Integrating Clinical, Morphological, and Molecular Data to Assess Prognosis in Patients with Primary Myelofibrosis: A Practical Approach

Abstract Current prognostic scoring systems are not able to easily integrate clinical, histological and molecular data in primary myelofibrosis (PMF) as they required additional information, mainly concerning non-driver mutations, which are available only in a very limited number of research laboratories. The present multicenter study developed a simple method to integrate, at diagnosis, the prognostic information from two well-defined prognostic scoring systems [IPSS and bone marrow fibrosis grade (GBMF)] with the molecular status (MS) concerning the so-called driver mutations to obtain an overall prognostic stratification of PMF patients applicable worldwide. The study included 401 PMF patients who were diagnosed at three Italian Hematological Centers (Milan, Monza, and Bologna) between November 1983 and December 2016 and were followed up for a minimum of 12 months. Follow-up information was updated in December 2017. An integrated score (ISC) was developed based on the sum of the scores attributed to the following variables: IPSS risk categories (low risk = 0 point; intermediate-1 risk = 1 point; intermediate-2 and high risk = 2 points), GBMF (pre-fibrotic stage = 0 point; overt fibrotic stage = 1 point), and MS (CALR type 1 = 0 point; CALR type 2 or other / JAK2V617F / MPL = 1 point; triple-negative = 3 points). An ISC ranging from 0 to 6 was obtained using the following formula: ISC = IPSS + GBMF score + MS score. Based on the ISC results, patients were divided into four prognostic categories: ISC-low risk, score = 0-1 (126 patients); ISC-intermediate-1 risk, score = 2 (142 patients); ISC-intermediate-2 risk, score = 3 (70 patients); and ISC-high risk, score = 4-6 (63 patients). Considering patients with an ISC-low risk as the reference group, the odds of death was 3.5 times higher (95% CI, 1.7-7.0) for ISC-intermediate-1 risk, 5.6 times higher (95% CI, 2.6-12.1) for ISC-intermediate-2 risk, and 10.5 times higher (95% CI, 4.8-22.6) for ISC-high risk patients. Interestingly, the ISC was significantly associated (p<0.004) with constitutional symptoms, splenomegaly, and transfusion need, and a higher frequency of cytoreductive therapy. In addition, median time from diagnosis to the development of an index event (including thrombotic events and leukemic evolution) was shorter in ISC-high risk patients than in ISC-low risk patients: 2.8 vs. 6.8 years for thrombotic events, and 3.5 vs. 4.8 years for leukemic evolution. As reported in Figure 1, the median overall survival (Kaplan-Meier estimate) was 11.9 years in ISC-intermediate-1 risk, 8.8 years in ISC-intermediate-2 risk, and 6.4 years in ISC-high risk patients (log-rank test <0.0001). The results were confirmed using the multivariate Cox model: the Hazard Ratio (HR) for death using the ISC-low risk group as reference was 4.3 (95% CI, 2.2-8.3) for the ISC-intermediate-1 risk group, 7.0 (95% CI, 3.5-14.0) for the ISC-intermediate-2 risk group, and 13.9 (95% CI, 7.1-27.3) for the ISC-high risk group. When patients were instead stratified according to the IPSS, the median overall survival was 10.8 years in IPSS-intermediate-1 risk, 6.9 years in IPSS-intermediate-2 risk, and only 4 years in IPSS-high risk patients. The HR for death was 13.0-times higher for intermediate-2 risk and 35.3-times higher for high risk than for the low IPSS risk categories. Accordingly, these results suggest that the prognostic stratification of risk according to the IPSS can be modulated by applying the ISC score, thereby preventing the overestimation of the real risk of death. The present study had two main limitations related to its retrospective nature and the inability to evaluate the impact of new drugs such as JAK1/2 inhibitors on the natural history of this disease, mainly because of the wide range of the time of diagnosis. Therefore, additional prospective studies involving other Hematological Centers and a larger number of patients are needed to draw definite conclusions. In conclusion, the comprehensive approach proposed in the present study is an improved tool for predicting mortality in PMF patients. The proposed model will allow clinicians to evaluate the mutual interactions between IPSS, GBMF, and MS to identify high-risk patients with a poor prognosis who may benefit from more aggressive treatments. In addition, the present model is applicable worldwide in the real-life clinical practice. Figure 1. Figure 1. Disclosures Palandri: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Cortelezzi:roche: Consultancy; novartis: Consultancy; abbvie: Consultancy; janssen: Consultancy.

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P3609Temporal trends of the management and outcomes of patients after myocardial infarction according to the risk for recurrent cardiovascular events

European Heart Journal ◽

10.1093/eurheartj/ehz745.0468 ◽

2019 ◽

Vol 40 (Supplement_1) ◽

Author(s):

T Grinberg ◽

T Bental ◽

Y Hammer ◽

A R Assali ◽

H Vaknin-Assa ◽

...

Keyword(s):

Myocardial Infarction ◽

High Risk ◽

Cardiovascular Events ◽

Risk Group ◽

Temporal Trends ◽

High Risk Group ◽

Low Risk ◽

Intermediate Risk ◽

High Risk Patients ◽

Risk Patients

Abstract Background Following Myocardial Infarction (MI), patients are at increased risk for recurrent cardiovascular events, particularly during the immediate period. Yet some patients are at higher risk than others, owing to their clinical characteristics and comorbidities, these high-risk patients are less often treated with guideline-recommended therapies. Aim To examine temporal trends in treatment and outcomes of patients with MI according to the TIMI risk score for secondary prevention (TRS2°P), a recently validated risk stratification tool. Methods A retrospective cohort study of patients with an acute MI, who underwent percutaneous coronary intervention and were discharged alive between 2004–2016. Temporal trends were examined in the early (2004–2010) and late (2011–2016) time-periods. Patients were stratified by the TRS2°P to a low (≤1), intermediate (2) or high-risk group (≥3). Clinical outcomes included 30-day MACE (death, MI, target vessel revascularization, coronary artery bypass grafting, unstable angina or stroke) and 1-year mortality. Results Among 4921 patients, 31% were low-risk, 27% intermediate-risk and 42% high-risk. Compared to low and intermediate-risk patients, high-risk patients were older, more commonly female, and had more comorbidities such as hypertension, diabetes, peripheral vascular disease, and chronic kidney disease. They presented more often with non ST elevation MI and 3-vessel disease. High-risk patients were less likely to receive drug eluting stents and potent anti-platelet drugs, among other guideline-recommended therapies. Evidently, they experienced higher 30-day MACE (8.1% vs. 3.9% and 2.1% in intermediate and low-risk, respectively, P<0.001) and 1-year mortality (10.4% vs. 3.9% and 1.1% in intermediate and low-risk, respectively, P<0.001). During time, comparing the early to the late-period, the use of potent antiplatelets and statins increased among the entire cohort (P<0.001). However, only the high-risk group demonstrated a significantly lower 30-day MACE (P=0.001). During time, there were no differences in 1-year mortality rate among all risk categories. Temporal trends in 30-day MACE by TRS2°P Conclusion Despite a better application of guideline-recommended therapies, high-risk patients after MI are still relatively undertreated. Nevertheless, they demonstrated the most notable improvement in outcomes over time.

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Screening Efectiveness with SERUM Galactomannan in High and Low Risk Patients for Fungal Infection in the Post ALLO-HTC

Blood ◽

10.1182/blood.v126.23.5452.5452 ◽

2015 ◽

Vol 126 (23) ◽

pp. 5452-5452

Author(s):

Fabio Augusto Ruiz Gómez ◽

Valentin García Gutierrez ◽

Elia Gomez ◽

Pilar Herrera Puente ◽

Isabel Page Herráez ◽

...

Keyword(s):

High Risk ◽

Fungal Infection ◽

Hodgkin Lymphoma ◽

Risk Group ◽

False Positives ◽

Low Risk ◽

Cell Transplant ◽

Aspergillus Infection ◽

High Risk Patients ◽

Risk Patients

Abstract Background and aims: Serum galactomannan (GM) is used as a screening test for the early diagnosis of Aspergillus infection in high risk patients for fungal invasive infection. Serial GM levels analysis have proven to be useful in the high risk clinical setting patients, specially when neutropenic and not receiving anti-mold agents prophylaxis. There is a lack of information regarding the benefit of GM in patients undergoing allogeneic hematopoietic cell transplant (HCT). The aim of this work is to measure the real clinical benefit of the serial periodic determination of GM in the post allo-HCT period. Material and methods: 139 consecutive patients who receivedan allo-HCT (59% related family member donorsand 41% unrelated donors) in our centre for five years (since January 2010 to February 2015) were included in the study. Median age was 46 years. Baseline characteristics of these patients are shown in figure 1. Patients were monitored with GM weekly and received primary prophylaxis with fluconazole since the admission until the immunosuppression was tapered. In order to find a population that could benefit the most for AGA monitoring, we classified our population in low risk patients for invasive fungal infection (IFI) versus high risk patients (those with previous proven or probable IFI or those suffering from GVHD; high risk patients received anti-mold prophyllaxis, mainly with voriconazole or posaconazole). Patients considered as low risk who suffered from Graft versus Host Disease (GVHD) in the ulterior outcome, were censored for low risk and considered as high risk since the development of GVHD, and therefore anti-mold agent prophylaxis was started. GM positivity was determined according standard criteria. When GM positivity was detected, radiological and clinical studies (chest/sinus CT scans, cultures, etc.) to discard Aspegillosis were done as soon as possible. Every patient was followed up prospectively until the last medical consultation or decease. Results: Global overall survival (OS) for the entire cohort was 55.39% and cumulative incidence for severe GVHD grade III/IV was 49.5%. During the follow up, GM became positive in 31/139 (22%) cases. With this approach, the global false positive and false negative rate was 31% and 6% respectively.110/139 (79.14%) patients were identificated as low risk cases. We observed GM positivization in 1.81% (2/110) and 37.18% (29/78) for low and high group respectively. All 2 positive GM in the low risk group were false positives. Regarding the high risk group, 34.48% (10/29) were false positives while in the rest 19 patients (65.52%), subsequent radiological and clinical findings allowed us to diagnose Aspergillus infection (besides they received anti-mold agent prophylaxis). Conclusions: In our experience there is not enough evidence for supporting making serial monitoring with GM in low risk patients for IFI in the post allo-HCT period. However it may be an useful tool in high risk patients. Table 1. N (%) Age (years) Mean 46.18 Median 48.01 Sex (man vs woman) 91 vs 48 (65 vs 35%) Hematology disease Acute Mieloid Leukemia Acute Limphoblastic Leukemia Multiple Myeloma Chronic Mieloid Leukemia Non Hodgkin Lymphoma Hodgkin Lymphoma Others diseases 79 (56.8%) 18 (12.9%) 9 (6.5%) 3 (2.2%) 13 (9.4%) 9 (6.5%) 8 (5.6%) Pre allo-HSCT IFI 17 (12.2%) Aconditioning Myeloablative Reduced Intensity 95 (68.3%) 44 (31.7%) Source of progenitors Peripherical blood Bone marrow 132 (95.0%) 7 (5.0%) Type of donor Related Non-related 82 (59.0%) 57 (41.0%) Graft time (days) Neutrophils (>500 in two consecutive determinations) Platelets (>30.000 in two consecutive determinations) 15.52 17.75 Post-transplant CMV viremia (number of patients with >600 copies in the post-HSCT period) 48 (34.5%) Disclosures No relevant conflicts of interest to declare.

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Assessing a prognostic model for predicting VTE occurrence in cancer patients.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.1577 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 1577-1577

Author(s):

Deesha Sarma ◽

So Yeon Kim ◽

David H. Henry

Keyword(s):

High Risk ◽

Cancer Patients ◽

Risk Group ◽

Low Risk ◽

Risk Category ◽

Valuable Insight ◽

Intermediate Risk ◽

High Risk Patients ◽

Prophylactic Measures ◽

Risk Patients

1577 Background: Venous thromboembolism (VTE) poses a significant health risk to cancer patients and is one of the leading causes of death among this population. The most effective way to prevent VTE and reduce its prominence as a public health burden is by identifying high-risk patients and administering prophylactic measures. In 2008, Khorana et al. developed a model that classified patients by risk based on clinical factors. Methods: We conducted a retrospective study to test this model’s efficacy, on 150 patients with cancer receiving chemotherapy at an outpatient oncology clinic between January 1 and August 1, 2011. We aggregated data and assigned points based on the five factors in the Khorana model: site of cancer with 2 points for very high-risk site and 1 point for high-risk site, 1 point each for leukocyte counts more than 11 x 109/L, platelet counts greater than 350 X 109/L, hemoglobin levels less than 100 g/L and/or the use of erythropoiesis-stimulating agents, and BMI greater than 35 kg/m2 (Khorana et al., Blood 2008). Based on this scoring system, patients with 0 points were grouped into the low-risk category, those with 1-2 points were considered intermediate-risk, and those with 3-4 points were classified as high-risk. Results: As shown in the table, VTE incidence for the low-risk group was 1.9%, intermediate-risk group was 3.9%, and high-risk group was 9.1%. Conclusions: High-risk patients were about 4.5 times more likely to develop a VTE than low risk patients. These results provide valuable insight in determining which patients might benefit from prophylaxis and in motivating the design of prospective clinical trials that assess the VTE predictive model in various ambulatory cancer settings. [Table: see text]

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A Ferroptosis and Pyroptosis Molecular Subtype-Related Signature Applicable for Prognosis and Immune Microenvironment Estimation in Hepatocellular Carcinoma

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.761839 ◽

2021 ◽

Vol 9 ◽

Author(s):

Junyu Huo ◽

Jinzhen Cai ◽

Ge Guan ◽

Huan Liu ◽

Liqun Wu

Keyword(s):

High Risk ◽

Risk Score ◽

Risk Group ◽

Molecular Subtype ◽

Risk Groups ◽

High Risk Group ◽

Low Risk ◽

Type I ◽

Immune Microenvironment ◽

Risk Patients

Background: Due to the heterogeneity of tumors and the complexity of the immune microenvironment, the specific role of ferroptosis and pyroptosis in hepatocellular carcinoma (HCC) is not fully understood, especially its impact on prognosis.Methods: The training set (n = 609, merged by TCGA and GSE14520) was clustered into three subtypes (C1, C2, and C3) based on the prognosis-related genes associated with ferroptosis and pyroptosis. The intersecting differentially expressed genes (DEGs) among C1, C2, and C3 were used in univariate Cox and LASSO penalized Cox regression analysis for the construction of the risk score. The median risk score served as the unified cutoff to divide patients into high- and low-risk groups.Results: Internal (TCGA, n = 370; GSE14520, n = 239) and external validation (ICGC, n = 231) suggested that the 12-gene risk score had high accuracy in predicting the OS, DSS, DFS, PFS, and RFS of HCC. As an independent prognostic indicator, the risk score could be applicable for patients with different clinical features tested by subgroup (n = 26) survival analysis. In the high-risk patients with a lower infiltration abundance of activated B cells, activated CD8 T cells, eosinophils, and type I T helper cells and a higher infiltration abundance of immature dendritic cells, the cytolytic activity, HLA, inflammation promotion, and type I IFN response in the high-risk group were weaker. The TP53 mutation rate, TMB, and CSC characteristics in the high-risk group were significantly higher than those in the low-risk group. Low-risk patients have active metabolic activity and a more robust immune response. The high- and low-risk groups differed significantly in histology grade, vascular tumor cell type, AFP, new tumor event after initial treatment, main tumor size, cirrhosis, TNM stage, BCLC stage, and CLIP score.Conclusion: The ferroptosis and pyroptosis molecular subtype-related signature identified and validated in this work is applicable for prognosis prediction, immune microenvironment estimation, stem cell characteristics, and clinical feature assessment in HCC.

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The Effect Of Low Dose Intravenous Heparin On Anti-Factor Xa And Antithrombin III

10.1055/s-0038-1653109 ◽

1981 ◽

Author(s):

S A Jennings ◽

B P Heather ◽

R M Greenhalgh

Keyword(s):

High Risk ◽

Low Dose ◽

Antithrombin Iii ◽

Risk Group ◽

Factor Xa ◽

Low Risk ◽

Heparin Infusion ◽

High Risk Patients ◽

Intravenous Heparin ◽

Risk Patients

Preoperative blood samples from 17 patients undergoing major abdominal surgery were examined by the thrombelasto-graph saline dilution test, which has previously been shown to be a predictor of the risk of early postoperative deep vein thrombosis (DVT)(Heather et al 1980). By this test 8 patients were predicted to be at low risk of developing a DVT and received no special prophylaxis. 9 patients were considered to be at risk and were treated with a subcutaneous dose of 1000 units of heparin with the premedication together with a low dose of intravenous heparin infusion from the induction of anaesthesia until 2 hours after operation. Plasma antithrombin III (ATIII) concentration and anti-factor Xa activity were measured preoperatively, on day 1 and on day 3. No early DVT occurred, as assessed by I125 fibrinogen scanning, in either the untreated low risk patients or in the high risk patients receiving heparin infusion. The high risk patients had lower levels of ATIII before operation than the low risk patients (75±9%; 98±39%) and significantly lower levels on day 3 (64±25%; 106±34% p<0.02). However, these lowered levels of ATIII appeared in the high risk group to be augmented by the significant increase in anti-factor Xa activity 127±64%. before operation, 217±89%, on day 1 (p<0.02). Furthermore, on day 3 the high risk patients had significantly greater activity than those patients in the low risk group (212±76%; 106±34% p<0.02).These results show that those patients at risk of developing a postoperative DVT had a significantly enhanced activation of anti-factor Xa, as a result of intravenous low dose heparin with the subsequent abolition of early venous thrombosis.

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Development and validation of a novel disease risk model for patients with AML receiving allogeneic hematopoietic cell transplantation.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.7016 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 7016-7016

Author(s):

Piyanuch Kongtim ◽

Omar Hasan ◽

Jorge Miguel Ramos Perez ◽

Ankur Varma ◽

Julianne Chen ◽

...

Keyword(s):

High Risk ◽

Risk Score ◽

Hematopoietic Cell Transplantation ◽

Risk Model ◽

Disease Risk ◽

Risk Group ◽

Molecular Data ◽

Hematopoietic Cell ◽

Low Risk ◽

Related Factors

7016 Background: Molecular data and minimal residual disease (MRD) have been shown to influence outcomes in AML patients undergoing allogeneic hematopoietic cell transplantation (AHCT). Here we developed and validated a novel AML-specific Disease Risk Group (AML-DRG) and revise our previously developed Hematopoietic Cell Transplant - Composite Risk (HCT-CR) model by incorporating molecular data and MRD status before transplant to predict post-transplant outcomes of patients with AML. Methods: The study included 1414 consecutively treated adult AML patients, who received first AHCT between 1/2005-8/2018 at our institution. Patients were randomly assigned into a training (N = 944) and validation set (N = 470). To develop the AML-DRG model, the coefficient of all significant AML-related variables in multivariable Cox’s regression analysis (MVA) in a training dataset was converted into scores.The AML-DRG was the sum of scores from all significant covariates, while the AML-HCT-CR was the sum of disease-related factors assessed by the AML-DRG model with the addition of weighted scores from patient-related factors. Results: Based on results of MVA, the following scores were assigned to each AML-related variable; 1 point to secondary AML; 1 point to the 2017 ELN adverse risk; 2 points to CR with MRD positive/unknown; and 4 points to active disease at transplant. These were used to generate the AML-DRG (low-risk score 0-2; intermediate-risk score 3-4; and high-risk score > 4) with significantly different OS with HR of 2.02 (P < 0.001), and 3.85 (P < 0.001) for intermediate and high risk group compared with low risk group. By adding 1 point for patients > / = 60 years or HCT-CI > 3 to the AML-DRG, we created 4 risk groups of AML-HCT-CR (low-risk: score 0-2; intermediate-risk: score 3; high-risk: score 4 and very high-risk: score ≥5) with distinct survival outcomes. The AML-DRG and AML-HCT-CR model had C-index of 0.672 and 0.715, respectively which were better compared with DRI, ELN2017 and cytogenetic risk model. Conclusions: Prognostic models incorporating molecular data and MRD status before transplant allow better stratification and improved survival estimates of AML patients post-transplant.

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Abstract 3259: Intra-Aortic Balloon Pump Insertion Prior to LVAD Implantation Improves Short-term Survival in High-Risk LVAD Recipients

Circulation ◽

10.1161/circ.116.suppl_16.ii_733-a ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Tariq M Naseem ◽

George M Comas ◽

Abeel A Mangi ◽

Timothy P Martens ◽

Faisal H Cheema ◽

...

Keyword(s):

High Risk ◽

Risk Score ◽

Risk Group ◽

Venous Pressure ◽

Left Ventricular ◽

Low Risk ◽

Hemodynamic Stability ◽

Term Survival ◽

Intra Aortic Balloon Pump ◽

Risk Patients

INTRODUCTION: Intra-aortic balloon pump (IABP) insertion can augment cardiac function in the setting of acutely decompensated heart failure. The aim of this study was to determine if IABP insertion prior to left ventricular assist device (LVAD) implantation improves outcomes in LVAD recipients. HYPOTHESIS: We assessed the hypothesis that pre-operative IABP insertion for hemodynamic stability and improved organ perfusion would lead to better outcomes post-LVAD implant METHODS: We have previously described a preoperative LVAD risk score (LRS), which is based on preoperative characteristics associated with inferior outcomes after LVAD insertion (e.g. previous cardiac surgery, ventilator dependence, elevated central venous pressure, elevated prothrombin time). We retrospectively reviewed the records of 245 patients undergoing LVAD implantation (Heartmate I, Heartmate II & DeBakey) at our center between 1996 and 2006, including preoperative LRS and 30-day survival. Patients were categorized as those who received an IABP prior to LVAD implant for hemodynamic stability and those who did not. Data were analyzed by Chi-square and Mann-Whitney U tests. RESULTS: Of 245 patients having LVAD implants during the study period, 174 (71%) had a LRS of 1–5 (low-risk group), while 71 (29%) had a LRS of 6 –10 (high-risk group). A total of 95 patients received an IABP prior to LVAD insertion during this period: 54 (31%) of the low-risk patients and 41 (58%) of the high-risk patients. In the high-risk cohort, patients receiving pre-operative IABP (n = 41) had superior 30-day survival compared with patients who did not receive an IABP (n = 30) (78% vs. 57%, p < 0.05). Conversely, in the low-risk group, IABP insertion was associated with a trend toward lower 30-day survival (78% vs. 92%, p < 0.1). In the low-risk group, the rate of successful bridging to transplantation was higher in patients who did not receive pre-operative IABP support (86% vs. 69%, p < 0.01). CONCLUSION: LVAD candidates with a high LVAD risk score, a preoperative surrogate of increased perioperative risk, have improved 30-day survival if stabilized with an IABP prior to LVAD implantation.

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Catheter Management and Risk Stratification of Patients With in Inpatient Treatment Due to Acute Epididymitis

Frontiers in Surgery ◽

10.3389/fsurg.2020.609661 ◽

2020 ◽

Vol 7 ◽

Author(s):

Mike Wenzel ◽

Marina Deuker ◽

Maria N. Welte ◽

Benedikt Hoeh ◽

Felix Preisser ◽

...

Keyword(s):

Risk Factors ◽

High Risk ◽

Risk Stratification ◽

Risk Score ◽

Inpatient Treatment ◽

Low Risk ◽

High Risk Patients ◽

Catheter Group ◽

Risk Patients ◽

Acute Epididymitis

Objective: This study aims to evaluate catheter management in acute epididymitis (AE) patients requiring inpatient treatment and risk factors predicting severity of disease.Material and Methods: Patients with diagnosed AE and inpatient treatment between 2004 and 2019 at the University Hospital Frankfurt were analyzed. A risk score, rating severity of AE, including residual urine > 100 ml, fever > 38.0°C, C-reactive protein (CRP) > 5 mg/dl, and white blood count (WBC) > 10/nl was introduced.Results: Of 334 patients, 107 (32%) received a catheter (transurethral (TC): n = 53, 16%, suprapubic (SPC): n = 54, 16%). Catheter patients were older, exhibited more comorbidities, and had higher CRP and WBC compared with the non-catheter group (NC). Median length of stay (LOS) was longer in the catheter group (7 vs. 6 days, p < 0.001), whereas necessity of abscess surgery and recurrent epididymitis did not differ. No differences in those parameters were recorded between TC and SPC. According to our established risk score, 147 (44%) patients exhibited 0–1 (low-risk) and 187 (56%) 2–4 risk factors (high-risk). In the high-risk group, patients received a catheter significantly more often than with low-risk (TC: 22 vs. 9%; SPC: 19 vs. 12%, both p ≤ 0.01). Catheter or high-risk patients exhibited positive urine cultures more frequently than NC or low-risk patients. LOS was comparable between high-risk patients with catheter and low-risk NC patients.Conclusion: Patients with AE who received a catheter at admission were older, multimorbid, and exhibited more severe symptoms of disease compared with the NC patients. A protective effect of catheters might be attributable to patients with adverse risk constellations or high burden of comorbidities. The introduced risk score indicates a possibility for risk stratification.

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Low Von Willebrand Factor: Cut-Off Value for Diagnosis and Risk Score to Predict Bleeding Incidence

Blood ◽

10.1182/blood-2020-142375 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 18-19

Author(s):

Ferdows Atiq ◽

Esmee Wuijster ◽

Moniek P.M. de Maat ◽

Marieke J.H.A. Kruip ◽

Marjon H. Cnossen ◽

...

Keyword(s):

High Risk ◽

Risk Score ◽

Research Funding ◽

Low Risk ◽

Intermediate Risk ◽

Spontaneous Bleeding ◽

High Risk Patients ◽

Risk Patients ◽

Surgical Bleeding

Introduction Although large studies have recently provided valuable insights on the diagnosis, bleeding phenotype, and treatment outcomes of VWD patients, these aspects remain poorly understood in individuals with low VWF. Firstly, there is no clear evidence which cut-off value should be used to diagnose low VWF. Although 0.50 IU/mL is the most recommended cut-off value, some centers use the lower limit of normal (0.60 IU/mL). Secondly, the incidence of post-surgical bleeding, postpartum hemorrhage (PPH) and traumatic- or spontaneous bleeding after diagnosis of low VWF are still unknown. Lastly, it is hard to predict which individuals with low VWF have an increased bleeding risk. Therefore, we investigated the bleeding phenotype of individuals with historically lowest VWF levels of 0.31-0.50 IU/mL and 0.51-0.60 IU/mL, and the incidence of post-surgical bleeding, PPH and traumatic- and spontaneous bleeding after their initial diagnosis of "low VWF". Methods We performed a retrospective cohort study from January 2007 to November 2019 at the Erasmus MC, University Medical Center Rotterdam. All patients evaluated for the presence of a bleeding disorder with VWF antigen (VWF:Ag) and/or VWF activity (VWF:Act) and/or VWF collagen binding (VWF:CB) levels between 0.31-0.60 IU/mL, were included. Patients with VWF:Ag and/or VWF:Act and/or VWF:CB ≤0.30 IU/mL, acquired VWD and those with a concomitant bleeding disorder were excluded. For each individual we collected data from electronic patient files on baseline characteristics, reason for referral, family history of bleeding disorders, ISTH-BAT and laboratory measurements at diagnosis. Retrospective follow-up started from initial date of low VWF diagnosis through November 2019, during which we collected data on surgical procedures, pregnancies, and incidence of spontaneous- and traumatic bleeding. Results We included 439 patients; 269 patients with historically lowest VWF levels 0.31-0.50 IU/mL and 170 patients 0.51-0.60 IU/mL. Mean age at diagnosis was 28.8 ±17.7 years. Most patients were female (74.3%) and had blood group O (76.4%, Table 1). The bleeding score (BS) was similar in patients with historically lowest VWF levels of 0.31-0.50 IU/mL (3.7 ±3.0) and 0.51-0.60 IU/mL (4.0 ±2.9, p=0.209, Table 1). During the mean follow-up period of 6.3 ±3.7 years, 259 surgical procedures were performed in 146 patients, 81 deliveries in 56 women, and 109 spontaneous- or traumatic bleedings in 71 patients. The incidence of post-surgical bleeding was 7 (2.7%) during follow-up, whereas 8 deliveries (10%) were complicated by PPH. Overall, 65 out of 439 patients (14.8%) had a bleeding episode requiring treatment during follow-up, resulting in an incidence of bleeding requiring treatment of 0.5 ±1.9 per patient per decade. No difference was found in the incidence of bleeding requiring treatment between patients with historically lowest VWF levels of 0.31-0.50 IU/mL and 0.51-0.60 IU/mL (Figure 2A, p=0.154). We found that referral for a personal bleeding diathesis, a younger age at diagnosis and an abnormal BS at diagnosis were strong and independent risk factors for bleeding requiring treatment during follow-up, respectively HR=2.32 (95%CI: 1.16-4.63), HR=1.18 (95%CI: 1.01-1.38) and HR=1.77 (95%CI: 1.04-3.01). These risk factors were combined to develop a risk score to identify low VWF patients with an increased risk for bleeding requiring treatment (Figure 2B). The risk score performed excellent to differentiate in bleeding requiring treatment between low risk, intermediate risk and high risk patients (p<0.001, Figure 2C). The number of patients with bleeding requiring treatment was 8/126 (6.3%) in patients with low risk, 18/143 (12.6%) in intermediate risk and 39/170 (22.9%) in high risk patients (p<0.001). Likewise, the incidence of bleeding requiring treatment per patient per decade was 0.22 ±1.08 in low risk, 0.28 ±1.25 in intermediate risk and 0.87 ±2.61 in high risk patients (p=0.004, Figure 2D). Conclusion To conclude, there is no difference in the bleeding phenotype of individuals with historically lowest VWF levels of 0.31-0.50 IU/mL and 0.51-0.60 IU/mL. Therefore, the cut-off value to diagnose low VWF should be set at 0.60 IU/mL. Furthermore, the risk score developed in the current study may assist to identify low VWF patients with low, intermediate and high risk for future bleeding. Disclosures Atiq: SOBI: Other: travel grant; CSL Behring: Research Funding. Kruip:Boehringer Ingelheim: Research Funding; Pfizer: Research Funding; Bayer: Research Funding; Daiichi Sankyo: Research Funding; SOBI: Research Funding; Bayer: Speakers Bureau. Cnossen:Takeda: Research Funding; Shire: Research Funding; Baxter: Research Funding; Bayer: Research Funding; Sobi: Research Funding; CSL behring: Research Funding; Nordic Pharma: Research Funding; Novo Nordisk: Research Funding; Pfizer: Research Funding. Leebeek:CSL Behring: Research Funding; Shire/Takeda: Research Funding; Uniqure: Consultancy; Shire/Takeda: Consultancy; Novo Nordisk: Consultancy; SOBI: Other: Travel grant; Roche: Other: DSMB member for a study.

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Identification of Previously Unrecognized Multiple Myeloma Risk Subgroups with a Novel Biological Disease Stratifier

Blood ◽

10.1182/blood-2021-148718 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4718-4718

Author(s):

Afsaneh M. Shariatpanahi ◽

Sarah Grasedieck ◽

Matthew C. Jarvis ◽

Faezeh Borzooee ◽

Reuben S. Harris ◽

...

Keyword(s):

Multiple Myeloma ◽

High Risk ◽

Risk Score ◽

Risk Group ◽

Low Risk ◽

Intermediate Risk ◽

Disease Biology ◽

Kaplan Meier ◽

Risk Patients ◽

Patient Subgroups

Abstract Background: The prognosis of MM is determined by affected organs, tumor burden as measured by e.g., the international staging system (ISS), disease biology such as cytogenetic abnormalities, and response to therapy. The outcome of high-risk MM patients classified by ISS or adverse risk cytogenetics is not uniform and patients show heterogeneous survival. Recent insights into the pathogenesis of MM highlighted genome/transcriptome editing as well as inflammation as drivers for the onset and progression of MM. We hypothesized that inclusion of molecular features into risk stratification could potentially resolve the challenge of accurately distinguishing between high-risk and low-risk MM patients at initial diagnosis and improve outcome. Aim: We aimed to create a simple molecular risk score to identify unrecognized patient subgroups, who have been previously misclassified by current risk stratifiers. Method: The Multiple Myeloma Research Foundation CoMMpass study genomics dataset, combining mRNA Seq and clinical data from more than 700 MM patients, allowed us to evaluate the prognostic value of demographic and clinical parameters, cytogenetics, and gene expression levels of APOBEC genes as well as inflammation-modulating cytokines in MM patients. We calculated hazard ratios and Kaplan-Meier survival estimates for all extracted features. Combining clinical variables that were significantly associated with PFS and OS, we then applied machine learning approaches to identify the most accurate classification model to define a new risk score that is easy to compute and able to stratify NDMM patients more accurately than cytogenetics-based classifiers. Based on a Kaplan-Meier survival curve analysis, we then evaluated the performance of our newly built EI score in sub-classifying of current multiple myeloma risk stratifiers. Results: Based on machine learning models, we defined a weighted OS/PFS risk score (Editor-Inflammation (EI) score) based on mRNA expression of APOBEC2, APOBEC3B, IL11, TGFB1, TGFB3, as well as ß2-microglobulin and LDH serum levels. We showed that the EI score subclassified patients into high-risk, intermediate-risk, and low-risk prognostic groups and demonstrated superior performance (C-index: 0.76) compared to ISS (C-index: 0.66) and R-ISS (C-index: 0.64). We further showed that EI low-risk patients do not benefit from autograft and maintenance therapy. Re-classification of ISS (Figure 1a, b, c) and R-ISS risk groups further confirmed the superiority of the EI score. In addition, the EI score identified previously unrecognized distinct subgroups of MM patients with adverse risk cytogenetics but good prognosis (Figure 1d, e, f). For example, the EI score excellently subclassified del(17p) MM patients into three main risk subgroups including a super low-risk group (none of them has p53 mut) with 5-year OS of 100%, an intermediate-risk group (30% of these patients also have p53 mut) with 5-year OS rate of 75%, and a very poor prognosis group of patients (40% of these patients also have p53 mut) with 5-year OS rate of 0% (2y OS: 40%) (Figure 1f). In line, we could show that patients with del(17p) and high EI score exhibit an enrichment of APOBEC induced genomic mutations compared to intermediate-risk and low-risk patients supporting the hypothesis that del(17p) along with high APOBEC expression levels activate the APOBEC mutation program and thus create an optimal environment for tumor progression. These findings support the necessity of a prognostic score that more accurately reflects MM disease biology. Conclusion: Although MM is considered as an incurable disease, an improved risk stratification could help to identify previously unrecognized low- and high-risk patient subgroups that are over- or undertreated and lead to improved outcomes. Our EI score is a simple score that is based on recent insights into MM biology and accurately identifies high-risk and low-risk newly diagnosed MM patients as well as misclassified MM patients in different cytogenetic and ISS risk subgroups. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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