Incidence Of Acute Myeloid Leukemia Research Articles

Identification of PANoptosis-based signature for predicting the prognosis and immunotherapy response in AML

BackgroundIn recent years, the incidence of acute myeloid leukemia (AML) has increased rapidly with a suboptimal prognosis. In AML, cell death is independent of tumorigenesis, tumor invasion, and drug resistance. PANoptosis is a newly discovered form of cell death that combines pyroptosis, apoptosis, and necroptosis. However, no studies have explored the role of PANoptosis-based signatures in AML. MethodsWe screened for PANoptosis-related genes and established a PANoptosis-risk signature using the least absolute shrinkage and selection operator (LASSO) and Cox regression analysis. We combined TCGA, bulk RNA sequencing, and single-cell sequencing to investigate the correlation between candidate genes and the AML tumor microenvironment. ResultsThe PANoptosis risk signature effectively predicted prognosis with good sensitivity and specificity. The risk score emerged as an independent prognostic factor. Functional enrichment analysis of PANoptosis-related differentially expressed genes suggested that the risk score may be related to cell immunity. Patients with high-risk scores exhibited increased immune cell infiltration, implying a hot tumor immune microenvironment. The risk score was positively correlated with the immune scores and expression levels of immune checkpoints. Therefore, we identified three model factors, BIRC3, PELI1, and PRKACG, as predictors for immunotherapy efficacy. Single-cell sequencing analysis demonstrated that PELI1 and BIRC3 may participate in the regulation of the AML immune microenvironment. Finally, we performed a drug sensitivity analysis to target BIRC3 and PELI1 using molecular docking and molecular dynamics simulations. ConclusionOur study established and verified a PANoptosis risk signature to predict the survival and immunological treatment response in AML.

SPAG6 overexpression decreases the pro-apoptotic effect of daunorubicin in acute myeloid leukemia cells through the ROS/JNK MAPK axis in a GSTP1-dependent manner.

As a malignant hematological disease, the incidence of acute myeloid leukemia (AML) has exhibited an upward trend in recent years. Nevertheless, certain limitations persist in the treatment of AML. Sperm-associated antigen 6 (SPAG6) has been implicated in the onset and progression of various human cancers, with its expression levels significantly elevated in AML. Consequently, we undertook a series of experiments to investigate the role and underlying mechanisms of SPAG6 in AML cell lines. In the in vitro experiments of this study, DEPs and GO and KEGG enrichment analysis subsequent to SPAG6 down-regulation were detected by TMT. CCK8 was employed to determine cell viability. The levels of apoptosis and ROS were measured by flow cytometry. In the in vivo experiments, a xenografted tumor model was constructed, and the expression of SPAG6 and GSTP1 in tumor tissues was detected by IHC. Ultimately, our findings indicated that over-expression of SPAG6 promoted cell growth and decreased reactive oxygen species (ROS) and malondialdehyde levels. Furthermore, SPAG6 knockdown was found to diminish mitochondrial membrane potential and facilitate cell apoptosis. In vivo, SPAG6 could also promote tumor growth, suggesting that SPAG6 may serve as a pro-tumor factor. In addition, daunorubicin (DNR) may cause oxidative stress and initiate apoptosis, resulting in oxidative damage to AML cells. However, the overexpression of SPAG6 may attenuate the efficacy of DNR. This was due to SPAG6 promoted GSTP1 expression, thereby reducing ROS levels. Simultaneously, the elevation of GSTP1 and JNK complex may reduce the expression of p-JNK and inhibit the activation of JNK pathway, which might inhibit cell apoptosis. In conclusion, our experiments suggested that upregulated SPAG6 might mitigate the pro-apoptotic effects of DNR through ROS/JNK MAPK axis in a GSTP1-dependent manner.

Lenalidomide in Transfusion-Dependent IPSS Low- or Intermediate-1-Risk Myelodysplastic Syndromes and Isolated Del(5q): Results of a European Postauthorization Safety Surveillance Study

BackgroundThis noninterventional postauthorization safety study assessed the safety and effectiveness of lenalidomide in patients with transfusion-dependent, International Prognostic Scoring System (IPSS) Low- or Intermediate (Int)-1-risk myelodysplastic syndromes (MDS) associated with isolated deletion of 5q (del[5q]) who were treated in routine care. Patients and MethodsEligible adult patients in the lenalidomide cohort had transfusion-dependent, IPSS Low- or Int-1-risk MDS and isolated del(5q) and had received ≥ 1 dose of lenalidomide between 2014 and 2022. The primary endpoint was the 24-month cumulative incidence of acute myeloid leukemia (AML) progression. Overall survival (OS) was estimated by Kaplan–Meier analysis and safety data were collected. ResultsIn total, 296 patients received ≥ 1 dose of lenalidomide (lenalidomide cohort, safety population) and 277 had received ≥ 1 complete cycle of lenalidomide (primary population). In the safety population, 44.3% of patients completed 3-year follow-up and 55.1% discontinued, with 33.1% discontinuing due to death. In the primary population, 24-month cumulative incidence of AML progression was 12.7% (95% confidence interval, 8.9%-17.1%) and estimated OS probability was 78.3% at 24 months and 63.9% at 36 months. Grade 3/4 treatment-emergent adverse events were experienced by 67.2% of the safety population, and these led to discontinuation in 35.5% of patients. There were no new safety signals. ConclusionThese real-world data support the established benefit-risk profile of lenalidomide in transfusion-dependent IPSS Low- or Int-1-risk MDS with isolated del(5q).

Coagulation aberrations in adult patients with acute leukemia: A single center experience

Background and objective: Acute leukemia (AL) patients are at high risk for bleeding and thrombotic events due to the disruption of the normal hemostatic system associated with this disease. As a result of the lack of data on coagulopathy in AL patients in our locality, we conducted this study to assess the hemostatic parameters in patients with newly diagnosed AL at the time of presentation. Methods: This prospective cross-sectional study included 59 patients with de novo AL, along with 35healthy control subjects. The study was conducted at Nanakali Hemato-Oncology Center between September 2021 and May 2022. Coagulation markers, including prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen levels (FBG), D-dimer (D-Di), antithrombin (AT), protein C (PC), and protein S (PS) were measured for each patient and control. Results: The median age of the patients was 41 years, with a male to female ratio of 1.1:1. Thirty-eight (64.4%) patients had acute myeloid leukemia (AML) and 21 (35.6%) patients had acute lymphoblastic leukemia (ALL). D-Dilevels were significantly raised in both AML and ALL compared to controls. PT was significantly higher, and PC and AT were significantly lower in AML compared to ALL or control groups. The Bleeding incidence in AML was significantly higher than in ALL (65.8% versus 23.8%). Thrombosis occurred in two (3.4%) patients. Conclusion: Coagulation abnormalities were common in AL. The hemostatic derangement and bleeding at the time of presentation were more pronounced in patients with AML than in ALL.

HLA alleles, haplotypes frequencies, and their association with hematological disorders: a report from 1550 families whose patients underwent allogeneic bone marrow transplantation in Egypt.

HLA alleles are representative of ethnicities and may play important roles in predisposition to hematological disorders. We analyzed DNA samples for HLA-A, -B, -C, -DRB1, and -DQB1 loci, from 1550 patients and 4450 potential related donors by PCR-SSO (Polymerase chain reaction sequence-specific oligonucleotides) and estimated allele frequencies in donors and patients from 1550 families who underwent bone marrow transplantation (BMT) in Egypt. We also studied the association between HLA allele frequencies and incidence of acute myeloid leukemia, acute lymphoblastic leukemia, and severe aplastic anemia. The most frequently observed HLA class I alleles were HLA- A*01:01 (16.9%), A*02:01 (16.1%), B*41:01 (8.7%), B*49:01 (7.3%), C*06:02 (25.1%), and C*07:01 (25.1%), and the most frequently observed class II alleles were HLA-DRB1*11:01 (11.8%), DRB1*03:01 (11.6%), DQB1*03:01 (27.5%), and DQB1*05:01 (18.9%). The most frequently observed haplotypes were A*33:01~B*14:02 ~ DRB1*01:02 (2.35%) and A*01:01~B*52:01~DRB1*15:01 (2.11%). HLA-DRB1*07:01 was associated with higher AML odds (OR, 1.26; 95% CI, 1.02-1.55; p = 0.030). Only HLA-B38 antigen showed a trend towards increased odds of ALL (OR, 1.52; 95% CI, 1.00-2.30; p = 0.049) HLA-A*02:01, -B*14:02, and -DRB1*15:01 were associated with higher odds of SAA (A*02:01: OR, 1.35; 95% CI, 1.07-1.70; p = 0.010; B*14:02: OR, 1.43; 95% CI, 1.06-1.93; p = 0.020; DRB1*15:01: OR, 1.32; 95% CI, 1.07-1.64; p = 0.011). This study provides estimates of HLA allele and haplotype frequencies and their association with hematological disorders in an Egyptian population.

Real-World Treatment Patterns and Clinical Outcomes in Unfit AML Patients: Results of Current Retrospective Study in Romania

Aim: The incidence of acute myeloid leukemia (AML) increases along with the aging population and its prognosis worsens with increasing age. Limited data is available on the real-world survival, clinical outcomes, and treatment patterns in Romanian AML patients unfit for intensive chemotherapy. Given the rapidly changing AML treatment landscape, this retrospective chart review aimed to understand historical AML treatment pathways, their associated outcomes, and the economic impact. Material and methods. Adult patients across Romania with primary or secondary AML, ineligible for intensive induction chemotherapy, for whom the first-line systemic therapy (FLST) or best supportive care (BSC) was initiated between January 2015 and December 2018 were evaluated. The outcomes assessed included overall survival (OS), progression-free survival (PFS), response rates and healthcare resource utilization (HRU). Results. Of the 98 patients included, 85.7% received FLST and 14.3% received BSC as first-line therapy. The median OS was 10.0 months in those who received a hypomethylating agent as FLST and 3.4 months in the BSC group. Median PFS was 8.0, 6.4, and 3.4 for hypomethylating agents and low-dose cytarabine as FLST, and BSC, respectively. During the first line therapy the best response was stable disease and was achieved in 20.2% of the FLST patients and 14.3% of the BSC patients. HRU was generally numerically higher in patients with FLST as compared to the ones who received BSC as first-line therapy. Conclusion. The survival and outcomes of unfit AML patients in Romania remain poor highlighting the unmet need for effective treatment options in this population.

Survey on the Oxidative Stress Status and the Role of Antioxidants in Acute Myeloid Leukemia Therapy

Acute myeloid leukemia (AML) is a heterogeneous disease with multiple mutations in hematopoietic stem cells characterized by abnormality increases in immature or dysfunctional white blood cells. The precise mechanisms of AML development have not been clear but there are many factors increase to developing leukemia such as familial history of leukemia, elderly, life style, genetics and some chronic disease like diabetic. Multiple mutilations happen in the hematopoietic stem cells, acquire some form of genetic instability lead to improve expression of some protein kinase and transduction protein following that increase ROS formation, which is associated with increased DNA damage. Nowadays, the use antioxidant drugs are growingly accepted in universal due to their safety and efficiency to diminish the adverse effects of free radicals and treatment of the many diseases such as cancer. In this article, we discussed the correlation between acute myeloid leukemia incidence and the oxidant biomarkers (oxidative stress), and more focusing on the great role of antioxidant biomarkers, whether the non-enzymatic or the enzymatic in the protection of the cells against harmful effects of free radicals in the acute myeloid leukemia patients.

A temporal and multinational assessment of acute myeloid leukemia (AML) cancer incidence, survival, and disease burden

Understanding the global epidemiology of AML is critical for assessing therapeutic demand and informing healthcare resource allocation. This study estimated current and future AML incidence in 27 countries, described AML survival trends in the United States, and calculated average years of life lost (AYLL). Incidence rates were age-standardized using rates from IARC’s Cancer Incidence in Five Continents and SEER databases and ranged from 0.70 to 3.23 cases per 100,000 persons. Crude incidence rates were projected from 2024 to 2040; growth varied from +1% to +46%. Median overall survival was derived from SEER databases and increased from 4 to 11 months over the last 40 years. Median AYLL of 18.6 years was estimated for 27 countries. This study projected significant growth in new AML diagnoses over the next two decades. Despite improvements in survival over the last four decades, median survival among AML patients remains poor highlighting the need for novel treatments.

Trends on treatment patterns in patients with newly diagnosed AML: Preliminary findings from a real-world analysis.

e18506 Background: In the last two decades, new therapeutic options have emerged to complement traditional intensive chemotherapy (IC) regimens in the treatment of Acute myeloid leukemia (AML). Hypomethylating agents (HMAs), the B-cell lymphoma 2 (BCL-2) protein inhibitor Venetoclax, and other targeted therapies are examples. Guideline-based treatment decisions are intricate, considering both patient fitness to IC and disease characteristics. AML real-word studies on treatment patterns typically focus on specific subpopulations (e.g., elderly or unfit patients), and few studies analyze broader populations. We analyzed an US electronic health records (EHR) database to describe AML treatment patterns. Methods: Study was designed as retrospective, descriptive analysis of deidentified secondary data from COTA database in the US. Data was abstracted for AML patients diagnosed for the first time between January 2017 and September 2022. Follow-up period (FP) was defined as the period starting at the diagnosis until the last information available for: death, or last contact, or the emergence of other malignancies. To improve descriptive analysis, treatment categories were classified accordingly: IC and non-IC. We conducted descriptive statistics (expressed as counts, percentages or means and medians [with SD or IQR]) for the different assessed features. Results: From the 3,500 patients included on the database, 1,436 were eligible for the analysis with a newly diagnosed AML disease after January 2017. Individuals’ age at diagnosis falls between 60 and 74 years old for 41% of the cohort with mean age of 64[15] years and 60% were followed on community centers. Male patients slightly outnumber female patients (53% and 47%, respectively). Primary AML accounted for 41% of the population and secondary for 28%. Mean time to first treatment after diagnosis was 14[42] days for the overall cohort, the main reason for the end of follow-up was death for 58% of individuals and 47% of the patients had a follow-up inferior to one year. While analyzing treatment patterns according to line of therapies (LoT) sequences, IC only was predominant for 30% of the population, followed by non-IC only for 28%. Remaining counts (42%) correspond to association of both categories. Most prevalent regimen on IC only group was High-dose Cytarabine monotherapy (HIDAC) (12%), and HMA (Azacitidine)+Venetoclax (27%) for the non-IC only group. Conclusions: Our preliminary and recent findings demonstrate that incidence of AML remains high in elderly groups. Despite the introduction of novel therapies, IC remains the predominant treatment approach for newly diagnosed AML patients. Our ongoing real-world analysis aims to assess a more detailed description of LoT sequences in AML population.

Clinical characteristics of acute myeloid leukaemia patients with a large number of azurophilic granules: A single-centre retrospective study.

Large amounts of azurophilic granules are considered to be a morphological feature of acute promyelocytic leukaemia (APL). However, a small percentage of acute myeloid leukaemia (AML) patients also have a large number of azurophilic granules. A large cohort of 3210 AML patients in our hospital was screened to identify AML patients who had a large number of azurophilic granules. The clinical parameters of these patients were collected and compared with typical AML patients (control Group 1) and APL patients (control Group 2). The incidence of AML with a large number of azurophilic granules was 1.26%. The fibrinogen and D-dimer levels of patients in the study group were more similar to those of patients in control Group 2, as was the incidence of bleeding events. Additionally, patients in the study group had higher FLT3-ITD and NPM1 mutation rates than patients in control Group 1. Finally, patients in the study group had a higher 30-day mortality rate than those in control Group 2 (24.2% vs. 9.09%) and showed a higher 30-day mortality trend than those in control Group 1. Therefore, we should pay more attention to the prevention of coagulation dysfunction and bleeding events for these patients.

Adhesion GPCR ADGRE2 Maintains Proteostasis to Promote Progression in Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is an aggressive and heterogeneous hematologic malignancy. In elderly patients, AML incidence is high and has a poor prognosis due to a lack of effective therapies. G protein-coupled receptors (GPCR) play integral roles in physiologic processes and human diseases. Particularly, one third of adhesion GPCRs, the second largest group of GPCRs, are highly expressed in hematopoietic stem and progenitor cells or lineage cells. Here, we investigate the role of adhesion GPCRs in AML and whether they could be harnessed as antileukemia targets. Systematic screening of the impact of adhesion GPCRs on AML functionality by bioinformatic and functional analyses revealed high expression of ADGRE2 in AML, particularly in leukemic stem cells, which is associated with poor patient outcomes. Silencing ADGRE2 not only exerts antileukemic effects in AML cell lines and cells derived from patients with AML in vitro, but also delays AML progression in xenograft models in vivo. Mechanistically, ADGRE2 activates phospholipase Cβ/protein kinase C/MEK/ERK signaling to enhance the expression of AP1 and transcriptionally drive the expression of DUSP1, a protein phosphatase. DUSP1 dephosphorylates Ser16 in the J-domain of the co-chaperone DNAJB1, which facilitates the DNAJB1-HSP70 interaction and maintenance of proteostasis in AML. Finally, combined inhibition of MEK, AP1, and DUSP1 exhibits robust therapeutic efficacy in AML xenograft mouse models. Collectively, this study deciphers the roles and mechanisms of ADGRE2 in AML and provides a promising therapeutic strategy for treating AML. Significance: Increased expression of the adhesion GPCR member ADGRE2 in AML supports leukemia stem cell self-renewal and leukemogenesis by modulating proteostasis via an MEK/AP1/DUSP1 axis, which can be targeted to suppress AML progression.

Факторы риска развития рецидивов перианальных инфекционных осложнений у пациентов с опухолевыми заболеваниями системы крови: результаты одноцентрового проспективного исследования

Aim. To study risk factors for relapses of perianal infection (PI) in patients with hematological tumors.
 Materials & Methods. This single-center prospective clinical trial (2016–2020) enrolled all oncohematological patients at the National Research Center for Hematology who developed PI at various stages of chemotherapy. To assess the impact of some factors on relapsing perianal infectious complications, the distribution of clinical characteristics in groups of patients with single or multiple PI episodes was analyzed.
 Results. The trial addressed 158 PI episodes in 132 patients; there were 64 men and 68 women, the median age was 40 years (range 18–77 years). PI relapses were identified in 22 (16.67 %) patients, with a higher incidence in acute myeloid leukemia (AML) patients (63.64 %). Recurrent PI episodes were usually registered on program therapy of acute leukemias (73.08 %), more often at consolidation stage (38.46 %) than at other stages of treatment (17.42 %) (hazard ratio [HR] 2.96; 95% confidence interval [95% CI] 1.19–7.35; p < 0.031). With the follow-up of 360 days from the first episode, the probability of PI relapses was 16.2 %, and it was higher in AML patients (24.3 %). In non-remission AML patients having the first PI episode, the probability of PI relapses considerably increased and accounted for 52.6 %. In case of cryptogenic pararectal abscesses, it was 20 %, if solely abscess drainage was performed at the first stage. However, no relapses were registered after the surgical treatment of pararectal fistulas. The risk factors for recurrent PI, as was shown by univariate analysis, were AML diagnosis (HR 2.94; 95% CI 1.14–7.62; p < 0.032) and the lack of remission of hematological tumor by the time of the first PI episode (HR 2.98; 95% CI 1.13–7.90; p < 0.034). By multivariate analysis, the significant risk factor was non-remission AML diagnosis by the time of the first PI episode (HR 6.94; 95% CI 2.93–16.66; p < 0.0001).
 Conclusion. The significant risk factor for PI relapses is non-remission AML diagnosis by the time of the first infectious episode. This category of patients shows the maximal probability of relapsing perianal infectious complications, which is 52.6 %. To prevent PI relapses in patients with cryptogenic pararectal abscesses, abscess drainage should be combined with scheduled surgery of anal fistulas.

Global, national, and regional burden of acute myeloid leukemia among 60-89 years-old individuals: insights from a study covering the period 1990 to 2019.

Our study examined the global, national, and regional trends in the incidence, mortality, and disability-adjusted life years (DALYs) associated with older people's acute myeloid leukemia (AML) over a 30 years period. AML, which predominantly affects individuals aged 60-89, is known for its severity and unfavorable prognosis. By providing insights into the growing burden of AML, our research highlights the urgent need for effective interventions and support at various levels. In this study, we analyzed older people with AML aged 60-89 using the Global Burden of Disease (GBD) database for 2019. Our goal was to assess trends and characteristics by examining the incidence rate, mortality rate, DALYs, and estimated annual percentage change (EAPC). We aimed to provide a comprehensive understanding of the disease's trajectory and development. In 2019, the older age group of 60 to 89 years reported 61,559 new cases of AML, with the corresponding number of deaths being 53,620, and the estimated DALYs standing at 990,656. Over the last 30 years, the incidence rate of AML in this age bracket increased by 1.67 per 100,000 people, the mortality rate rose by 1.57 per 100,000 people, and the rate of DALYs, indicative of disease burden, climbed by 1.42 per 100,000 people. High Socio-demographic Index (SDI) regions, particularly high-income North America and Australia, had the highest incidence rates. Germany had the highest incidence rate among the 204 countries analyzed, while Monaco reported the highest mortality and DALY rates. Smoking, high body mass index, occupational exposure to benzene, and formaldehyde were identified as significant risk factors associated with mortality from older people with AML in 2019. Our study showed that the incidence, mortality, and DALY rates of AML in the older population were strongly correlated with the SDI, and these rates have been steadily increasing. This had become an increasingly serious global health issue, particularly in areas with a high SDI. We highlighted the urgency to focus more on this disease and called for the prompt implementation of appropriate preventive and control measures.

Pre-Existing Myeloid Subclones May Account for a Subset of Acute Myeloid Leukemias and Myelodysplastic Neoplasms in Patients with Pre-Existing or Contemporary Lymphoid Disorders

Background: Myelodysplastic neoplasms (MDS) and acute myeloid leukemia (AML) are occasionally observed in association with lymphoid tumors. Most cases of myeloid disorders detected in patients with lymphoid tumors are attributed to chemotherapy, however, there is a subset of patients who receive a contemporary diagnosis of myeloid and lymphoid disease, and it is well known that, even in patients who were exposed to chemotherapy, the myeloid disease may both arise from clonal hematopoiesis substrate or harbor chemotherapy signature (Diamond, Blood 2023). Biological differences justified by the ontogenesis of the myeloid disease may justify prognosis and suggest appropriate intervention methods. Methods: We searched our patient database for AML and MDS which were diagnosed together with lymphoid diseases. Data was collected under the study NCT04298892, after approval of the ethical committee. Statistics were performed with Kaplan-Meyer estimation. Nonparametric tests were used as appropriate. Results: Out of 164 patients who were referred to our service from May 2021 to Jul 2023 for MDS or AML, 11 patients were diagnosed with AML or MDS together with a concomitant or previous lymphoid disease. In this population, the median age at AML or MDS diagnosis was 67 (range 58 - 82); 9/11 (82%) patients were male. Four out of 11 (36%) patients were diagnosed with AML, 7/11 with MDS (6 with blast < 5% and 1 with blast ≥ 5%). The diagnosis of myeloid and lymphoid diseases was concomitant in 2 patients (18%) and sequential in 9 patients (82%). The lymphoid diseases were smoldering multiple myeloma (3/11, 27%), multiple myeloma (5/11, 45%), diffuse large B-cell lymphoma (1/11, 9%), mantle cell lymphoma (1/11, 9%), marginal zone lymphoma (1/11, 9%). Eight out of 11 patients (73%) with lymphoid and myeloid disease had a history of chemotherapy before the diagnosis of MDS or AML; 5 patients (45%) were exposed to high-dose alkylating agents, 2 (18%) low-dose alkylating agents, 2 (18%) anthracyclines. Interestingly, 7 patients (64%) were diagnosed while they were receiving lenalidomide after a median exposure to lenalidomide of 8.8 months (4.9 - 30.73). In the 9 patients with consecutive lymphoid and myeloid disease diagnosis, AML or MDS were diagnosed after a median of 23 months (range 8 - 76; history of patients is plotted in figure 1). Regarding the AML or MDS, 3/11 patients (27%) had complex karyotype of which 1 had t(3;21)(q26;q22) RUNX1/MECOM rearrangement, 2/11 had TP53 mutation (both also had complex karyotype). The remaining patients mainly harbored methylation or splicing mutations and normal karyotype or karyotype single non-high-risk alterations. When compared, patients with complex alterations had similar times of onset from their first tumor and baseline characteristics; those patients however had an increased risk of death. Conclusions: The incidence of AML or MDS associated with lymphoid disease is low.Furthermore, the population is remarkably heterogeneous. The characteristics and the timing of onset of the disease account for different ontogenesis; a portion of the patient has a disease that harbors complex alterations, while the most frequent origin of AML and MDS can be researched in pre-existing or contemporary hematopoietic clones, that overall account for a whole bone-marrow disease. The relation between chemotherapy exposition and the biology of the AML or MDS is not univocal. This difference could be therapeutically relevant.

Association between BMI and Survival in Adolescents and Young Adults (AYA) with Acute Myeloid Leukemia Treated with Intensive Chemotherapy

Introduction: Obesity is linked to a higher incidence of acute myeloid leukemia (AML) in older adults as well as B-cell acute lymphoblastic leukemia in children and adolescents and young adults (AYA). To date, however, the relationship between weight and clinical outcomes in AYA patients (pts) diagnosed with AML has not been clearly established. We hypothesized that obesity reflected by higher body mass index (BMI) would confer worse prognosis in AYA pts treated with intensive chemotherapy and/or allogeneic stem cell transplant (SCT) for AML. Methods: We conducted a single institute retrospective chart review of AYA patients aged 18 to 39 years diagnosed with AML between Jan 2006 and Oct 2022. All patients received intensive chemotherapy with cytarabine- and anthracycline-based induction and consolidation chemotherapy followed in some cases by SCT. BMI was calculated based on height and weight on the date of AML diagnosis. Additional information including European Leukemia Net (ELN) 2022 risk classification, therapy response (complete remission (CR), CR with incomplete count recovery [CRi]), receipt of SCT, relapsed disease, event-free (EFS), overall survival (OS) and percentage of pts alive at 2- and 5-years after diagnosis were collected. All data was de-identified and procured on an IRB-approved protocol. Results: Seventy-six AYA patients were identified. Median age was 25.2 (range 18-39) years. 39 (51%) were female. The majority (65, 86%) were Caucasian. Per ELN 2022 risk classification, 24 (32%) had favorable, 36 (47%) had intermediate, and 16 (21%) had adverse risk disease. The CR rates based on ELN 2022 risk classification were 86%, 72% and 50%, respectively. Median OS for all pts was 791 days and per risk group was 1379, 569, and 595 days, respectively. Pts were then categorized per initial BMI into 4 categories. The majority of pts (44, 58%) had above average BMI (≥ 25), with 21 (28%) considered overweight with BMI 25-29.9 and 23 (30%) obese defined as BMI >30. Only 3 pts (4%) were underweight with BMI <18.5 (Table 1). Of note, 43% of obese pts had ELN favorable risk vs 33% of overweight pts and 24% of normal weight pts. Overall response rates in each BMI category were similar, ranging from 96-100% except in overweight pts where only 6 of 21 pts (29%) obtained CR. Relapse occurred in approximately one third (29-35%) of pts in the three highest BMI categories. Two thirds of all pts with BMI ≥18.5 underwent SCT. Excluding underweight pts due to small numbers (n=3), there was a trend to decreased survival in pts with BMI ≥18.5. Median overall survival among normal, overweight, and obese pts was 1403, 1295, and 777 days, respectively, with a significant difference between healthy and obese pts (p-value 0.0274 by log rank test). The percentage of pts alive after 5 years was 41%, 29%, and 17%, respectively (Table 2). Conclusion: Our real-world single-institute retrospective analysis suggests that AYA pts aged 18-39 yrs old diagnosed with AML and with higher BMI have decreased overall survival following intensive chemotherapy and/or allogeneic transplant. Obese patients with the highest BMI (>30) had a markedly shorter overall survival (median 777 days) and lower percentage of pts (17%) alive after five years following therapy than AYA AML pts with normal BMI (median 1403 days, 41% 5-year survival). This was despite over 40% of obese pts having favorable ELN risk. Potential reasons for this include biological heterogeneity in BMI cohorts, chemotherapy dosing, weight-related medical co-morbidities (i.e. cardiovascular disease) and/or transplant-related complications leading to shorter survival. Additional analyses to rule out the contribution of these and other factors and to confirm these results in a larger cohort are ongoing.

Statewide Burden and Trends of Acute Myeloid Leukemia in the United States between 1990-2019: A Benchmarking Analysis for the Global Burden of Disease Study 2019

Background: Acute myeloid leukemia (AML) ranks as the 15th leading cause of death, accounting for 1.75% of all cancer-related deaths in the United States of America (USA) in 2019, following Myeloma. Despite its significance, statewide disparities in AML burden have not been previously studied. Thus, this research aimed to assess the burden and trends of AML across the USA over the last three decades, spanning from 1990 to 2019. Method: Employing the Global Burden of Disease methodology, we evaluated AML prevalence, incidence, mortality, and disability-adjusted life years (DALYs) using standardized approaches and statistical modeling. The results were presented in absolute counts and age-standardized rates (per 100,000 person-years). Results: The total number of AML prevalence cases rose from 10,124 (95% uncertainty interval (UI): 9,259-11,482) in 1990 to 21,370 (95% UI: 17,759-24,830) in 2019. Correspondingly, deaths increased from 6,849 (95% UI: 6,301-7,724) in 1990 to 13,620 (95% UI: 11,632-14,664) in 2019, while DALYs increased from 185,960 (95% UI: 171,985-210,122) in 1990 to 301,526 (95% UI: 268,606-323,608) in 2019. The age-standardized incidence rate (ASIR) rose from 2.75 (95% UI: 2.52-3.09) to 3.23 (95% UI: 2.71-3.73) cases per 100,000 from 1990 to 2019. Similarly, the age-standardized mortality rate (ASMR) increased from 2.20 (95% UI: 2.03-2.48) to 2.54 (95% UI: 2.19-2.72) cases per 100,000 during the same period. In 2019, the greatest AML incidence was observed in California (1,677), followed by Florida (1,268) and Texas (1,155), while the lowest incidence was observed in the District of Columbia (24). Regarding the annual percentage of change (APC), the highest percentage increase in deaths was observed in Nevada (328%), followed by Alaska (224%), while the District of Columbia had the lowest APC (6%) from 1990 to 2019. In terms of incidence, Nevada (332%) and Arizona (227%) had the highest APC during the same period. The age group of 70-74 years had the highest number of deaths (2,264) and incidence (2,665), as well as DALYs (43,918) in 2019. Notably, the older age groups exhibited the highest APC in deaths and incidence. Males had a higher burden of AML compared to females. Conclusion: Our study underscores significant disparities in AML burden across different states in the USA from 1990 to 2019. We have also identified that males and elderly individuals face a higher likelihood of AML burden. Consequently, policymakers must prioritize enhancing healthcare systems, advancing early diagnosis and treatment approaches, and promoting health education to reduce individual exposures to relevant risk factors.

Real-World Study in Acute Leukemia: Epidemiology, Treatment Patterns and Outcomes for Newly Diagnosed AML in Adult Patients from Latin America - Loyal Study

Introduction. Acute myeloid leukemia (AML) is the most frequent leukemia among adults and representing 90% of all cases of acute leukemia in adults. Differences in incidence and burden of AML among regions of the world have been reported. When compared with registries from the US, UK and Sweden, Latin-America (LA) AML has a younger age at diagnosis (median age of 40-47 versus 64 -67 years old). Furthermore, single center studies have suggested poor treatment outcomes in LA. For example, Silveira et al reported a median age at diagnosis of 46 y, frequency of favorable cytogenetics of 26% and median overall survival (mOS) of 12 months in the Brazilian cohort of patients with newly diagnosed AML (nAML) whereas the respective values at Oxford University were 51.5y, 11% and 48 months in British patients. However, wider studies across the region are scarce and there is a need to further explore AML patient characteristics and treatment outcomes in LA. Methods. This is a non-interventional, retrospective multicenter study that aims to describe the epidemiology, clinical and demographic characteristics, treatment patterns, survival outcomes and healthcare resource use of adult patients with nAML in Argentina, Brazil, Chile, and Colombia. Data from medical records of eligible patients that met the inclusion criteria (≥ 18 years old at diagnosis, confirmed diagnosis of nAML between 01 January 2015 and 31 December 2019, and receiving at least one line of treatment) in these LA countries were considered for the analysis, which was descriptive in nature as no hypothesis has been tested. Results: A total of 518 nAML patients were included in the study, 166 from Argentina, 205 from Brazil, 63 from Chile, and 84 from Colombia. Table 1 shows the demographics and clinical characteristics. At treatment initiation, an evaluation of fitness (eligibility) for intensive chemotherapy was available for 94% of the patients (n=489). The majority were considered fit (75.5%; n=391) and received standard 7+3 therapy. About 11% of patients (n=9) were refractory to induction therapy. Median OS for fit patients was 11.9 months, whereas for unfit patients was 5.8 months. Mutational status of genes listed by the European LeukemiaNet (ELN) Classification of 2017 was not available for the majority of cases; risk categories were assigned based on cytogenetics. Patients in the favorable-risk category had a mOS of 30.5 months, whereas those in the intermediate- and unfavorable-risk had 11.1 and 9.1 months, respectively (Figure 1). The probability of 5year OS rates for favorable, intermediate- and unfavorable-risk groups were of 38.8%, 16.6% and 20.9%, respectively. Eighty-six patients (17%) discontinued treatment with reasons being adverse event/toxicity (33%; n=28), death (32%; n=27), and disease progression (17%; n=14). Only 24% of patients (n=125) underwent a subsequent stem cell transplantation (SCT), mainly allogenic (98%; n=121). For SCTs, identical (matched) related (50%; n= 59) and haploidentical donor (35%; n=41) were the most common. Patients not eligible to intensive chemotherapy were treated with HMA (9%; n=47) and LDAC (5%; n=25), with 10% of the patients receiving palliative/supportive care. The most common treatment protocols used in relapsed or refractory (R/R) patients were high-dose cytarabine (HDAC) (31%; n=85), followed by FLAG-IDA (24%; n=66). Conclusions: This study of newly diagnosed acute leukemia characterizes real-world treatment patterns and outcomes in LA clinical practices. Prior to this study, there has been limited published data on the epidemiology and treatment patterns across LA. This study highlights that for nAML patients, the most common treatment in LA is 7+3 and most patients are classified as fit. The vast majority of patients had their risk accessed by cytogenetics analysis only, reflecting the limited access to molecular tests. Fewer patients underwent stem cell transplantation as part of the treatment compared to that reported in US and Europe, probably due to restricted availability of hospital beds dedicated to bone marrow transplantation. When evaluating the overall survival, the study shows higher mOS for favorable risk. In addition, mOS for intermediate and poor cytogenetic risk were similar. A broader access in the region to molecular tests, transplant and new therapies are needed in order to reduce the gap in outcome, especially for patients with intermediate-risk.

State‐Level Acute Myeloid Leukemia Incidence and Mortality Trends and Association with Obesity in the United States

Background : Acute myeloid leukemia (AML) is the most common type of leukemia among adults and carries a dismal prognosis. Recent evidence suggests increasing AML risk in obese individuals. However, state-level temporal trends and whether obesity is associated with temporal changes remain largely unknown. Methods: We obtained data on age-adjusted AML incidence and mortality from 1999 to 2019 for all 50 states and the District of Columbia (DC) from the US Cancer Statistics database maintained by the Centers for Disease Control and Prevention (CDC). Using the JoinPoint regression program, we calculated the annual percent change (APC), average annual percent change (AAPC), and correspondent p values. A positive APC indicated an increasing trend, while a negative APC meant a decreasing trend. State-level obesity information was retrieved from the Behavioral Risk Factor Surveillance System maintained by CDC. Obesity was defined as a body mass index ≥30. Pearson correlation coefficients were used to test state-level correlations between obesity and AAPC of incidence and mortality. Results: During 1999-2019, a total of 271,930 AML cases were diagnosed in the US yielding an incidence rate of 3.99 per 100,000 person-years (PYs). Non-Hispanic White population had the highest incidence of 4.1 per 100,000 PYs. Among Non-Hispanic Black, Hispanic, Asian, and American Indian population, AML incidences were 3.2-3.4 per 100,000 PYs. AML incidence varied across states. The incidence rate ratio between the highest and lowest incidence of states was 1.66. The three states with the highest incidences were Iowa (4.49 per 100,000 PYs), Wisconsin (4.41 per 100,000 PYs) and Maine (4.41 per 100,000 PYs). The lowest incidences were observed in DC (2.71 per 100,000 PYs), Wyoming (3.37 per 100,000 PYs), and New Mexico (3.41 per 100,000 PYs). The national AML incidence decreased by 0.5% each year in 1999-2008 (p = 0.05), followed by an average yearly increase of 6.1% in 2008-2011 (p=0.03), then plateaued in 2011-2019. As shown in Figure 1, during 20-year period, among 45 states with non-suppress yearly incidence, incidence increased in 17 states, and plateaued in all other states. The states with the highest increases were in Kentucky (AAPC = 2.4%, p < 0.01), Tennessee (AAPC = 1.7%, p = 0.01), Virginia (AAPC = 1.4% p<.01), Utah (AAPC = 1.4%, p = 0.01) and North Carolina (AAPC = 1.4%, p<.01). The US Cancer Statistics collected 190,193 AML deaths in 1999-2019 with a mortality rate of 2.77 per 100,000 PYs. Across race and ethnicity groups, mortality rate ranged from 1.8 per 100,000 PYs among American Indian or Alaska Natives to 2.9 per 100,000 PYs among Non-Hispanic White population. The mortality rate ratio between the highest and lowest mortality of states was 1.60. Iowa (3.36 per 100,000 PYs), Washington (3.32 per 100,000 PYs), North Dakota (3.29 per 100,000 PYs) and Wisconsin (3.26 per 100,000 PYs) had the highest mortality rates. The mortality rates were lowest in Hawaii (2.30 per 100,000 PYs), New Mexico (2.26 per 100,000 PYs), and DC (2.10 per 100,000 PYs). National AML mortality plateaued in 1999-2009, then fell on average 0.4% per year over 2009-2019 (p = 0.01). Among 45 states with non-suppressed yearly mortality, mortality decreased in Montana (AAPC = -1.8%, p=0.01), Washington (AAPC = -1.0%, p<0.01), Iowa (AAPC = -0.8%, p = 0.04), and Florida (AAPC = -0.5%, p = 0.03); however, mortality increased in Virginia (AAPC = 0.6%, p = 0.03), Pennsylvania (AAPC = 0.7%, p<0.01), Nebraska (AAPC = 1.1%, p < 0.01), Kentucky (AAPC = 1.3%, p < 0.01), and Nevada (AAPC = 1.3%, p = 0.02) (Figure 2). At state-level, AAPC of AML incidence was positively correlated with percentage of obesity (r = 0.31, p = 0.04). No correlation was observed between percentage of obesity and AAPC of AML mortality at state-level. Conclusion: The findings of this cross-sectional study suggest that large state-level variation in AML incidence and mortality. Despite AML incidence plateauing in the US since 2011, it continued to increase in one-third of the states and may be connected with the differential distribution of obesity. Although AML mortality in the US has been significantly reduced since 2009, the AML mortality continued to increase in some states. Reduction of obesity should be investigated as a potential way to reduce AML incidence and related deaths.

Prognostic Role of Molecular MRD Variations during Treatment of Pediatric AML: A Retrospective AIEOP AML2013/01 Study

Background. Measurable residual disease (MRD) is a key parameter to evaluate response to cytotoxic treatment in leukemia patients and, thus, to guide therapeutic strategies. In fact, the identification of persisting leukemia cells after chemotherapy is associated with an increased risk of disease recurrence, and many patients with acute myeloid leukemia (AML) experiencing relapse have a fatal outcome. Many somatic genetic aberrations are under investigation for assessing molecular quantitative MRD (qMRD). However, while flow cytometry is already recognized as useful in measuring residual disease levels, the impact of qMRD monitoring is still debated. Methods and Results. We set up a qPCR assay to quantify mRNA fusion or mutated transcripts for 23 AML rearrangements identified at diagnosis in 247 patients (67% of the whole population) enrolled in our recently concluded AIEOP-AML2013/01 trial, with a sensitivity reaching 10 -5/-6. We measured qMRD after the induction therapy courses (n=202) and identified 66 cases with qMRD>1x10 -3 (cut-off determined by ROC curve method, qMRD with respect to disease levels found at disease onset) and 136 with qMRD<1x10 -3 after the II induction course. Patients with qMRD>1x10 -3 had a significantly worse OS and EFS with respect to patients with qMRD<1x10 -3 (77% vs 89%, p=0.016 and 61% vs 78%, p=0.016, respectively). qMRD assessment within each AML risk group, namely Standard (SR, n=64), Intermediate (IR, n=38) or High (HR, n=101), showed that the persistence of qMRD>1x10 -3 after the II induction course in SR patients did not correlated with worse EFS with respect to patients who reduced qMRD levels below the cut-off, mainly due to NPM1 mutated patients all relapsing (7/7) with qMRD<1x10 -3 after the second induction course. By contrast, qMRD>1x10 -3 was a predictive variable able to discriminate, among the patients assigned to the IR (EFS 46% vs 81% for IR, p=0.009) those children with poorer outcome. For the HR patients, qMRD 1x10 -3 predicted a worse, although not statistically significant, outcome (61% vs 80% for HR, p=0.08). When we interrogated qMRD role within the different genetic subtypes, we showed that qMRD significantly impacted on EFS of patients harboring t(8;21) RUNX1-RUNX1T1 (47% for qMRD>1x10 -3vs 88% for qMRD<1x10 -3, p=0.004), this finding corroborating results previously published by our group. A similar trend, although not significant, was also obtained for patients harboring isolated FLT3-ITD mutation, who had a dismal EFS when qMRD levels after the II induction course were above 1x10 -3 (40% (n=5) vs 71% (n=7) for qMRD<1x10 -3, p=ns). qMRD reduction for KMT2A-rearranged AML cases and for other genetic markers having a lower incidence in AML, needs to be evaluated in larger cohorts to obtain robust results. Additionally, we interrogated if qMRD maintains the same clinical relevance when measured after the III or IV chemotherapy blocks. We calculated proper cut-off for this analysis by ROC curve method, finding again 1x10 -3 for the third chemotherapy cycle; we observed that AML cases with qMRD>1x10 -3 had a worse EFS with respect to patients with lower levels of qMRD (39% n=30 vs 80% n=82, p<0.0001). As concerns the IV chemotherapy block, we calculated an appropriate cut-off corresponding to 1x10 -4, and once again we confirmed that patients with qMRD above the cut-off displayed a lower probability of experiencing adverse events (EFS 49% n=46 vs 85% n=65, p=0.0003). In conclusion, this is the first study that considers a serial and continuous qMRD monitoring all along an entire trial demonstrating a significant prognostic role of qMRD after II, III and IV therapy courses. These findings demonstrate that qMRD represents a useful tool in supporting therapeutic decisions and suggest that harmonization of currently used molecular MRD detection methods is the best solution to face MRD challenge in pediatric AML. Further comparisons between molecular and cytofluorimetric methods will increase the chances to identify those patients at high risk of relapse, despite negative MRD measured by flow cytometry.

Genomic Characterization of Newly Diagnosed Acute Myeloid Leukemia in Patients Age 60 Years and Older; A Report from the Beat AML Master Trial

Background. Acute myeloid leukemia (AML) is a heterogenous disease that occurs primarily in older adults with a median age of 69 years at diagnosis. Most studies that characterize the genomic landscape of AML include younger adults with the majority of patients being younger than 60 years of age. We aimed to study the mutational landscape of newly diagnosed AML patients aged 60 years or older. Methods.Samples were collected from the multi-center Beat AML Master Trial (Burd, Nat Med 2020). Patients were enrolled between 2016 and 2023. Informed consent was obtained according to the Declaration of Helsinki. Patients diagnosed with non-APL AML and who were aged ≥ 60 years old were included. Patients underwent bone marrow aspiration and biopsy, cytogenetic analysis, FLT3-ITD ratio assessment (LeukoStrat CDx FLT3 Mutation Assay, Invivoscribe) and next generation sequencing (NGS) using FoundationOne®Heme(Foundation Medicine) to interrogate the entire coding region of 406 genes and select introns of 31 genes involved in rearrangements, as well as RNA sequencing to interrogate 265 genes known to be somatically altered in human hematological malignancies. The presence of multiple hotspot mutations within one gene in an individual patient was counted as one gene mutation. Patterns of co-occurrence between gene mutations were calculated using the Phi correlation coefficient. Statistical analyses were performed using R statistical software. P<0.01 was considered statistically significant. Results. A total of 1088 newly diagnosed AML patients were identified, of whom 1032 were 60 years or older. Patients had a median age of 72 years at time of diagnosis (range 60-92 years). Forty-two percent of the patients were female, most patients were non-Hispanic and 79% were Caucasian. NGS data were available for 1024 patients and mutations were identified in 461 different genes. Patients had a median number of 11.0 mutations (range 3.0 to 28.0). The most frequently mutated genes were DNMT3A (n=257; 25.1%), TP53(n=255; 24.9%), TET2 (n=243; 23.7%), RUNX1 (n=225; 22.0%), SRSF2 (n=221; 21.6%), ASXL1 (n=216; 21.1%), NPM1 (n=206; 20.1%), FLT3 (n=205; 20.0%), IDH2 (n=190; 18.6%), NRAS (n=208; 16.9%), PTPN11(n=104; 10.2%), STAG2 (n=101, 9.9% and IDH1 (n=99; 9.7%) (Figure 1A). FLT3-ITD was present in 98 (12.1%) of the 810 patients who were tested. Strongest significant co-occurrence was found between FLT3and NPM1 (n=103), STAG2 and ASXL1 (n=63), ASXL1 and RUNX1 (n=92), ASXL1 and SRSF2 (n=88), RUNX1 and SRSF2 (n=94), STAG2 and SRSF2 (n=51) and DNMT3A and NPM1 (n=92) (p<0.01). Pairwise negative correlations were observed between TP53 and NPM1 (n=6), TP53 and SRSF2 (n=17), and between NPM1 and RUNX1 (n=6) (p<0.01) (Figure 1B). The cytogenetic profiles and the full genomic landscape will be presented during the ASH meeting. Discussion. This is the largest study investigating the mutational profile in older adults with AML aged 60 years and older. Due to the 7-day screening period of the Beat AML study, patient selection was biased towards less-rapidly proliferative AML. We showed that the pattern of gene mutations was markedly different from other studies in AML that mainly included younger AML patients (Papaemmanuil, NEJM 2016; TCGA, NEJM 2013 ). The frequency of mutated TP53 was substantially higher in older AML patients, as was the occurrence of myelodysplasia-related gene mutations (e.g., SRSF2, RUNX1, ASXL1, STAG2, U2AF1, and SF3B1) and gene mutations in IDH1, IDH2 and TET2. In contrast, NPM1 mutation was less frequently mutated in older AML patients. Furthermore, we demonstrated that a large proportion (46%) of the AML patients older than 60 years of age do have a mutation that is potentially targetable for treatment ( FLT3 IDH1 IDH2 and NPM1). The high incidence of mutated TP53 and MDS-related gene mutations underscores the increased incidence of high-risk AML and the need for innovative personalized therapies in this older age group. Figure 1. A. Co-occurrence of the 15 most frequently mutated genes, and B. co-correlation between the 15 most frequently mutated genes. Blue indicates positive correlation, red indicated negative correlation. Only significant correlations (p<0.01) are shown.