The Philadelphia Chromosome, from Negative to Positive: A Case Report of Relapsed Acute Lymphoblastic Leukemia Following Allogeneic Stem Cell Transplantation.

Relapsed acute lymphoblastic leukemia (ALL) represents a continuous challenge for the clinician. Despite recent advances in treatment, the risk of relapse remains significant. The clinical, biological, cytogenetic, and molecular characteristics may be different at the time of relapse. Current comprehensive genome sequencing studies suggest that most relapsed patients, especially those with late relapses, acquire new genetic abnormalities, usually within a minor clone that emerges after ALL diagnosis. We report the case of a 23-year-old young woman diagnosed with Philadelphia chromosome-negative B cell acute lymphoblastic leukemia. The patient underwent allogeneic stem cell transplantation (allo-HSCT) after complete remission. Despite having favorable prognostic factors at diagnosis, the disease relapsed early after allo-HSCT. The cytogenetic and molecular exams at relapse were positive for the Philadelphia chromosome, respectively for the Bcr-Abl transcript. What exactly led to the recurrence of this disease in a more aggressive cytogenetic and molecular form, although there were no predictive elements at diagnosis?

Primary, secondary or less frequent causes of immune thrombocytopenia: A case report.

Primary immune thrombocytopenia (ITP) is characterized by isolated low platelet count and it is a diagnosis of exclusion, contrasting to secondary ITP. Therefore, a positive diagnosis is difficult and requires extensive investigation. Some of the underlying conditions that are associated with ITP are lymphoproliferative disorders and infections, especially viral ones. In the present study, the case of a patient diagnosed with diffuse large B-cell lymphoma, who received chemotherapy and autologous hematopoietic stem cell transplantation is presented. After a complete remission of four years, the patient presented with sudden intense hemorrhagic syndrome and severely decreased platelet count. The most frequent causes of secondary ITP were excluded, including lymphoma relapse, and intravenous corticosteroids were started. However, shortly after hospital admission, the patient developed neuro-psychiatric anomalies, fever and pancytopenia, and West-Nile encephalitis was diagnosed. Although the initial development was favorable, he started to complain of progressive severe muscle weakness and eventually succumbed to infectious complications in the setting of prolonged hospitalization, corticotherapy, and immobilization.

Platelet Defects in Acute Myeloid Leukemia-Potential for Hemorrhagic Events.

BACKGROUND AND OBJECTIVES: In acute myeloid leukemia (AML), extensive bleeding is one of the most frequent causes of death. Impaired activation and aggregation processes were identified in previous studies on platelet behaviour associated with this disease. This study's aim was to examine platelet function in correlation with other haemorrhage risk factors (fever, sepsis, recent bleeding, uraemia, leucocytosis, haematocrit value, treatment). DESIGN AND METHODS: The analysis of platelet surface proteins (Glycoprotein Ib-IX (CD42b, CD42a), Glycoprotein IIb-IIIa (CD41, CD61), p-selectin (CD62P), granulophysin (CD63)) was conducted by flowcytometry from samples of whole blood in patients with acute myeloid leukaemia in different stages of diagnosis and therapy (n = 22) in comparison with healthy human controls (n = 10). RESULTS AND INTERPRETATIONS: Our results show a significant decrease in fluorescence level associated with platelet activation markers (CD63 (14.11% vs. 40.78 % p < 0.05); CD62P (15.26% vs. 28.23% p < 0.05)); adhesion markers (CD42b (69.08% vs. 84.41% p < 0.05)) and aggregation markers (CD61 (83.79% vs. 98.62% p < 0.001)) in patients compared to controls. The levels of CD41 (80.62% vs. 86.31%, p = 0.290) and CD42a (77.98% vs. 94.15%, p = 0.99) demonstrate no significant differences in the two groups. CONCLUSION: The AML patients present changes in adhesion receptors and activation markers, suggesting a functional defect or denatured intracellular signalling in platelets. The exposed data indicate that flow cytometry can effectively identify multiple functional platelet impairments in AML pathogenesis.

POEMS syndrome complicated with multiple ischemic vascular events: case report and review of literature.

POEMS syndrome (acronym consisting of: polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes) is an uncommon disorder associated with an underlying plasma cell dyscrasia. There is no single specific test for POEMS, and due to its rarity and heterogeneity, patients are often mis- or underdiagnosed. Castleman disease (CD) is a rare lymphoproliferative disorder, closely related to POEMS syndrome; ~11%-30% of POEMS patients are associated with concomitant CD. In contrast to frequently published reports on vascular events in POEMS syndrome affecting coronary arteries or lower limbs, cases of cerebrovascular events are rarely mentioned in literature. We hereby report a patient with POEMS syndrome accompanied by CD who presented recurrent strokes and splenic infarction.

MECOM, HBS1L-MYB, THRB-RARB, JAK2, and TERT polymorphisms defining the genetic predisposition to myeloproliferative neoplasms: A study on 939 patients.

Polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF) are classical myeloproliferative neoplasms (MPN), characterized by specific somatic mutations in JAK2, CALR or MPL genes. JAK2 46/1 and TERT rs2736100 polymorphisms are known to significantly predispose to MPN. This study aimed to establish the additional contribution of the recently described MECOM rs2201862, HBS1L-MYB rs9376092 and THRB-RARB rs4858647 polymorphisms to the occurrence of MPN. These three polymorphisms, along with JAK2 46/1 and TERT rs2736100 were genotyped in 939 MPN patients (454 with ET, 337 with PV and 148 with PMF) and 483 controls. MECOM rs2201862 associated significantly with each MPN entity, except for ET, and with all major molecular sub-types, especially those CALR-mutated (OR = 1.4; 95% CI = 1.1-1.8; P-value = .005). HBS1L-MYB rs9376092 associated only with JAK2 V617F-mutated ET (OR = 1.4; 95% CI = 1.1-1.7; P-value = .003). THRB-RARB rs4858647 had a weak association with PMF only (OR = 1.5; 95% CI = 1-2.1; P-value = .04). Surprisingly, JAK2 46/1 haplotype was associated significantly not only with JAK2 V617F-mutated MPN, but also with CALR-mutated MPN (OR = 1.4; 95% CI = 1.1-1.8; P-value = .01). TERT rs2736100 was associated equally strong with all MPN, regardless of phenotype or molecular sub-type. In conclusion, JAK2 46/1, TERT rs2736100 and MECOM rs2201862 are the chief predisposing polymorphisms to MPN.

[Pathogenesis of thrombotic and hemorrhagic complications in myeloproliferative and myelodysplastic syndromes]. / Patogeneza complicatiilor trombotice si hemoragice în sindroamele mieloproliferative si mielodisplazice.

Chronic myeloproliferative disorders (CMD) and Myelodisplastic Syndromes (MDS) represents a group of clonal pluripotent stem-cell pathologies. During their natural history, the clinical picture reveals both thrombosis and hemorrhage. The thrombosis could affect the microvessels, and also the large vessels, including even less usual territories (suprahepatic veins, porta vein, pulmonary vein). There are many factors contributing to thrombosis in myeloproliferative chronic disorders--the associated comorbidities, the numeric alterations of blood elements and also the disorders of the platelet's function. Thus, there were described quantitative and qualitative anomalies of platelet's receptors: GP Ib, GP IIb/IIIa, GP IV, GP VI, thrombopoietin receptor of the platelet cMPL, the increase of platelet activation; the increase of P selectin and thrombospondin and the increase on GP IIb/IIIa expression--they were all correlated with thrombosis. An important role has been attributed to JAK2 mutation, which affects the platelet receptor for thrombopoietin cMPL. Regarding the hemorrhage in chronic myeloproliferative syndrome, it is favored by many disorders in platelet's function, such as: the decrease of von Willebrand factor's receptor of the platelet, which leads to acquired Bernard Soulier syndrome; quantitative and qualitative disorders of dense granules of the platelet, decrease of the secretion and platelet aggregation after epinephrine, ADP and collagen stimulation. It was also described the acquired von Willebrand syndrome, most frequently type 2.

The impact of hepatitis viruses on chronic lymphoproliferative disorders--preliminary results.

UNLABELLED: The aim of this study is to analyze a group of patients with chronic lymphoproliferative disorders associated with B, C, D hepatitis viral infection. This group of chronic lymphoproliferative disordered patients with associated hepatitis viral infection has been diagnosed and monitored in the Hematology Department of the University Emergency Hospital of Bucharest, between December 2007 and January 2009. Our study is meant to observe the influence of the viral infection on clinical and biological evolution of the enrolled patients. The diagnosis of the chronic lymphoproliferative disorder was based on the bone marrow/ lymph node biopsy and flow-cytometry analysis. The positive diagnosis for hepatitis viral infection was established by ELISA serological tests and viremia was performed by TaqMan method at INBI "Matei Bals" Bucharest. The analyzed group is made up of 41 patients, 25/41 (60.97%) females and 16/41 (39.02%) males, with ages: 20-50 years old--6/41 (14.63%), 51-70 years old--23/41 (56.09%) and over 71 years old--12/41 (29.26%) patients. The histological types of CLD: B-cell non-Hodgkin's lymphoma--in 28/41 (68.29%) patients, T-cell non-Hodgkin's lymphoma--2/41 (4.87%) patients, Hodgkin's lymphoma--2/41 (4.87%), chronic lymphocytic leukemia--7/41 (17.07%), Waldenström disease--2/41 (4.87%) patients. Regarding the type of CLD, 19/41 (46.34%) of the patients have an aggressive type of CLD and 22/41 (53.65%) a non-aggressive type of CLD. The hepatitis viral infection distribution in our patients: 14/41 (34.14%) have HBV infection, 24/41 (58.53%) have HCV infection, double/triple association of viral infection was found in 3/41 (7.31%) patients. Within HBV infection subgroup 9/14 (64.28%) patients have an aggressive type of CLD and 5/14 (35,71%) patients have a non-aggressive type, whereas within the group with HCV infection we found a different distribution: 9/24 (37,5%) patients with aggressive type and 15/24 (62.5%) with non-aggressive type of CLD. The clinical parameters monitored were: B signs were present in 19/41 (43.34%) patients, the superficial or profound adenopathies--were found in 29/41 (70,73%) patients, hepatomegaly--in 38/41 (92,68%) patients, splenomegaly--in 21/41 (51.21%) patients, extra-nodal involvements in 10/41 (24,39%) patients and most frequent in the non-aggressive type of CLD--6/10 (60%) patients. The hematological and biochemical parameters were: the presence of anemia and thrombocytopenia--found in a small number of patients; lymphocytosis--positive in 33/41 (80.48%) patients, most with HCV infection and non-aggressive type of disease, the presence of autoimmune hemolytic anemia--in 4/41 (9.75%) patients, cryoglobulins--8/41 (19.51%) patients, all with HCV infection; also the liver function was monitored. Antiviral therapy was administered to 12/41 (29.26%) patients--Lamivudine to 8/41 (19.51%) patients and Ribavirine/Interferon to 4/41 (9.75%) patients. Chemotherapy was given in 32/41 (78%) patients. Monoclonal antibodies anti CD20 (Rituximab) therapy was associated in 6/41 (14.63%) patients. CONCLUSIONS: A high incidence in female sex of over 50 years old was noticed. A strong association between B-cell chronic lymphoproliferative disorders and hepatitis viral infection B, C, D was revealed, the most frequent being the C hepatitis virus, associated with the non-aggressive type of CLD, extra-nodal involvement, splenomegaly, lymphocytosis, cryoglobulins, cytolysis and colestasis. The clinical and biological disease history will be monitored during chemotherapy and antiviral treatment.

Preliminary data on the involvement of B, C and D hepatitis viruses in the etiopathogenesis of chronic lymphoproliferative syndromes in Romania.

UNLABELLED: THE AIMS OF THE STUDY: Evaluation of the prevalence of HBV, HCV, HDV infection in patients with chronic lymphoproliferative diseases (CL), identification of the most involved viral genotypes, correlation between viremia dynamics and CL evolution, detection of molecular mechanisms implicated in CL pathogenesis, identification of lymphocytic receptors for viral antigens and biologic markers for early diagnosis of CL. METHODS: We present preliminary results of the first year of our research grant. This is a prospective, analytic, observational study in patients diagnosed with CL and HBV, HCV, HDV chronic infection. We included the following forms of CL: non-Hodgkin malignant lymphoma (NHL), Hodgkin lymphoma (HL) and chronic lymphocytic leukemia (CLL). We used the following commercial test kits: HCV RNA Real time PCR on a COBAS TaqMan (Roche Diagnostics) analyzer with 28 to 140.000.000 UI/ml detection range for HCV viremia, HBV DNA Real time PCR on a COBAS TaqMan (Roche Diagnostics) analyzer with 6 to 110.000.000 UI/ml detection range for HBV and the Roboscreen-RoboGene AJ kit with 10-10.000.000 replica/ml detection range for HDV. RESULTS: We have included 20 patients with CL and chronic hepatitis infection so far. Median age of the patients was 61 years. The identified CL forms were: B cell NHL (15 cases), T cell NHL (1 case), CLL (3 cases), Hodgkin lymphoma (1 case), equally distributed in aggressive and indolent forms of CL. HCV infection was diagnosed in 10 patients with CL, HBV infection was found in 10 patients with CL, 3 of them having co-infection HBV + HDV. In 4 patients with HBV infection viremia was over 20.000 IU/ml and the pattern of the CL was the aggressive form of the disease. The feature of the co-infection HBV + HDV was the predominance of indolent forms of CL. Among patients with HCV infection, only 3 cases were detected with viremia over 600.000 IU/ml and CL was represented by aggressive forms of the disease. We also have immunohistochemical data available in 19 cases, which seem to confirm the role of hepatitis viruses in lymphoproliferative disease etiopathogenesis. CONCLUSIONS: We ascertained an almost equally represented prevalence of HCV and HBV infection in patients with CL. The levels of HBV, HCV and HDV viremia were low in most of the cases. The most frequent form of CL was B cell NHL. We found an equal distribution between indolent and aggressive forms of NHL associated to hepatitis virus infection.

Splenectomy--a therapeutic option in splenic marginal zone cell lymphoma.

We present the case of a 65 years old male, admitted in the Hematology Department of the Universitary Emergency Hospital Bucharest, complaining of physical asthenia and weight loss; periodical medical examination has revealed splenomegaly and leucocytosis with lymphocytosis, persistent for the past 3 years. The clinical and paraclinical exam demonstrated splenomegaly (21 cm in diameter on computer tomography scan), hepatomegaly and generalized lymphadenopathies. The laboratory tests confirmed leucocytosis with lymphocytosis--a clonal population of B lymphocytes CD20+ CD19+ CD23+/- CD79b+(low), CD43+ FMC7+ CD5+ CD38+ ZAP70+ cyclin D1-. Lymph node and bone marrow biopsy together with flowcytometry established the diagnosis of Malignant non-Hodgkin Lymphoma--Atypical Splenic Marginal Zone B-cell lymphoma (aberrant expression of CD5) stage IVB, with leukemic picture, complicated with autoimmune hemolytic anemia with highly positive Coombs' tests. We performed therapeutic splenectomy, which was difficult because of the dimensions of the organ. The short term evolution was complicated by acute complete thrombosis of the splenic vein, but the long term evolution (1 year follow-up) was favorable--remission of anemia, significant improvement of performance status, decrease of leucocytosis and reduction of the tumoral mass.

An update on the platelet dysfunction in chronic myeloproliferative syndromes.

The thrombotic and hemorrhagic diathesis represents a frequent complication in myeloproliferative disorders (CMPD). They are correlated with the number of platelets, but also with their qualitative disorders, such as membrane glycoprotein changes. The latter are revealed by many platelet essays including flow-cytometry and include modified activation, secretion and aggregation patterns. The thrombopoietin platelet receptor (cMPL), affected by the JAK2 V617 mutation encountered in CMPD, may be associated with a prothrombotic status. Its implication reveals the importance of the molecular genetics profile in defining molecular diagnostic hallmarks and makes it a candidate in the early diagnosis of myeloproliferative disorder and a predictor of thrombotic complications in this group of diseases.