Variant Philadelphia translocations with different breakpoints in six chronic myeloid leukemia patients.

OBJECTIVE: The Philadelphia (Ph) chromosome, consisting of the t(9;22)(q34;q11) translocation, is observed in ~90% of patients with chronic myeloid leukemia (CML). Variant Ph translocations are observed in 5%-10% of CML patients. In variant translocations 3 and possibly more chromosomes are involved. Herein we report 6 CML patients with variant Ph translocations. METHODS: Bone marrow samples were examined using conventional cytogenetic meth ods. Fluorescence in situ hybridization (FISH) with whole-chromosome paints and BCR-ABL 1D probes were used to confirm and/or complement the findings, and identify rearrangements beyond the resolution of conventional cytogenetic methods. RESULTS: Variant Ph translocations in the 6 patients were as follows: t(7;22)(p22;q11), t(9;22;15)(q34;q11;q22), t(15;22)(p11;q11), t(1;9;22;3)(q24;q34;q11;q21), t(12;22)(p13;q11), and t(4;8;9;22)(q11;q13;q34;q11). CONCLUSION: Among the patients, 3 had simple and 3 had complex variant Ph translocations. Two of the presented cases had variant Ph chromosomes not previously described, 1 of which had a new complex Ph translocation involving chromosomes 1, 3, 9, 22, and t(1;9;22;3)(q24;q34;q11;q21) apart from a clone with a classical Ph, and the other case had variant Ph translocation with chromosomes 4, 8, 9, and 22, and t(4;8;9;22)(q11;q13;q34;q11) full complex translocation. Number of studies reported that some patients with variant Ph translocation were poor responders to imatinib. All of our patients with variant Ph translocations had suboptimal responses to imatinib, denoting a poor prognosis also. Variant Ph translocations may be important as they are associated with prognosis and therapy for CML patients.

T-cell-rich B-cell lymphoma: a clinicopathologic study of 21 cases and comparison with 43 cases of diffuse large B-cell lymphoma.

Clinicopathologic features of 21 patients with T-cell-rich B-cell lymphoma (TCRBCL) were reviewed and compared to 43 patients with diffuse large B-cell lymphoma (DLBCL) to determine if there were distinguishing clinical characteristics and differences in response or survival to CHOP therapy. For the diagnosis of TCRBCL, the current WHO criteria was used. In all of our cases, the majority of cells are non-neoplastic T cells and <10% large neoplastic B cells are present. The initial pathologic diagnosis was nodular lymphocyte predominant Hodgkin's lymphoma (NLPHL) in two cases. Patients with TCRBCL were significantly younger (median: 46 years) and had a significantly higher incidence of B symptoms (62%), hepatomegaly (33%) and marrow infiltration (33%) at presentation when compared to DLBCL (P<0.03). The CR rate after treatment was 48% for TCRBCL patients versus 79% for the DLBCL (P<0.003). Although the CR rates in between the two groups are significant, the difference in 3 years survival rates in each CR groups was insignificant (80% versus 77%). The overall survival time in the two groups was 17 months. Event-free survival time in TCRBCL was 12 months, compared with 17 months in the DLBCL (P>0.05). The frequency of patients with TCRBCL achieving CR was 52.6% whereas that of patients with DLBCL was 79% (P<0.003). The TCRBCL 3 years event-free survival 48% and overall survival 64% were 63 and 72% for DLBCL, respectively.

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.

Hematopoetic stem celi transplantation activity at a single center: Cerrahpasa experience.

At our institution 94 transplantations have been performed in an 8 year period up to December 2001. Forty-three females and 49 males with ages ranging from 14 to 61 years received 67 allogeneic (allo) and 27 autologous (auto) transplants; 2 patients were transplanted twice. The diagnosis of allo transplants were AML (27 patients-pts), CML (17 pts), ALL (16 pts) and AA (5 pts); those of auto transplants were NHL (13 pts), HD (10 pts), MM (3 pts) and AML (l pt). Of the patients with acute leukemia 69.7% were in first CR and ali but öne of the patients with CML were in first chronic phase. Source of hematopoetic stem cells were bone marrow (BM) in 61.9% (allo 81.5%, auto 14.8%) and peripheral blood (PB) in 38.1% (allo 18.5%, auto 85.2%). Ail donors were HLA-full matched siblings with öne exception. ConditionIng regimens were BU-CY (31 pts), TBI-CY (28 pts) and Flag-lda (öne pî) for leukemia, CY-ATG for AA, CBV for lymphoma and Mel-200 for MM. Median 2.69 x 108 nucieated celIsAg (BM) and 21.7 x 106 CD34 + celIsAg (PB) were infused to allo transplant recipients; 4 patients faiied to engraft and öne patient was inevaluable due to early death. Acute GVHD was observed in 11 patients (16.9% - grade ll-IV in 10.7%) and chronic GVHD was documented in 18 patients (33.9%- extensive in 9.43%). VOD was seen in 8 patients (12.3%). Early response was CR in 91.6% in patienîs wîth leukemia; patients with lymphoma showed a 73.1% response (CR & PR) rate and 23.1% had resistant disease. So far 27.6% of the patients have relapsed ör showed progression and 45.7% have died (disease-related 27.2%, transplant-related 18.5%). At a median follow-up time of 32 months (range 0.6-96) DFS is 50.8% and OS is 53.9% in the allo transplant group. With a shorter follow-up (median 16 months, range 1-65) the same figures for the auto transplant group are 51.9 and 55.5%, respectively, in this cohort overall, OS and DFS are significantly superior in patients with early-stage disease: 71.7% vs. 26.7% in advanced-stage disease for OS and 71.4% vs. 36.8% for DFS, respectively and this trend applies to both transplant groups (p< 0.001 for ali comparisons).

JAK2 (V617F) mutation is not associated with thrombosis in Behcet syndrome.

The Janus kinase 2(V617F) (JAK2 (V617F)) mutation is an acquired genetic defect that is considered to enhance thrombosis in Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs). Thrombosis is also a well-defined component of Behcet syndrome (BS). The aim of this study was to determine the frequency of JAK2 ( V617F ) mutation in BS-associated thrombosis. A total of 152 patients with BS (62 with thrombosis and 90 without thrombosis) were enrolled. An additional 186 patients with MPNs and 107 healthy blood donors were included to serve as diseased and healthy controls, respectively. None of the patients with BS and healthy controls carried the JAK2 (V617F) mutation, whereas 67% of patients with MPNs were positive for JAK2 ( V617F ). The frequency of thrombosis in patients with MPNs was not statistically different between carriers and non-carriers of JAK2 ( V617F ) mutation. Our data suggest that JAK2 (V617F) is not directly related to thrombosis in MPNs and in other thrombotic entities, such as BS.

Successful management of cryoglobulinemia-induced leukocytoclastic vasculitis with thalidomide in a patient with multiple myeloma.

Leukocytoclastic vasculitis (LV) is a systemic inflammatory disorder involving mostly the small vessels. It is characterised by segmental angiocentric neutrophilic inflammation, endothelial cell damage and fibrinoid necrosis. LV is related to a variety of clinical disorders including cryoglobulinemia and, very rarely, multiple myeloma (MM), among many others. The development of LV in patients with MM has been linked to cryoglobulinemia, infections, drugs and paraneoplasia. It has been speculated that myeloma patients with a poorer prognosis and progressive disease are more prone to develop LV. Thalidomide is a rediscovered old drug with anti-angiogenic, immunomodulatory and anti-inflammatory properties. It is highly effective in the treatment of MM and other clinical disorders such as leprosy, various cancers, graft-versus-host disease and autoimmune diseases. We report here a female patient with Durie-Salmon stage IIA MM who initially presented with cryoglobulinemia and LV. LV in this patient was primarily considered to be the result of progressive cryoglobulinemia, which was closely associated with MM. She was successfully managed with thalidomide and dexamethasone.

An overview of young CLL patients: a single-centre experience from Turkey.

Chronic lymphocytic leukaemia (CLL) is generally considered to be a disease of the older population. The aim of this retrospective study was to determine whether younger subjects with CLL (< or = 55 years of age) were different from older patients in their clinical features and prognoses. A total of 198 CLL patients registered to the centre were analyzed: 47 (24%) were 55 years of age or younger and 37 who were followed up regularly were included in the study. The male/female ratio was significantly higher in young patients (3.7 vs. 1.51; p = 0.02). More young patients were asymptomatic than old patients at initial presentation (38.3% vs. 28.5%; p > 0.05). The clinical features, laboratory findings, the distribution of both age groups into clinical stages, and the overall response rate to treatment were similar. The median time to follow-up was 62 months. During this period, 14 of the young patients died (48.3%); all were males. The median survival was longer in the young (64.5 vs. 47 months, p > 0.05). The 5-year survival rate of young patients was more than the old (57% vs. 31%), but the 10-year survival rates did not differ between the two groups (7% vs. 8%). The rate of CLL-related death was higher in young patients (71% vs. 59%; p > 0.05). Univariate analysis revealed no prognostic factor which could influence the survival probability of young patients. In this study, the prognostic values of some variables could not be assessed accurately as the number of regularly followed young patients was low and some data were missing. However, it is expected that survival will be longer in young CLL patients, so the search for different curative treatment strategies will continue.

Chronic lymphocytic leukemia in Turkey: experience of a single center in Istanbul.

BACKGROUND: In this study, the clinical characteristics, survival, and prognostic factors of 200 patients diagnosed as having chronic lymphocytic leukemia (CLL) were analyzed. METHODS: The medical charts of 200 CLL patients registered to our center between 1984 and 2000 were retrospectively evaluated. RESULTS: Of all patients, 129 were men and 71 were women (male/female ratio, 1.82). The median age at the time of initial diagnosis was 63 years (range, 38-90 years). Sixty patients were classified as Binet's Stage A, 49 as Stage B, and 91 as Stage C. Sixty-two cases were diagnosed during routine laboratory examinations when they were asymptomatic. Forty-three patients were lost to follow-up, and 157 patients have been followed regularly until the end of the study period. Hemolytic anemia developed in nine (5.7%) patients, second primary cancer in six (3.8%), and Richter's syndrome in two (1.2%). Forty-eight percent of CLL patients were treated immediately after initial diagnosis. The overall response (complete or partial) to first-line and second-line therapies was 61.6% and 54.4%, respectively. The median time of follow-up for patients followed up regularly was 47 months (range, 1-195 months). Sixty-three patients died during the follow-up: the deaths of 39 (62%) of these were attributable to CLL-related causes. The median survival time was 48 months. The 5-year survival rate was 36.5% and the 10-year survival rate was 8%. Stage according to Rai's classification, lymphocyte count, and age showed a significant prognostic effect on survival by univariate analysis. On multivariate analysis, advanced age and lymphocyte count were independent prognostic parameters. CONCLUSION: In our study, more asymptomatic CLL patients have been diagnosed in recent years. The survival, especially of our early-stage patients, was shorter than that in other CLL series of Western origin. Rai's staging system was seen to determine prognosis better than Binet's staging system.