Intermediate Risk Stratification Research Articles

Characteristics of FLT3-ITD and Efficacy of Sorafenib Treatment in Pediatric AML: A Report from AML-BFM Study Group

Introduction Internal tandem duplication (ITD) of FMS-related tyrosine kinase 3 ( FLT3) gene is one of the most common somatic mutations in acute myeloid leukemia (AML). We and others have previously shown that the prognostic significance of FLT3-ITD in children and young adults relies on its characteristics e.g., co-occurrence with WT1 mutationsand NUP98::NSD1 fusions (Niktoreh et al. 2019) or higher allelic ratio (AR) (Tarlock et al. 2018) lead to worse survival outcomes. Also, recent studies suggested that treatment with FLT3 inhibitors, including sorafenib, might be effective in children with FLT3-ITD positive AML. In this report, we summarize the characteristics of FLT3-ITD and outcomes of treatment with sorafenib in patients recruited in AML-BFM consecutive trials. Methods Patients aged 0-21 years old, diagnosed with FLT3-ITD positive de novo AML between Jan. 2004 and Dec. 2021 in Germany and recruited in AML-BFM 2004 and 2012 studies or the 2012 and 2017 registries were retrospectively analyzed. All patients with FLT3-ITD with high- or intermediate risk stratification (HR or IR) were recommended to receive 100 mg/m² sorafenib taken orally twice daily on days 7 to 21 of their induction and consolidation chemotherapy blocks, the final decision however was made by the treating physicians. Patient samples were examined in AML-BFM reference laboratory in Essen, Germany using standard methods. Patients with Down syndrome and AML-M3 were excluded from the current analysis and survival rates were calculated using Kaplan-Meier method and Log-Rank test (significance threshold p<0.05). Results In total, 137 patients (51% male) with median age of 7.78 (1.3-19, IQR=7.27) years at diagnosis were included. Most of the patients were initially stratified in IR group (70%, N=95) followed by HR (26%, N=35). FABs M2, M4 and M1 consisted 74% of all morphologic subtypes with 26%, 25% and 23% of patients, respectively and with a median of 64,000 (500 -700,400, IQR=53,178) x10 9/L, the majority of patients showed a leukocytosis at diagnosis. The median ITD length in the 107 patients with available data was 51 (9-111, IQR=39) bps and 54% of the 91 patients with available data had an AR above 0.5. WT1 mutations and NUP98::NSD1 were detected in 25% (N=34) and 7% (N=10) of patients, respectively and 4% (N=6), harbored both mutations simultaneously. The three-year probability of overall and event-free survival (3y-OS and 3y-EFS, respectively) in all FLT3-ITD patients were 68.8% (±4.3) and 47.6% (±4.5), respectively and although harboring ITDs longer than the median length had a tendency to worsen the 3y-OS (54.4% in ITD>51 bps vs. 73.3% in ITDs<51 bps, p=0.071), it did not influence the 3-y EFS (41.7% vs. 54.2%, p=0.204). Similarly, an AR higher than 0.5 did not affect the survival outcomes (3y-OS: 67.4% vs. 60.4%, p=0.744, 3y-EFS: 46.8% vs. 47%, p=0.618). In total, 36 patients (27%) were treated with sorafenib of which, 23 (63%) received a consecutive HSCT. We observed no survival advantage between sorafenib-treated and sorafenib-naive groups of patients (3y-OS: 73.7% vs. 67.3%, p=0.408, 3y-EFS: 48.3% vs. 47.5%, p=0.929). Patients with longer ITDs did not benefit from sorafenib treatment (3y-OS: 68% vs. 54.3%, p=0.279, 3y-EFS: 48.9% vs. 38.4 %, p=0.649) but higher AR, showed a tendency of improved survival outcomes when sorafenib treatment was implicated (3y-OS: 80.8 % vs. 61.9 %, p=0.159, 3y-EFS: 67.3 % vs. 39.9 %, p=0.131). Although the number of patients were limited, we observed a possible survival advantage in double or triple FLT3-ITD, NUP98::NSD1 and WT1 mutated patients who received Sorafenib: from 28 patients with WT1 mutations only, four patients received sorafenib three of which, are currently alive and in CR but contrarily, from the 24 untreated patients, 14 (58%) are deceased (78% due to relapse). Additionally, from 10 patients with NUP98::NSD1 (w/o WT1 mutations), two who were treated with sorafenib are alive and in CR, whereas from the remaining 8 patients, 6 (75%) experienced relapse and unfortunately did not survive. Conclusions Our preliminary analysis implicates that although addition of sorafenib to the intensive chemotherapy of children and adolescence with FLT3-ITD positive AML, did not improve the survival outcomes in allpatients; specific genetic subgroups might benefit from this treatment. These results must be validated in bigger cohorts of patients with longer follow-ups.

Predictors of Non-Obstructive Coronary Artery Disease in Patients Undergoing Elective Coronary Angiography.

Appropriate patient selection for coronary angiography (CAG) is essential to minimize the unnecessary risk of morbidities and exposure to radiation and iodinated contrast. This becomes even more relevant in low-to-middle-income settings where most health expenditures are out-of-pocket due to lack of medical insurance. We determined predictors of non-obstructive coronaries (NOC) in patients undergoing elective CAG. CathPCI Registry®, single-center data was extracted for 25,472 patients who had CAG over an eight year period. After excluding patients for compelling conditions or known CAD, 2,984 (11.7%) patients were included in this study. Non-Obstructive Coronaries was defined as <50% left main coronary artery and major epicardial vessel stenosis. Multiple Cox proportional algorithm was employed to report prevalence ratios (PR) of predictors of NOC along with 95% confidence interval. Mean age of patients was 57.9 ± 9.7 years, 23.5% were women. Preprocedural non-invasive testing (NIT) was performed in 46% of the patients; of which 95.5% reported to be positive but only 67.3% were stratified as high risk. Of 2,984 patients undergoing elective CAG, 711 (24%) had NOC. Predictors of NOC included younger age <50 years (PR: 1.3, CI: 1.0-1.5), Women (1.8, 1.5-2.1), low (1.9, 1.5-2.5) and intermediate risk stratification (1.3, 1.0-1.6) on Modified Framingham Risk Score and inappropriate (2.7, 1.6-4.3) and uncertain (1.3, 1.1-1.6) classification of CAG on Appropriate Use Criteria. Patients with heart failure as an indication of CAG (1.7, 1.4-2.0) and No NIT or positive low risk NIT (1.8, 1.5-2.2) were more likely to have NOC. Approximately one out of four patients undergoing elective CAG had NOC. Yield of diagnostic catheterization can be improved by adjudicating NIT especially in younger patients, women, patients with heart failure as an indication of CAG, patients classified as inappropriate on Appropriate Use Criteria and patients categorized as low or intermediate risk on MFRS.

Investigation of distinct gene expression profile patterns that can improve the classification of intermediate-risk prognosis in AML patients.

Background: Acute myeloid leukemia (AML) is a heterogeneous type of blood cancer that generally affects the elderly. AML patients are categorized with favorable-, intermediate-, and adverse-risks based on an individual's genomic features and chromosomal abnormalities. Despite the risk stratification, the progression and outcome of the disease remain highly variable. To facilitate and improve the risk stratification of AML patients, the study focused on gene expression profiling of AML patients within various risk categories. Therefore, the study aims to establish gene signatures that can predict the prognosis of AML patients and find correlations in gene expression profile patterns that are associated with risk groups. Methods: Microarray data were obtained from Gene Expression Omnibus (GSE6891). The patients were stratified into four subgroups based on risk and overall survival. Limma was applied to screen for differentially expressed genes (DEGs) between short survival (SS) and long survival (LS). DEGs strongly related to general survival were discovered using Cox regression and LASSO analysis. To assess the model's accuracy, Kaplan-Meier (K-M) and receiver operating characteristic (ROC) were used. A one-way ANOVA was performed to assess for differences in the mean gene expression profiles of the identified prognostic genes between the risk subcategories and survival. GO and KEGG enrichment analyses were performed on DEGs. Results: A total of 87 DEGs were identified between SS and LS groups. The Cox regression model selected nine genes CD109, CPNE3, DDIT4, INPP4B, LSP1, CPNE8, PLXNC1, SLC40A1, and SPINK2 that are associated with AML survival. K-M illustrated that the high expression of the nine-prognostic genes is associated with poor prognosis in AML. ROC further provided high diagnostic efficacy of the prognostic genes. ANOVA also validated the difference in gene expression profiles of the nine genes between the survival groups, and highlighted four prognostic genes to provide novel insight into risk subcategories poor and intermediate-poor, as well as good and intermediate-good that displayed similar expression patterns. Conclusion: Prognostic genes can provide more accurate risk stratification in AML. CD109, CPNE3, DDIT4, and INPP4B provided novel targets for better intermediate-risk stratification. This could enhance treatment strategies for this group, which constitutes the majority of adult AML patients.

Evaluating Patient Profile, Follow-Up Rates and Barriers to Follow-Up at a Student-Run, Community-Based Tuberculosis Testing Program

Background: The Tulane Student-Run Tuberculosis (TB) Program provides TB risk evaluation, skin testing (TST), and referrals at six homeless shelters and rehabilitation facilities. To date, there has been no evaluation of the program’s patient profile. The objective of this study was to determine the symp-toms and risk factors for TB present in the program's clients, calculate follow-up rates for TST reading, and determine factors associated with an increased rate of missing reading appointments. &#x0D; Methods: This retrospective chart review examines the prevalence of risk factors and TB symptoms, evaluates risk stratification, and determines barriers to follow-up for TST over a 33-month period. Rel-ative risks (RR) were calculated to determine the association between risk stratification, positive TST, and loss to follow-up. Z-values were calculated, and p-values were determined as the area of the dis-tribution outside of +/- z. P-values &lt;0.05 were considered statistically significant. &#x0D; Results: Of 6,198 individuals seen, 479 were referred to higher care, 238 received 30-day clearances, 34 deferred testing, and four were sent to the hospital. Of 5,443 TSTs placed, 4,155 were read and 214 were positive. Individuals who had any risk factors were at significantly increased risk of not attending TST reading (RR 2.14, 95% Confidence interval [CI] 1.96-2.34, p&lt;0.01) and, for those who did attend, of having a positive TST (RR 1.52, 95% CI 1.17-1.98, p&lt;0.01). Higher risk of no-show and positive TST was also seen in homeless individuals (RR 3.44, 95% CI 2.92-4.07, p&lt;0.01 and RR 2.10, 95% CI 1.52-2.90, p&lt;0.01, re-spectively) and those with intermediate-risk stratification (RR 1.25, 95% CI 1.11-1.41, p&lt;0.01 and RR 1.32, 95% CI 1.01-1.72, p=0.04, respectively). &#x0D; Conclusions: Individuals experiencing homelessness and those with intermittent TB risk stratification are at increased risk for positive TST. Both homelessness and the presence of any TB risk factors in-crease the risk of loss to follow-up.

The Prognostic Significance of C-Reactive Protein to Albumin Ratio in Newly Diagnosed Acute Myeloid Leukaemia Patients.

BackgroundThe ratio of C-reactive protein to albumin (CAR) is an inflammatory marker that has been demonstrated to be a simple and reliable prognostic factor in several solid tumours and chronic lymphocytic leukaemia (CLL). However, no studies have investigated the prognostic value of the CAR in patients with acute myeloid leukaemia (AML).Objectives and MethodsWe retrospectively analysed 212 newly diagnosed non-M3 AML patients. Using the receiver operating characteristic curve (ROC) method, the optimal cut-off value for CAR was determined. We investigated the correlations of the pretreatment CAR levels with clinical characteristics, treatment response of induction chemotherapy, overall survival (OS) and event-free survival (EFS). We also assessed the prognostic value of the CAR compared with other inflammation-based prognostic parameters by the area under the curve (AUC).ResultsAccording to the ROC curve, the optimal cut-off value of CAR was 1.015. CAR was associated with age, C-reactive protein (CRP) levels, albumin levels, ferritin levels, bone marrow blast percentage, French-American-British (FAB) classification, immunophenotype and 2017 European Leukemia Net (2017 ELN) risk stratification. Importantly, we found that high CAR was a powerful indicator of a lower complete remission (CR) rate (p<0.001), worse OS (p<0.001) and worse EFS (p<0.001). Subgroup analysis showed that a high CAR was associated with shorter OS and EFS in patients with intermediate risk stratification or those aged ≤65 years or those without haematopoietic stem cell transplantation (HSCT). In the multivariate analysis, the CAR was an independent prognostic factor for OS and EFS. Furthermore, the predictive value of CAR for OS is superior to that of CRP, albumin and GPS in de novo AML patients aged ≤65 years old.ConclusionCAR is a simple and effective prognostic marker in patients with AML. It could be an additional prognostic factor that help further precise the current risk stratification of non-M3 AML, particularly for patients in intermediate risk stratification and those aged ≤65 years and those who did not undergo HSCT.

Lymphocyte-to-monocyte ratio prior to radioiodine ablation in low- and intermediate-risk, papillary thyroid cancer.

We aimed to investigate inflammation indices based on preablation hematological parameter of the lymphocyte-to-monocyte ratio (LMR) to predict the clinical outcome in papillary thyroid cancer (PTC) patients with low- and intermediate-risk stratification. This retrospective study analyzed 772 patients with low- and intermediate-risk PTC who underwent total thyroidectomy followed by radioiodine therapy between July 2005 and July 2009 with a median of 10 years. Kaplan-Meier statistics were used to test differences in recurrence-free survival (RFS) between groups based on the optimal cutoff point of biomarkers identified using receiver operating characteristic curves. With an optimal cutoff point of 7.05, 215 patients (29.8%) were classified as having low LMR and 557 patients (71.2%) were classified as having high LMR. High LMR was significantly associated with a prolonged RFS (hazard ratio [HR]: 2.048, 95% confidence interval [CI]: 1.062-4.359, p = 0.001). Multivariate analysis showed that low LMR (HR = 2.035, 95% CI: 1.011-4.095, p = 0.012), tumor size over 2 cm (HR = 2.762, 95% CI: 1.303-5.852, p = 0.008), and high preablative simulated thyroglobulin level over 10 ng/ml (HR = 7.826, 95% CI: 2.353-26.033, p < 0.001) were independent prognostic markers for worse RFS in the enrolled PTC patients. LMR at the time of radioiodine therapy has comparable predictor for the clinical outcome with both tumor size and preablative simulated thyroglobulin level in low- to intermediate-risk PTC patients.