Prognostic Impact of microRNAs (miR-155, miR-10a, let-7a) on the Outcome of Adult Patients with Acute Myeloid Leukemia.

Abstract Background Acute myeloid leukemia (AML) is a disorder characterized by a rapid onset of symptoms attributable to bone marrow failure due to clonal proliferation of primitive hematopoietic stem cells or progenitor cells. Epigenetic abnormalities play an important role in the development and progression of acute leukemia. Long non-coding ribonucleic acid (lncRNA) plays an important role in epigenetic regulation. Homeobox (Hox) transcript antisense intergenic RNA (HOTAIR) is a lncRNA which has been determined to be a negative prognostic indicator in various solid-tumor patients. However, its role in hematopoietic tumors as AML is to be assessed. This study aimed at measuring lncRNA HOTAIR expression level on bone marrow (BM) mononuclear cells in newly diagnosed AML patients and correlating its expression with their outcome and different prognostic variables. This provides new prospective for a novel marker involved in development and progression of AML which can be used as a diagnostic marker and a target of therapy. The current study included 65 subjects divided into 35 newly diagnosed AML adult patients (before initiation of chemotherapy) and 30 non-leukemic adult patients who are candidates for BM aspiration for causes other than hematological malignancies as immune thrombocytopenic purpura and hypersplenism as controls. HOTAIR expression was measured on BM mononuclear cells by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Results HOTAIR expression was found to be significantly upregulated in AML patients (probability (p) value = 0.000) and it can be used as a diagnostic biomarker of AML as confirmed by a significant difference between cases and controls using receiver operating characteristic curve (ROC) analysis. However, it was not significantly correlated with event free survival (EFS) or prognostic variables. Conclusion This study showed that the expression of HOTAIR is upregulated in de novo AML patients and can be used as a diagnostic marker. However, highly expressed HOTAIR is not associated with poor prognosis.

Download Full-text

HighEVI1Expression Predicts Outcome in Younger Adult Patients With Acute Myeloid Leukemia and Is Associated With Distinct Cytogenetic Abnormalities

Journal of Clinical Oncology ◽

10.1200/jco.2009.26.0646 ◽

2010 ◽

Vol 28 (12) ◽

pp. 2101-2107 ◽

Cited By ~ 155

Author(s):

Stefan Gröschel ◽

Sanne Lugthart ◽

Richard F. Schlenk ◽

Peter J.M. Valk ◽

Karina Eiwen ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Splice Variants ◽

Quantitative Polymerase Chain Reaction ◽

Prognostic Significance ◽

Adult Patients ◽

Prognostic Impact ◽

Monosomy 7 ◽

Free Survival ◽

Acute Myeloid

PurposeThe purpose of this study was to investigate frequency and prognostic significance of high EVI1 expression in acute myeloid leukemia (AML).Patients and MethodsA diagnostic assay detecting multiple EVI1 splice variants was developed to determine the relative EVI1 expression by single real-time quantitative polymerase chain reaction in 1,382 newly diagnosed adult patients with AML younger than 60 years. Patients were treated on four Dutch-Belgian HOVON (n = 458) and two German-Austrian AML Study Group protocols (n = 924).ResultsThe EVI1 assay was tested in the HOVON cohort and validated in the AMLSG cohort. High EVI1 levels (EVI1+) were found with similar frequencies in both cohorts combined, with a 10.7% incidence (148 of 1,382). EVI1+independently predicted low complete remission (CR) rate (odds ratio, 0.54; P = .002), adverse relapse-free survival (RFS; hazard ratio [HR], 1.32; P = .05), and event-free survival (EFS; HR, 1.46; P < .001). This adverse prognostic impact was more pronounced in the intermediate cytogenetic risk group (EFS; HR, 1.64; P < .001; and RFS; HR, 1.55; P = .02), and was also apparent in cytogenetically normal AML (EFS; HR, 1.67; P = .008). Besides inv(3)/t(3;3), EVI1+was significantly associated with chromosome abnormalities monosomy 7 and t(11q23), conferring prognostic impact within these two cytogenetic subsets. EVI1+was virtually absent in favorable-risk AML and AML with NPM1 mutations. Patients with EVI1+AML (n = 28) who received allogeneic stem cell transplantation in first CR had significantly better 5-year RFS (33% ± 10% v 0%).ConclusionEVI1 expression in AML is unequally distributed in cytogenetic subtypes. It predicts poor outcome, particularly among intermediate cytogenetic risk AML. Patients with EVI1+AML may benefit from allogeneic transplantation in first CR. Pretreatment EVI1 screening should be included in risk stratification.

Download Full-text

NPM1+/FLT3- Patients with Acute Myeloid Leukemia (AML) Have Excellent Clinical Outcome Independent of Age When Treated with Cytotoxic Chemotherapy: Mayo Clinic Experience

Blood ◽

10.1182/blood.v124.21.5331.5331 ◽

2014 ◽

Vol 124 (21) ◽

pp. 5331-5331

Author(s):

Mehrdad Hefazi Torghabeh ◽

Mustaqeem A Siddiqui ◽

Mrinal M. Patnaik ◽

Alexandra Wolanskyj ◽

Darci Zblewski ◽

...

Keyword(s):

Overall Survival ◽

Acute Myeloid Leukemia ◽

Elderly Patients ◽

Myeloid Leukemia ◽

Cytotoxic Chemotherapy ◽

Adult Patients ◽

Prognostic Impact ◽

Mutational Status ◽

Significant Difference ◽

Acute Myeloid

Abstract Background: Molecular profiling has revolutionized the field of hematology, and in particular myeloid neoplasms. NPM1+/FLT3- mutational status has been shown to have a favorable prognostic impact in patients with acute myeloid leukemia (AML). However, little is known about its interaction with age. Methods: We retrospectively analyzed the overall survival (OS) in newly diagnosed AML patients, whose FLT3 and NPM1 data were available, and were treated with cytotoxic chemotherapy at our institution between 2003 and 2013. Patients 18 to 60 years of age were categorized as adult, and those above 60 years were classified as elderly. Each of the elderly or adult groups were further divided according to the presence or absence of combined NPM1+/FLT3- mutational status. Estimated probabilities of overall survival were calculated using the Kaplan-Meier method, with the log-rank test to compare groups. Demographics and continuous variables were compared using the Wilcoxon rank sum test. Appropriate IRB approval was obtained. Results: Out of 835 patients with AML, 86 patients with both known FLT3/NPM1 mutation status and receiving induction chemotherapy were found. NPM1+/FLT3- mutational status was present in 11 elderly (median age 68 yr, hemoglobin (Hb) 8.7 g/dL, white blood cells (WBC) 9.6 x109/L, platelets (PLT) 100 x109/L, peripheral blood blasts percentage (PB%) 31), and in 11 adult patients (median age 49 years, Hb 9.1 g/dL, WBC 14 x109/L, PLT 67 x109/L, and PB% 21). Twenty-eight elderly patients (median age 66 yr, Hb 9.4 g/dl, WBC 15.7 x109/L, PLT 66 x109/L, and PB% 33), and 36 adult patients (median age 49 years, Hb 9.1 g/dL, WBC 14 x109/L, PLT 67 x109/L, and PB% 21) were carrying genotypes other than NPM1+/FlT3-. There was no statistical significant difference in the median age, Hb, WBC, PLT, and PB% at the time of diagnosis. Out of 86 patients, 79 had intermediate, 6 had adverse, and 1 had favorable cytogenetic risk. All elderly and adult patients with NPM1+/FLT3- genotype had intermediate risk cytogenetics. When treated with cytotoxic chemotherapy, elderly patients with NPM1+/FLT3- genotype demonstrated a significantly better overall survival compared to elderly patients without this genotypes (p=0.015), and interestingly also to adult AML carrying other genotypes (p=0.028). Surprisingly, there was not an improved survival in adults with NPM1+/FLT3- genotype compared to adults carrying other genotypes (p=0.14), but this may have been related to the small numbers in each group. No significant difference in the overall survival was observed between elderly and adult patients who were carrying NPM1+/FLT3- mutational status (p=0.4). The estimated 5-year survival rates for elderly with and without NPM1+/FLT3- status were 71% vs. 14%, and for adults with and without this genotype were 49% vs. 19%, respectively. Conclusion: Age does not have an impact on the OS in AML patients with NPM1+/FLT3- mutational status, arguing strongly for intense chemotherapy in this group. Elderly AML patients with NPM1+/FLT3- genotype have a superior OS compared to both adult and elderly patients carrying other genotypes, when treated with cytotoxic chemotherapy. Further validation in large prospective studies is warranted. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

Download Full-text

Prognostic Significance of CEBPA Mutations in a Large Cohort of Younger Adult Patients With Acute Myeloid Leukemia: Impact of Double CEBPA Mutations and the Interaction With FLT3 and NPM1 Mutations

Journal of Clinical Oncology ◽

10.1200/jco.2009.26.2501 ◽

2010 ◽

Vol 28 (16) ◽

pp. 2739-2747 ◽

Cited By ~ 160

Author(s):

Claire L. Green ◽

Kenneth K. Koo ◽

Robert K. Hills ◽

Alan K. Burnett ◽

David C. Linch ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Prognostic Significance ◽

Adult Patients ◽

Prognostic Impact ◽

Single Mutation ◽

Npm1 Mutation ◽

Double Mutation ◽

Cebpa Mutations ◽

Acute Myeloid

Purpose To determine the clinical relevance of mutations in the CCAAT/enhancer binding protein α (CEBPA) gene in acute myeloid leukemia (AML) and to examine factors that might modify prognostic impact. Patients and Methods The entire CEBPA coding sequence was screened in 1,427 young adult patients with AML, excluding acute promyelocytic leukemia, using denaturing high-performance liquid chromatography and direct sequencing. Results Of 107 patients (7%) with CEBPA mutations, 48 patients (45%) had one mutation (CEBPA-single), and 59 patients (55%) had two mutations (CEBPA-double). The incidence of CEBPA-double patients was similar in intermediate cytogenetic risk patients with and without a normal karyotype (6% and 5%, respectively). CEBPA-double patients had evidence of a lower coincidence with FLT3/ITDs (P = .04) and were highly unlikely to have an NPM1 mutation (P < .0001). CEBPA-double but not CEBPA-single patients had a significantly better overall survival (OS) at 8 years (34%, 31%, and 54% for CEBPA–wild-type [WT], CEBPA-single, and CEBPA-double, respectively, P = .004). This benefit was lost in the presence of a FLT3/ITD (OS for CEBPA-WT, CEBPA-single, and CEBPA-double FLT3/ITD-negative patients: 36%, 35%, 59%, respectively, P = .002; OS for CEBPA-WT, CEBPA-single, and CEBPA-double FLT3/ITD-positive patients: 26%, 21%, 14%, respectively, P = .05). There was no evidence of any additional favorable benefit for a CEBPA-single mutation in the presence of an NPM1 mutation (OS, 45%, 44%, and 56%, P = .2, for NPM1-positive/CEBPA-WT, NPM1-positive/CEBPA-single, and NPM1-negative/CEBPA-double patients, respectively). Conclusion Screening for CEBPA mutations can be restricted to patients with intermediate-risk cytogenetics lacking an FLT3/ITD or NPM1 mutation. Only the presence of a CEBPA-double mutation should be used for therapy risk stratification.

Download Full-text

AML1/RUNX1 mutations in 470 adult patients with de novo acute myeloid leukemia: prognostic implication and interaction with other gene alterations

Blood ◽

10.1182/blood-2009-05-223784 ◽

2009 ◽

Vol 114 (26) ◽

pp. 5352-5361 ◽

Cited By ~ 211

Author(s):

Jih-Luh Tang ◽

Hsin-An Hou ◽

Chien-Yuan Chen ◽

Chieh-Yu Liu ◽

Wen-Chien Chou ◽

...

Keyword(s):

Overall Survival ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

De Novo ◽

Remission Rate ◽

Adult Patients ◽

Poor Prognostic Factor ◽

The Impact ◽

Runx1 Mutation ◽

Acute Myeloid

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

Evolving patterns of care and outcomes in relapsed/refractory FLT3 mutated acute myeloid leukemia adult patients

Leukemia & Lymphoma ◽

10.1080/10428194.2021.1938031 ◽

2021 ◽

pp. 1-10

Author(s):

Blanca Boluda ◽

David Martínez-Cuadrón ◽

Lorenzo Algarra ◽

Isabel Cano ◽

María J. Sayas ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Adult Patients ◽

Patterns Of Care ◽

Acute Myeloid

Download Full-text

FLT3 mutated acute myeloid leukemia: 2021 treatment algorithm

Blood Cancer Journal ◽

10.1038/s41408-021-00495-3 ◽

2021 ◽

Vol 11 (5) ◽

Author(s):

Naval Daver ◽

Sangeetha Venugopal ◽

Farhad Ravandi

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Single Agent ◽

Prognostic Significance ◽

Treatment Algorithm ◽

Molecular Testing ◽

Prognostic Impact ◽

Cell Transplant ◽

Newly Diagnosed ◽

Acute Myeloid

AbstractApproximately 30% of patients with newly diagnosed acute myeloid leukemia (AML) harbor mutations in the fms-like tyrosine kinase 3 (FLT3) gene. While the adverse prognostic impact of FLT3-ITDmut in AML has been clearly proven, the prognostic significance of FLT3-TKDmut remains speculative. Current guidelines recommend rapid molecular testing for FLT3mut at diagnosis and earlier incorporation of targeted agents to achieve deeper remissions and early consideration for allogeneic stem cell transplant (ASCT). Mounting evidence suggests that FLT3mut can emerge at any timepoint in the disease spectrum emphasizing the need for repetitive mutational testing not only at diagnosis but also at each relapse. The approval of multi-kinase FLT3 inhibitor (FLT3i) midostaurin with induction therapy for newly diagnosed FLT3mut AML, and a more specific, potent FLT3i, gilteritinib as monotherapy for relapsed/refractory (R/R) FLT3mut AML have improved outcomes in patients with FLT3mut AML. Nevertheless, the short duration of remission with single-agent FLT3i’s in R/R FLT3mut AML in the absence of ASCT, limited options in patients refractory to gilteritinib therapy, and diverse primary and secondary mechanisms of resistance to different FLT3i’s remain ongoing challenges that compel the development and rapid implementation of multi-agent combinatorial or sequential therapies for FLT3mut AML.

Download Full-text