Clinical implications of molecular genetic aberrations in acute myeloid leukemia

The role of different cytogenetic changes has been extensively evaluated in patients with acute myeloid leukemia (AML), and cytogenetic analysis of AML blasts is essential to form prognostic subgroups in order to stratify for the extent of therapy. Nevertheless, 40–45% of AML patients lack such cytogenetic markers, i.e., cytogenetically normal AML (CN-AML). In the past decade, different molecular aberrations were identified in AML and especially CN-AML can now be discriminated into certain prognostic subgroups. This review considers the latest advances to define the prognostic impact of molecular aberrations in AML and gives insights how such molecular markers can be applied for analysis of minimal residual disease. Furthermore, therapeutic implications as well as the potential role of new methodological techniques in analyzing expression patterns of AML blasts are discussed.     

维奈克拉联合阿扎胞苷治疗老年急性髓系白血病的疗效及其对患者免疫功能的影响

目的 观察维奈克拉联合阿扎胞苷治疗老年急性髓系白血病(AML)的疗效及其对患者免疫功能的影响,为维奈克拉治疗老年AML提供依据.方法 选取2021年1月-2021年12月在郴州市第一人民医院收治的60例老年AML患者,采用数字表法随机分为观察组(n=30)和对照组(n=30).对照组给予阿扎胞苷治疗,观察组在与对照组相...     

Combination of azacitidine,venetoclax and ruxolitinib in blast phase myeloproliferative neoplasms

Myeloproliferative neoplasms in blastic phase (MPN-BP) have a dreadful prognosis. We report the characteristics and outcomes of five MPN-BP patients treated with a never-before-described combination of azacytidine and venetoclax (to control BP transformation), added to ruxolitinib (needed to control constitutional symptoms). Median age was 76 years (range 72–84), and worst performance status was 2. The overall response rate was 80%, and the complete remission rate was 40%. With median follow-up of 10.0 months (range 4.2–13.4), median overall survival was 13.4 months (95% CI 4.2–13.4). We did not detect any unexpected treatment-related toxicity, and quality of life was improved.     

Patient-specific microRNA expression profiles as a marker for minimal residual disease in acute myeloid leukemia

MicroRNAs are a class of small noncoding RNAs playing a crucial role in physiological and pathological conditions, including acute myeloid leukemia. We aimed at examining whether in clinical settings the identification of patient-specific leukemia-associated profiles (LAMPs) of overexpressed microRNAs could be used for minimal residual disease (MRD) detection. Patients with identified LAMPs at diagnosis were further tested for the presence of LAMP after induction therapy. Those with identifiable MRD defined by LAMP expression after induction showed a trend toward a shorter overall survival. Larger studies are needed to confirm the utility of patient-specific LAMPs for MRD follow-up.     

FLT3-ITD-associated gene-expression signatures in NPM1-mutated cytogenetically normal acute myeloid leukemia

Concomitance of the FLT3-ITD mutation is associated with poor prognosis in NPM1-mutated cytogenetically normal acute myeloid leukemia (CN-AML) patients, and precise studies on its role in leukemogenesis are needed; these may be elucidated at the molecular level by gene express profiling. In the present study, we built a gene-expression-based classifier using prediction analysis of microarray to characterize the FLT3-ITD signature in NPM1-mutated CN-AML patients, which comprised 10 annotated genes, and demonstrated an overall accuracy of 83.8?% in cross-validation. To characterize the signature in another way, differential expression was revealed for 34 genes by class comparison, and the up-regulation of LAPTM4B and MIR155HG was validated by quantitative RT-PCR in our small cohort of NPM1-mutated CN-AML samples, which appeared to be associated with this specific subtype. The 10-gene classifier and differentially expressed genes identified in this study indicate a potential utility for risk-assessed treatment stratification, and suggest new therapeutic targets for these high-risk AML patients.     

TdT expression in acute myeloid leukaemia

Summary A total of 412 cases of acute leukaemia were examined for the presence of nuclear terminal deoxynucleotidyl transferase (TdT) by indirect immunofluorescence. Of the 129 cases of acute myeloblastic leukaemia (AML FAB groups M1/M2) examined, 18% (n=23) had significant proportions (>10%) of TdT-positive blasts. Although most of these AML cases (n=18) were of poorly differentiated (M1) type; 5 cases of AML showing features of granulocytic differentiation (M2) were also found to be TdT-positive. Even though TdT was generally more strongly expressed in the M1 group and associated with other markers of myeloid immaturity (Ia positive and lack of chloroacetate esterase), there was no inverse relationship with Sudan black or myeloperoxidase activity. In addition, although the proportion of AML-M1 cases with increased TdT-positive cells was slightly higher (18/95, 19%) than for the AML-M2 group (5/34, 15%) the results suggest that the presence of nuclear TdT in leukaemic myeloblasts may not only reflect cellular immaturity but may also be due to maturational asynchrony in otherwise well-differentiated blasts.     

Measurable residual disease in patients undergoing allogeneic transplant for acute myeloid leukemia

The most common indication for allogeneic hematopoietic cell transplant (alloHCT) is maintenance of remission after initial treatment for patients with acute myeloid leukemia (AML). Loss of remission, relapse, remains however the most frequent cause of alloHCT failure. There is strong evidence that detectable persistent disease burden (“measurable residual disease”, MRD) in patients with AML in remission prior to alloHCT is associated with increased risk of post-transplant relapse. MRD status as a summative assessment of response to pre-transplant therapy may allow superior patient-personalized risk stratification compared with models solely incorporating pre-treatment variables. An optimal methodology for AML MRD detection has not yet been established, but molecular methods such as DNA-sequencing may have additional prognostic utility compared to current approaches. There is growing evidence that intervention on AML MRD positivity may improve post-transplant outcomes. New initiatives will generate actionable data on the clinical utility of AML MRD testing for patients undergoing alloHCT.     

Serum enzyme concentrations in untreated acute myeloid leukaemia

Summary Serum concentrations of lactate dehydrogenase (LDH), -hydroxybutyrate dehydrogenase (HBD), phosphohexose isomerase (PHI), leucine aminopeptidase (LAP), -glucuronidase (-gluc) and angiotensin-converting enzyme (ACE), were measured in 107 cases of untreated acute myeloid leukaemia which were classified by morphological, immunological and cytochemical criteria. The results show that serum LDH was increased in most cases, irrespective of leukaemic subtype, serum PHI and LAP were significantly higher in monocytic variants and serum -gluc and ACE levels were generally within normal limits. In addition, significant (p<0.05) relationships were found between serum LDH, PHI, LAP and -gluc concentrations and the numbers of circulating leucocytes.     

The value of molecular stratification for CEBPADM and NPM1MUTFLT3WT genotypes in older patients with acute myeloid leukaemia

Older adult patients (≥60 years) with acute myeloid leukaemia (AML) are generally considered to be poor‐risk and there is limited information available regarding risk stratification based on molecular characterization in this age group, particularly for the double‐mutant CEBPA (CEBPA^DM) genotype. To investigate whether a molecular favourable‐risk genotype can be identified, we investigated CEBPA, NPM1 and FLT3 status and prognostic impact in a cohort of 301 patients aged 60 years or more with intermediate‐risk cytogenetics, all treated intensively. Overall survival (OS) at 1 year was highest in the 12 patients (4%) that were CEBPA^DM compared to the 76 (28%) with a mutant NPM1 and wild‐type FLT3 (NPM1^MUTFLT3^WT) genotype or all other patients (75%, 54%, 33% respectively), with median survival 15·2, 13·6 and 6·6 months, although the benefit was short‐term (OS at 3 years 17%, 29%, 12% respectively). Combination of the CEBPA^DM and NPM1^MUTFLT3^WT genotype patients defined a molecular group with favourable prognosis (P < 0·0001 in multivariate analysis), with 57% of patients alive at 1 year compared to 33% for all other patients. Knowledge of genotype in older cytogenetically intermediate‐risk patients might influence therapy decisions.