A Review of FLT3 Kinase Inhibitors in AML.

Acute myeloid leukemia (AML) is a highly aggressive illness distinguished by the accumulation of abnormal hematopoietic precursors in both the bone marrow and peripheral blood. The prevalence of FLT3 gene mutations is high and escalates the probability of relapse and mortality. The survival rates for AML patients, particularly those over 65, are low. FLT3 mutation screening at diagnosis is mandatory, and FLT3 inhibitors are crucial in treating AML patients with mutations. There are two categories of FLT3 mutations: FLT3-ITD located in the juxtamembrane domain and FLT3-TKD in the tyrosine kinase domain. FLT3-ITD is the most common type, affecting nearly a quarter of patients, whereas FLT3-TKD only affects 6-8% of patients. FLT3 inhibitors are now crucial in treating AML patients with FLT3 mutations. When dealing with FLT3-mutated AML, the recommended course of treatment typically involves chemotherapy and midostaurin, followed by allogeneic hematopoietic cell transplantation (HCT) to maximize the likelihood of success. Maintenance therapy can lower the risk of relapse, and gilteritinib is a better option than salvage chemotherapy for relapsed or refractory cases. Clinical trials for new or combined therapies are the most effective approach. This review discusses treatment options for patients with FLT3-mutated AML, including induction chemotherapy and options for relapsed or refractory disease. Additional treatment options may become available as more studies are conducted based on the patient's condition and susceptibility.

Delineation of Molecular Lesions in Acute Myeloid Leukemia Patients at Diagnosis: Integrated Next Generation Sequencing and Cytogenomic Studies.

Acute myeloid leukemia (AML) is a heterogeneous disorder characterized by a wide range of genetic defects. Cytogenetics, molecular and genomic technologies have proved to be helpful for deciphering the mutational landscape of AML and impacted clinical practice. Forty-eight new AML patients were investigated with an integrated approach, including classical and molecular cytogenetics, array-based comparative genomic hybridization and targeted next generation sequencing (NGS). Various genetic defects were identified in all the patients using our strategy. Targeted NGS revealed known pathogenic mutations as well as rare or unreported variants with deleterious predictions. The mutational screening of the normal karyotype (NK) group identified clinically relevant variants in 86.2% of the patients; in the abnormal cytogenetics group, the mutation detection rate was 87.5%. Overall, the highest mutation prevalence was observed for the NPM1 gene, followed by DNMT3A, FLT3 and NRAS. An unexpected co-occurrence of KMT2A translocation and DNMT3A-R882 was identified; alterations of these genes, which are involved in epigenetic regulation, are considered to be mutually exclusive. A microarray analysis detected CNVs in 25% of the NK AML patients. In patients with complex karyotypes, the microarray analysis made a significant contribution toward the accurate characterization of chromosomal defects. In summary, our results show that the integration of multiple investigative strategies increases the detection yield of genetic defects with potential clinical relevance.

Increased Dkk-1 plasma levels may discriminate disease subtypes in myeloproliferative neoplasms.

Alterations in the bone marrow niche induced by abnormal production of cytokines and other soluble factors have been associated with disease progression in classical BCR-ABL1 negative myeloproliferative neoplasms (MPN). Variations in circulating proteins might reflect local disease processes and plasma proteome profiling could serve to identify possible diagnostic and prognostic biomarkers. We employed a human cytokine array to screen for 105 distinct analytes in pooled plasma samples obtained from untreated young MPN patients (<35 years) with different clinical phenotypes and driver mutations, as well as from healthy individuals. Among molecules that exhibited significantly increased levels in MPN patients versus controls, the top of the list was represented by Dickkopf-related protein 1 (Dkk-1), which also showed the highest potential for discrimination between MPN subtypes. In the next step, a quantitative ELISA was used to measure plasma Dkk-1 levels in 30 young-onset MPN-10 essential thrombocythemia (ET), 10 polycythemia vera (PV), 10 pre-fibrotic primary myelofibrosis (pre-PMF)-and 10 controls. The results suggested that plasma Dkk-1 levels could differentiate ET from pre-PMF, in JAK2 V617F-positive as well as in CALR-positive patients, and also ET from PV in JAK2 V617F-positive patients.

Perioperative Patient Blood Management Programme. Multidisciplinary recommendations from the Patient Blood Management Initiative Group.

Patients with untreated anaemia or iron deficiency who undergo surgical procedures have an increased risk for mortality and morbidity. Patient Blood Management programmes address this issue worldwide and try to improve patient outcomes through a complex set of measures targeting anaemia correction, minimisation of bleeding and improvement of anaemia tolerance, in all phases of perioperative care. The Patient Blood Management Initiative Group is a multidisciplinary team of physicians from specialties including anaesthesiology, nephrology, surgery, orthopaedics, haematology, gastroenterology and transfusion medicine. The team has elaborated ten recommendations, divided into five categories, in order to implement a Patient Blood Management programme in Romania, using the most recent and relevant evidence. The document was discussed during three meetings which took place during October 2016 and May 2017 and the result was modified and updated via e-mail.

The Impact of 2-(18) Fluoro-2-Deoxyglucose Positron Emission Tomography/Computed Tomography (FDG-PET/CT) in Treatment Strategy of Hodgkin Lymphoma-Current Hematologic Concepts.

Positron emission tomography/computed tomography (PET/CT) is useful in staging of Hodgkin lymphoma (HL), for early response - adapted therapy and choosing an individualized therapy, and is useful in determination of disease extent in relapsed and refractory Hodgkin lymphoma. Interim PET using 2-(18) fluoro-2-deoxyglucose(FDG) and low dose CT performed in one scanning session (FDG-PET/ CT) helps to predict outcome in Hodgkin lymphoma and to asses therapeutic stratification.

Indolent lymphoma: diagnosis and prognosis in medical practice.

INTRODUCTION: Non-Hodgkin lymphomas represent malignant tumors of lymphoid cells. These chronic lymphoproliferative disorders stand for malignancies with varied histological aspects, clinical features, evolution, prognosis and aggressiveness. Follicular lymphomas are the most frequent form of indolent lymphomas and they represent around 25% of all malignant lymphomas in adults. MATERIAL AND METHOD: Between 2011 and 2012, we have retrospectively observed, analyzed and described a group of 24 patients diagnosed with follicular lymphomas in the Department of Hematology from Coltea Hospital. The admittance criteria were: age, gender, hemoglobin and LDH levels, number lymph nodes affected and the Ann Arbor lymphoma staging system. Also used as patient study parameters were the following immunohistochemical criteria: CD20, UCHL1, CD79a, expression of Bcl 2 and Bcl 6, CD10 and the proliferative index (Ki-67). RESULTS: Multiple studies have shown that prognosis depends far more on clinical and histology parameters, including age, the presence of extra-node diseases and the performance status. In our study, regarding the ratio between the two genders, the male patients were more numerous than the female patients. The impairment of the male patients is associated with an unfavorable prognosis. From the age perspective, most of the diagnosed patients were part of the age group over 60. The age exceeding 60 is considered a negative prognosis factor. The serum lactate dehydrogenase (LDH) level is also considered an unfavorable prognosis factor. In our study, stage III and IV were frequently and this represents a poor prognosis factor. CONCLUSIONS: Although it was a small number of patients, the results obtained correspond to the results existing in literature.

Onset risk factors and treatment response features of refractory hodgkin lymphoma.

BACKGROUND: The International Prognostic Factors Project on Advanced Hodgkin lymphoma (HL) developed a seven factor prognostic score consisting of gender, age, stage, serum albumin, hemoglobin, leukocytosis and lymphocytopenia for the newly diagnosed Hodgkin disease patients in advanced stages, who receive chemotherapy. OBJECTIVES: The purpose of this study was to determine whether this prognostic score would also be useful for refractory Hodgkin lymphoma patients in monitoring response to treatment. MATERIAL AND METHOD: In the period 2000-2012, we performed a study on a group of 91 patients to show that the prognostic factors identified by the International Prognostic Factors (IPF) score affect the event- free survival (EFS) and the overall survival (OS). Our study also intends to show that the results of these factors change with the treatment response in patients with HL included in the category of patients with refractory disease. RESULTS: B symptoms, onset lymph node, more than 3 areas involved, bulky disease, extranodal involvement, low serum albumin, erythrocytes sedimentation rate (ESR), C reactive protein (CRP), lactic dehydrogenase (LDH) and anemia were associated with poorer EFS and OS. Male gender, stage, histological type, age (>45 years) and leukocytosis were not associated with significantly poorer outcomes. CONCLUSIONS: the prognostic score for advanced disease is also useful in predicting relapse in patients with HL and early detection of response in patients with refractory HL.

Prognostic factors in myelodysplastic syndromes.

BACKGROUND: Myelodysplastic syndromes (MDS) are clonal disorders of hematopoietic stem cell and are characterized by ineffective hematopoiesis with normo- or hyper cellular bone marrow and cytopenia(s).The natural evolution of the disease consists of bone marrow failure (leading to infectious and hemorrhagic episodes or anemia related complications) and transformation to acute myeloid leukemia. Because MDSs display remarkable clinical, pathologic, and cytogenetic heterogeneity, with variable evolution and survival ranging from months to years, the predictive factors of prognosis have a key role in optimal therapeutic decisions.The purpose of this paper is to analyze prognostic factors within a group of patients diagnosed with myelodysplastic syndromes. The prognostic factors taken into account are: the number and depth of cytopenias, percentage of bone marrow blasts, cytogenetic abnormalities, intensity of anemia and transfusional dependence. These factors are related to overall survival, leukemia free survival, bone marrow failure complications, leukemic evolution, treatment decisions and the response to treatment. MATERIAL AND METHOD: The study group comprises of 119 patients diagnosed with de novo MDS, between 2008 and 2011 in the Hematology Department of Coltea Clinical Hospital. In this monitoring period the patients were stratified according to the FAB (French-American-British) morphologic classification. RESULTS: This study revealed that the outcomes of patients with MDS is influenced by the percentage of bone marrow blasts at diagnosis, the number and severity of hematopoietic lineage affected by cytopenia and by the presence of chromosomal abnormalities. CONCLUSIONS: The studied prognostic factors have predictive value in terms of survival, leukemic transformation, treatment response and development of bone marrow failure-related characteristic complications.

Peculiarities in the Diagnosis Approach of MDS /MPN-U Patients.

The most recent WHO Classification of Tumors of Haematopoietic and Lymphoid Tissues describes a set of diseases framed as the MDS / MPN (myelodysplastic / chronic myeloproliferative syndromes). There are four subtypes comprised in this category: chronic myelomonocytic leukemia, juvenile myelomonocytic leukemia, atypical chronic myeloid leukemia and unclassifiable MDS / MPN. They combine both myelodysplastic and myeloproliferative features. Although the unclassifiable MDS/ MPN subtype specifically associates the myelodysplastic and myeloproliferative features, it does not meet the criteria defining the first 3 subtypes. The RARS-T subtype (refractory anemia with ringed sideroblasts associated with marked thrombocytosis) is included in the MDS / MPN-U as a temporary entity. There are two cases described in this article: one diagnosed with RARS-T and one with MDS / MPN-U. Both cases evolved towards acute myeloid leukemia.