Molecular characterization of mutant TP53 acute myeloid leukemia and high-risk myelodysplastic syndrome

Substantial heterogeneity within mutant TP53 acute myeloid leukemia (AML) and myelodysplastic syndrome with excess of blast (MDS-EB) precludes the exact assessment of prognostic impact for individual patients. We performed in-depth clinical and molecular analysis of mutant TP53 AML and MDS-EB to dissect the molecular characteristics in detail and determine its impact on survival. We performed next-generation sequencing on 2200 AML/MDS-EB specimens and assessed the TP53 mutant allelic status (mono- or bi-allelic), the number of TP53 mutations, mutant TP53 clone size, concurrent mutations, cytogenetics, and mutant TP53 molecular minimal residual disease and studied the associations of these characteristics with overall survival. TP53 mutations were detected in 230 (10.5%) patients with AML/MDS-EB with a median variant allele frequency of 47%. Bi-allelic mutant TP53 status was observed in 174 (76%) patients. Multiple TP53 mutations were found in 49 (21%) patients. Concurrent mutations were detected in 113 (49%) patients. No significant difference in any of the aforementioned molecular characteristics of mutant TP53 was detected between AML and MDS-EB. Patients with mutant TP53 have a poor outcome (2-year overall survival, 12.8%); however, no survival difference between AML and MDS-EB was observed. Importantly, none of the molecular characteristics were significantly associated with survival in mutant TP53 AML/MDS-EB. In most patients, TP53 mutations remained detectable in complete remission by deep sequencing (73%). Detection of residual mutant TP53 was not associated with survival. Mutant TP53 AML and MDS-EB do not differ with respect to molecular characteristics and survival. Therefore, mutant TP53 AML/MDS-EB should be considered a distinct molecular disease entity

Review: Aberrant EVI1 expression in acute myeloid leukaemia

Deregulated expression of the ecotropic virus integration site 1 (EVI1) gene is the molecular hallmark of therapy-resistantmyeloid malignancies bearing chromosomal inv(3)(q21q262) or t(3;3)(q21;q262) [hereafter referred to as inv(3)/t(3;3)] abnormalities. EVI1 is a haematopoietic stemness and transcription factor with chromatin remodelling activity. Interestingly, the EVI1 gene also shows overexpression in 6-11% of adult acute myeloid leukaemia (AML) cases that do not carry any 3q aberrations. Deregulated expression of EVI1 is strongly associated with monosomy 7 and 11q23 abnormalities, which are known to be associated with poor response to treatment. However, EVI1 overexpression has been revealed as an important independent adverse prognostic marker in adult AML and defines distinct risk categories in 11q23-rearranged AML. Recently, important progress has been made in the delineation of the mechanism by which EVI1 becomes deregulated in inv(3)/t(3;3) as well as the cooperating mutations in this specific subset of AML with dismal prognosis

Molecular minimal residual disease detection in acute myeloid leukemia

Initial induction chemotherapy to eradicate the bulk of acute myeloid leukemia (AML) cells results in complete remission (CR) in the majority of patients. However, leukemic cells persisting in the bone marrow below the morphologic threshold remain unaffected and have the potential to proliferate and re‐emerge as AML relapse. Detection of minimal/measurable residual disease (MRD) is a promising prognostic marker for AML relapse as it can assess an individual patients’ risk profile and evaluate their response to treatment. With the emergence of molecular techniques, such as next generation sequencing (NGS), a more sensitive assessment of molecular MRD markers is available. In recent years, the detection of MRD by molecular assays and its association with AML relapse and survival has been explored and verified in multiple studies. Although most studies show that the presence of MRD leads to a worse clinical outcome, molecular‐based methods face several challenges including limited sensitivity/specificity, and a difficult distinction between mutations that are representative of AML rather than clonal hematopoiesis. This review describes the studies that have been performed using molecular‐based assays for MRD detection in the context of other MRD detection approaches in AML, and discusses limitations, challenges and opportunities

FLT3-ITD mutations in acute myeloid leukaemia – molecular characteristics, distribution and numerical variation

Recurrent somatic internal tandem duplications (ITD) in the FMS-like tyrosine kinase 3 (FLT3) gene characterise approximately one third of patients with acute myeloid leukaemia (AML), and FLT3-ITD mutation status guides risk-adapted treatment strategies. The aim of this work was to characterise FLT3-ITD variant distribution in relation to molecular and clinical features, and overall survival in adult AML patients. We performed two parallel retrospective cohort studies investigating FLT3-ITD length and expression by cDNA fragment analysis, followed by Sanger sequencing in a subset of samples. In the two cohorts, a total of 139 and 172 mutant alleles were identified in 111 and 123 patients, respectively, with 22% and 28% of patients presenting with more than one mutated allele. Further, 15% and 32% of samples had a FLT3-ITD total variant allele frequency (VAF) < 0.3, while 24% and 16% had a total VAF ≥ 0.7. Most of the assessed clinical features did not significantly correlate to FLT3-ITD numerical variation nor VAF. Low VAF was, however, associated with lower white blood cell count, while increasing VAF correlated with inferior overall survival in one of the cohorts. In the other cohort, ITD length above 50 bp was identified to correlate with inferior overall survival. Our report corroborates the poor prognostic association with high FLT3-ITD disease burden, as well as extensive inter- and intrapatient heterogeneity in the molecular features of FLT3-ITD. We suggest that future use of FLT3-targeted therapy could be accompanied with thorough molecular diagnostics and follow-up to better predict optimal therapy responders

Clinical Pathways for Non-ST Elevation Acute Coronary Syndrome in Oman: An Oman Heart Association Protocol for Hospital Quality Improvement Initiative

In 2012, Oman Heart Association (OHA) published its own guidelines for the management of patients with unstable angina/non–ST-elevation myocardial infarction, the aim was not to be comprehensive but rather simplified and practical in order to reduce the gap between the long comprehensive guidelines and our actual practice. However, we still feel that the busy registrars and residents need simpler and direct clinical pathways or protocol to be used in the emergency departments, coronary care units and in the wards. Clinical pathways are now one of the main tools used to manage the quality in healthcare concerning the standardization of care processes. It has been shown that their implementation reduces the variability in clinical practice and improves outcomes in acute care