CRc Rate Research Articles

Utilization of SDC2 gene in conjunction with SEPTIN9 gene methylation analysis for the diagnosis and efficacy assessment of colorectal cancer.

240 Background: SDC2 gene encodes the transmembrane proteoglycan molecule Syndecan-2. Syndecan-2 protein affects the proliferation, migration and invasion of colorectal cancer cells by participating in the regulation of cell adhesion, tissue differentiation and angiogenesis. Plasma methylated SEPTIN9 gene has been shown to be a sensitive and specific biomarker for the detection of CRC, which is involved in apoptosis, pseudopod projection, tumor cell migration and invasion. The aim of this study is to validate the value of SDC2 and S9 gene methylation detection in the diagnosis and efficacy evaluation of CRC. Methods: A total of 102 patients were enrolled in the study. The methylation levels of fecal SDC2 gene and blood SEPTIN9 gene were detected by fluorescence PCR. The clinical diagnostic accuracy of SDC2 kit was evaluated by patients with benign gastrointestinal lesions, gastrointestinal tumors and healthy subjects. Combined detection of SDC2 and S9 to improve the detection rate of CRC. SDC2m levels were analyzed in 26 patients with partial remission or stable disease after palliative treatment and 32 patients with complete remission after radical surgery. Results: The detection rate of SDC2 in patients was 0.0% for UC and CD, 66.7% for AA and 60.0% for NA, 25.0% for HOP. For 8 healthy subjects with negative colonoscopies, the true negative rate was 100%. The detection rates of GC and EC were 50.0% and 0.0%, respectively. Data from 72 patients with CRC were evaluated, with a sensitivity of 89.1% (41/46,95%CI 0.798-0.985) for patients with untreated CRC. The sensitivity of SDC2 was 46.2% (12/26,95%CI 0.256-0.667) in patients with partial response or stable disease after palliative treatment. The difference was statistically significant (P < 0.001). The sensitivity of S9 for CRC detection was 88.2% (15/17, 95%CI 0.712-1.053). By two tests, 94.1%(16/17, 95%CI 0.816-1.066) of CRC cases could be detected.The sensitivity was 89.1% (41/46 95%CI 0.798-0.985) in untreated CRC and 46.2% (12/26 95%CI 0.256-0.667) in patients with PR and SD after chemotherapy/radiotherapy/targeted/immunotherapy. The difference rate of SDC2m between two groups was statistically significant (P < 0.001). Among 46 untreated patients with CRC, 32 patients with positive SDC2m underwent radical surgery, of which 30 CR patients turned SDC2m test negative after surgery. We found reduced SDC2m in stool from patients with clinical benefit (CR+PR+SD). Conclusions: Detection of SDC2m in untreated CRC patients has high sensitivity and has the potential to become a non-invasive diagnostic tool for CRC. Combination of S9 and fecal SDC2 could improve the detection rate of SDC2 in non-dominant population. The methylation level of SDC2 may be helpful for postoperative follow-up of CRC after radical surgery, prediction of recurrence, and monitoring the efficacy of a series of palliative treatments for CRC.

Assessing the Colorectal Cancer Landscape: A Comprehensive Exploration of Future Trends in 216 Countries and Territories from 2021 to 2040

BackgroundColorectal cancer (CRC) has become a significant global concern, presenting formidable challenges to healthcare systems and leading to substantial healthcare expenses. This study examines the projected prevalence and trends of CRC worldwide, encompassing 21 regions and 195 nations.MethodsWe employed an illness-death model (IDM) in order to forecast the anticipated prevalence of CRC by the year 2040. To accomplish this, we utilized data retrieved from the Global Health Data Exchange (GHDx) query tool spanning from 1990 to 2021. The primary objective of this study is to furnish sex-specific estimations encompassing various geographical regions.ResultsBy 2040, the global age-standardized prevalence rate (ASPR) of CRC among the total population is projected to rise, reaching 145.82 per 100,000, which reflects an increase of 8.15%. East Asia is forecasted to have the highest ASPR at 330.17 per 100,000, representing a substantial rise of 94.81%. Notably, the most rapid percentage increase is projected in Andean Latin America, with an anticipated rise of 106.2%. In contrast, many countries, particularly in developed nations, are expected to see a decline in ASPR during this period. The United Arab Emirates is projected to experience the most significant decrease in ASPR, at -86.51%, while Mauritius is anticipated to have the largest increase in CRC prevalence rate, at 226.26%. Globally and regionally, the ASPR among males is expected to remain higher than that among females over the next 21 years.ConclusionsThe global prevalence of CRC is increasing, particularly in developing countries, while developed countries are anticipated to observe a declining trend. This highlights the significance of appropriately allocating resources and implementing effective preventive measures, especially in developing nations.

Single or Double Induction With 7 + 3 Containing Standard or High-Dose Daunorubicin for Newly Diagnosed AML: The Randomized DaunoDouble Trial by the Study Alliance Leukemia.

To determine the optimal daunorubicin dose and number of 7 + 3 induction cycles in newly diagnosed AML, this randomized controlled trial compared a once daily dose of 60 mg/m2 with 90 mg/m2 daunorubicin in the first 7 + 3 induction and one versus two cycles of 7 + 3 induction. Patients age 18-65 years with newly diagnosed AML were randomly assigned to 60 versus 90 mg/m2 daunorubicin once daily plus cytarabine. Patients with marrow blasts below 5% on day 15 after first induction were randomly assigned to receive a second induction cycle or no second induction cycle. Eight hundred and sixty-four patients with a median age of 52 years were randomly assigned. After a preplanned interim analysis showing no significant difference in response between 60 and 90 mg/m2, all consecutive patients received 60 mg/m2 daunorubicin once daily. The proportion of good early responders was 44% versus 48% (P = .983) with a composite complete remission (CRc) rate of 90% versus 89% after induction (P = .691); the 3-year relapse-free survival (RFS) after 60 versus 90 mg/m2 once daily was 54% versus 50% (P = .561), and the 3-year overall survival (OS) was 65% versus 58% (P = .242). Among 389 good responders, CRc rates at the end of induction were 87% after single induction and 85% after double induction. The 3-year RFS was 51% versus 60% (hazard ratio [HR], 1.3; P = .091), and the 3-year OS was 76% versus 75% after single versus double induction (HR, 1.0; P = .937). The use of 90 mg/m2 daunorubicin once daily in the context of classical 7 + 3 induction does not significantly improve early response and does not lead to higher remission rates or longer survival than 60 mg/m2 once daily. In patients with a good early response after first induction, a second induction has only a limited impact on RFS and does not result in an OS benefit.

A phase 1/2 study of gilteritinib in combination with chemotherapy in newly diagnosed patients with AML in Asia

ObjectiveThis interim analysis of a phase 1/2, open-label, single-arm study assessed the safety, efficacy, and pharmacokinetics of gilteritinib plus chemotherapy in adults with newly diagnosed FLT3 mutation-positive acute myeloid leukemia.MethodsIn sequential phase 1 and 2 studies, induction and consolidation therapy with gilteritinib 120 mg/day plus chemotherapy (induction: idarubicin/cytarabine once daily; consolidation: cytarabine twice daily) was followed by maintenance gilteritinib 120 mg/day monotherapy. Endpoints included maximum tolerated dose (MTD), recommended expansion dose (RED), and dose-limiting toxicity (phase 1), and complete remission (CR) rate following induction therapy (primary endpoint), overall survival (OS), safety, and pharmacokinetics (phase 2).ResultsIn phase 1, MTD was not reached and RED was 120 mg/day. In phase 2, the CR rate was 50.0% after induction (90% confidence interval [CI] 40.4, 59.6); however, the lower confidence limit did not exceed the pre-defined 55% benchmark. Composite CR (CRc) rates were high following induction (86.6%, 95% CI [77.3, 93.1]), consolidation, and maintenance therapy (87.8%, 95% CI [78.7, 94.0], each). The probability of OS was 86.6% at 12 months. No new safety findings were reported.ConclusionIn this interim analysis, gilteritinib 120 mg/day in combination with chemotherapy was well tolerated, with similar CRc rates to previous studies.

Caspase-4 Has Potential Utility as a Colorectal Tissue Biomarker for Dysplasia and Early-Stage Cancer

Background and AimsColorectal cancer (CRC) is the second most deadly cancer globally. The rapidly rising incidence rate of CRC, coupled with increased diagnoses in individuals <50 years, indicates that early detection of CRC, and those at an increased risk of CRC development, is paramount to improve the survival rates of these patients. Here, we profile caspase-4 expression across two distinct CRC development pathways, sporadic CRC (sCRC) and inflammatory bowel disease-associated CRC (IBD-CRC), to examine its utility as a novel biomarker for CRC risk and diagnosis. MethodsTissue samples from patients with CRC, colonic polyps, IBD-associated CRC, and sporadic CRC were assessed by Immunohistochemistry (IHC) for caspase-4 expression in epithelial and stromal compartments. RNAseq expression data for caspase-4 in CRC and normal tissue samples were mined from online databases. ResultsEpithelial caspase-4 expression is selectively elevated in CRC tumour tissue compared to adjacent-normal tissue, where it is not expressed. In the sCRC pathway, caspase-4 is expressed in the epithelial and stromal tissue of all histological subtypes of colonic polyps, with a significant increase in epithelial expression from LGD to HGD progression. For the IBD-CRC pathway, caspase-4 epithelial expression was specifically upregulated in dysplastic and neoplastic tissue of IBD-CRC but was not expressed in normal or inflamed tissue. ConclusionsThis study demonstrates that epithelial caspase-4 is selectively expressed in colon tissue during the development of dysplasia. As such, epithelial caspase-4 represents a promising novel tissue biomarker for CRC risk and diagnosis.

A systematic review of venetoclax for the treatment of unfit AML patients in real-world: is all thatglitters gold?

Acute myeloid leukemia (AML) is an aggressive hematological disease that mainly affects elderly patients. Following the randomized VIALE-A trial, current standard treatment in patients who are not candidates for intensive chemotherapy consists of the combination of venetoclax (VEN), a selective inhibitor of the anti-apoptotic protein BCL-2, with azacitidine (AZA) or decitabine (DEC). We performed a systematic review to critically assess the growing existing evidence regarding the effectiveness of the VEN-based combinations in unfit adult patients with newly diagnosed AML in the real-world setting. Following PRISMA guidelines, a systematic search of published manuscripts and conference abstracts (European Hematology Association and American Society of Hematology) was conducted (updated March 2024). Primary outcomes were composite complete remission (CRc) and median overall survival (mOS). A total of 73 studies fulfilled inclusion criteria, with a median age of 73years old. The weighted mean mOS was 10.3months among 7 138 patients, significantly lower than expected according to the VIALE-A trial (14.7months), while the weighted mean CRc rate was 58.2% among 5 831 patients, slightly lower to that reported in the VIALE-A (66.4%). Early death rates at 30 and 60days were 5% and 13%, respectively. The weighted mean percentage of subsequent allogeneic transplant was 15.4%. In conclusion, breakthrough mOS reported in the VIALE-A trial using VEN-AZA was not well reproduced in real world for unfit newly diagnosed AML patients, while CRc rates were more consistent. Strategies to optimize patient selection, dosing regimens, and supportive care are crucial to improve outcomes in real-world.

Identification of Potent SFRP1 Inhibitors for Colorectal Cancer using a Comprehensive Computational Approach.

The incidence of CRC has increased worldwide over the past decade. The statistics report from WHO highlights the increased severity and fatality rate of CRC among the populations. Wnt/β-catenin is recognized as the resource for cell regeneration and cancer signaling pathways driven by frizzled receptor cofactors. Aberrant regulation of Wnt/β- catenin suppression is an important challenge in treating CRC management. The SFRP1 comprises a cysteine-rich region that is homologous to the putative Wnt-binding sites of Frizzled proteins, with the potential to impede and alter the cascade of Wnt signaling. Indirect regulation, like targeting Wnt antagonist SFRP1, is an alternative strategy to suppress the cancer signals by enhancing the apoptotic activity. Hence, this study aimed to approach the SFRP1 protein as a therapeutic target to inhibit Wnt signaling in colorectal cancer. Further, it aimed to identify the lead compounds against the SFRP1 protein, which inhibit the oncogenic expression of CRC, which might be possible using computational approaches, recognizing the importance of the SFRP1 protein role in CRC. The homology-modeled SFRP1 structure was refined, and virtual screening was performed against the anti-cancer drugs and natural drug databases to find the best hit molecules. The molecular docking, MD, and MMGBSA analysis confirmed the firm binding of SFRP1 complexes to identify the potent CRC inhibitors. The amino acid residues Arg5, Arg11, Ala13, Lys 245, Lys274, Phe147, Pro99, and Ser277 are essential for ligand binding and show similar interactions for SFRP1 complexes. The ADME/T profile for top hits is acceptable in range and obtains the drug-likeness property. The 100ns run for MD simulation confirms the stability of protein complexes. Overall, the findings of this study reveal that the lead compounds screened are capable of inhibiting SFRP1 against CRC. Targeting SFRP1 paves the way for new platforms in the field of cancer and the therapeutic sector for new approachable finds.

Segmental colitis associated with diverticulosis (SCAD) in a colorectal cancer screening population: Prevalence, endoscopic features and oncological outcomes

BackgroundSegmental colitis associated with diverticulosis (SCAD) is characterized by a chronic inflammatory response involving the inter-diverticular colonic mucosa, sparing the rectum and the right colon. Aims: to assess the prevalence of SCAD in a CRC screening program and to evaluate the differences in terms of oncological outcomes between SCAD and diverticulosis. Methodsretrospective analysis from a prospectively-maintained database including all subjects undergoing first screening colonoscopy. Results1518 patients were included (51.8 % male, mean age 63.48 ± 6.39). Adenomas were detected in 638 patients (ADR 42 %), CRC was diagnosed in 5.7 %. Diverticulosis was described in 37.5 %, while SCAD in 4.5 %. Among them, 69.6 % presented crescentic-fold disease, 20.3 % mild-to-moderate UC-like pattern, 8.7 % CD-like pattern and 1.4 % severe UC-like pattern. When SCAD was compared to uncomplicated/asymptomatic diverticulosis (501 patients), we found no differences in terms of gender (p = 0.46) or age (p = 0.47). Interestingly, the use of anticoagulant/antiplatelet (p = 0.79), anti-hypertensive (p = 0.89) or anti-hyperglycaemic drugs (p = 0.52) had no effect on SCAD onset as compared to diverticulosis. SCAD patients had significant lower rate of adenomas (ADR 31.9% vs 47.3 %, p = 0.018, OR 0.52, 95 %CI 0.31–0.89), and lower–but not significant–rate of CRC (1.4% vs 6.2 %, p = 0.14, OR 0.22, 95 %CI 0.02–1.66). ConclusionsSCAD can be diagnosed in about 5 % of population undergoing screening colonoscopy and in 12 % of those with diverticulosis. SCAD seems to be associated with a reduced rate of adenomas or CRC as compared with diverticulosis.

A retrospective comparison of abbreviated course “7+7” vs standard hypomethylating agent plus venetoclax doublets in older/unfit patients with newly diagnosed acute myeloid leukemia.

6507 Background: Hypomethylating agent (HMA) plus venetoclax (VEN) regimens are standard of care in older/chemotherapy ineligible patients with acute myeloid leukemia (AML). While the VEN label recommends continuous 28-day cycles, shortened VEN durations may mitigate cytopenias and improve tolerability. It is unknown how shorter VEN cycles compare to standard HMA+VEN in terms of efficacy/safety. Methods: We performed a retrospective comparison of patients with newly diagnosed (ND) AML treated with azacitidine (AZA) x 7 days plus VEN x 7 days (“7+7” regimen) at 7 French centers (n=82, Willekens, ASH 2022) vs patients treated with standard dose HMA+VEN (s-HMA/VEN) at a US center (n=173), generally consisting of 21-28 days of VEN. We compared composite complete remission rate (CRc, consisting of CR + CRi), overall survival (OS), event-free survival (EFS), and myelosuppression between regimens. Results: Baseline characteristics are shown in the table. The s-HMA-VEN group consisted of 10-day decitabine (DAC) in 59% with the remaining patients receiving 5-day DAC or 7-day AZA. The CRc rate was similar; 72% with “7+7” vs 71% with s-HMA/VEN (p=0.89). The CR rate was 57% with “7+7” vs 55% with s-HMA/VEN (p=0.72). Median cycles to first response was 1 in both groups, however 42% of responders on “7+7” required more than 1 cycle for first response whereas almost all responders on s-HMA-VEN (99%) had a first response after cycle 1. Median cycles to best response was 2 with “7+7” vs 1 with s-HMA-VEN (p=0.02). 4-week mortality was similar (2% with “7+7”, 6% with s-HMA-VEN; p=0.24). 8-week mortality was higher with s-HMA-VEN (17%) compared to “7+7” (6%) (p=0.02). The median OS was 11.2 months (2-year 28%) with “7+7” vs 10.1 months (2-year 33%) with s-HMA/VEN (p=0.93). Outcomes stratified by molecular groups will be updated at the meeting. Fewer patients required platelet transfusions during cycle 1 with “7+7” compared to s-HMA/VEN (62% vs 77%, p=0.01). The cycle 1 rates of neutropenic fever and red cell transfusion requirements were similar. Conclusions: Acknowledging the limitations of a retrospective comparison across multiple centers, we did not observe a signal for a difference in efficacy between "7+7" vs standard VEN-based HMA doublets in ND-AML. The “7+7” regimen was associated with lower platelet transfusion requirements and lower 8-week mortality. [Table: see text]

High risk features in colorectal adenomatous polyps: A multi-institutional study

High risk features in colorectal adenomatous polyps include size >1 cm and advanced histology: high-grade dysplasia and villous architecture. We investigated whether the diagnostic rates of advanced histology in colorectal adenomatous polyps were similar among institutions across the United States, and if not, could differences be explained by patient age, polyp size, and/or CRC rate. Nine academic institutions contributed data from three pathologists who had signed out at least 100 colorectal adenomatous polyps each from 2018 to 2019 taken from patients undergoing screening colonoscopy. For each case, we recorded patient age and sex, polyp size and location, concurrent CRC, and presence or absence of HGD and villous features. A total of 2700 polyps from 1886 patients (mean age: 61 years) were collected. One hundred twenty-four (5 %) of the 2700 polyps had advanced histology, including 35 (1 %) with HGD and 101 (4 %) with villous features. The diagnostic rate of advanced histology varied by institution from 1.7 % to 9.3 % (median: 4.3 %, standard deviation [SD]: 2.5 %). The rate of HGD ranged from 0 % to 3.3 % (median: 1 %, SD: 1.2 %), while the rate of villous architecture varied from 1 % to 8 % (median: 3.7 %, SD: 2.5 %). In a multivariate analysis, the factor most strongly associated with advanced histology was polyp size >1 cm with an odds ratio (OR) of 31.82 (95 % confidence interval [CI]: 20.52–50.25, p < 0.05). Inter-institutional differences in the rate of polyps >1 cm likely explain some of the diagnostic variance, but pathologic subjectivity may be another contributing factor.

Abstract 6696: Microbial signatures and serum markers in colon cancer of African American patients

Abstract Among all the racial/ethnic groups, African American (AA) patients have the highest incidence of CRC and mortality rate. There is growing evidence indicating that the oral bacteria might translocate to the intestine, potentially causing disruptions in the balance of gut microbes. Our study delves into the complex interplay between oral pathogens, gut microbiota, and colon carcinogenesis in AA patients. Methods: 16S rRNA sequencing of tumor and non-tumor tissues, utilized qPCR for detection of oral bacteria Fusobacterium nucleatum (Fn) and Porphyromonas gingivalis (Pg) relative abundance, performed cytokine profiling via multiplex ELISA, and employed NAPPA for antibody response assessment. Results: Colon tumor tissues had lower microbial diversity, notably in right-sided tumors, with distinct biofilm-associated bacteria. Novel discoveries emerged from differential abundance testing, revealing Prevotella intermedia and Treponema socranski to be associated with early cancer stage and left-sided location, and Fusobacterium necrophorum with advanced cancer stage and right-sided location. qPCR demonstrated Fn and Pg elevation in right-sided tumors and late cancer stages. Both were detected in 45% of tumors versus 37% in non-tumor tissues and 19.15% of tumors and 25.53% in non-tumor tissues, respectively. Fn-positive groups exhibited distinct microbial signatures, with altered bacterial abundances and dysbiosis, including increased CRC-associated bacteria Faecalibacterium and Helicobacter, increased oral pathogen abundance (Fusobacterium, Porphyromonas, Prevotella, Treponema), and reduced beneficial bacteria. Serological analysis highlighted elevated levels of IL-2, IL-10, IFN-γ, and RANK in advanced cancer stages and increased CRP levels in right-sided tumors. By NAPPA analysis, 30 bacterial proteins (anti-IgG) showed a seroprevalence of more than 15% in the samples, with those being the most seroprevalent anti-HP131 and anti-HP-1564 (68% and 61% of all samples) of Helicobacter pylori, and anti-msnK (64%) of Streptococcus gallolyticus. Conclusions: Our study emphasized the reduced diversity in tumor tissues, particularly in right-sided tumors in AA colon cancer. Fn presence in colonic tumors correlated with CRC-associated bacteria and oral pathogen aggregation, suggesting its potential role in cancer pathogenesis. Combining the analysis of cytokines and pathogenic bacteria antibodies may serve as broader serological biomarkers for disease severity and location. These findings advance our comprehension of microbiota-cancer interactions, directing personalized diagnostics and treatments in this population. Citation Format: Sofia Carolina Tortora, Emily Vogtmann, Laura Martello-Rooney. Microbial signatures and serum markers in colon cancer of African American patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6696.

Abstract 2746: MAGE-A3 co-expression with IDH1-R132H and IL-1β in colon cancer

Abstract Colorectal cancer (CRC) remains a significant cause of cancer death worldwide with an estimated 52,000 deaths in 2023. Over the past few decades, the incidence rate of CRC in individuals younger than 50 has been steadily increasing. Currently, diagnostic biomarkers play an important role in the detection and treatment of CRC. MAGE-A3 has been shown to be expressed in many tumor types, including colon cancer by RNA expression. Due to their high sequence homology, members of the MAGEA family have been difficult to evaluate and screen for their protein expression. However, in a previous study, highly specific antibodies were identified using CytoSections for MAGE-A3 immunohistochemistry. IL-1β is a cytokine that induces inflammatory responses and when localized to the nucleus in colon cancer cells it can promote stemness. IL-1β expression has been shown to be increased in wildtype IDH1 positive glioblastoma. However, the relationship between IL-1β and IDH1 has not been studied in colon cancer. In this study, the difference in the expression of MAGE-A3, IL-1β, and wildtype IDH1 compared to mutant IDH1-R132H in colon cancer tissues was evaluated. The results show that IL-1β, wildtype IDH1, and MAGE-A3 were co-expressed in 27 of the 38 colon cancer tumors. However, IDH1-R132H expression was only seen in 20% of the tumors. This study suggests that MAGE-A3, IL-1β, and IDH1 are candidate biomarkers for immunotherapy due to their high expression in colon cancer tissues. Citation Format: Andy/Xi Han, Rachel Gonzalez, Jina Yom, Zhaoying Guo, Bailey Gilmore, Eden Zewdu, Tianli Qu, Hailey/YiChen Guo, Qi Ren, Xiaomin Hu, Ranran Zhang, Zhaohui Wu, Xuan Liu, Wei Fu. MAGE-A3 co-expression with IDH1-R132H and IL-1β in colon cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2746.

Venetoclax plus a hypomethylating agent versus cytarabine, aclarubicin, and granulocyte colony-stimulating factor chemotherapy as a first-line therapy for newly diagnosed acute myeloid leukemia: A propensity score-matched analysis.

Both venetoclax plus a hypomethylating agent (VEN/HMA) and cytarabine, aclarubicin, and granulocyte colony-stimulating factor (CAG) are low-intensity regimens for older patients with acute myeloid leukemia (AML) that show good efficacy and safety. It is unknown how VEN/HMA compares with the CAG regimen for the treatment of newly diagnosed AML. The outcomes of patients with newly diagnosed AML treated with VEN/HMA were compared with those of patients treated with a CAG-based regimen. Propensity score matching between these two cohorts at a 1:1 ratio was performed according to age at diagnosis, sex, Eastern Cooperative Oncology Group performance status, state of fitness, and European LeukemiaNet (ELN) 2022 risk stratification to minimize bias. A total of 84 of 96 patients in the VEN/HMA cohort were matched with 84 of 147 patients in the CAG cohort. VEN/HMA resulted in a better response than the CAG-based regimens, as indicated by a higher composite complete remission (CRc) rate (82.1% vs. 60.7%; p=.002) and minimal residual disease negativity rate (88.2% vs. 68.2%; p=.009). In patients with an ELN adverse risk, VEN/HMA was associated with a higher CRc rate compared to CAG (80.5% vs. 58.3%; p=.006). VEN/HMA was associated with longer event-free survival (EFS) (median EFS, not reached vs. 4.5 months; p=.0004), whereas overall survival (OS) was comparable between the two cohorts (median OS, not reached vs. 18 months; p=.078). The VEN/HMA regimen may result in a better response than CAG-based treatment in older patients with newly diagnosed AML.

Venetoclax plus cytarabine and azacitidine in relapsed/refractory AML: An open-label, single-arm, phase 2 study

BackgroundThe outcome of relapsed/refractory (R/R) acute myeloid leukemia (AML) remains extremely poor. Venetoclax (VEN)-based regimens have shown promise in treating R/R AML. ObjectiveThis phase 2 study aimed to systematically evaluate the efficacy and safety of the VAA regimen (VEN plus Cytarabine and Azacitidine) in R/R AML patients. MethodsThirty R/R AML patients were enrolled. The study adopted a stepwise ramp-up of VEN dosing, starting with 100 mg on day 1, escalating to 200 mg on day 2, and reaching 400 mg from day 3 to day 9. Cytarabine (10 mg/m2, q12h) was administered intravenously twice daily from days 1 to 10, and Azacitidine (75 mg/m2) was administered via subcutaneous injection once daily from days 1–7. The primary efficacy endpoint was the composite complete remission rate (CRc), including complete response (CR) and complete response with incomplete blood count recovery (CRi). Secondary endpoints included overall survival (OS), duration of response (DOR), and safety analysis. ResultsThe CRc rate was 63.3% (19/30), with CR in 36.7% of patients and CRi in 26.7%. Notably, 14 (73.7%) of 19 patients achieving CRc showed undetectable measurable residual disease by flow cytometry. With a median follow-up of 10.7 months, the median OS had not been reached, and the median DOR was 18.3 months. The most common grade 3–4 adverse events (AEs) were neutropenia (100%), anemia (96.7%), thrombocytopenia (90.0%), and leukopenia (90.0%). Infections, with pneumonia being the most prevalent (43.3%), were observed, including one fatal case of Pseudomonas aeruginosa septicemia. There were no treatment-related deaths. ConclusionThe VAA regimen is an effective and safe option for patients with R/R AML, demonstrating a high CRc rate and manageable safety profile.

Venetoclax plus daunorubicin and cytarabine in newly diagnosed acute myeloid leukemia patients: A propensity score-matched analysis.

Venetoclax plus 3+7 daunorubicin and cytarabine chemotherapy (DAV) has shown safety and efficacy in eligible patients with newly diagnosed acute myeloid leukemia (AML). However, there are no direct comparisons between DAV and 3+7 daunorubicin and cytarabine chemotherapy (DA) alone. We performed a propensity score-matched analysis to compare the outcomes of DAV group with historical DA group and identify the clinical and molecular characteristics of patients who might benefit from the DAV regimen. The DAV group had a higher Complete remission (CR) rate than the DA group (90% vs. 55%, p=0.008). 25 (96%) patients in the DAV group had a higher MRD-negative CRc rate compared with 13 (62%) patients in the DA group (p=0.006). After a median follow-up duration of 19.15 (IQR 17.13-21.67) months, the DAV group had an improved overall survival (p=0.001) and event-free survival (p=0.069), but not disease-free survival (p=0.136). Collectively, DAV regimen induced high CR rates and deep MRD-negative CRc rates after one cycle of induction therapy, as well as prolonged the overall survival, in young adult patients with AML who were eligible for intensive chemotherapy. The addition of venetoclax to intensive chemotherapy should be considered in the future to achieve better survival advantages in eligible AML patients.

The National Burden of Colorectal Cancer in the United States from 1990 to 2019.

CRC accounts for approximately a tenth of all cancer cases and deaths in the US. Due to large differences in demographics among the different states, we aim to determine trends in the CRC epidemiology and across different states, age groups, and genders. CRC rates, age-adjusted to the standard US population, were obtained from the GBD 2019 database. Time trends were estimated as annual percentage change (APC). A pairwise comparison was conducted between age- and gender-specific trends using the tests of parallelism and coincidence. Age-specific trends were also assessed in two age subgroups: younger adults aged 15-49 years and older adults aged 50-74 years. We also analyzed the prevalence, incidence, mortality, and DALYs in the US between 1990 and 2019. A total of 5.53 million patients were diagnosed with CRC in the US between 1990 and 2019. Overall, CRC incidence rates have significantly increased in younger adults (11.1 per 100,000 persons) and decreased in older adults (136.8 per 100,000 persons) (AAPC = 1.2 vs. -0.6; AAPC difference = 1.8, p < 0.001). Age-specific trends were neither identical (p < 0.001) nor parallel (p < 0.001), suggesting that CRC incidence rates are different and increasing at a greater rate in younger adults compared to older adults. However, for both men and women (49.4 and 35.2 per 100,000 persons), incidence rates have decreased over the past three decades at the same rate (AAPC = -0.5 vs. -0.5; AAPC difference = 0, p = 0.1). Geographically, the southern states had the highest mortality rates with Mississippi having the highest rate of 20.1 cases per 100,000 population in 2019. Massachusetts, New York, and the District of Colombia had the greatest decreases in mortality over the study period (-42.1%, -41.4%, and -40.9%). Decreased mortality was found in all states except Mississippi, where the mortality of CRC increased over the study period (+1.5%). This research provides crucial insights for policymakers to tailor resource allocation, emphasizing the dynamic nature of CRC burden across states and age groups, ultimately informing targeted strategies for prevention and intervention.

Clinical and genetic characteristics predict outcomes of acute myeloid leukemia patients with FLT3 mutations receiving venetoclax-based therapy.

Acute myeloid leukemia (AML) is a heterogeneous disease, and its heterogeneity is associated with treatment response. Despite the demonstrated success of venetoclax (VEN)-based therapy for AML, the effect of FLT3 mutations on the efficacy of the therapy is poorly understood. We aimed to compare the efficacy of VEN-based therapy between FLT3-mutated (FLT3mut ) and FLT3 wild-type (FLT3wt ) patients and identify the predictors of efficacy in FLT3mut patients. A total of 266 AML patients (127 newly diagnosed [ND] and 139 refractory/relapsed [R/R]) receiving VEN-based regimens were enrolled in this study. A retrospective analysis was performed, and the treatment responses and overall survival (OS) of FLT3mut and FLT3wt patients were compared. Logistic regression and Cox proportional hazards model were applied to examine the clinical and genetic predictors of outcomes. With a median of two cycles of VEN-based therapy, for the ND AML cohort, the FLT3mut group had a comparable composite complete remission (CRc) rate with the FLT3wt group (79.3% vs. 61.2%, p = 0.072). For the R/R AML cohort, the FLT3mut group exhibited a lower CRc rate than the FLT3wt group. With a median follow-up of 8.6 months (95% confidence interval [CI], 8.0-10), the median OS observed in the FLT3mut and FLT3wt groups for both cohorts were close (14.0 vs. 19.9 months, p = 0.356; 10.0 vs. 11.9 months, p = 0.680). For the ND AML cohort, in FLT3mut patients, MRD-positive and RNA-splicing mutation predicted inferior survival (hazard ratio [HR], 10.3; 95% CI: 2.0-53.8; p = 0.006; HR 11.3; 95% CI: 1.2-109.3; p = 0.036, respectively). For the R/R AML cohort, in FLT3mut patients, adverse ELN risk was associated with an inferior response (odds ratio [OR], 0.2; 95% CI: 0.1-0.8; p = 0.025), whereas NPM1 co-mutation was associated with a superior response (57.1%; OR, 6.7; 95% CI: 1.5-30.1; p = 0.014). CR/CRi predicted a better survival (HR 0.2; 95% CI: 0.1-0.8; p = 0.029), while DNMT3A mutation predicted an inferior survival (HR, 4.6; 95% CI: 1.4-14.9; p = 0.011). FLT3 mutations may influence response to VEN-based therapy in R/R AML patients but not in ND AML patients. Furthermore, clinical and genetic characteristics could predict outcomes of FLT3mut patients receiving VEN-based therapy.

Reduced duration and dosage of venetoclax is efficient in newly diagnosed patients with acute myeloid leukemia

ABSTRACT Objectives The combination of Venetoclax (VEN) and Azacitidine (AZA) increases survival outcomes and yields excellent responses in patients with acute myeloid leukemia (AML). However, dose reduction (or discontinuation) is commonly encountered due to therapy-related toxicity. Thus, this study aimed to investigate the efficiency and safety of a lower dosage of venetoclax for the treatment of AML. Methods This observational study analyzed the characteristics and outcomes of newly diagnosed AML patients who received 100 mg VEN combined with AZA for 14 days at our institution. Results A total of 36 patients were enrolled, and the median age at diagnosis was 64 years. After a median follow-up of 15 (range 4–29) months, the median overall survival (OS) and progression-free survival (PFS) for the whole cohort were 17 (4–29) months and 12 (1–28) months, respectively. Meanwhile, the overall response rate (ORR) was 69.4%, and the CRc rate was 66.7% in the whole cohort. Subgroup analysis revealed that NPM1 mutations and FAB-M5 subtype were associated with higher response rates, whereas the adverse ELN risk group was predictive of an inferior response. Moreover, ASXL1, NPM1, and IDH1/2 mutations negatively impacted PFS. Discussion Our study optimized the administration of venetoclax plus azacytidine for the treatment of AML patients. Response rates were favorable, with median survival in agreement with the findings of earlier reports, offering valuable insights for optimizing VEN-based regimens. Conclusion In summary, the VEN combination regimen is effective for the treatment of newly diagnosed AML patients in the real world despite VEN dose reductions .

Update Results of a Phase II Trial of Venetoclax in Combination with Azacitidine and Chidamide in Relapsed/Refractory Acute Myeloid Leukemia

Background: Therapies for relapsed or refractory (R/R) AML remain limited, with low response rates and short duration of response, especially in patients ineligible for intensive cytotoxic chemotherapy. Combinations of venetoclax (VEN), chidamide (CHI) plus azacytidine (AZA) have shown to be synergistic with low intensity and intensive chemotherapy in preclinical data and in relapsed or refractory (R/R) setting (Phase II, 2022 ASH). Here we present updated results of this Phase II trial. Methods: Eligible patients were &amp;gt;18 yrs old with R/R AML, defined as lack of response rate after at least one cycle of induction or relapsed disease with any prior number of treatments. Patients received AZA 100mg on D1-7, VEN 200mg on D1-14, and CHI 30mg biweekly in 28-day cycles. The primary objective was evaluation of CR/CRi. Secondary objectives included event-free survival (EFS), overall survival (OS) and adverse events (AEs). Clinical responses were determined using the 2017 ELN criteria. Results: Between January 2022 and April 2023, 53 patients with R/R AML were enrolled in the study. The median age was 51 years (range 18-73). This regimen was salvage 1 in 79% (42) of patients, salvage 2 in 11% (6) and salvage 3 in 9% (5). 17%, 36%, and 47% of patients were classified as favorable, intermediate, and adverse ELN risk, respectively ( Table 1). 11% of patients had TP53 mutation, 22% had DNMT3A mutation, 21% had FLT3-ITD mutation, 9% had ASXL1 mutation, 19% had NPM1 mutation, 9% had IDH1 mutation, 11% had IDH2 mutation ( Fig. A). Among the 53 patients, the ORR of these patients was 68% with CRc rate of 53% after one cycle, and 81% with CRc rate of 72% after two cycles ( Fig. B). By ELN risk, ORR and CRc rates were 70% and 50% for favorable risk, 40% and 40% for intermediate risk, and 43% and 30% for adverse risk. Pretreatment IDH1 and IDH2 mutations were associated with higher CRc rates (75% and 50%, respectively). The CRc rate in patients with TP53 mutations was 67%, with response noted among patients with concurrent IDH1/ IDH2 mutations. With a median follow-up of 6.7 months, the median EFS and OS were 6 (95%CI 3.3-8.6) months and not reached (NR), respectively. Among patients with CRc, the 6-month EFS and OS were 64% and 88%, respectively, among those receiving this regimen as first salvage had encouraging outcomes (median EFS, NR) ( Fig. C-D). Of the 8 patients that proceeding with allogeneic hematopoietic stem cell transplant (allo-HSCT), the median EFS and OS were not reached after transplant ( Fig. E-F) No non-hematologic AEs of grade ≥3 were observed. The most common grade 1-2 non-hematologic AEs included nausea (28%), fatigue (28%), hypokalemia (17%), hypoproteinemia (17%), elevated transaminase levels (33%) and hyperbilirubinemia (11%). The occurrence rates of grade 3/4 hematologic adverse events (AEs) were as follows: white blood cell decrease (87%), median time to white blood cell recovery 23 (range 4-29) days; neutropenia (96%), neutropenia with fever (17%), median time to neutrophil recovery 25 (range 10-29) days; platelet decrease (68%), median time to platelet recovery 28.5 (range 7-44) days; anemia (64%), median time to hemoglobin recovery 29 (range 13-56) days. 30-day and 60-day mortality were 0% and 5.7%, respectively. 3 deaths occurred within 60 days in patients with persistent leukemia. Conclusions: Thecombination of VEN and CHI plus AZA (VCA) demonstrated manageable safety and encouraging efficacy in patients with R/R AML. IDH1/ IDH2 mutations were associated with the sensitivity of VCA, even in some patients with concurrent TP53 mutations.

Real World Use of Azacitidine and Venetoclax in Acute Myeloid Leukemia in Frontline and Relapse/Refractory Settings: A Multicentric Study from French Auraml Group

Azacytidine and venetoclax combination regimen (AZA/VEN) is the standard of care in frontline acute myeloid leukemia (AML) settings for unfit to intensive chemotherapy patients. However, AZA/VEN is also associated with an increased hematological toxicity compared to azacytidine alone. In this context, alternative AZA/VEN regimens emerged progressively based on each physician experience and local procedures. Moreover, AZA/VEN is also recognized as a valuable therapeutic option in relapse/refractory settings. In this multicentric study, we aimed to evaluate the efficacy and safety of various AZA/VEN regimen in frontline and relapse/refractory (R/R) patients diagnosed with AML in real life setting. We retrospectively analyzed 331 patients from 11 different French centers (Saint-Etienne, Clermont-Ferrand, Lyon (Hopital Lyon Sud, Centre Léon Bérard), Vichy, Annecy, Chambery, Valence, Bourgoin-Jallieu, Grenoble, Roanne) in Auvergne Rhône Alpes (AURA) region, between January 2019 and February 2023. Composite complete remission was defined as in VIALE-A trial. Measurable residual disease (MRD) negativity was defined as ≤ 10 -3 by flow cytometry (on bone marrow) and/or ≤ 10 -4 for NPM1 by RT-qPCR. Overall, the entire cohort was composed of 186 and 146 patients in frontline and R/R settings respectively. In frontline setting, median age was 74.5 (19.1-86.1) and ELN 2022 risk groups were favorable, intermediate and unfavorable in 14.5, 16.7 and 68.8% respectively. De novo AML, MRC-AML, post-MPN/MDS AML and t-AML were 32.4%, 29.7%, 23.2% and 14.5% respectively. After 6 cycles, median CRc, morphologic leukemia free state (MLFS) and refractory rate were 66.4%, 5.4% and 28.2% respectively. Regarding probability of CRc, there was no significant difference between favorable and intermediate ELN 2022 risk group. Within unfavorable risk group, only complex karyotype was associated with lower CRc rate ( figure 1). Venetoclax dosage (400mg vs 100mg/d) and duration per cycle (28 days vs 21 days vs others) did not influence significantly CRc rate probability and OS. With a median follow-up of 7.3 months, median overall survival (OS) was 12.4 months (IC95%: 3.4-18.5). There was no significant difference in terms of OS according to ELN 2022 risk group classification ( figure 2). Among unfavorable risk group, only patients with unfavorable karyotype had a worst OS (median OS: 4.9 months), while patients with secondary AML mutations had similar OS than favorable/intermediate risk group (19.5 vs 20.2 vs 18.2 months, p=0.32). Reaching MRD negativity at any time during the first 6 cycles was associated with a better OS (26.1 vs 10.3 months, p&amp;lt;0.001). In responding patients, 22/122 withdrew VEN after a median of 5 cycles (range:1-17), while continuing AZA, mainly due to excessive hematological toxicity. Relapse free survival was similar between patients who stopped compared to those who continued up to progression. In multivariate analysis, only ECOG (continuous, HR= 1.52, p=0.04), IDH status (WT vs MUT: HR = 3.13, p=0.04, normal karyotype (yes vs no, HR=0.25, p=0.04) and CR type (CRMRD- vs other, HR= 0.21, p=0.001) significantly influence OS, whereas ELN 2022 did not In R/R settings, CRc rate was 43.8% and OS was 7.9 months. As in frontline setting, venetoclax dosage and duration per cycle did not influence CRs rate and OS. Febrile neutropenia (FN) occurred in 52.9%, 35.1% and 27.1% in cycle 1,2 and 3, respectively. Toxic death rates (TDR) range from 16.6% prior 2020 to 8.6% in 2021 and 6.25% from 2022 to 2023 (p=0.01). In or outpatient management for cycle 1 did not influence FN incidence. Azole prophylaxis did not significantly influence FN incidence. During cycle 1, shorter venetoclax duration regimens (&amp;lt;21 days/cycle) was associated with lower FN (41.5 vs 54.8%, p=0.042) compared to ≥21 days VEN cycle. In this real life settings study, our results suggest that outcome in frontline AZA/VEN treated patients is mainly driven by deep responses. Alternative AZA/VEN regimens were not associated with lower response rate and overall survival, while reducing venetoclax exposure during cycle 1 may reduce FN incidence without significant consequences on CR rate. TDR reduction through time suggest a learning curve and might be related to physician's skills improvement regarding AZA/VEN dosage schedules and supportive care management. An update with additional patients and longer follow-up will be presented at the meeting.