Athanasios Anastasiadis

CD1d expression as a prognostic marker for chronic lymphocytic leukemia

Abstract We analyzed the expression of CD1d, an antigen-presenting molecule, on peripheral blood leukemic cells of cases of chronic lymphocytic leukemia (CLL) by flow cytometry. We demonstrated variable expression of CD1d on leukemic lymphocytes and an association between high expression of CD1d with shorter time to treatment and overall survival of patients. CD1d was positively associated with CD38 expression, but not with unmutated heavy chain variable (VH) mutational status or adverse cytogenetics of leukemic lymphocytes. Our findings support that CD1d expression is a prognostic marker for CLL.

Successful treatment of lymph node extramedullary plasmacytoma with bortezomib

Dear editor, The extramedullary plasmacytomas (EMPs) are localized mainly in the upper respiratory tract. Lymph node plasmacytoma is defined as a lymph node tumor composed of monoclonal proliferation of plasma cells. The diagnosis of lymph node EMP is based not only on the finding of a plasma cell tumor at an extramedullary site (lymph node) but also on the exclusion of multiple myeloma (MM). Radiotherapy with or without local resection is the current treatment of choice because these tumors are usually radiosensitive. With radiation doses of 4,000–5,000 cGy, local recurrence develops in 5%, and systemic progression develops in less than 30% of the patients [1]. The size of EMP has been reported to be a bad prognostic factor regarding the likelihood of control [2]. Therefore, the treatment of large EMP presented in other sites than the upper respiratory system remains a challenge. Chemotherapy is considered as a treatment option in systemic progression to MM or recurrent relapses. The proteasome inhibitor bortezomib has recently been evaluated in the setting of relapsed and therapy–refractory plasmacytic malignancies with some evidence of effectiveness in MM with extramedullary manifestations of the disease [3, 4]. We report here a patient suffering from refractory EMP who received bortezomib and achieved complete remission. A 63-year-old male patient presented with retroperitoneal mass, measuring 8×10 cm, and after total surgical excision, histological examination of the mass, and a bone marrow biopsy, as well as a detailed biochemical and radiological evaluation to exclude MM, the patient was diagnosed as having retroperitoneal lymph node EMP (previously reported by Pantelidou et al. 2005 [5]). Despite radiotherapy to a total dose of 4,400 cGy, he relapsed 20 months later. Computed tomography (CT) disclosed seven enlarged paraaortic lymph nodes with diameters of 1.0– 3.8 cm on axial images. Bone marrow aspiration and biopsy, detailed biochemical evaluation, and skeletal survey did not reveal any evidence of systemic MM. Four courses of vincristine, adriamycin, and dexamethasone (VAD) followed by high-dose melphalan with autologous stem cell transplantation were given, and partial remission was achieved. Unfortunately, the patient relapsed again after 4 months. The CT demonstrated enlargement of celiac axis, retropancreatic, pericaval, and periaortic lymph nodes; a total of 22 enlarged lymph nodes were identified, measuring 1.0–4.2 cm in diameter on axial images. The involved nodes exhibited homogeneous soft tissue densities and mild enhancement after iodinated contrast media administration (Figs. 1a, 2a). Based on the early relapse after high-dose melphalan supported by autologous stem cell transplantation and the extended lymph node involvement, treatment with the proteasome inhibitor bortezomib was considered. After obtaining the patient’s informed consent, he received bortezomib (1.3 mg/m) as intravenous bolus injections D. Pantelidou (*) . C. Tsatalas . D. Margaritis . A. G. Anastasiadis . G. Bourikas Hematology Department, School of Medicine, Democritus University of Thrace, Alexandroupolis, Greece e-mail: dpantelidou@yahoo.gr Tel.: +30-25510-74511 Fax: +30-25510-76154

Pure red cell aplasia as first manifestation of splenic marginal zone lymphoma-successful treatment with rituximab: a case report

IntroductionAcquired pure red cell aplasia is a rare disorder, usually appearing secondary to various pathologic conditions such as thymoma, systemic autoimmune diseases or in the course of lymphomas. Conventional treatment consists of immunosuppression with corticosteroids, antithymocyte globulin or cyclosporin-A.Case presentation8 weekly courses of rituximab were administered to a patient who presented with pure red cell aplasia secondary to newly diagnosed splenic marginal zone lymphoma. Transfusion independence was achieved after the 6th course, and pure red cell aplasia receded completely with therapy.ConclusionPure red cell aplasia may ensue early in the course of splenic marginal zone lymphoma and other low grade lymphomas. Rituximab is a safe and effective alternative treatment for pure red cell aplasia secondary to lymphoproliferative disorders.

Proteolytic Matrix Metallopeptidases and Inhibitors in BCR-ABL1-Negative Myeloproliferative Neoplasms: Correlation with JAK2V617F Mutation Status

Background/Aims: Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) share the same acquired lesion JAK2V617F and may exhibit substantial overlap. Variability in JAK activation and allele burden, complemented by host, genetic and non-genetic modifiers, determine the phenotype. The aim of this study was to investigate the presence of the JAK2 mutation in association with the ratio of metallopeptidases inhibitors (TIMPs) to tissue metallopeptidases (MMPs) in MPNs, where inhibitory rather than proteolytic activity in marrow microenvironment appears to predominate. Methods: 94 patients with polycythemia vera, essential thrombocythemia and primary myelofibrosis, and 102 healthy individuals were evaluated. Allele-specific PCR and RFLP were used to detect JAK2 and genomic status. Serum concentrations of MMP and TIMP were measured by ELISA. The parameters were assessed with covariance analysis, and adjusted for gender, age and co-morbidity. Results: Mutation frequency was 81.91%. Abnormal TIMP/MMP ratios were identified in all three diseases. JAK2 mutation was correlated with significant changes in TIMP concentrations. Conclusions: Identification of an abnormal TIMP/MMP ratio in all three diseases, regardless of the JAK2 status, indicates invariable marrow remodeling. In this particular group of patients, presence of a JAK2V617F mutation, being associated with even higher ratios, appears to be a concurring participant in bone marrow-reforming processes. Additional research may delineate correlates with the JAK2 allelic burden.

Long-term bone marrow cultures (LTBMC) from essential thrombocythemia (ET) patients with or without JAK2617V>F mutation

Approximately half of essential thrombocythemia (ET) patients and almost all with polycythemia vera (PV) bear the activating JAK2617V>F point mutation, which arises at the multipotent haemopoietic progenitor cell level. Although ET is mainly characterized by megacaryocyte proliferation, the cases that are positive for the JAK2617V>F mutation also show increased bone marrow cellularity and higher erythrocyte and granulocyte counts. After establishing short- and long-term bone marrow cultures we found that the frequency of committed haemopoietic progenitors in the bone marrow, was not increased in JAK2617V>F positive ET compared to the negative ones, whereas in long-term cultures (LTBMC) JAK2617V>F positive ET display a growth pattern more similar to that observed in LTBMC produced by PV marrow cells. Our data support the notion that JAK2617V>F positive ET and PV represents a continuum spectrum of alterations within the same disease.

In vitro Effects of the Farnesyltransferase Inhibitor Tipifarnib on Myelodysplastic Syndrome Progenitors

Background: Farnesyltransferase inhibitors (FTIs) target proteins needing prenylation for functioning. Tipifarnib (Zarnestra®), a potent and specific inhibitor of farnesyltransferase, showed considerable activity in phase I and II studies in myelodysplastic syndrome (MDS), but the optimal regimen achieving high response rates with minor myelosuppression remains to be determined. Additionally, a direct effect on purified human MDS progenitors has not yet been shown. Methods: MDS and normal CD34+ cells isolated by using immunomagnetic beads were plated for short-term cultures in semisolid media or liquid cultures for flow-cytometric assessment of apoptosis in the presence of either DMSO or various FTI concentrations. Results: Tipifarnib exerted selective in vitro toxicity against clonal MDS hematopoiesis at concentrations less than 10 nM the effect being more prominent in white cell progenitors. This action was not due to apoptosis induction as both normal and MDS progenitors displayed equivalent DiOC3 and annexin V expression up to 72 h after exposure to tipifarnib. Conclusion: The leukemic clone is more susceptible in tipifarnib than normal progenitors. Since myelosuppression represents the main obstacle in the clinical use of tipifarnib in MDS, further reduction of the currently employed dose will potentially result in a more tolerable regimen without compromising its antileukemic action.

National registry of hemoglobinopathies in Greece: updated demographics, current trends in affected births, and causes of mortality

National registries constitute an invaluable source of information and contribute to the improvement of hemoglobinopathy management. Herein, we present the second updated report of the National Registry for Haemoglobinopathies in Greece (NRHG) and critically discuss the time trends in demographics, affected births, and causes of mortality. Thirty-eight Greek hemoglobinopathy units reported data from diagnosis to the last follow-up or death by retrospectively completing an electronic form. Four thousand thirty-two patients were eligible for inclusion; more than half of them had thalassaemia major. Compared to the previous report, a reduction in the total number of all hemoglobinopathies except for hemoglobinopathy “Η” was evident. The total number of affected births was also reduced; most of them were attributable to diagnostic errors and lack of awareness. Importantly, data on iron overload are reported for the first time; although most patients had low or moderate liver iron concentration (LIC) values, a non-negligible proportion of patients had high LIC. The burden due to heart iron overload was less prominent. Cardiac- and liver-related complications are the major causes of morbidity and mortality. From 2000 to 2015, a decrease in heart-related deaths along with an increase in liver-associated fatalities was observed. The Hellenic Prevention Program along with advances in chelation regimens and iron status monitoring have resulted in improved patient outcomes. The NRHG gives insight into the effectiveness of prevention programs, the therapeutic management of hemoglobinopathies and associated outcomes. NRHG may contribute to the formulation of a roadmap for hemoglobinopathies in Europe and promote the implementation of effective public health policies.