Adult Acute Myeloid Leukemia – A Possible Relation to Disease Invasion and the Impact of Independent Prognostic Markers Associated with Survival Outcome

AbstractSomatic mutation of the AML1/RUNX1(RUNX1) gene is seen in acute myeloid leukemia (AML) M0 subtype and in AML transformed from myelodysplastic syndrome, but the impact of this gene mutation on survival in AML patients remains unclear. In this study, we sought to determine the clinical implications of RUNX1 mutations in 470 adult patients with de novo non-M3 AML. Sixty-three distinct RUNX1 mutations were identified in 62 persons (13.2%); 32 were in N-terminal and 31, C-terminal. The RUNX1 mutation was closely associated with male sex, older age, lower lactic dehydrogenase value, French-American-British M0/M1 subtypes, and expression of HLA-DR and CD34, but inversely correlated with CD33, CD15, CD19, and CD56 expression. Furthermore, the mutation was positively associated with MLL/PTD but negatively associated with CEBPA and NPM1 mutations. AML patients with RUNX1 mutations had a significantly lower complete remission rate and shorter disease-free and overall survival than those without the mutation. Multivariate analysis demonstrated that RUNX1 mutation was an independent poor prognostic factor for overall survival. Sequential analysis in 133 patients revealed that none acquired novel RUNX1 mutations during clinical courses. Our findings provide evidence that RUNX1 mutations are associated with distinct biologic and clinical characteristics and poor prognosis in patients with de novo AML.

Download Full-text

Actin cytoskeleton deregulation confers midostaurin resistance in FLT3-mutant acute myeloid leukemia

Communications Biology ◽

10.1038/s42003-021-02215-w ◽

2021 ◽

Vol 4 (1) ◽

Author(s):

Andoni Garitano-Trojaola ◽

Ana Sancho ◽

Ralph Götz ◽

Patrick Eiring ◽

Susanne Walz ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Actin Cytoskeleton ◽

Myeloid Leukemia ◽

Actin Polymerization ◽

Cell Stiffness ◽

Adhesion Forces ◽

Frequent Mutations ◽

New Perspective ◽

The Impact ◽

Acute Myeloid

AbstractThe presence of FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) is one of the most frequent mutations in acute myeloid leukemia (AML) and is associated with an unfavorable prognosis. FLT3 inhibitors, such as midostaurin, are used clinically but fail to entirely eradicate FLT3-ITD + AML. This study introduces a new perspective and highlights the impact of RAC1-dependent actin cytoskeleton remodeling on resistance to midostaurin in AML. RAC1 hyperactivation leads resistance via hyperphosphorylation of the positive regulator of actin polymerization N-WASP and antiapoptotic BCL-2. RAC1/N-WASP, through ARP2/3 complex activation, increases the number of actin filaments, cell stiffness and adhesion forces to mesenchymal stromal cells (MSCs) being identified as a biomarker of resistance. Midostaurin resistance can be overcome by a combination of midostaruin, the BCL-2 inhibitor venetoclax and the RAC1 inhibitor Eht1864 in midostaurin-resistant AML cell lines and primary samples, providing the first evidence of a potential new treatment approach to eradicate FLT3-ITD + AML.

Download Full-text

The impact of the combination of KIT mutation and minimal residual disease on outcome in t(8;21) acute myeloid leukemia

Blood Cancer Journal ◽

10.1038/s41408-021-00461-z ◽

2021 ◽

Vol 11 (4) ◽

Author(s):

Ya-Zhen Qin ◽

Qian Jiang ◽

Yu Wang ◽

Hao Jiang ◽

Lan-Ping Xu ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Minimal Residual Disease ◽

Myeloid Leukemia ◽

Residual Disease ◽

Kit Mutation ◽

The Impact ◽

Minimal Residual ◽

Acute Myeloid

Download Full-text

Early human cytomegalovirus replication after transplantation is associated with a decreased relapse risk: evidence for a putative virus-versus-leukemia effect in acute myeloid leukemia patients

Blood ◽

10.1182/blood-2010-08-304121 ◽

2011 ◽

Vol 118 (5) ◽

pp. 1402-1412 ◽

Cited By ~ 198

Author(s):

Ahmet H. Elmaagacli ◽

Nina K. Steckel ◽

Michael Koldehoff ◽

Yael Hegerfeldt ◽

Rudolf Trenschel ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Human Cytomegalovirus ◽

Myeloid Leukemia ◽

Homogeneous Population ◽

Relapse Risk ◽

Pp65 Antigenemia ◽

Hcmv Replication ◽

The Impact ◽

Early Human ◽

Acute Myeloid

Abstract The impact of early human cytomegalovirus (HCMV) replication on leukemic recurrence was evaluated in 266 consecutive adult (median age, 47 years; range, 18-73 years) acute myeloid leukemia patients, who underwent allogeneic stem cell transplantation (alloSCT) from 10 of 10 high-resolution human leukocyte Ag-identical unrelated (n = 148) or sibling (n = 118) donors. A total of 63% of patients (n = 167) were at risk for HCMV reactivation by patient and donor pretransplantation HCMV serostatus. In 77 patients, first HCMV replication as detected by pp65-antigenemia assay developed at a median of 46 days (range, 25-108 days) after alloSCT. Taking all relevant competing risk factors into account, the cumulative incidence of hematologic relapse at 10 years after alloSCT was 42% (95% confidence interval [CI], 35%-51%) in patients without opposed to 9% (95% CI, 4%-19%) in patients with early pp65-antigenemia (P < .0001). A substantial and independent reduction of the relapse risk associated with early HCMV replication was confirmed by multivariate analysis using time-dependent covariate functions for grades II to IV acute and chronic graft-versus-host disease, and pp65-antigenemia (hazard ratio = 0.2; 95% CI, 0.1-0.4, P < .0001). This is the first report that demonstrates an independent and substantial reduction of the leukemic relapse risk after early replicative HCMV infection in a homogeneous population of adult acute myeloid leukemia patients.

Download Full-text

New Strategies for the Treatment of Acute Myeloid Leukemia Including Antibodies and Other Novel Agents

Hematology ◽

10.1182/asheducation-2005.1.143 ◽

2005 ◽

Vol 2005 (1) ◽

pp. 143-150 ◽

Cited By ~ 40

Author(s):

Martin S. Tallman

Keyword(s):

Older Adults ◽

Acute Myeloid Leukemia ◽

Multidrug Resistance ◽

Myeloid Leukemia ◽

Cytotoxic Agents ◽

High Dose ◽

Farnesyltransferase Inhibitors ◽

Younger Adults ◽

The Impact ◽

Acute Myeloid

Abstract The prognosis for younger adults (≤ 55–60 years) with acute myeloid leukemia (AML) has improved during the last four decades. However, there has been little progress in the treatment of older adults. This disappointing observation is important because the median age of patients with AML is about 70 years. Approximately 60%–80% of younger adults with AML achieve complete remission (CR) with the cytotoxic agents cytarabine and an anthracycline such as daunorubicin or idarubicin or the anthracenedione mitoxantrone. However, only 30%–40% of such patients are alive and disease-free at 5 years. Among older adults, CR is achieved in 40%–55%, but there are very few long-term survivors. Many studies have evaluated the impact of alternative doses and schedules, as well as additional cytotoxic drugs, on the prognosis for this group of patients. The outcome has not improved substantially beyond that achieved with conventional doses of an anthracycline and cytarabine followed by high-dose cytarabine consolidation. Several factors identified at diagnosis can predict outcome. The most important of these is the karyotype of the leukemic cells. Another critical factor is the presence of transmembrane transporter proteins, which confer multidrug resistance and mutations in or overexpression of specific genes such as WT1, C/EBPα, BAX, and BCL-2/BAX ratio, BAALC, EVI1, KIT and FLT3. The development of specific agents directed at gene mutations, signal transduction pathways and unique cell surface antigens provide the foundation for new therapeutic strategies. Such agents include the immunoconjugate gemtuzumab ozogamicin, multidrug resistance inhibitors, farnesyltransferase inhibitors, histone deacetylase and proteosome inhibitors, antiangiogenesis agents, FLT3 inhibitors, apoptosis inhibitors, and nucleoside analogs. All of these agents can potentially address the heterogeneous abnormalities in AML and significantly improve the outcome for patients.

Download Full-text

Effectiveness of induction regimens on survival outcome in acute myeloid leukemia patients: a real-world data from 2001 to 2015

Annals of Hematology ◽

10.1007/s00277-021-04670-1 ◽

2021 ◽

Author(s):

Hsin-An Hou ◽

Huey-En Tzeng ◽

Hung-Yi Liu ◽

Wen-Chien Chou ◽

Hwei-Fang Tien ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Real World ◽

Myeloid Leukemia ◽

Survival Outcome ◽

Real World Data ◽

World Data ◽

Acute Myeloid

Download Full-text

Stable Isotope Labeling Highlights Enhanced Fatty Acid and Lipid Metabolism in Human Acute Myeloid Leukemia

International Journal of Molecular Sciences ◽

10.3390/ijms19113325 ◽

2018 ◽

Vol 19 (11) ◽

pp. 3325 ◽

Cited By ~ 16

Author(s):

Lucille Stuani ◽

Fabien Riols ◽

Pierre Millard ◽

Marie Sabatier ◽

Aurélie Batut ◽

...

Keyword(s):

Fatty Acids ◽

Acute Myeloid Leukemia ◽

Fatty Acid ◽

Lipid Metabolism ◽

Myeloid Leukemia ◽

Metabolic Reprogramming ◽

Frequent Relapses ◽

The Impact ◽

Mutant Cells ◽

Acute Myeloid

Background: In Acute Myeloid Leukemia (AML), a complete response to chemotherapy is usually obtained after conventional chemotherapy but overall patient survival is poor due to highly frequent relapses. As opposed to chronic myeloid leukemia, B lymphoma or multiple myeloma, AML is one of the rare malignant hemopathies the therapy of which has not significantly improved during the past 30 years despite intense research efforts. One promising approach is to determine metabolic dependencies in AML cells. Moreover, two key metabolic enzymes, isocitrate dehydrogenases (IDH1/2), are mutated in more than 15% of AML patient, reinforcing the interest in studying metabolic reprogramming, in particular in this subgroup of patients. Methods: Using a multi-omics approach combining proteomics, lipidomics, and isotopic profiling of [U-13C] glucose and [U-13C] glutamine cultures with more classical biochemical analyses, we studied the impact of the IDH1 R132H mutation in AML cells on lipid biosynthesis. Results: Global proteomic and lipidomic approaches showed a dysregulation of lipid metabolism, especially an increase of phosphatidylinositol, sphingolipids (especially few species of ceramide, sphingosine, and sphinganine), free cholesterol and monounsaturated fatty acids in IDH1 mutant cells. Isotopic profiling of fatty acids revealed that higher lipid anabolism in IDH1 mutant cells corroborated with an increase in lipogenesis fluxes. Conclusions: This integrative approach was efficient to gain insight into metabolism and dynamics of lipid species in leukemic cells. Therefore, we have determined that lipid anabolism is strongly reprogrammed in IDH1 mutant AML cells with a crucial dysregulation of fatty acid metabolism and fluxes, both being mediated by 2-HG (2-Hydroxyglutarate) production.

Download Full-text

Low expression of MN1 associates with better treatment response in older patients with de novo cytogenetically normal acute myeloid leukemia

Blood ◽

10.1182/blood-2011-06-357764 ◽

2011 ◽

Vol 118 (15) ◽

pp. 4188-4198 ◽

Cited By ~ 40

Author(s):

Sebastian Schwind ◽

Guido Marcucci ◽

Jessica Kohlschmidt ◽

Michael D. Radmacher ◽

Krzysztof Mrózek ◽

...

Keyword(s):

Overall Survival ◽

Acute Myeloid Leukemia ◽

Older Patients ◽

Myeloid Leukemia ◽

Hox Genes ◽

De Novo ◽

Prognostic Significance ◽

The Impact ◽

Favorable Group ◽

Acute Myeloid

AbstractLow MN1 expression bestows favorable prognosis in younger adults with cytogenetically normal acute myeloid leukemia (CN-AML), but its prognostic significance in older patients is unknown. We analyzed pretherapy MN1 expression in 140 older (≥ 60 years) de novo CN-AML patients treated on cytarabine/daunorubicin-based protocols. Low MN1 expressers had higher complete remission (CR) rates (P = .001), and longer overall survival (P = .03) and event-free survival (EFS; P = .004). In multivariable models, low MN1 expression was associated with better CR rates and EFS. The impact of MN1 expression on overall survival and EFS was predominantly in patients 70 years of age or older, with low MN1 expressers with mutated NPM1 having the best outcome. The impact of MN1 expression was also observed in the Intermediate-I, but not the Favorable group of the European LeukemiaNet classification, where low MN1 expressers had CR rates and EFS similar to those of Favorable group patients. MN1 expresser-status-associated gene- and microRNA-expression signatures revealed underexpression of drug resistance and adverse outcome predictors, and overexpression of HOX genes and HOX-gene–embedded microRNAs in low MN1 expressers. We conclude that low MN1 expression confers better prognosis in older CN-AML patients and may refine the European LeukemiaNet classification. Biologic features associated with MN1 expression may help identify new treatment targets.

Download Full-text

Impact of CMV reactivation on relapse of acute myeloid leukemia after HCT is dependent on disease stage and ATG

Blood Advances ◽

10.1182/bloodadvances.2021005509 ◽

2021 ◽

Author(s):

Amin T. Turki ◽

Nikolaos Tsachakis-Mück ◽

Saskia Leserer ◽

Pietro Crivello ◽

Tobias Liebregts ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Hematopoietic Cell Transplantation ◽

Advanced Disease ◽

Survival Rates ◽

Disease Stage ◽

The Impact ◽

Cmv Reactivation ◽

Acute Myeloid

Cytomegalovirus (CMV) reactivation is a frequent complication after allogeneic hematopoietic cell transplantation (HCT), whose impact on clinical outcome, in particular on leukemic relapse is controversial. We retrospectively analyzed 687 HCT recipients with acute myeloid leukemia (AML) and ciclosporin-based immunosuppression to better understand the differential impact of CMV on transplant outcomes depending on AML disease stage and in-vivo T-cell depletion with anti-thymocyte globulin (ATG). Without ATG, CMV reactivation associated with significantly reduced relapse, yet its effect was more pronounced for advanced disease AML (p=0.0002) than for patients in first complete remission (CR1, p=0.0169). Depending on the disease stage, ATG exposure abrogated relapse protection following CMV reactivation in advanced stages (p=0.796), while it inverted its effect into increased relapse for CR1 patients (p=0.0428). CMV reactivation was associated with significantly increased non-relapse mortality in CR1 patients without ATG (p=0.0187), but not in those with advanced disease and ATG. Following CMV reactivation, only patients with advanced disease had significantly higher event-free survival rates as compared to patients without CMV. Overall, our data suggest that both ATG and disease stage modulate the impact of post-HCT CMV reactivation in opposite directions, revealing a level of complexity that warrants future studies regarding the interplay between anti-virus and anti-tumor immunity.

Download Full-text

Pretreatment platelet count predicts survival outcome of patients with de novo non-M3 acute myeloid leukemia

PeerJ ◽

10.7717/peerj.4139 ◽

2017 ◽

Vol 5 ◽

pp. e4139 ◽

Cited By ~ 6

Author(s):

Qianying Zhang ◽

Kanchun Dai ◽

Laixi Bi ◽

Songfu Jiang ◽

Yixiang Han ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Platelet Count ◽

Predictive Value ◽

Myeloid Leukemia ◽

De Novo ◽

Univariate Analysis ◽

Survival Outcome ◽

Cox Regression Analysis ◽

High Platelet Count ◽

Acute Myeloid

Background Pretreatment platelet count has been reported as a potential tool to predict survival outcome in several solid tumors. However, the predictive value of pretreatment platelet count remains obscure in de novo acute myeloid leukemia (AML) excluding acute promyelocytic leukemia (M3). Methods We conducted a retrospective review of 209 patients with de novo non-M3 AML in our institute over a period of 8 years (2007–2015). Receiver operating characteristic (ROC) curve analysis was used to determine the optimal platelet (PLT) cutoff in patients. We analyzed the overall survival (OS) and disease free survival (DFS) using the log-rank test and Cox regression analysis. Results By defining the platelet count 50 × 109/L and 120 × 109/L as two cut-off points, we categorized the patients into three groups: low (<50 × 109/L), medium (50–120 × 109/L) and high (>120 × 109/L). On univariate analysis, patients with medium platelet count had longer OS and DFS than those with low or high platelet count. However, the multivariate analysis showed that only longer DFS was observed in patients with medium platelet count than those with low or high platelet count. Conclusion Our findings indicate that pretreatment platelet count has a predictive value for the prognosis of patients with non-M3 AML.

Download Full-text