Introduction Poly [ADP-ribose] polymerase 1 (PARP1) is the major member of a family of nuclear en... more Introduction Poly [ADP-ribose] polymerase 1 (PARP1) is the major member of a family of nuclear enzymes that participate in DNA repair and gene transcription, by recruiting various proteins involved in DNA repair to sites of DNA damage. PARP1 overexpression has been correlated to poor treatment response in children with acute lymphoblastic leukemia, while PARP1-driven apoptosis is important in patients with chronic lymphocytic leukemia. Moreover, PARP1 inhibitors have been tested in vitro in lymphoid malignancies, acute myeloid leukemia, myelodysplastic syndrome (MDS) and acute promyelocytic leukemia. We have recently shown that bone marrow PARP1 mRNA levels correlate to the prognosis of patients with MDS (Diamantopoulos et al. Blood Cancer 2017). Moreover, PARP1 has been related to hypermethylation through DNA methyltransferase-1 (DNMT1) gene upregulation and protein activation (Zampieri et al. PLoS One. 2009). This correlation with DNA methylation is very important, since hypermethylation is a major event in the pathogenesis of high risk MDS, and hypomethylating agents, such as 5-azacytidine, are the most effective available treatment option for patients with higher risk MDS. Aim Based on the relation of PARP1 with hypermethylation, we investigated the correlation of bone marrow PARP1 mRNA levels of patients with MDS with treatment response to 5-azacytidine. Methods Bone marrow samples were collected from patients with MDS at diagnosis. Only samples from patients that were eventually treated with 5-azacytidine were selected for analysis. RNA extraction and reverse transcription were performed using standard protocols. Primers for PARP1 and beta-actin were designed using the primer3 software (University of Massachusetts, USA) and a SYBR green based real-time PCR was performed on a CFX96 RT-PCR system (Bio-Rad Laboratories, Hercules, CA, USA). PARP1 mRNA levels were expressed as a PARP1/beta-actin ratio. IBM SPSS statistics, version 23.0 (IBM Corporation, North Castle, NY, USA) was used for the analysis of the results. Results Sixty-seven patients diagnosed with MDS per the WHO 2008 classification and treated with 5-azacytdine were included in the study. The basic characteristics of the patients are shown in Table 1. The median follow-up of the patients was 25.8 (2.6-117.0) months. Response to treatment with 5-azacytidine per the International Working Group (IWG) criteria is shown in Table 1. The median PARP1 mRNA level was 0.0793 (range (0.0000424 - 3.43). Response to treatment differed between patients with high and low PARP1 mRNA levels (Independent samples Kruskal-Wallis test, 2-sided p=0.009). More precisely, the median level of PARP1 mRNA was 4 times higher in responders (partial response, complete response, hematologic improvement) than in non-responders (failure and stable disease), Independent samples Mann-Whitney U test, 2-sided p=0.006. We found no correlation of any other of the studied factors (MDS type, IPSS, IPSS-R, WPSS, karyotype risk, number of cytopenias, marrow blast percentage, hemoglobin level, neutrophil and platelet count, dose reduction of 5-azacytidine) to response to treatment in this cohort of patients. Although there was no correlation of PARP1 mRNA levels with overall survival, survival of patients after 5-azacytidine treatment tended to be longer in patients with higher PARP1 mRNA levels (38.7 versus 19.8 months, log rank test, p=0.136). Discussion We found that patients with MDS and high PARP1 mRNA levels have a better response to treatment with 5-azacytidine. This correlation has a theoretical basis, since upregulation of PARP1 is correlated to DNA hypermethylation, and hypomethylating agents may be more effective in cells with higher methylation levels. Moreover, in our cohort of patients, PARP1 level was the only factor affecting treatment response, although this response was not translated into a survival benefit. PAPR1 is the only biological factor and one of very few identified factors to predict response to treatment with hypomethylating agents - low hemoglobin and platelet count were found to be an independent factor of poor response to hypomethylating agents (Jung et al. Oncotarget 2016), and absence of aberrant myeloid progenitor cells were found to predict response to treatment (Alhan et al. Cytometry B Clin Cytom 2014). A possible synergy between PARP1 inhibitors and hypomethylating agents in MDS should be further investigated. Disclosures Vassilakopoulos: Amgen: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Celgene/GenesisPharma: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding.
Spontaneous remission of acute myeloid leukemia (AML) in adults is a rare but well documented phe... more Spontaneous remission of acute myeloid leukemia (AML) in adults is a rare but well documented phenomenon. This study reports on a 64-year-old male patient with acute myelogenous leukemia (AML-M4, according to the French-American-British classification) that was developed on a background of chronic myelomonocytic leukemia (CMML) and then underwent remission after treatment with the gonadotropin-releasing hormone agonist (GnRH agonist) triptorelin for presumed prostate cancer. Remission persisted for at least 4 years before the patient was lost to follow-up. To the author' knowledge, this is the first report of remission in an AML-M4 case associated with hormone manipulation. Possible mechanisms of this phenomenon are discussed.
Background and objectives: Serum beta(2)-microglobulin (s beta(2)m) is an established prognostic ... more Background and objectives: Serum beta(2)-microglobulin (s beta(2)m) is an established prognostic factor for multiple myeloma and non-Hodgkin's lymphoma, but only limited data suggest an adverse prognostic significance for Hodgkin's lymphoma (HL). This study was undertaken to examine the impact of s beta(2)m on the prognosis of patients with HL. Design and methods: s beta(2)m was measured by a radioimmunoassay (upper normal limit 2.4 mg/L), in pretreatment serum samples of 232 patients with HL, who were then treated with ABVD or equivalent regimens with or without radiotherapy. Multivariate survival analysis was based on Cox's proportional hazards model. Results: Main patients' characteristics: median age 30.5 years (14-78); 58% males; 68% nodular sclerosis, 20% mixed cellularity and 12% lymphocyte predominance; 34% B-symptoms; 24% Ann Arbor stage I, 49% II, 18% III and 9% IV. Elevated s beta(2)m levels were detected in 65/232 patients (28%) and correlated with older age (p<0.001), mixed cellularity (p=0.03), B-symptoms (p=0.002), advanced stage (p=0.02), > or = 5 involved sites (p=0.02), inguinal/iliac involvement (p=0.009), lymphocytopenia (p=0.002) and elevated lactate dehydrogenase (p=0.01). The 7-year failure free survival (FFS) was 75% vs. 72% for patients with normal vs. elevated s beta(2)m (p=0.15). The corresponding 7-year overall survival (OS) rates were 86% vs. 52% (p=0.003). In multivariate analysis, elevated s beta(2)m was not predictive of FFS, but was independently associated with inferior OS (p=0.01), along with the number of involved sites (p<0.001). Interpretation and conclusions: s beta(2)m is not a potent prognostic factor for FFS in optimally treated patients with HL. However s beta(2)m may be predictive of OS, probably due to its effect on the timing of treatment failure.
Abstract 2712 Treatment of splenic marginal zone lymphomas (SMZL) is traditionally based on splen... more Abstract 2712 Treatment of splenic marginal zone lymphomas (SMZL) is traditionally based on splenectomy. However, preliminary data suggest that rituximab monotherapy is highly effective in SMZL patients. The aim was to assess the efficacy of rituximab administration in a large series of patients with SMZL, as upfront therapy. Fifty-eight patients with the diagnosis of SMZL were prospectively treated, between September 2003 and July 2011, with rituximab monotherapy.…
Waldenström&#39;s macroglobulinemia (WM) is a lymphoplasmacytic lymphoma characterized by the... more Waldenström&#39;s macroglobulinemia (WM) is a lymphoplasmacytic lymphoma characterized by the presence in patients&#39; serum of an IgM monoclonal component. We report on our experience with 60 WM patients, focusing on their clinical findings, response to treatment, and the possible identification of prognostic factors. Of these patients, 70% presented with fatigue, and lymphadenopathy was observed in 22%, splenomegaly in 18%, hepatomegaly in 13%, and extranodal site of involvement in 6%. Bleeding tendency was seen in 17%, infections in 17%, hyperviscosity syndrome in 12%, and cardiac failure in 25% of the patients. The median of IgM levels was 30 g/l with hypoalbuminemia in 20% of cases, hypogammaglobulinemia in 27%, polyclonal hypergammaglobulinemia in 15%, kappa light-chain restriction in 78%, and Bence-Jones proteinuria in 54%. Anemia was frequent (85%), followed by leukocytosis (18%), lymphocytosis (12%), leukopenia (10%), and thrombocytopenia (10%). Cryoglobulinemia and autoimmune hemolytic anemia were encountered in 5%. In all cases but two, bone marrow was involved. Of 50 patients initially treated with intermittent oral chlorambucil, 46 (92%) responded. Median overall survival was 108 months. Factors associated with adverse prognosis were age &gt; or =65 years (p=0.06), presence of lymphadenopathy (p=0.06), bone marrow infiltration &gt; or =50% (p=0.007), international prognostic index (IPI) &gt; or =3 (p=0.0001), and Morel&#39;s scoring system (p=0.04). Concluding, we found in this series of WM patients that chlorambucil is an effective treatment and that the parameters of age, lymphadenopathy, percentage of bone marrow infiltration, IPI, and Morel&#39;s scoring system carry prognostic significance.
Transplant‐ineligible relapsed/refractory (rr) diffuse large B‐cell lymphoma (DLBCL) patients rep... more Transplant‐ineligible relapsed/refractory (rr) diffuse large B‐cell lymphoma (DLBCL) patients represent an unmet medical need. Polatuzumab vedotin (Pola), an anti‐CD79b antibody‐drug‐conjugate (ADG), with bendamustine‐ rituximab(BR) has recently gained approval for these patients, both in the USA and Europe, based on the GO29365 phase IIb trial. Real‐life data with Pola are extremely limited. We report the outcomes of 61 Greek patients, who received Pola‐(B)R mainly within a compassionate use program. Treatment was given for up to six 21‐day cycles. Bendamustine was omitted in three cases due to previous short‐lived responses. Fourty‐nine rrDLBCL(efficacy cohort‐EC) and 58 rr aggressive B‐NHL (safety cohort‐SC) patients received at least 1 Pola‐BR cycle. Twenty‐one (43%) patients of the EC responded with 12/49 (25%) CR and 9/49 (18%) PR as best response. Median progression–free survival, overall survival and duration of response were 4.0, 8.5, and 8.5 months respectively, while 55% ...
Background: In all EBV – associated malignancies, the virus displays a latency program of infecti... more Background: In all EBV – associated malignancies, the virus displays a latency program of infection, which represents a restricted pattern of gene expression. Among the products of its genes, latent membrane protein 1 (LMP1) has been characterized as a potent transforming protein. LMP1 is expressed at widely different levels in cells of a single clone, a fact that may explain the stimulation of multiple distinct pathways, such as oncogenesis, cytotoxicity, and apoptosis. Studies in LMP1-positive cell lines have shown the coexisting apoptotic properties of LMP1. Survivin, a member of the inhibitor of apoptosis (IAP) family, is suggested to be an important regulator of the mitochondrial apoptotic pathway. The literature lacks information about the expression of LMP1 in the peripheral blood of patients with non-EBV-related lymphoproliferative diseases. Aim: To examine the apoptotic properties of LMP1 oncoprotein, in patients with low grade B-cell lymphomas, by studying the expression o...
Fc-γ RIIA (CD32), a member of the family of Fc-γ receptors, participates in the phagocytosis of b... more Fc-γ RIIA (CD32), a member of the family of Fc-γ receptors, participates in the phagocytosis of bound to antibody antigens. The effectiveness of this function varies for its several haplotypes, and it participates in the pathogenesis of viral infections, according to recent studies. The genetic locus of Fc-γ RIIA consists of two allelic genes: 131-Arg (R131) and 131-His (H131). Our aim was to correlate Fc-γ RIIA polymorphisms, by studying the prevalence of each allele using PCR-RFLPs (polymerase chain reaction-restriction fragment length polymorphisms), with latent Epstein-Barr virus (EBV) infection and the expression of latent membrane protein 1 (LMP1) in 40 patients with leukemic low grade B-cell lymphomas. R131 was found in 84.2% of EBV-positive patients, but only in 28.5% of EBV-negative patients (p = 0.001). A similar correlation was found for R131 and LMP1 expression (84.6% vs. 28.5%) (p = 0.002). Our results support the hypothesis that Fc-γ RIIA polymorphisms are a genetic risk factor for latent EBV infection and the expression of its oncogenic latency proteins.
Waldenstrom’s Macroglobulinemia (WM) is a rare lymphoproliferative disorder characterized by lymp... more Waldenstrom’s Macroglobulinemia (WM) is a rare lymphoproliferative disorder characterized by lymphoplasmacytic infiltration of the bone marrow and/or other tissues and the presence of a serum monoclonal IgM. The etiology of the disease is still unknown but the identification of family clusters may contribute to the understanding of its pathogenesis. In this study we present a family with 4 members affected by WM consisting of three generations; 2 sisters of the first generation were both suffering from WM. One of them presented to our section with mild anemia, a monoclonal serum IgM compound, 80% infiltration by lymphoplasmacytes in the bone marrow and the diagnosis of WM was made. Her sister was also suffering from WM but followed in another Centre. Our patient had two sons that at the age of 52 and 46 years presented a serum monoclonal IgM. At presentation, the first one had a monoclonal IgM value of 1680 mg/dl and a 40% BM lymphoplasmacytic infiltration with no other findings, signs or symptoms; he is regularly followed in our section for 30 months and his disease is stable. The second son, presented with a serum monoclonal IgM value of 886 mg/dl and a 10% BM infiltration by monoclonal lymphoplasmacytes and plasmacytes and was initially characterized as having an IgM-MGUS; while under follow-up examination only, he developed peripheral neuropathy with positive anti-Mag antibodies and improved with rituximab administration. Nor the mother or the sons had HCV antibodies. The first son has 3 children and the second two. Buccal and blood DNA was analysed for the IgH rearrangement by PCR. The PCR products after ligation and cloning were sequenced in an automated sequencer. Sequences obtained from each sample were aligned with germline sequences in the BLAST directory. No Ig rearrangements were detected in buccal DNA. Monoclonality was demonstrated in all affected members and in 2 healthy individuals of the third generation by PCR while immunophenotyping did not show evidence of disease in those two members. VH3 family was expressed at the highest frequency (80%). Different gene segments were recognized for the analysed sequences. D segments were attributed in all sequences. All affected and 1 healthy member had mutated VH genes. This is the first study of a family with WM consisting of three generations and reporting blood monoclonality of healthy individuals by molecular methods. The biologic value of the finding remains to be seen. Further study and a long follow-up is needed to clarify this issue.
Introduction Poly [ADP-ribose] polymerase 1 (PARP1) is the major member of a family of nuclear en... more Introduction Poly [ADP-ribose] polymerase 1 (PARP1) is the major member of a family of nuclear enzymes that participate in DNA repair and gene transcription, by recruiting various proteins involved in DNA repair to sites of DNA damage. PARP1 overexpression has been correlated to poor treatment response in children with acute lymphoblastic leukemia, while PARP1-driven apoptosis is important in patients with chronic lymphocytic leukemia. Moreover, PARP1 inhibitors have been tested in vitro in lymphoid malignancies, acute myeloid leukemia, myelodysplastic syndrome (MDS) and acute promyelocytic leukemia. We have recently shown that bone marrow PARP1 mRNA levels correlate to the prognosis of patients with MDS (Diamantopoulos et al. Blood Cancer 2017). Moreover, PARP1 has been related to hypermethylation through DNA methyltransferase-1 (DNMT1) gene upregulation and protein activation (Zampieri et al. PLoS One. 2009). This correlation with DNA methylation is very important, since hypermethylation is a major event in the pathogenesis of high risk MDS, and hypomethylating agents, such as 5-azacytidine, are the most effective available treatment option for patients with higher risk MDS. Aim Based on the relation of PARP1 with hypermethylation, we investigated the correlation of bone marrow PARP1 mRNA levels of patients with MDS with treatment response to 5-azacytidine. Methods Bone marrow samples were collected from patients with MDS at diagnosis. Only samples from patients that were eventually treated with 5-azacytidine were selected for analysis. RNA extraction and reverse transcription were performed using standard protocols. Primers for PARP1 and beta-actin were designed using the primer3 software (University of Massachusetts, USA) and a SYBR green based real-time PCR was performed on a CFX96 RT-PCR system (Bio-Rad Laboratories, Hercules, CA, USA). PARP1 mRNA levels were expressed as a PARP1/beta-actin ratio. IBM SPSS statistics, version 23.0 (IBM Corporation, North Castle, NY, USA) was used for the analysis of the results. Results Sixty-seven patients diagnosed with MDS per the WHO 2008 classification and treated with 5-azacytdine were included in the study. The basic characteristics of the patients are shown in Table 1. The median follow-up of the patients was 25.8 (2.6-117.0) months. Response to treatment with 5-azacytidine per the International Working Group (IWG) criteria is shown in Table 1. The median PARP1 mRNA level was 0.0793 (range (0.0000424 - 3.43). Response to treatment differed between patients with high and low PARP1 mRNA levels (Independent samples Kruskal-Wallis test, 2-sided p=0.009). More precisely, the median level of PARP1 mRNA was 4 times higher in responders (partial response, complete response, hematologic improvement) than in non-responders (failure and stable disease), Independent samples Mann-Whitney U test, 2-sided p=0.006. We found no correlation of any other of the studied factors (MDS type, IPSS, IPSS-R, WPSS, karyotype risk, number of cytopenias, marrow blast percentage, hemoglobin level, neutrophil and platelet count, dose reduction of 5-azacytidine) to response to treatment in this cohort of patients. Although there was no correlation of PARP1 mRNA levels with overall survival, survival of patients after 5-azacytidine treatment tended to be longer in patients with higher PARP1 mRNA levels (38.7 versus 19.8 months, log rank test, p=0.136). Discussion We found that patients with MDS and high PARP1 mRNA levels have a better response to treatment with 5-azacytidine. This correlation has a theoretical basis, since upregulation of PARP1 is correlated to DNA hypermethylation, and hypomethylating agents may be more effective in cells with higher methylation levels. Moreover, in our cohort of patients, PARP1 level was the only factor affecting treatment response, although this response was not translated into a survival benefit. PAPR1 is the only biological factor and one of very few identified factors to predict response to treatment with hypomethylating agents - low hemoglobin and platelet count were found to be an independent factor of poor response to hypomethylating agents (Jung et al. Oncotarget 2016), and absence of aberrant myeloid progenitor cells were found to predict response to treatment (Alhan et al. Cytometry B Clin Cytom 2014). A possible synergy between PARP1 inhibitors and hypomethylating agents in MDS should be further investigated. Disclosures Vassilakopoulos: Amgen: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Celgene/GenesisPharma: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding.
Spontaneous remission of acute myeloid leukemia (AML) in adults is a rare but well documented phe... more Spontaneous remission of acute myeloid leukemia (AML) in adults is a rare but well documented phenomenon. This study reports on a 64-year-old male patient with acute myelogenous leukemia (AML-M4, according to the French-American-British classification) that was developed on a background of chronic myelomonocytic leukemia (CMML) and then underwent remission after treatment with the gonadotropin-releasing hormone agonist (GnRH agonist) triptorelin for presumed prostate cancer. Remission persisted for at least 4 years before the patient was lost to follow-up. To the author&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; knowledge, this is the first report of remission in an AML-M4 case associated with hormone manipulation. Possible mechanisms of this phenomenon are discussed.
Background and objectives: Serum beta(2)-microglobulin (s beta(2)m) is an established prognostic ... more Background and objectives: Serum beta(2)-microglobulin (s beta(2)m) is an established prognostic factor for multiple myeloma and non-Hodgkin's lymphoma, but only limited data suggest an adverse prognostic significance for Hodgkin's lymphoma (HL). This study was undertaken to examine the impact of s beta(2)m on the prognosis of patients with HL. Design and methods: s beta(2)m was measured by a radioimmunoassay (upper normal limit 2.4 mg/L), in pretreatment serum samples of 232 patients with HL, who were then treated with ABVD or equivalent regimens with or without radiotherapy. Multivariate survival analysis was based on Cox's proportional hazards model. Results: Main patients' characteristics: median age 30.5 years (14-78); 58% males; 68% nodular sclerosis, 20% mixed cellularity and 12% lymphocyte predominance; 34% B-symptoms; 24% Ann Arbor stage I, 49% II, 18% III and 9% IV. Elevated s beta(2)m levels were detected in 65/232 patients (28%) and correlated with older age (p<0.001), mixed cellularity (p=0.03), B-symptoms (p=0.002), advanced stage (p=0.02), > or = 5 involved sites (p=0.02), inguinal/iliac involvement (p=0.009), lymphocytopenia (p=0.002) and elevated lactate dehydrogenase (p=0.01). The 7-year failure free survival (FFS) was 75% vs. 72% for patients with normal vs. elevated s beta(2)m (p=0.15). The corresponding 7-year overall survival (OS) rates were 86% vs. 52% (p=0.003). In multivariate analysis, elevated s beta(2)m was not predictive of FFS, but was independently associated with inferior OS (p=0.01), along with the number of involved sites (p<0.001). Interpretation and conclusions: s beta(2)m is not a potent prognostic factor for FFS in optimally treated patients with HL. However s beta(2)m may be predictive of OS, probably due to its effect on the timing of treatment failure.
Abstract 2712 Treatment of splenic marginal zone lymphomas (SMZL) is traditionally based on splen... more Abstract 2712 Treatment of splenic marginal zone lymphomas (SMZL) is traditionally based on splenectomy. However, preliminary data suggest that rituximab monotherapy is highly effective in SMZL patients. The aim was to assess the efficacy of rituximab administration in a large series of patients with SMZL, as upfront therapy. Fifty-eight patients with the diagnosis of SMZL were prospectively treated, between September 2003 and July 2011, with rituximab monotherapy.…
Waldenström&#39;s macroglobulinemia (WM) is a lymphoplasmacytic lymphoma characterized by the... more Waldenström&#39;s macroglobulinemia (WM) is a lymphoplasmacytic lymphoma characterized by the presence in patients&#39; serum of an IgM monoclonal component. We report on our experience with 60 WM patients, focusing on their clinical findings, response to treatment, and the possible identification of prognostic factors. Of these patients, 70% presented with fatigue, and lymphadenopathy was observed in 22%, splenomegaly in 18%, hepatomegaly in 13%, and extranodal site of involvement in 6%. Bleeding tendency was seen in 17%, infections in 17%, hyperviscosity syndrome in 12%, and cardiac failure in 25% of the patients. The median of IgM levels was 30 g/l with hypoalbuminemia in 20% of cases, hypogammaglobulinemia in 27%, polyclonal hypergammaglobulinemia in 15%, kappa light-chain restriction in 78%, and Bence-Jones proteinuria in 54%. Anemia was frequent (85%), followed by leukocytosis (18%), lymphocytosis (12%), leukopenia (10%), and thrombocytopenia (10%). Cryoglobulinemia and autoimmune hemolytic anemia were encountered in 5%. In all cases but two, bone marrow was involved. Of 50 patients initially treated with intermittent oral chlorambucil, 46 (92%) responded. Median overall survival was 108 months. Factors associated with adverse prognosis were age &gt; or =65 years (p=0.06), presence of lymphadenopathy (p=0.06), bone marrow infiltration &gt; or =50% (p=0.007), international prognostic index (IPI) &gt; or =3 (p=0.0001), and Morel&#39;s scoring system (p=0.04). Concluding, we found in this series of WM patients that chlorambucil is an effective treatment and that the parameters of age, lymphadenopathy, percentage of bone marrow infiltration, IPI, and Morel&#39;s scoring system carry prognostic significance.
Transplant‐ineligible relapsed/refractory (rr) diffuse large B‐cell lymphoma (DLBCL) patients rep... more Transplant‐ineligible relapsed/refractory (rr) diffuse large B‐cell lymphoma (DLBCL) patients represent an unmet medical need. Polatuzumab vedotin (Pola), an anti‐CD79b antibody‐drug‐conjugate (ADG), with bendamustine‐ rituximab(BR) has recently gained approval for these patients, both in the USA and Europe, based on the GO29365 phase IIb trial. Real‐life data with Pola are extremely limited. We report the outcomes of 61 Greek patients, who received Pola‐(B)R mainly within a compassionate use program. Treatment was given for up to six 21‐day cycles. Bendamustine was omitted in three cases due to previous short‐lived responses. Fourty‐nine rrDLBCL(efficacy cohort‐EC) and 58 rr aggressive B‐NHL (safety cohort‐SC) patients received at least 1 Pola‐BR cycle. Twenty‐one (43%) patients of the EC responded with 12/49 (25%) CR and 9/49 (18%) PR as best response. Median progression–free survival, overall survival and duration of response were 4.0, 8.5, and 8.5 months respectively, while 55% ...
Background: In all EBV – associated malignancies, the virus displays a latency program of infecti... more Background: In all EBV – associated malignancies, the virus displays a latency program of infection, which represents a restricted pattern of gene expression. Among the products of its genes, latent membrane protein 1 (LMP1) has been characterized as a potent transforming protein. LMP1 is expressed at widely different levels in cells of a single clone, a fact that may explain the stimulation of multiple distinct pathways, such as oncogenesis, cytotoxicity, and apoptosis. Studies in LMP1-positive cell lines have shown the coexisting apoptotic properties of LMP1. Survivin, a member of the inhibitor of apoptosis (IAP) family, is suggested to be an important regulator of the mitochondrial apoptotic pathway. The literature lacks information about the expression of LMP1 in the peripheral blood of patients with non-EBV-related lymphoproliferative diseases. Aim: To examine the apoptotic properties of LMP1 oncoprotein, in patients with low grade B-cell lymphomas, by studying the expression o...
Fc-γ RIIA (CD32), a member of the family of Fc-γ receptors, participates in the phagocytosis of b... more Fc-γ RIIA (CD32), a member of the family of Fc-γ receptors, participates in the phagocytosis of bound to antibody antigens. The effectiveness of this function varies for its several haplotypes, and it participates in the pathogenesis of viral infections, according to recent studies. The genetic locus of Fc-γ RIIA consists of two allelic genes: 131-Arg (R131) and 131-His (H131). Our aim was to correlate Fc-γ RIIA polymorphisms, by studying the prevalence of each allele using PCR-RFLPs (polymerase chain reaction-restriction fragment length polymorphisms), with latent Epstein-Barr virus (EBV) infection and the expression of latent membrane protein 1 (LMP1) in 40 patients with leukemic low grade B-cell lymphomas. R131 was found in 84.2% of EBV-positive patients, but only in 28.5% of EBV-negative patients (p = 0.001). A similar correlation was found for R131 and LMP1 expression (84.6% vs. 28.5%) (p = 0.002). Our results support the hypothesis that Fc-γ RIIA polymorphisms are a genetic risk factor for latent EBV infection and the expression of its oncogenic latency proteins.
Waldenstrom’s Macroglobulinemia (WM) is a rare lymphoproliferative disorder characterized by lymp... more Waldenstrom’s Macroglobulinemia (WM) is a rare lymphoproliferative disorder characterized by lymphoplasmacytic infiltration of the bone marrow and/or other tissues and the presence of a serum monoclonal IgM. The etiology of the disease is still unknown but the identification of family clusters may contribute to the understanding of its pathogenesis. In this study we present a family with 4 members affected by WM consisting of three generations; 2 sisters of the first generation were both suffering from WM. One of them presented to our section with mild anemia, a monoclonal serum IgM compound, 80% infiltration by lymphoplasmacytes in the bone marrow and the diagnosis of WM was made. Her sister was also suffering from WM but followed in another Centre. Our patient had two sons that at the age of 52 and 46 years presented a serum monoclonal IgM. At presentation, the first one had a monoclonal IgM value of 1680 mg/dl and a 40% BM lymphoplasmacytic infiltration with no other findings, signs or symptoms; he is regularly followed in our section for 30 months and his disease is stable. The second son, presented with a serum monoclonal IgM value of 886 mg/dl and a 10% BM infiltration by monoclonal lymphoplasmacytes and plasmacytes and was initially characterized as having an IgM-MGUS; while under follow-up examination only, he developed peripheral neuropathy with positive anti-Mag antibodies and improved with rituximab administration. Nor the mother or the sons had HCV antibodies. The first son has 3 children and the second two. Buccal and blood DNA was analysed for the IgH rearrangement by PCR. The PCR products after ligation and cloning were sequenced in an automated sequencer. Sequences obtained from each sample were aligned with germline sequences in the BLAST directory. No Ig rearrangements were detected in buccal DNA. Monoclonality was demonstrated in all affected members and in 2 healthy individuals of the third generation by PCR while immunophenotyping did not show evidence of disease in those two members. VH3 family was expressed at the highest frequency (80%). Different gene segments were recognized for the analysed sequences. D segments were attributed in all sequences. All affected and 1 healthy member had mutated VH genes. This is the first study of a family with WM consisting of three generations and reporting blood monoclonality of healthy individuals by molecular methods. The biologic value of the finding remains to be seen. Further study and a long follow-up is needed to clarify this issue.
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Papers by Marina Siakantaris