Minimal residual disease monitoring in acute myeloid leukemia: Focus on MFC-MRD and treatment guidance for elderly patients.

Acute myeloid leukemia (AML) is distinguished by clonal growth of myeloid precursor cells, which impairs normal hematopoiesis. Minimal residual disease (MRD) refers to the residual leukemia cells that persist after chemotherapy. Patients who test positive for MRD have a higher likelihood of experiencing a recurrence, regardless of the specific chemotherapy approach used. Multi-parameter flow cytometry (MFC), polymerase chain reaction (PCR), and next-generation sequencing (NGS) are commonly employed techniques for identifying MRD. In the context of AML, patients are frequently monitored for measurable residual disease via multi-parameter flow cytometry (MFC-MRD). In order to explore recent advancements in AML and MRD diagnosis, an extensive search of the PubMed database was conducted, focusing on relevant research in the past 20 years. This review aims to examine various MRD monitoring methods, the optimal time points for assessment, as well as different specimen types used. Additionally, it underscores the significance of MFC-MRD assessment in guiding the treatment of elderly AML.

The outcome in pediatric acute myeloblastic leukemia; results of the first-line treatment and contribution of hematopoietic stem cell transplantation to survival of relapsed patients.

Background/aim: To analyze the long-term outcome of pediatric patients with acute myeloblastic leukemia. Materials and methods: Data from 69 patients 0-18 years of age diagnosed between December 2001 and October 2019 were analyzed in April 2023. Patients received MRC-AML10 chemotherapy (2ADE+MACE+MidAC). No maintenance chemotherapy or preventive cranial radiotherapy was administered. Twelve patients with Down syndrome and 15 patients with promyelocytic leukemia were in the cohort. Patients with Down syndrome received reduced chemotherapy (cumulative anthracycline 420 mg/m2, cytarabine 3.4 g/m2, etoposide 1400 mg/m2). ATRA was added to chemotherapy in promyelocytic leukemia. Results: Four patients (5.8%) died in the induction (two typhlitis, one intracranial hemorrhage, and one resistant disease). The complete remission rate of 66 patients was 87.8%. There was one death due to cardiotoxicity. Total infection-related deaths were 7.2%. Seven patients with high-risk criteria and one with resistant disease underwent hematopoietic stem cell transplantation (HSCT) following the first-line treatment. All seven patients in remission were alive and disease-free. The relapse rate was 34.4% (n = 21). Four patients developing marrow relapse were disease-free in the second remission after salvage and maintenance chemotherapy. Thirteen patients (18.84%) underwent HSCT in the second remission and 8 are alive and disease-free. The mean follow-up period of patients from diagnosis was 185 ± 13 months. Thirty-four patients (49.2%) were alive and disease-free in the first remission whereas another two patients in the first remission developed secondary malignancy. In good, standard, and poor risk groups, event-free survival (EFS) rates were 68.2%, 52.9%, and 10%, and overall survival (OS) rates were 86.4%, 79.4%, and 20%, respectively. Fifteen years of EFS and OS of the whole cohort were 49.3% and 69.6%, respectively. Conclusion: When compared with national data and multicenter studies of developed countries, survival rates were acceptable.

[Management of pediatric leukemia]. / Prise en charge des leucémies pédiatriques.

Acute leukemias are the most common pediatric cancer. With a cure rate of about 80%, their treatment is based on a combination of cytotoxic chemotherapies whose intensity is adapted to prognostic factors. Sometimes, allogeneic hematopoietic stem cell transplantation is indicated. New therapeutic options are being developed, such as CAR T-cells.

Control of graft-versus-host disease with rabbit anti-thymocyte globulin, rituximab, and bortezomib in TCRαß/CD19-depleted graft transplantation for leukemia in children: a single-center retrospective analysis of two GVHD-prophylaxis regimens.

Both acute GVHD and chronic GVHD remain the leading cause of morbidity and death after allogeneic HSCT. We conducted a retrospective analysis comparing two GVHD-prophylaxis regimens: 35 patients received "Regimen 1" (horse ATG, tacrolimus, and methotrexate) and 46 "Regimen 2" (rabbit ATG, rituximab, and peritransplant bortezomib). All 81 patients with a median age of 9 (0.6-23) years with ALL (n = 31) or AML (n = 50) in complete remission received TCRαß/CD19-depleted transplants between May 2012 and October 2016, from 40 HLA-matched unrelated and 41 haploidentical donors. After a median follow-up of 3.9 years, the CI of acute GVHD II-IV was 15% (95% CI: 7-30) in the "Regimen 2" group and 34% (95% CI: -54) in the "Regimen 1" group, P = .05. "Regimen 2" was also more effective in the prevention of chronic GVHD; the CI at 1 year after HSCT was 7% (95% CI: 2-19) vs 31% (95% CI: 19-51), P = .005. The CI of relapse at 3 years adjusted for the GVHD-prophylaxis regimen groups 31% (95% CI: 19-51) for the "Regimen 1" vs 21% (95% CI: 11-37) for the "Regimen 2", P = .3. The retrospective observation suggests that the use of the rATG, rituximab, and bortezomib was associated with significantly lower rate of GVHD without the loss of anti-leukemic activity.

Design, synthesis, and biological evaluation of tetrahydroquinolin derivatives as potent inhibitors of CBP bromodomain.

CREB-binding protein (CBP) is a large multi-domain protein containing a HAT domain catalyzing transacetylation and a bromodomain responsible for acetylated lysine recognition. CBPs could act as transcription co-activators to regulate gene expression and have been shown to play a significant role in the development and progression of many cancers. Herein, through in silico screening two hit compounds with tetrahydroquinolin methyl carbamate scaffold were discovered, among which DC-CPin7 showed an in vitro inhibitory activity with the TR-FRET IC50 value of 2.5 ± 0.3 µM. We obtained a high-resolution co-crystal structure of the CBP bromodomain in complex with DC-CPin7 to guide following structure-based rational drug design, which yielded over ten DC-CPin7 derivatives with much higher potency, among which DC-CPin711 showed approximately 40-fold potency compared with hit compound DC-CPin7 with an in vitro TR-FRET IC50 value of 63.3 ± 4.0 nM. Notably, DC-CPin711 showed over 150-fold selectivity against BRD4 bromodomains. Moreover, DC-CPin711 showed micromolar level of anti-leukemia proliferation through G1 phase cell cycle arrest and cell apoptosis. In summary, through a combination of computational and crystal-based structure optimization, DC-CPin711 showed potent in vitro inhibitory activities to CBP bromodomain with a decent selectivity towards BRD4 bromodomains and good cellular activity to leukemia cells, which could further be applied to related biological and translational studies as well as serve as a lead compound for future development of potent and selective CBP bromodomain inhibitors.

Assessment of chimerism and immunomodulation to prevent post-transplantation relapse in childhood acute myeloblastic leukemia: is it the right approach?

Relapse of acute myeloblastic leukemia (AML) after first allogenic hematopoietic stem-cell transplantation (allo-HSCT) is a fatal complication. Sixty-five children transplanted for AML were included in a prospective national study from June 2005 to July 2008 to explore the feasibility of preemptive immune modulation based on the monitoring of blood chimerism. Relapse occurred in 23 patients (35%). The median time between the last complete chimerism and relapse was 13.5 days (2-138). Prompt discontinuation of cyclosporin and the administration of donor lymphocyte infusions (DLIs) based on chimerism monitoring failed as a preemptive tool, either for detecting relapse or certifying long-term remission.

Survival in patients with acute myeloblastic leukemia in Germany and the United States: Major differences in survival in young adults.

Previous epidemiologic studies on AML have been limited by the rarity of the disease. Here, we present population level data on survival of patients with AML in Germany and the United States (US). Data were extracted from 11 population-based cancer registries in Germany and the Surveillance, Epidemiology, and End Results (SEER13) database in the US. Patients diagnosed with AML in 1997-2011 were included. Period analysis was used to estimate 5-year relative survival (RS) and trends in survival in the early 21st century. Overall 5-year age-adjusted RS for patients with AML in 2007-2011 was greater in Germany than in the US at 22.8% and 18.8%, respectively. Five-year RS was higher in Germany than in the US at all ages, with particularly large differences at ages 15-24 for whom 5-year RS was 64.3% in Germany and 55.0% in the US and 35-44, with 5-year RS estimates of 61.8% in Germany and 46.6% in the US. Most of the difference in 5-year RS was due to higher 1-year RS, with overall 1-year RS estimates of 47.0% in Germany and 38.5% in the US. A small increase in RS was observed between 2003-2005 and 2009-2011 in both countries, but no increase in survival was observed in either country for ages 75+. To our knowledge, this is the first detailed description of AML survival in Germany. Comparison to the US suggests that further analysis into risk factors for poor outcomes in AML in the US may be useful in improving survival.

Genomic and transcriptomic profiles and in vitro resistance to mitoxantrone and idarubicin in pediatric acute leukemias.

BACKGROUND: A major problem in the treatment of leukemia is the development of drug resistance to chemotherapeutic agents. METHODS: To determine the ex vivo drug resistance profile to anthracyclines, an 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazoliumbromide (MTT) cytotoxicity assay was performed on mononuclear cells obtained from 155 patients with acute lymphoblastic leukemia (ALL) or acute myeloblastic leukemia (AML). Gene expression profiles (for 51 patients with ALL and 16 with AML) were prepared on the basis of cRNA hybridization to oligonucleotide arrays of the human genome (Affymetrix). Hierarchical clustering, assignment location and biological function were investigated during the correlation analysis for identified probe sets. Comparative genomic hybridization (CGH) array profiles (34 patients with ALL and 12 with AML) were prepared on the basis of DNA hybridization to oligonucleotide arrays of the human genome (Agilent). The validation of the array results was performed by a quantitative reverse transcriptase polymerase chain reaction. RESULTS: The collected expression and CGH microarray experiment results indicate that the ITGB2, SCL6A7, CASP1 and DUSP genes may comprise a resistance marker for acute leukemia cells correlated with anthracyclines. Moreover, there were also identified chromosome rearrangements associated with drug resistance, such as del5q32-35.3 and amp8p12-p11.21. Precise genes, as well as genome aberrations, might be classified as targets in therapy. CONCLUSIONS: In AML, the resistance of blasts to idarubicin and mitoxantrone may reflect an impaired integrin pathway. In ALL, the development of resistance is caused by the inhibition of B and T cell activation. Copyright © 2016 John Wiley & Sons, Ltd.

Successful acute lymphoblastic leukemia-type therapy in two children with mixed-phenotype acute leukemia.

Mixed-phenotype acute leukemia (MPAL) is a rare type of leukemia expressing both myeloid and lymphoid markers. There is limited information, especially on pediatric cases. Therefore, the optimal therapeutic approach to pediatric MPAL has not been defined. Here, we report two pediatric cases of MPAL. According to the 2008 World Health Organization (WHO) classification and European Group for the Immunological Characterization of Leukemias (EGIL) criteria, patient 1 was diagnosed with overt MPAL positive for the myeloid marker myeloperoxidase (MPO), and B-lymphoid markers. Patient 2 was diagnosed with T-cell acute lymphoblastic leukemia (T-ALL) using EGIL criteria. According to the 2008 WHO classification, however, patient 2 was diagnosed with overt MPAL positive for CD3, T-lymphoid markers and MPO. We chose an ALL-type therapy consisting of both lymphoid- and myeloid-directed agents; these patients have maintained complete remission following treatment. Further information on pediatric MPAL is needed to establish an appropriate therapeutic strategy including stem cell transplantation for this rare condition.

[Primary granulocytic sarcoma of lacrimal gland]. / Pervichnaia mieloidnaia sarkoma sleznoi zhelezy.

The article presents clinical description and instrumental findings (ultrasound examination and multi-slice computed tomography of the orbits) of a rare lacrimal gland tumor, which precedes or concurs with acute myeloblastic leukemia. Due to the low incidence of myeloid (granulocytic) sarcoma, it is not possible to develop a proper algorithm for its diagnosis and treatment. Few descriptions that are available in the literature neither give an idea of the variety of manifestations and the order of organ involvement, nor allow any vital prognosis. Verification of the diagnosis can only be based on immunohistochemical findings of the primary tumor and bone marrow biopsy material. The authors emphasize the importance of combination treatment (radiation therapy of the orbits and chemotherapy) in the prevention of leukemia.

A meta-analysis of the association between NQO1 C609T variation and acute myeloid leukemia risk.

Quinone oxidoreductase (NQO1) C609T polymorphisms have been implicated in acute myeloblastic leukemia (AML) risk, but previously published studies are inconsistent and recent meta-analyses have not been adequate. To derive a more precise estimation of the relationship, a meta-analysis was performed. Medline, PubMed, Embase, and Web of Science were searched. The quality of studies was evaluated by using the Newcastle-Ottawa Scale (NOS). Crude ORs with 95% CIs were used to assess the strength of association between the NQO1 C609T polymorphisms and AML risk. A total of 14 studies including 2,245 cases and 3,310 controls were involved in this meta-analysis. Overall, significantly elevated AML risk was associated with NQO1 C609T variant genotypes when all studies were pooled into the meta-analysis (TT vs. CC: OR = 1.44, 95% CI = 1.15-1.81; dominant model: OR = 1.35, 95% CI = 1.09-1.68). In the subgroup analysis by ethnicity, significantly increased risks were found for Asians (OR = 1.47, 95% CI = 1.13-1.93, P = 0.005, I(2) = 48.4%, P = 0.071 for heterogeneity). When stratified by studies of adults or children, statistically significantly elevated risks were found among adults (OR = 1.37, 95% CI = 1.06-1.76, P = 0.017, I(2) = 42.2%, P = 0.097 for heterogeneity). The accumulated evidence indicates that NQO1 C609T seems to confer a risk factor for AML among Asians and adults. Significant between-study heterogeneity was observed, thus more studies based on larger case-control population are required to further evaluate the role of NQO1 C609T polymorphism in AML.

WT1-guided pre-emptive therapy after allogeneic hematopoietic stem cell transplantation in patients with acute myeloid leukemia.

Measurable residual disease (MRD)-guided pre-emptive therapies are now widely used to prevent post-transplant hematological relapse in patients with acute myeloid leukemia (AML). This single-center retrospective study aimed to clarify the significance of pre-emptive treatment based on Wilms' tumor gene-1 mRNA (WT1) monitoring for MRD in patients with AML who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT). Patients with AML who received chemotherapy for hematological relapse or WT1 increase after allo-HSCT were eligible for inclusion. From January 2017 to June 2022, 30 patients with a median age of 57 (16-70) years were included and stratified into two groups: 10 with WT1 increase and 20 with hematological relapse. The median times from HCT to WT1 increase or hematological relapse were 309 days (range: 48-985) or 242 days (range: 67-1116), respectively. Less intensive chemotherapy using azacitidine or cytarabine was selected for all patients with WT1 increase and 12 (60%) with hematological relapse. The 1-year overall survival and event-free survival rates for WT1 increase and hematological relapse were 70% vs. 44% (P = 0.024) and 70% vs. 29% (P = 0.029), respectively. These real-world data suggest that WT1-guided pre-emptive therapy may be superior to therapy after hematological relapse in patients with AML who have undergone allo-HSCT.

Association of Leukemia With ABO Blood Group Distribution and Discrepancy: A Review Article.

The ABO system is an essential blood group in clinical transfusion medicine implicated in several human diseases. The ABO system has been investigated for over a century, with various studies exploring potential links to disease susceptibility. The study examines the possible relationship between leukemia and the distribution and the ABO blood group system discrepancy. A comprehensive review was conducted on the recommended databases to review the ABO blood groups, their association with leukemia, and the expected changes in blood groups among leukemia patients. The study highlights different kinds of leukemia, such as acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and chronic lymphocytic leukemia (CLL), their characteristics, and their relationship with ABO blood groups. The document concludes that studying ABO blood group distributions among leukemia patients showed that the most common blood group in acute leukemia is the A group, while in chronic leukemia, the O group is predominant; more studies are required. This study also confirmed an association between leukemia and ABO blood group discrepancy.

Iron Overload in Children with Acute Lymphoblastic and Acute Myeloblastic Leukemia-Experience of One Center.

Transfusions of packed red blood cells (PRBCs), given due to an oncological disease and its acute complications, are an indispensable part of anticancer therapy. However, they can lead to post-transfusion iron overload. The study aim was to evaluate the role of ferritin as a nonspecific marker of leukemic growth and marker of transfusion-related iron overload. We performed a longitudinal study of PRBC transfusions and changes in ferritin concentrations during the oncological treatment of 135 patients with childhood acute lymphoblastic and acute myeloblastic leukemia (ALL and AML, median age 5.62 years). At the diagnosis, 41% of patients had a ferritin level over 500 ng/mL, and 14% of patients had a ferritin level over 1000 ng/mL. At the cessation of the treatment, 80% of the children had serum ferritin (SF) over 500 ng/mL, and 31% had SF over 1000 ng/mL. There was no significant difference between SF at the beginning of the treatment between ALL and AML patients, but children with AML finished treatment with statistically higher SF. AML patients had also statistically higher number of transfusions. We found statistically significant positive correlations between ferritin and age, and weight and units of transfused blood. Serum ferritin at the moment of diagnosis can be a useful marker of leukemic growth, but high levels of SF are connected with iron overload in both AML and ALL.

A comparison of haploidentical versus HLA-identical sibling outpatient hematopoietic cell transplantation using reduced intensity conditioning in patients with acute leukemia.

Background: Hematopoietic cell transplantation (HCT) increases survival for acute leukemia. Outpatient allogeneic HCT reduces costs and increases transplant rates in developing countries. We report outcomes of outpatient HLA-identical and haploidentical HCT in acute leukemia. Methods: This single-center retrospective cohort study analyzed 121 adult patients with acute myeloblastic (AML) and acute lymphoblastic leukemia (ALL) receiving an outpatient allogeneic HCT with peripheral blood allografts after reduced-intensity conditioning (RIC) from 2012-2022. Results: There were 81 (67%) haploidentical and 40 (33%) HLA-identical transplants. Complete chimerism (CC) at day +100 was not different in HLA-identical compared to haploidentical HCT (32.5% and 38.2%, P=0.054). Post-HCT complications, including neutropenic fever (59.3% vs. 40%), acute graft-versus-host-disease (aGVHD) (46.9% vs. 25%), cytokine release syndrome (CRS) (18.5% vs. 2.5%), and hospitalization (71.6% vs 42.5%) were significantly more frequent in haploidentical HCT. Two-year overall survival (OS) was 60.6% vs. 46.9%, (P=0.464) for HLA-identical and haplo-HCT, respectively. There was no difference in the 2-year disease-free-survival (DFS) (33.3% vs. 35%, P=0.924) between transplant types. In multivariate analysis, positive measurable residual disease (MRD) at 30 days (HR 8.8, P=0.018) and 100 days (HR 28.5, P=0.022) was associated with lower OS, but not with non-relapse mortality (NRM) (P=0.252 and P=0.123, univariate). In univariate analysis, both 30-day and 100-day MRD were associated with lower DFS rates (P=0.026 and P=0.006), but only day 30 MRD was significant in multivariate analysis (P=0.050). In the case of relapse, only MRD at day 100 was associated with increased risk in the univariate and multivariate analyses (HR 4.48, P=0.003 and HR 4.67, P=0.008). Chronic graft-versus-host-disease (cGVHD) was protective for NRM (HR 0.38, P=0.015). There was no difference in cumulative incidence of relapse (CIR) between transplant types (P=0.126). Forty-four (36.4%) patients died, with no difference between HCT type (P=0.307). Septic shock was the most frequent cause of death with 17 cases, with no difference between transplant types. Conclusions: Outpatient peripheral blood allogenic HCT after RIC is a valid and effective alternative for adult patients suffering acute myeloblastic or lymphoblastic leukemia in low-income populations.

The Potential Role of NOD2/CARD15 Genotype as a Prognostic Indicator for Bone Marrow Transplantation Outcomes in Patients With Acute Lymphoblastic Leukemia and Acute Myeloid Leukemia: A Systematic Review.

Hematopoietic stem-cell transplantation (HSCT) has emerged as a groundbreaking therapeutic option for acute myeloid leukemia (AML) and specific subtypes of acute lymphoblastic leukemia (ALL). The prognostic significance of the NOD2/CARD15 gene has been explored alongside various factors, encompassing diverse patient cohorts and gene variants. Siblings and unrelated donors used for stem cell transplantation exhibit significant associations between their genetic variations and graft-versus-host disease incidence. The transplantation of stem cells for leukemia patients involves numerous considerations, including patient survival, relapse rates, disease stage, donor and recipient ages, and compatibility. This study delved into research on the NOD2/CARD15 gene and its mutations to assess its suitability as a screening tool. A comprehensive literature search encompassing PubMed, ScienceDirect, and Google Scholar articles yielded 4,840 articles. After removing duplicates and applying inclusion and exclusion criteria, we narrowed the search results to 876 articles. Subsequent screening of abstracts and titles resulted in the selection of 230 relevant articles. Further exclusion of 198 articles unrelated to the research question led to the scrutinizing of 32 full-text articles, which were assessed against inclusion and exclusion criteria. Emphasis was placed on articles that specifically investigated the role of NOD2/CARD15 as a predictive factor for HSCT outcomes, ultimately resulting in the inclusion of 19 articles in this study. Single nucleotide polymorphisms (SNPs) such as NOD2 and CARD15 have demonstrated their potential as reliable genetic markers for predicting post-transplantation relapse and disease outcomes. Patients positive for these genetic markers have exhibited reduced overall survival and event-free survival and increased transplant-related mortality. Interventions with interferon-gamma and muramyl tripeptide phosphatidylethanolamine have been considered to mitigate the inflammatory effects of these SNPs, thus enhancing the influence of natural killer cells on abnormal cells and potentially extending patient survival. NOD2/CARD15 typing may aid in identifying patients at higher risk for relapse and improving their clinical outcomes after allogeneic stem cell transplant, particularly in ALL patients. However, no remarkable change was observed in AML patients. Additionally, this study underscores the pivotal roles of adaptive and innate immune responses and their interplay in stem cell transplant immunology.

Human Umbilical Cord Mesenchymal Stem Cell-Derived Microvesicles Could Induce Apoptosis and Autophagy in Acute Myeloid Leukemia.

Background: Microvesicles (MV) have been identified as candidate biomarkers for treating acute myeloid leukemia (AML). This study investigated the effects of human umbilical cord-derived mesenchymal stem cell (hUCMSC)-derived MVs on apoptosis and autophagy in the KG-1 leukemic cell line. Methods: The hUCMSCs were cultured and characterized by flow cytometry. MVs were isolated by ultracentrifugation, and the concentration was determined using the Bradford method. The characteristics of MVs were confirmed using transmission electron microscopy, flow cytometry, and dynamic light scattering methods. KG-1 cells were treated with the desired concentrations of MVs for 24 h. The apoptosis induction and reactive oxygen species production were evaluated using flow cytometry. RT-PCR was performed to evaluate apoptosis- and autophagy-related genes expression. Results: Following tretment of KG-1 cells with 25, 50, and 100 µg/ml concentrations of MVs, the apoptosis rates were 47.85%, 47.15%, and 51.35% (p < 0.0001), and the autophagy-induced ROS levels were 73.9% (p < 0.0002), 84.8% (p < 0.0001), and 85.4% (p < 0.0001), respectively. BAX and ATG7 gene expression increased significantly at all concentrations compared to the control, and this level was higher at 50 µg/ml than that of the other concentrations. In addition, LC3 and Beclin 1 expression increased significantly in a concentration-dependen manner. Conversely, BCL2 expression decreased compared to the control. Conclusion: Our findings indicate that hUCMSC-MVs could induce cell death pathways of autophagy and apoptosis in the KG-1 cell lines and exert potent antiproliferative and proapoptotic effects on KG-1 cells in vitro. Therefore, hUCMSC-MVs may be a potential approach for cancer therapy as a novel cell-to-cell communication strategy.

Impact of different chemotherapy regimens on intestinal mucosal injury assessed with bedside ultrasound: a study in 213 AML patients.

Introduction: Neutropenic enterocolitis (NEC) is a life-threatening complication reported in patients with acute myeloid leukemia (AML) following chemotherapy (CHT). Intensive induction and consolidation CHT may damage intestinal mucosa leading to a NEC episode (NECe). NEC reported mortality may be up to 30-60%. Early US-guided bed-side diagnosis and prompt treatment may substantially improve the survival. An emerging worldwide concern is the intestinal colonization by multi-drug-resistant bacteria especially when patients are exposed to chemotherapy regimens potentially correlated to mucosal damage. Methods: In our study we prospectively enrolled all AML patients admitted in our leukemia unit to receive intensive induction and consolidation chemotherapy and experiencing chemotherapy-induced-neutropenia (CHTN). Results and discussion: Overall, we enrolled N=213 patients from 2007 to March 2023. We recorded N=465 CHTN, and N=42 NECe (9.0% incidence). The aim of our study was to assess which chemotherapy regimens are more associated with NEC. We found that ALM1310, followed by 7 + 3 (daunorubicin), 7 + 3 (idarubicin), 5 + 3 + 3 (cytarabine, etoposide, idarubicin), and AML1310 (consolidation) were associated with a statistically higher incidence of NEC. We did not detect NEC episodes in patients treated with CPX-351, 5 + 2 (cytarabine, idarubicine), and high-dose cytarabine. Thus, we found that cytarabine could determine mucosal damage when associated with an anthracycline but not if delivered either alone or as dual-drug liposomal encapsulation of daunorubicin/cytarabine. We also describe NEC mortality, symptoms at diagnosis, intestinal sites involvement, and prognostic significance of bowel wall thickening.

[Prognostic value of residual disease detection in acute myeloid leukemia with normal karyotype and negative FLT3-ITD]. / Intérêt pronostique de la détection de la maladie résiduelle dans les leucémies aiguës myéloïdes avec caryotype normal et FLT3-ITD négatif.

INTRODUCTION: Complete remission (CR) in patients with acute myeloid leukemia (AML) is still morphologicaly defined, thus corresponding to a wide range of tumor burden. OBJECTIVES: we aimed to evaluate the residual disease (MRD) status in patients with AML, as well as perform a molecular analysis of the FLT3/ITD gene in patients with normal karyotype. MATERIAL AND METHODS: adult patients with AML, diagnosed according to the WHO 2016 criteria, were included. MRD was detected using flow cytometric techniques after induction treatment resulting in CR. RESULTS: thirty patients met our inclusion criteria. 83 % of them had an intermediate risk status, 67 % of which (20/30) having a normal karyotype. MRD and leukemic stem cell (LSC) positivity in this group was predominant with considerable decrease in benign progenitor count. The relapse-free survival (RFS) in the group of MRD negative patients with normal cytogenetics and non-mutated FLT3 gene was better than the RFS in all of our patients studied. CONCLUSION: MRD and LSC are powerful prognostic factors for relapse. They should be routinely integrated to guide better management of AML.

Cuproptosis-related lncRNAs as potential biomarkers of AML prognosis and the role of lncRNA HAGLR/miR-326/CDKN2A regulatory axis in AML.

Acute myeloblastic leukemia (AML) is the most prevalent form of AML in adults. Despite the availability of various treatment options, including radiotherapy and chemotherapy, many patients fail to respond to treatment or relapse. Copper is a necessary cofactor for all organisms; however, it turns toxic when concentrations reach a certain threshold maintained by homeostatic systems that have been conserved through evolution. However, the mechanism through which excess copper triggers cell death remains unknown. In this study, data on long non-coding RNAs (lncRNAs) related to cuproptosis were retrieved from publicly available databases. LASSO and univariate and multivariate Cox regression analyses were performed to establish an lncRNA model associated with cuproptosis specific to AML. To investigate the risk model, the Kaplan-Meier curve, principal component analysis, functional enrichment analysis, and nomographs were employed. The underlying clinicopathological characteristics were determined, and drug sensitivity predictions against the model were identified. Six cuproptosis-related lncRNA-based risk models were identified as the independent prognostic factors. By regrouping patients using a model-based method, we were able to more accurately differentiate patients according to their responses to immunotherapy. In addition, prospective compounds targeting AML subtypes have been identified. Using qRT-PCR, we examined the expression levels of six cuproptosis-associated lncRNAs in 30 clinical specimens. The cuproptosis-associated lncRNA risk-scoring model developed herein has implications in monitoring AML prognosis and in the clinical prediction of the response to immunotherapy. Furthermore, we identified and verified the ceRNA of the cuproptosis-related lncRNA HAGLR/miR-326/CDKN2A regulatory axis using bioinformatic tools. HAGLR is highly expressed in AML and AML cell lines. HAGLR inhibition significantly reduced the proliferation of AML cells and promoted apoptosis. Elesclomol promotes the degradation of CDKN2A and inhibits the proliferation of AML cells. Elesclomol combined with si-HAGLR inhibited the AML progression of AML both in vitro and in vivo.