[New Drugs in the Treatment of Acute Myeloid Leukemia in the Elderly]. / Nové léky v terapii akutní myeloidní leukemie u starsích pacientu.

BACKGROUND: At the time of diagnosis, most patients with acute myeloid leukemia are older than 65 years of age. Treatment of this group of patients is challenging because they become less tolerant to aggressive chemotherapy with increasing age. Less than one-third of elderly patients are considered eligible for intensive treatment; nevertheless, the survival analysis for this population remains poor. Due to numerous comorbidities and an overall deteriorating condition, most elderly patients with acute myeloid leukemia receive only palliative or best supportive care, which are associated with a high mortality rate. New therapeutic approaches are expected to improve the overall survival and quality of life of this group of patients. These promising treatments include cell kinase inhibitors, cytotoxic agents, monoclonal antibodies, and epigenetic therapy including hypomethylating agents and inhibitors of isocitrate dehydrogenase and histone deacetylase. In monotherapy, these new drugs show lower levels of toxicity than those commonly used in chemotherapy; however, they do not lead to a better long-lasting treatment response. To enhance therapeutic efficacy, combinations of the above-mentioned treatments are often used, and, during clinical trials, combinations with standard cytostatics are also common. The promising results of these studies show that even low-toxicity therapies can lead to a better overall treatment response and to longer overall survival. AIM: This article provides a brief overview of new drugs that are evaluated for their mechanism of effect, efficacy and toxicity in therapy of patients suffering from acute myeloid leukemia.Key words: acute myeloid leukemia - elderly - FLT3 inhibitors - epigenetic therapy - monoclonal antibodies The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.Submitted: 4. 11. 2016Accepted: 13. 12. 2016.

[Molecular Genetic Testing for Acute Myeloid Leukemia]. / Molekulárne genetické vysetrení u akutní myeloidní leukemie.

BACKGROUND: Acute myeloid leukemia (AML) is a clinically complex and very heterogeneous disease at the molecular level. Conventional cytogenetic analysis and FISH (fluorescence in situ hybridization) tests provide important information about the biological and clinical background of the disease and enable the classification of AML patients into three risk groups. However, up to half of patients have normal cytogenetics. Determining prognosis and treatment strategies in this group of patients is challenging. The development of molecular genetic methods, including next generation sequencing in the last decade, has led to the discovery of a number of recurrent mutations that have contributed to increasing the accuracy of prognosis of those patients with cytogenetically normal AML. Besides the prognostic value of these mutations, they may also be used to monitor minimal residual disease during and after treatment of AML and additionally constitute potential targets for the development of new therapeutic agents. The importance of molecular genetic testing of all patients with AML is highlighted by the WHO classification of 2008 in which subgroups of AML are purely defined by molecular genetics markers. AIM: In this article, we provide an overview of the most significant mutations in patients with cytogenetically normal AML. We describe their significance for prognosis, their importance in monitoring minimal residual disease, and their potential for the development of new targeted therapies. Further, we briefly draw attention to the significance of gene mutation accumulation in clonal disease development and how it affects the time of AML relapse.

Cytochrome P450 2D6 phenotype and genotype in hypertensive patients on long-term therapy with metoprolol.

OBJECTIVE: The aim was to compare cytochrome P450 2D6 phenotype and genotype using metoprolol as a probe drug. Further, to investigate the influence of P450 2D6 activity on metoprolol pharmacokinetics and pharmacodynamics in patients on metoprolol therapy. BACKGROUND: Cytochrome P450 2D6 is a highly polymorphic enzyme that contributes to the variability of metoprolol. However, environmental factors also modify drug disposition. METHODS: Forty-nine hypertensive patients were enrolled. Serum metoprolol and α-hydroxymetoprolol concentrations, resting heart rate were measured before, 1, 3 and 4 hours post-dose. RESULTS: Significantly higher normalized metoprolol serum concentrations, normalized metoprolol AUC0-4 and metoprolol oral clearance were observed in patients with lower P450 2D6 metabolic activity. A trend towards a lower resting heart rate before metoprolol intake was also observed in this group of patients. The differences in metoprolol disposition were more expressed when P450 2D6 phenotype instead of genotype was determined. CONCLUSION: Significant variations exist in metoprolol disposition in hypertensive patients. Both genotyping and phenotyping provides a valuable method in determining the enzymatic activity and in optimising metoprolol therapy (Tab. 3, Fig. 8, Ref. 35).

Increasing hematopoietic microchimerism is a reliable indicator of incipient AML relapse.

INTRODUCTION: The reoccurrence or increase in autologous hematopoiesis after allogeneic transplantation has been linked to incipient leukemia relapse. However, the importance of such an emergency regarding microchimerism (i.e. mixed chimerism below 1% of autologous cells) still remains controversial, as fluctuating microchimerism can be observed for a very long time after transplantation. METHODS: Using real-time PCR (RQ-PCR), we compare peripheral blood samples obtained from patients with acute myeloid leukemia (AML) before hematological relapse and those taken during complete remission (i.e. either complete cytogenetic remission or complete molecular remission where applicable). By comparison of these two groups, we describe microchimerism dynamics clearly connected with imminent AML relapse. Additionally, we compare applicability of RQ-PCR and conventional PCR with fragment analysis. RESULTS: Mere reappearance of autologous hematopoiesis within patients with complete donor chimerism is alarming, and another sample with further increase confirms ongoing relapse. In case of patients with continuous microchimerism, another two consecutive samples with increasing trend are required. RQ-PCR predicted a significantly higher number of hematological relapses (87%vs. 39%) with a median anticipation period of 33 days, 26 days earlier than conventional PCR (P= 0.0002). Moreover, the outcome of microchimerism dynamics was in complete agreement with monitoring of minimal residual disease when analyzed from the same cell compartment. CONCLUSION: Within this paper, we emphasize the importance of microchimerism monitoring as a reliable indicator of incipient AML relapse, especially in patients where no other specific molecular marker is available.

Germline variants of the promyelocytic leukemia tumor suppressor gene in patients with familial cancer.

The promyelocytic leukemia (PML) gene is an important tumor suppressor gene. We tested the hypothesis that germline disruption of the PML gene may be associated with a cancer predisposition syndrome. Mutation analysis of the PML gene was performed in 111 patients with familial adult cancer or young age-onset adult cancer. These were mostly breast and colon cancer, or colon polyposis patients in whom mutation analyses of the BRCA1, BRCA2, MLH1, MSH2, APC or TP53 genes did not detect a pathogenic germline mutation. Heteroduplex analysis and direct sequencing were used for mutation screening. Mutation-specific methods were designed for frequency determination of novel variants in the general population. No deleterious nonsense or frameshift germline mutations were detected. Several missense single-nucleotide substitutions were found, including two novel missense variants, c.83C>T (p.Thr28Ile) in exon 1 in a 42-year-old breast cancer patient and c.1558C>T (p.Pro520Ser) in exon 6 in a 32-year-old colon cancer patient, that were not detected in 100 and 214 non-cancer persons, respectively. Frequency of the c.2260G>C (p.Ala754Pro) variant in isoform IV of the PML gene was higher in patients with colon polyposis and cancer than in the control group (P = 0.029). In conclusion, germline disruption of the PML gene is probably not associated with a highly penetrant susceptibility to adult-onset breast and colon cancer. Pathogenicity of c.83C>T and c.1558C>T variants in the PML gene is uncertain. Carriers of the c.2260 G>C variant in PMLIV isoform may be at an increased risk of colon polyposis and cancer.