Chromosomal and molecular abnormalities in the evolution of multiple myeloma

Multiple myeloma (MM) is a disease characterized by various clinical, biochemical, and molecular disorders in its evolution. The use of modern methods such as fluorescence in situ hybridization, next-generation sequencing for mutational analysis of genes, single nucleotide polymorphism genotyping, gene-expression profiling, and epigenetic profiling has identified significant chromosomal abnormalities in MM that have greatly enriched our knowledge of the pathogenesis of the disease. In the stage of monoclonal gammopathy of undetermined significance, hyperdiploid chromosomal abnormalities and translocations of chromosome 14 activating various oncogenes are characteristic. Later in the evolution of the pathological process, mutations that disrupt the coordinated and precise gene expression programs that govern cell growth and differentiation appear. In 20% of patients, the disease progresses with aggressive clinical and biochemical characteristics. The high risk cannot be defined by a single pathogenetic mechanism but by the interaction of several genetic lesions leading to high levels of proliferation, apoptosis evasion, and therapeutic resistance. This is achieved in part by strong dysregulation of the G1/S phase of the cell cycle, further proliferation signaling through the myc, RAS-ERK, and NFκB pathways, aberrant signaling in the bone marrow niche, and loss or mutation of the tumor suppressor genes RB1 and TP53. In-depth knowledge of these complex processes could lead to the development of new target drugs and an individualized approach to the treatment of MM patients

Outcome after azacitidine treatment in patients with high-risk myelodysplastic syndrome and acute myeloid leukemia in the Clinic of Hematology at St. Marina University Hospital, Varna

Introduction: Hypomethylating agents have become a standard therapy for high-risk myelodysplastic syndromes (MDS) and elderly patients with acute myeloid leukemia (AML).Aim: The aim of the study was to assess the efficacy of azacitidine treatment in patients with MDS and AML followed for 18 months.Materials and Methods: Twenty-seven patients with MDS and AML treated in the Clinic of Hematology at St. Marina University Hospital, Varna were included in the study. Azacitidine was administered subcutaneously in at a dose of 75 mg/m2 for 7 days. Disease assessment was performed on  the 3rd month, 6th month, and at progression.Results: Twenty-seven patients were analyzed. Their median age was 71.5 years. Nine had refractory anemia with excess of blasts II (RAEB II), 5 had chronic myelomonocytic leukemia II (CMML II), 1 was with unclassifiable MDS (MDS-U), and 12 with AML. The median number of administered cycles was 6 (1-19). Eleven patients completed 6 cycles of azacitidine. Partial response was achieved in 9 patients (33%) (7 MDS and 2 AML), stable disease in 8 (29%) (5 MDS and 3 AML). Progressive disease was observed in 10 patients (37%). The response correlated with the type of the disease (p=0.03), cytogenetic risk (p=0.01), and survival (p=0.000). At 18 months, 60% of MDS patients were alive compared to 41.7% in the AML group. The median time to death in the AML patient group was 2.5 months. The mean overall survival was 10.4 months (12.6 months for MDS patients and 5.4 months for AML patients).Conclusion: The therapy with azacitidine is an option for elderly patients with high-risk MDS.  In patients with AML a rapid progression is observed during the first two cycles with mortality rate of 58.3%

Novel approaches in the classification and risk assessment of patients with myelodysplastic syndromes-clinical implication

INTRODUCTION: New prognostic systems have been proposed aimed at improving the ability to predict survival and progression in myelodysplastic syndome (MDS) patients, as well as to select the accurate therapy.PURPOSE: The aim of this study was to determine the prognostic score for patients with MDS, diagnosed in the Hematology Clinic, University hospital, Varna, comparing different prognostic scoring systems.MATERIALS AND METHODS: 92 patients with MDS, diagnosed between 2004 and 2012 were included in the study. The mediana of age was 72 (20-91 years), 87% >60 years of age, 52 men and 41 women. The prognostic score was determined according to IPSS, WPSS, MDACSS. The parameters assessed were WHO type, karyotype, cytopenias, percentage of marrow blasts, age, performing status and transfusion dependence.RESULTS: Cytogenetic studies were performed in 100% of patients. Abnormalities were found In 34.8%, the most common-del-5q (14.6%), -Y (4.5%), complex karyotype (8%), +8 (2.2%). Patients were distributed according to the cytogenetic risk -low-87.2%, intermediate-7.7%, high-5.1%. According to IPSS 41% of the patients were with low risk, 34%-Int-1, 16%-Int-2, high-9%.  WPSS distributed the patients in 5 groups: very low-11%, low risk-43%, int-21%, high-20%, very high-5%. According to MDACSS 14% of the patients were with low, 54%-Int-1, 18%-Int2, 13% with high risk.CONCLUSION: Significant correlation was found between the risk groups and AML transformation and survival. However, the comparison between the different scoring systems demonstrated the advantage of prognostic systems, based on broader range of clinical parameters in better distribution of intermediate risk patients and the precise determination of high and very high risk.

Biomarkers for Assessing Bone Disease in Multiple Myeloma // Биомаркери за оценка на костната болест при мултиплен миелом

Multiple myeloma (MM) is an oncohematological disease with increasing incidence in recent years. A characteristic manifestation of MM is bone disease (BD), with 80% of patients having proven osteolytic lesions at diagnosis. Increased osteoclast activity and suppressed osteoblast function play a key role in its pathogenesis. The proteins Dkk-1, sclerostin, sRANKL, osteopontin and periostin, characterising osteoclast and osteoblast function in newly diagnosed patients with MM, are the object of study in this dissertation. Their levels at diagnosis are significantly higher in patients compared to control subjects. They adequately reflect the stage of the disease and the extent of bone involvement. The positive correlation of the studied biomarkers with bone marrow infiltration and beta-2-microglobulin, as well as the negative correlation with haemoglobin, probably reflect tumour growth and disease progression. The biomarkers studied have very good diagnostic potential to reliably discriminate patients from healthy individuals. They change in the course of treatment, with a decrease in their serum levels depending on the number of therapeutic courses performed. The scientific issue addressed in the thesis is both relevant and innovative, not only for Bulgaria but also worldwide, given the increasing incidence of the disease and the need for new, specific and reliable molecular biomarkers to detect and monitor the most common complication of MM, namely myeloma BD.Множественият миелом (ММ) е онкохематологично заболяване с нарастваща през последните години честота. Характерна проява на ММ е костната болест (КБ), като 80% от пациентите са с доказани остеолитични лезии още при поставяне на диагнозата. Ключова роля в патогенезата има повишената остеокластна активност и потисната остеобластна функция. Обект на изследване в дисертационния труд са белтъците Dkk-1, склеростин, sRANKL, остеопонтин и периостин, характеризиращи остеокластната и остеобластна функция при пациенти с новооткрит ММ. Проследени са нивата им при диагнозата, значимо по-високи при пациентите в сравнение с контролните индивиди. Те адекватно отразяват стадия на болестта и степента на костното засягане. Установената позитивна корелационна взаимозависимост на изследваните биомаркери с костномозъчната инфилтрация и бета-2-микроглобулин, както и отрицателната взаимовръзка с хемоглобин вероятно отразяват туморния растеж и прогресията на заболяването. Изследваните биомаркери се отличават с много добър диагностичен потенциал като надеждно дискриминират болни от здрави индивиди. Те се променят в хода на лечението, като намалението на серумните им нива е в зависимост от броя на проведените курсове. Поставеният научен проблем в дисертацията е актуален и иновативен, не само за България, но и в световен мащаб, предвид нарастващата заболеваемост и нуждата от нови специфични и надеждни молекулни биомаркери за установяване и мониториране на най-честото усложнение при ММ, каквото е КБ

A rare case and diagnostic process of `gray zone` lymphoma

Introduction: Gray Zone Lymphoma (GZL) is a rare subtype of lymphoid neoplasm with aggressive development and difficult diagnostics. The term `gray zone lymphoma` has been used to denote a new pathomorphological category of unclassified B - cell lymphoma with intermediate features between diffuse large B-cell lymphoma (DLBCL) and classical Hodgkin`s lymphoma (CHL). It typically occurs in young male and presents as a solitary mediastinal mass, although often its clinical manifestation is not specific. GZL requires a specific treatment approach, because of the fundamental differences in the development of CHL and traditionally more aggressive B - cell lymphoma.Materials and methods: A clinical case of 50-years-old female, complaining of generalized pruritus is presented. Conducted tests reveal anaemia, increased cholesterol, liver enzymes at the upper limit of the reference values and slightly elevated. A few months later the patient is admitted to a rheumatology clinic with constitutional symptoms and a small-joint inflammation, where conducted computed tomography of the chest revealed a solitary mediastinal mass, which also affects the right lung.Results: Diagnostic searching necessitates performing of fibrobronchoscopy with lavage and fine needle aspiration, followed by core biopsy. Microbiological testing proved no specific inflammation and cytological examination reveals evidence of Rosai - Dorfman disease. Histological conclusion from the biopsy describes inflammatory myofibroblastic tumor. After upper right lobectomy, pathomorphological examination of the resected material shows classical Hodgkin`s lymphoma of nodular sclerosis subtype (CHL-NS) with primary lung affection, although immunohistochemical analysis and flow cytometry prove expression of tumor markers, normally produced by DLBCL.Conclusion: These results lead to a new pathological revision, which determined the final diagnosis - Gray Zone Lymphoma. Currently the patient is undergoing treatment with 8 cycles of standard chemotherapy for diffuse large B-cell lymphoma

Efficacy of Inotuzumab Ozogamicin plus Ponatinib Followed by Allogeneic Stem Cell Transplantation in a Patient with Relapsed Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia

Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL) is an aggressive disease with poor outcomes. Despite the incorporation of tyrosine kinase inhibitors (TKIs) in the therapeutic strategies, patients who relapse after chemotherapy plus TKI have poor overall survival (OS) and less chance to proceed to hematopoietic stem cell transplantation (HSCT) which remains the only curative approach. Therefore, new drugs, such as antibody-targeted therapies alone or in combination with TKIs, offer new therapeutic options for those patients. However, the combination of inotuzumab plus ponatinib has limited application. We present a case of a patient affected by Ph + ALL with T315I mutation successfully treated after early relapse with inotuzumab plus ponatinib, followed by allogeneic HSCT and ponatinib maintenance

Circulating sRANKL, Periostin, and Osteopontin as Biomarkers for the Assessment of Activated Osteoclastogenesis in Myeloma Related Bone Disease

The hallmark of multiple myeloma is myeloma related bone disease. Interactions between myeloma plasma cells (MPCs), stromal cells, and the bone marrow (BM) microenvironment play a critical role in the pathogenesis of MBD. Bone remodeling is severely dysregulated with the prevalence of osteoclast activity. We aimed to assess circulating levels of sRANKL, periostin, and osteopontin as osteoclast activators in NDMM patients at diagnosis and in the course of treatment, correlations with clinical and laboratory data, and to evaluate their potential as additional biomarkers for the assessment of MBD. The current study involved 74 subjects (41 NDMM patients, 33 controls). MBD was assessed by whole-body low-dose computed tomography. sRANKL, periostin, and osteopontin were assayed by commercial ELISA kits. At diagnosis, all tested parameters were significantly higher in NDMM patients compared to the controls (p p p < 0.05). In conclusion, sRANKL, periostin, and osteopontin reflect MBD severity and could be promising markers for MBD monitoring and the effect of myeloma treatment