Polycythemia vera: diagnosis, clinical course, and current management

Very important developments related to polycythemia vera (PV) have occurred during the last two decades. The discovery of Janus kinase (JAK) 2 mutations has changed both the diagnosis and clinical management of PV. Currently JAK2 molecular testing is essential in the diagnostic work-up and JAK2 mutation positivity is a major diagnostic criterion. The discovery of JAK2 mutations suggested that abnormal JAK-STAT signaling was a pivotal feature in the pathogenesis of Philadelphia-negative myeloproliferative neoplasms. This idea led to the development of JAK inhibitors. Currently ruxolitinib, a JAK1/JAK2 inhibitor, is also approved for PV patients with hydroxyurea resistance or intolerance. International collaborations have made it possible to describe disease characteristics and evolution better. Presently it is possible to quantify the symptomatic burden of the disease and to estimate prognosis. In spite of these developments, management of PV still largely depends on estimation of thromboembolic risk and trying to decrease the risk with or without cytoreductive medications. Different approaches have been proposed by international disease experts for the diagnosis, thromboembolic risk estimation, and drug selection. This paper aims to review clinical aspects of PV and propose a management algorithm. The authors also point to still unresolved questions and unmet needs in diagnosis and management.

Turkish Chronic Myeloid Leukemia Study: Retrospective Sectional Analysis of CML Patients.

OBJECTIVE: here have been tremendous changes in treatment and follow-up of patients with chronic myeloid leukemia (CML) in the last decade. Especially, regular publication and updating of NCCN and ELN guidelines have provided enermous rationale and base for close monitorization of patients with CML. But, it is stil needed to have registry results retrospectively to evaluate daily CML practices. MATERIALS AND METHODS: In this article, we have evaluated 1133 patients' results with CML in terms of demographical features, disease status, response, resistance and use of second-generation TKIs. RESULTS: The response rate has been found relatively high in comparison with previously published articles, and we detected that there was a lack of appropriate and adequate molecular response assessment. CONCLUSION: We concluded that we need to improve registry systems and increase the availability of molecular response assessment to provide high-quality patient care. CONFLICT OF INTEREST: None declared.

Azacitidine has limited activity in 'real life' patients with MDS and AML: a single centre experience.

Myelodysplastic syndrome (MDS) represents a heterogeneous group of potentially malignant diseases of bone-marrow stem cells. Acute myelogenous leukaemia (AML) is an inevitable outcome for many patients with MDS. Azacitidine has been reported to result in comparably higher response rates and improved survival than other treatment strategies. In this retrospective study, we report the results on 25 'real life' patients with MDS, CMML or AML treated with azacitidine between 2005 and 2009. All patients fulfilled the World Health Organization criteria for MDS and AML. No eligibility criteria other than diagnosis were considered. Complete response (CR) rate was observed in three of the 25 'real life' patients (12%) with a median duration of CR of 5 months (4-6 months). Seven patients (28%) had mono- or bi-lineage haematologic improvement and 15 patients (60%) showed neither morphologic nor haematologic response. Among 17 non-AML patients, the median time from onset of Aza-C treatment to AML transformation was 10 months (4-15 months). Overall death rate was 72%. All of the eight AML patients died. The death rate under Aza-C among non-AML patients was 59%. Unlike the results of the clinical trials, our data show that Aza-C has a limited activity in 'real-life' patients with MDS and AML. It is obvious that Aza-C can induce complete or partial responses in a considerable number of MDS patients but responses are usually not durable as we observed in our patients.

Efficacy and Safety of Ombitasvir/Paritaprevir/ Ritonavir + Dasabuvir ± Ribavirin Combinations in Patients with Genotype 1 Hepatitis C and Inherited Bleeding Disorders.

BACKGROUND: Hepatitis C is one of the leading causes of death in patients with inherited bleeding disorders. Currently, direct-acting antiviral drugs used for the treatment of hepatitis C have become an effective and a reliable option for people with inherited bleeding disorders. The aim of this study is to report the efficacy and safety of ombitasvir + paritaprevir/ritonavir and dasabuvir combination in the treatment of hepatitis C in patients with inherited bleeding disorders. METHODS: In this retrospective study, we evaluated the efficacy and safety of the combination of ombitasvir + paritaprevir/ritonavir and dasabuvir in 10 adult patients with hemophilia A, 4 patients with hemophilia B, and 1 patient with von Willebrand disease who were infected with hepatitis C genotype 1. RESULTS: Five patients had genotype 1a and 10 patients had genotype 1b chronic hepatitis C. One patient had Child A cirrhosis, 14 patients had chronic hepatitis C without cirrhosis. Hepatitis C virus ribonucleic acid was negative in all patients at week 4 and at the end of the treatment. Sustained virologic response was obtained in all patients. Serious side effects were detected in 3 patients, which were intra- muscular bleeding, erosive gastritis-related gastrointestinal bleeding, and pneumonia. CONCLUSION: Ombitasvir + paritaprevir combined with ritonavir and dasabuvir ± ribavirin is an effective treatment for patients infected with genotype 1 hepatitis C who have coagulation disorders. Tolerance and side effects are similar to other treatment options.

Inhibitor screening for patients with hemophilia in Turkey.

Development of factor VIII inhibitors remains the most serious and life-threatening complication of hemophilia therapy. The aim of this study was to determine the prevalence of inhibitor development in Turkish patients with hemophilia. Totally 1226 patients were screened [HA: 1057, HB: 105, von Willebrand's disease (vWD): 64]. Ages ranged from 1 to 55 years (mean: 16.5 years). Sixty-two percent of patients (657/1057) were severe hemophilia. This study showed that inhibitor prevalence in Turkish hemophiliacs exposed to factor concentrates and fresh frozen plasma (FFP) is 11.2% for all HA and 15.8% for severe HA versus 1.9% for HB after eliminating transient inhibitors. Totally 122 patients were found inhibitor positive [high responder (HR) inhibitor= 60 and low responder (LR) inhibitor= 59 for HA/2 LR for HB/1 LR for vWD]. Thanks to this project, patients with inhibitor development can be treated with specific products such as recombinant factor VIIa or activated protrombin complex concentrates for their bleeding episodes or in their elective operations.

Case report of two haematopoietic stem cell transplanted patients with chronic graft-versus-host disease resembling acute viral hepatitis.

Chronic graft-versus-host disease (GVHD) of the liver usually presents as an indolent cholestatic syndrome associated with abnormalities in the skin, oral mucosa, and lacrimal glands observed beyond day 100 after allogeneic bone marrow transplantation. Because of its cholestatic nature, chronic liver GVHD is not generally considered in the differential diagnosis of markedly elevated serum transaminases and jaundice. However, sudden rise in serum transaminase levels after day 70 posttranplant should always raise the question of chronic liver GVHD. We report here two cases, in whom the presentation of chronic graft-versus-host disease of the liver strongly resembled acute viral hepatitis. Chronic GVHD of the liver should also be taken into account in the differential diagnosis of marked elevations of liver enzymes in allogeneic stem cell transplant recipients and appropriate diagnostic and therapeutic measures should be applied.

A mutation in a functional Sp1 binding site of the telomerase RNA gene (hTERC) promoter in a patient with Paroxysmal Nocturnal Haemoglobinuria.

BACKGROUND: Mutations in the gene coding for the RNA component of telomerase, hTERC, have been found in autosomal dominant dyskeratosis congenita (DC) and aplastic anemia. Paroxysmal nocturnal hemoglobinuria (PNH) is a clonal blood disorder associated with aplastic anemia and characterized by the presence of one or more clones of blood cells lacking glycosylphosphatidylinositol (GPI) anchored proteins due to a somatic mutation in the PIGA gene. METHODS: We searched for mutations in DNA extracted from PNH patients by amplification of the hTERC gene and denaturing high performance liquid chromatography (dHPLC). After a mutation was found in a potential transcription factor binding site in one patient electrophoretic mobility shift assays were used to detect binding of transcription factors to that site. The effect of the mutation on the function of the promoter was tested by transient transfection constructs in which the promoter is used to drive a reporter gene. RESULTS: Here we report the finding of a novel promoter mutation (-99C->G) in the hTERC gene in a patient with PNH. The mutation disrupts an Sp1 binding site and destroys its ability to bind Sp1. Transient transfection assays show that mutations in this hTERC site including C-99G cause either up- or down-regulation of promoter activity and suggest that the site regulates core promoter activity in a context dependent manner in cancer cells. CONCLUSIONS: These data are the first report of an hTERC promoter mutation from a patient sample which can modulate core promoter activity in vitro, raising the possibility that the mutation may affect the transcription of the gene in hematopoietic stem cells in vivo, and that dysregulation of telomerase may play a role in the development of bone marrow failure and the evolution of PNH clones.

Acute hepatitis B despite a previous high titer of anti-HBs.

INTRODUCTION: Loss of HBsAg and development of surface and core antibodies represent clinical cure. However, recent evidence suggests that hepatitis B virus (HBV) persists in a latent state even in those with mounted protective antibodies. After significant immunosuppression, anti-HBs may decrease and HBsAg may reappear (reverse seroconversion). Reverse seroconversion of HBV has been observed in association with hematopoietic stem cell transplantation, renal transplantation, intensive chemotherapy, human immunodeficiency infection, or rituximab usage. CASE REPORT: We present here a case study of a patient with a previous high titer of anti-HBs who later developed HBV reactivation following intensive chemotherapy for leukemia. CONCLUSION: We conclude that in immunosuppressed patients with a history of HBV infection may carry a risk for reverse seroconversion and monitoring anti-HBs levels may help recognising this risk.

Unilateral sudden hearing loss as the first sign of chronic myeloid leukemia.

Chronic myeloid leukemia (CML) is one of the etiologic causes of sudden hearing loss and vertigo. However, deafness in association with vestibular symptoms rarely occurs in CML as the first sign. In this article, a 50-year-old male with CML whose first signs and symptoms were unilateral sudden hearing loss and tinnitus in the right ear, vertigo and nausea was presented. Aetiopathogenetic mechanisms, clinical and radiological aspects and therapeutic options for CML with deafness and vertigo were discussed reviewing the literature.

The SOCS-1 gene methylation in chronic myeloid leukemia patients.

SOCS-1, an important protein in the JAK/STAT pathway, has a role in the down stream of BCR-ABL protein kinase. We investigated 56 CML patients and 16 controls for the methylation status of SOCS-1 gene promoter and Exon 2 regions. Exon 2 was found to be methylated in 58.9% of the patients and 93.8% of the controls [P = 0.020, OR = 0.121(0.015-0.957)%95CI]. The promoter region was found unmethylated in all patient samples and controls. Although previous studies revealed a relation between SOCS1 gene Exon-2 hypermethylation and CML development or progression, the results of this study showed no such correlation. On the contrary, our results might be indicating hypomethylation in CML patients, this hypothesis need to be studied in larger study population.