Exosome-carried microRNA-based signature as a cellular trigger for the evolution of chronic lymphocytic leukemia into Richter syndrome.

Even if considered a cumulative and not a proliferative CD5+ B-cell neoplasm, chronic lymphocytic leukemia (CLL) has a proliferation rate higher than that recognized earlier, especially in the lymphoid tissues. Some patients with CLL develop a clinical syndrome entitled Richter syndrome (RS). Understanding CLL genetics and epigenetics may help to elucidate the molecular basics of the clinical heterogeneity of this type of malignancy. In the present project we aimed to identify a microRNA species that can predict the evolution of therapy-resistant CLL towards RS. In the first phase of our study, microRNA-19b was identified as a possible target, and in the second phase, we transfected three different CLL cell lines with microRNA-19b mimic and inhibitor and assessed the potential role on leukemia cells in vitro. The mechanism by which miR-19b acts were identified as the upregulation of Ki67 and downregulation of p53. This was further supported through RT-PCR and western blotting on CLL cell lines, as well as by next generation sequencing on two patients diagnosed with CLL that evolved into RS.

A narrative review of central nervous system involvement in acute leukemias.

Acute leukemias (both myeloid and lymphoblastic) are a group of diseases for which each year more successful therapies are implemented. However, in a subset of cases the overall survival (OS) is still exceptionally low due to the infiltration of leukemic cells in the central nervous system (CNS) and the subsequent formation of brain tumors. The CNS involvement is more common in acute lymphocytic leukemia (ALL), than in adult acute myeloid leukemia (AML), although the rates for the second case might be underestimated. The main reasons for CNS invasion are related to the expression of specific adhesion molecules (VLA-4, ICAM-1, VCAM, L-selectin, PECAM-1, CD18, LFA-1, CD58, CD44, CXCL12) by a subpopulation of leukemic cells, called "sticky cells" which have the ability to interact and adhere to endothelial cells. Moreover, the microenvironment becomes hypoxic and together with secretion of VEGF-A by ALL or AML cells the permeability of vasculature in the bone marrow increases, coupled with the disruption of blood brain barrier. There is a single subpopulation of leukemia cells, called leukemia stem cells (LSCs) that is able to resist in the new microenvironment due to its high adaptability. The LCSs enter into the arachnoid, migrate, and intensively proliferate in cerebrospinal fluid (CSF) and consequently infiltrate perivascular spaces and brain parenchyma. Moreover, the CNS is an immune privileged site that also protects leukemic cells from chemotherapy. CD56/NCAM is the most important surface molecule often overexpressed by leukemic stem cells that offers them the ability to infiltrate in the CNS. Although asymptomatic or with unspecific symptoms, CNS leukemia should be assessed in both AML/ALL patients, through a combination of flow cytometry and cytological analysis of CSF. Intrathecal therapy (ITT) is a preventive measure for CNS involvement in AML and ALL, still much research is needed in finding the appropriate target that would dramatically lower CNS involvement in acute leukemia.

Paraneoplastic hypereosinophilia in a patient with peripheral T cell lymphoma, not otherwise specified.

Under normal physiological conditions, the bone marrow (BM) will have between 1% and 6% eosinophils, translating into a peripheral count of 0.05 - 0.5 ×109/L eosinophils in the blood smear. This process is coordinated by transcription factors with specific roles in differentiation and activation. Secondary eosinophilia may be a paraneoplastic syndrome, related to the presence of a subsequent malignancy, as presented in this case report. Such paraneoplastic manifestations should be addressed properly in order for the patient to receive the best treatment of choice. Even if eosinophilia was associated with B-cell malignancies before, this is a report associating this symptom to a peripheral T-cell lymphoma, not other specified, thus emphasizing the importance of a complex approach for the management of the oncological patient.

Next-generation sequencing-based characterization of the invasion by anatomical contiguity in a primary osseous diffuse large B-cell lymphoma. Correlation between the genetic profile of the malignancy and the clinical outcome of the patient.

Primary bone lymphoma is now a well-described entity in the World Health Organization (WHO) Classification of Tumors of Soft Tissue and Bone as a malignancy of the lymphoid tissue, with at least one mass within bone, without involvement of supraregional lymph nodes or other extranodal sites. In the current paper, we describe the complete characterization of the mutational landscape of a diffuse large B cell non-Hodgkin's lymphoma (DLBLCL) of the tibial plateau. Currently, there is very little data about the genetic landscape of primary osseous lymphomas and about the genetic background of this type of malignancy, resistant to chemotherapy and invading the surrounding tissues. In the current paper, we describe the complete characterization of the mutational landscape of a DLBCL of the tibial plateau. Our data is consistent with already published data, that have shown that MKI67 activation is correlated with lymphoma progression. Along with a high Ki67 index, resistance to chemotherapy occurs with neurogenic locus notch homolog protein 1 (Notch) and KRAS activation. This is the first molecular characterization for the invasion by anatomical contiguity for a primary bone lymphoma and while we only characterized one case and further deep sequencing analyses are required, we can explain the clinical dismal evolution of the patient by correlating them with the genetic landscape of this type of lymphoma.

Let's Talk About BiTEs and Other Drugs in the Real-Life Setting for B-Cell Acute Lymphoblastic Leukemia.

Background: Therapy for acute lymphoblastic leukemia (ALL) are currently initially efficient, but even if a high percentage of patients have an initial complete remission (CR), most of them relapse. Recent data shows that immunotherapy with either bispecific T-cell engagers (BiTEs) of chimeric antigen receptor (CAR) T cells can eliminate residual chemotherapy-resistant B-ALL cells. Objective: The objective of the manuscript is to present improvements in the clinical outcome for chemotherapy-resistant ALL in the real-life setting, by describing Romania's experience with bispecific antibodies for B-cell ALL. Methods: We present the role of novel therapies for relapsed B-cell ALL, including the drugs under investigation in phase I-III clinical trials, as a potential bridge to transplant. Blinatumomab is presented in a critical review, presenting both the advantages of this drug, as well as its limitations. Results: Bispecific antibodies are discussed, describing the clinical trials that resulted in its approval by the FDA and EMA. The real-life setting for relapsed B-cell ALL is described and we present the patients treated with blinatumomab in Romania. Conclusion: In the current manuscript, we present blinatumomab as a therapeutic alternative in the bridge-to-transplant setting for refractory or relapsed ALL, to gain a better understanding of the available therapies and evidence-based data for these patients in 2019.