 67.9%, p<0.001). In particular, hydroxychloroquine, azithromycin, steroids and anti-IL6/IL6R were more commonly used in the first 2 phases while antiviral and monoclonal antibodies (mAb) were mainly employed in the last 2 phases. Less patients were hospitalized (84.5% vs 67.3% vs 60.3% vs 45.8%, p<0.001), needed ICU admission (20.6% vs 17.2% vs 13.3% vs 8.1%, p<0.001) or died (29.8% vs 25.5% vs 21.8% vs 15.8%, p=0.002) through these phases. These improvements in patients' management led to an increase of OS, with 2-month OS of 70%, 74%, 81% and 83% for patients diagnosed during the 1st, 2nd,3rd and 4th phase (p=0.0015, Fig. 1B). CONCLUSION. We analyzed one of the largest series of patients with CLL infected by SARS-CoV2 over more than 2 years of COVID19 pandemic. Patients infected during the most recent phases, though carrying a higher comorbidity burden, were less frequently hospitalized, only rarely needed ICU admission and died due to the SARS-CoV2 infection in a lower proportion compared to initial phases. The improvement in COVID-19 management with effective antiviral drugs, mAb and the high rate of vaccination together with the change in SARS-CoV2 variants over time may have played an important role in this outcome. AV, LS, TC, AK, CD and GK equally contributed. KS and PG are both last authors. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Abstract 12482: Practical Adherence to AHA/ACC 2018 Guidelines Among Secondary Prevention Patients

Introduction: Patients with ASCVD are at increased risk for CV events. The 2018 AHA/ACC lipid guidelines recommend treating these patients with high intensity or maximally tolerated statin therapy. The objective of this study was to describe lipid lowering treatment (LLT) patterns and lipid values across 7 regional health systems. Methods: We conducted a cross-sectional analysis of electronic health records transformed into the PCORnet common data model (CDM) from 7 sites in the PaTH Clinical Research Network. Adults were eligible for inclusion if an LDL-C value was measured within the past year and &gt; 6 months of pre-index data were available prior to the first LDL-C value in the study period. We defined computable phenotypes for adults meeting AHA/ACC criteria for ASCVD at very high risk (VHR) and not at very high risk (NVHR). Medication use was assessed during the study period using the CDM prescribing table. Descriptive statistics were used to summarize LLT and lipid values within these groups and across sites. Results: NVHR patients (n=69,854) had mean (SD) LDL-C, TG and non-HDL-C of 92.1 (37), 138 (104) and 114.4 (43) mg/dl, respectively; 71% had LDL-C &gt; 70 mg/dL, 30% had TGs 150-500 mg/dL, and 61% had non-HDL-C ≥ 100 mg/dL. VHR patients (n=117, 689) had mean (SD) LDL-C, TG and non-HDL-C of 82.9 (43), 138.5 (99), and 106 (43) mg/dl, respectively; 58.6% had LDL-C &gt; 70 mg/dL, 30.5% had TGs 150-500 mg/dL, and 49.8% had non-HDL-C ≥ 100 mg/dL. Documented LLT in NVHR and VHR patients was 58% and 69% for statin therapy, 25% and 36% for high intensity statin therapy, 12% and 16% for statin therapy + another LLT, while 37% and 27% had no documented LLT. Conclusions: In this cross-sectional study of NVHR and VHR ASCVD patients, although most had documented statin therapy, only 25% and 36%, respectively were on high intensity statins while more than a quarter of patients had no documented LLT. Recorded LDL, TG and non-HDL-C lab values suggest there may be unaddressed risk in these populations.

Abstract 10111: Efficacy and Safety of Tafolecimab in Chinese Patients With Non-Familial Hypercholesterolemia (CREDIT-1): A 48-Week Randomized, Double-Blind, Placebo-Controlled Phase 3 Trial

Introduction: Currently approved proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies demonstrated robust low density lipoprotein cholesterol (LDL-C)-lowering efficacy at doses up to 420 mg monthly, while longer dosing intervals are largely unexplored. We assessed the efficacy and safety of tafolecimab, a potential long-acting fully human PCSK9 monoclonal antibody, in Chinese patients with non-familial hypercholesterolemia (ClinicalTrials.gov, NCT04289285). Methods: Patients were randomized 2:2:1:1 to receive subcutaneous tafolecimab 450 mg every 4 weeks (Q4W), tafolecimab 600 mg every 6 weeks (Q6W), placebo Q4W or placebo Q6W for 48 weeks. The primary endpoint was the percent change from baseline to week 48 in LDL-C levels. Secondary endpoints included proportion of patients achieving ≥50% LDL-C reductions, LDL-C &lt;1.8 mmol/L and LDL-C &lt;1.4 mmol/L. Results: A total of 618 patients (mean LDL-C level 2.85 mmol/L; 9.3% on ezetimibe; 72.8% at very-high cardiovascular risk) were randomized. Of 614 patients receiving at least one dose of the study treatment, 568 (92.5%) completed the study. At both dose regimens, tafolecimab treatment induced significant reductions in LDL-C levels, and significantly more patients treated with tafolecimab achieved ≥50% LDL-C reductions, LDL-C &lt;1.8 mmol/L and LDL-C &lt;1.4 mmol/L compared with corresponding placebo groups ( Table ). Meanwhile, significant reductions in non-high density lipoprotein cholesterol, apolipoprotein B and lipoprotein(a) levels were achieved with tafolecimab versus placebo at week 48. The most commonly-reported treatment-emergent adverse events were upper respiratory tract infection, urinary tract infection and hyperuricemia. Conclusions: Tafolecimab administered at either 450 mg Q4W or 600 mg Q6W yielded significant and durable reductions in LDL-C levels and showed a favorable safety profile in Chinese patients with non-familial hypercholesterolemia.

Agricultural drought risk assessment in the Caribbean region: The case of Haiti

Climate hazards are a particular concern for the Caribbean region, especially droughts, which cause significant damage in the agricultural sector. However, studies on agricultural drought risk mapping are lacking for the Caribbean region, including Haiti. Thus, a comprehensive agricultural drought risk assessment integrating all risk components with their respective influencing indicators is urgently needed to generate structured drought risk information for drought mitigation strategies and proactive response. This study performs an exhaustive assessment of agricultural drought risk, integrating all risk components (vulnerability, hazard, exposure, and the adaptive capacity) with their appropriate parameters essential to plant development. A total of eighteen corresponding spatial indicators are defined to develop agricultural drought risk maps. Fuzzy logic was applied to standardize the various drought aspects in a range of 0-1 followed by the aggregation of drought vulnerability, hazard, exposure, and adaptive capacity indicators to quantify and develop detailed agricultural drought risk maps. Drought risk was analyzed at two different stages: (i) using the risk equation without including the adaptive capacity, and (ii) including the adaptive capacity as a risk component in the risk equation. The first approach produces higher (45.8%) moderate to very-high drought risk than the second (30.7%). The resulting cartographic products can assist in visualizing critically drought-stressed areas and stakeholders, and policy makers can use them to make better decisions to cope with drought in the farming sector.

PSOR5 Presentation Time: 11:50 AM: Interstitial Hyperthermia and High Dose-Rate Brachytherapy Combined with Short-Term Androgen Deprivation Therapy and External-Beam Radiation in High- and Very High-Risk Prostate Cancer

<h3>Purpose</h3> Multimodality treatment of high- and very-high risk prostate cancer has evolved tremendously in recent years to incorporate long-term androgen deprivation therapy (ADT), external-beam radiation therapy (EBRT), and brachytherapy, resulting in improved biochemical progression-free survival (bPFS). However, outcomes remain imperfect, and many patients are unwilling or unable to tolerate long-term ADT use. Existing studies show that hyperthermia is a potent and well-tolerated radiosensitizer. We report the outcomes of patients treated with short-term ADT, EBRT, and high dose-rate (HDR) brachytherapy combined with interstitial hyperthermia. <h3>Materials and Methods</h3> In a single-institution, retrospective study, we reviewed all patients with high- or very high-risk prostate adenocarcinoma who began definitive treatment between December 2016 and March 2020 with up to six months of ADT, whole-pelvis EBRT, and a combination of HDR brachytherapy boost and interstitial hyperthermia. Our primary endpoint was bPFS based on the Phoenix definition (PSA nadir +2 ng/mL) calculated from time of ADT initiation. We also report data on type of failure, survival, and toxicity. <h3>Results</h3> 56 patients were reviewed, including 21 with high-risk and 35 with very high-risk prostate adenocarcinoma. Median age was 72 years (range 52-82 years). Median duration of ADT use was 4 months (range 0-6 months). All patients received whole-pelvis EBRT of 45Gy/25fx. 55 patients (98%) received a 5.4Gy/3fx EBRT boost to the prostate and seminal vesicles. All patients received two Iridium-192 HDR implants to further boost the prostate and seminal vesicles, with each implant separated by at least one week (median 2 weeks, range 1-6 weeks) and consisting of two fractions of 5.5Gy separated by five to seven hours, for a total of 22Gy/4fx. All patients received at least one interstitial hyperthermia treatment of at least 45 minutes in between fractions of the same implant. 50 patients (89%) received both planned hyperthermia treatments of at least 60 minutes each at a goal temperature of 42-43 degrees Celsius. Median duration of follow-up was 28 months for all patients, with 34 months for high-risk and 28 months for very-high risk disease. The estimated two/three-year bPFS-rates were 100%/100% for high-risk and 92.0%/87.7% for very high-risk disease. Figure 1 represents the Kaplan-Meier curve for bPFS. Of the three very high-risk patients who failed biochemically, one failed regionally at 25 months, and two failed distantly at 15 and 23 months. There were no local failures. Two patients with very-high risk disease have died, both of unrelated lung disease at nine and 13 months. Four patients stopped their hyperthermia treatment early due to intolerance, with one developing an acute perineal burn that fully healed three months later. There were otherwise no grade 3 or higher acute toxicities. Four patients (7%) developed late grade 3 toxicities, all genitourinary-related. <h3>Conclusions</h3> Multimodality treatment of prostate cancer with short-term ADT, EBRT, HDR brachytherapy, and interstitial hyperthermia is safe and well-tolerated. For patients with high-risk disease, it provides excellent biochemical control while sparing long-term use of ADT. Patients with very high-risk disease may benefit from long-term use of ADT and/or other forms of systemic therapy. Longer follow-up and prospective trials are needed to validate our findings.

Clinical and histopathological features of bladder cancer following radiotherapy for prostate cancer: A comparative study.

Low certainty exists on how bladder cancer (BCa) after pelvic radiotherapy (RT) differs from BCa in radiation-naive patients from a histopathological and clinical perspective. This study aims to compare histopathological features of bladder tumors between patients with previous RT for prostate cancer (PCa) and radiation-naive patients using single-institutional data and to estimate relapse-free survival (eRFS) and cystectomy-free survival (eCFS) in both groups. Comparative study in adult men diagnosed with BCa in Hospital Italiano de Buenos Aires, Argentina, between January 2015 and December 2020. Included patients were categorized as previously irradiated for PCa or radiation-naive. differences in prevalence of aggressiveness features of bladder tumors (variant histology; high-grade tumors; muscle-invasive disease; criteria compliance for high or very-high risk of progression) between irradiated and radiation-naive patients at diagnosis of BCa. differences in eRFS and eCFS between groups. In total, 34 and 291 patients were included in the Irradiated and Radiation-naive groups, respectively. Mean age at the time of diagnosis of BCa was 72.7 years (CI 95% 71.6-73.8). Median follow-up of the overall cohort was 25 months (IQR 11-45.5). Concerning primary outcomes, no statistical differences were found except for a higher prevalence of low-grade tumors between irradiated patients and high-grade tumors between radiation-naive patients (P 0.018). Regarding secondary outcomes, prior RT did not increase neither eRFS nor eCFS in both univariate and multivariate analysis. BCa after RT for PCa has similar histological features and cystectomy free-survival compared to BCa in a radiation-naive population. For patients with non-muscle invasive BCa arising after prostate RT, the risk of recurrences appears to be similar to non-irradiated patients.

Clinical significance of limited and extended pelvic lymph node dissection during robot-assisted radical prostatectomy for patients with localized prostate cancer: A retrospective, propensity score matching analysis.

We investigated the diagnostic and therapeutic benefits of limited or extended pelvic lymph node dissection during a robot-assisted radical prostatectomy for localized prostate cancer. Diagnostic and therapeutic benefits were assessed according to the rates of pN1 and biochemical recurrence, respectively. The primary outcome was the biochemical recurrence-free rate, and secondary outcomes included the diagnostic and therapeutic benefits of pelvic lymph node dissection. A total of 534 patients were analyzed. Out of the 534 patients, 207 (38.8%) received limited pelvic lymph node dissection while 134 (25.1%) received extended dissection. There were 297 patients with a Briganti index ≥5%. Extended dissections yielded significantly more resected lymph nodes (p < 0.0001), and 72.2% of cases of pN1 were located outside the obturator. The incidence rate of pN1 was 6.1%, and performance of extended lymph node dissection was an independent predictor for pN1 (odds ratio 9.0, 95% confidence interval 2.5-33.1). The rate of biochemical recurrence was 14.9%, and Cox proportional hazards regression analysis of the propensity score matched population revealed that patients with high or very-high risk tended to benefit from limited lymph node dissection (hazard ratio 8.4, 95% confidence interval 0.8-82.3) while the therapeutic benefit of extended dissection was unclear by comparison. Extended pelvic lymph node dissection significantly improves diagnostic accuracy; however, the therapeutic benefit of pelvic lymph node dissection was not observed in this study.

Simulation study on LDL cholesterol target attainment, treatment costs, and ASCVD events with bempedoic acid in patients at high and very-high cardiovascular risk.

Background and aimsThe LDL cholesterol (LDL-C) treatment goals recommended by the 2019 ESC/EAS guidelines are only achieved in a minority of patients. The study objective was to estimate the impact of bempedoic acid treatment on LDL-C target attainment, drug costs, and atherosclerotic cardiovascular disease (ASCVD) events.The simulation used a Monte Carlo approach in a representative cohort of German outpatients at high or very-high cardiovascular risk. Additionally to statins, consecutive treatment with ezetimibe, bempedoic acid, and a PCSK9 inhibitor was simulated in patients not achieving their LDL-C goal. Considered were scenarios without and with bempedoic acid (where bempedoic acid was replaced by a PCSK9 inhibitor when LDL-C was not controlled).ResultsThe simulation cohort consisted of 105,577 patients, of whom 76,900 had very-high and 28,677 high cardiovascular risk. At baseline, 11.2% of patients achieved their risk-based LDL-C target. Sequential addition of ezetimibe and bempedoic acid resulted in target LDL-C in 33.1% and 61.9%, respectively. Treatment with bempedoic acid reduced the need for a PCSK9 inhibitor from 66.6% to 37.8% and reduced drug costs by 35.9% per year on stable lipid-lowering medication. Compared to using only statins and ezetimibe, this approach is projected to prevent additional 6,148 ASCVD events annually per 1 million patients, whereas PCSK9 inhibition alone would prevent 7,939 additional ASCVD events annually.ConclusionsA considerably larger proportion of cardiovascular high- and very-high-risk patients can achieve guideline-recommended LDL-C goals with escalated lipid-lowering medication. Bempedoic acid is projected to substantially decrease the need for PCSK9 inhibitor treatment to achieve LDL-C targets, associated with reduced drug costs albeit with fewer prevented events.